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LEARN FROM YESTERDAY, LIVE FOR TODAY, HOPE FOR TOMORROW. THE IMPORTANT THING IS TO NOT STOP QUESTIONING. Albert Einstein I’m not a particularly nostalgic person. My instinct We have come together time and time again and is always to move forward, push on, keep going. collaborated and made a difference. There is much But when I take a moment to reflect and I think more work to be done. And I hope you will continue to about PPMD’s very humble beginnings – a few look to PPMD for leadership, friendship, and strength, just dozen families, a staff of two, focused on a disease as we have turned to you over the last twenty years and no one had heard of – I smile. will continue to do in the future. This conference is but a small representation of what we can do as a community. When I think of those humble beginnings and where we Twenty years have proven that strength happens are today, what we have accomplished, and even better, together. the promise tomorrow holds, I am incredibly proud. You were with us in the beginning. You are with us now. I am proud of every member of this community who You are the future. You are Parent Project Muscular when faced with a Duchenne diagnosis said, “No that Dystrophy. is unacceptable. I will change the progression of this disease for my [son/daughter/ brother/sister/nephew/ niece/friend/husband/myself]. Whatever it takes.” Pat Furlong, PPMD President & CEO 1 #CONNECT20 STRENGTH 20 YEARS OF “Passing the MD-CARE Act was a critical step…” SEN. ROGER WICKER “Pat and PPMD provided a voice to the community...” 2006 PPMD and CDC convene community thought leaders to develop Care Considerations ERIC HOFFMAN 2001 MD-CARE Act signed into law 1998 Steroids become gold standard 1994 PPMD founded and 1st Annual Connect Conference 2007 DuchenneConnect is born 2003 PPMD funds first Duchenne Drug Discovery Program 2000 1st Annual Advocacy Conference held 1997 PPMD invests in first Duchenne Muscular Dystrophy Research Center 2 #CONNECT20 “They’re doing everything.” 2013 PPMD announces two $1 million RFAs for exon skipping and late stage preclinical/early stage clinical projects MINDY CAMERON 2010 PPMD awards $1 million in End Duchenne Grant Program with NIH 2008 Reauthorization of the MD-CARE Act 2014 PPMD funding leads to 10 new potential therapies now in clinical trial ........ 2012 2011 PPMD invests $2 million in Cardiac Care Initiative PPMD helps lead the way for FDASIA to be passed by Congress mandating regulatory flexibility for rare diseases PPMD receives funding award from PCORI ........ PPMD certifies Nationwide Children’s Hospital as part of Certified Duchenne Care Center Program ........ PPMD leads community in drafting guidance for FDA. Presented to FDA in June 2014. 2009 Care Considerations published ........ PPMD creates FACES program uniting Duchenne families “...the Duchenne world would be years behind where it is today without PPMD.” LEE SWEENEY “PPMD has been the spark that ignited the flame of determination in all of us...” BRENDA WONG #CONNECT20 2015 AND BEYOND PPMD continues to invest in all promising research strategies, to leverage federal investments, to constantly change the face of care for Duchenne, and unite the community through expertise and leadership. 3 “COCKTAIL” APPROACH TREATING DUCHENNE WITH A As we were finalizing the agenda for this year’s Connect Conference, The chart below gives a good overview of the many targets for I was once again amazed at how much of a challenge it is to squeeze therapeutic intervention in Duchenne—with the idea that we will in all of the talks on different therapeutic approaches to treating ultimately treat Duchenne with a “cocktail” approach. PPMD is Duchenne—in fact, there are too many to cover comprehensively funding research in almost all of these areas. this year. Sometimes it’s good to remember that mutation-specific approaches like exon skipping, although promising and exciting, are not our only irons in the fire. And many of these other therapeutic approaches will be entering the clinic by the end of this year or the next, providing a variety of options for participating in trials. Stop-codon Readthrough Sharon Hesterlee, PhD, PPMD’s VP of Research Exon-Skipping Functional replacement with other proteins Gene Therapy Dystrophin Restoration / Replacement Anti-fibrotics Inflammation & Fibrosis Steroid Replacements Poloxymer Cardiac TREATING DUCHENNE Serca 2A Calcium Regulators Ryanodine Receptor GsMTx4 4 Traditional cardiac drugs Muscle Mass Muscle growth pathways Blood Flow Stem Cells PDE5 #CONNECT20 FAQ’S CLINICAL TRIAL ACTIVELY RECRUITING PAGE PRE-CLINICAL PAGE Becker Natural History Study 6 Biglycan 27 Clinical Evaluator Outcomes Reliability Study 7 BMS-986089 28 Coenzyme Q10 and Lisinopril 8 Carmeseal-MD 29 DP ARF Ultrasound 9 DMD: iPS Cell Therapy 30 Duchenne Natural History Study 10 DT-200 31 Duchenne Tissue Bank 11 GALGT2 Gene Therapy 32 EIM and Ultrasound 12 Laminin-111 33 Follistatin Gene Transfer 13 NBD Peptide 34 FOR-DMD 14 PRO052/PRO055 35 HT-100 16 RTC13 Read-Through Compound 36 Tadalafil 17 Rycal® ARM210 37 Translarna™ (ataluren) 18 Spironolactone 38 Tamoxifen 39 VBP15 40 NOT YET RECRUITING PAGE CAT100 19 DRISAPERSEN 20 Exon Skipping for DMD (Sarepta Therapeutics) 21 ISOFEN 24 PF-06252616 25 SMT C1100 26 ACTIVE BUT NOT RECRUITING Early Treatment of Cardiomyopathy 41 ImagingDMD 42 PRO044 43 PRO045 44 PRO053 45 COMPLETED #CONNECT20 PAGE PAGE CATENA® 46 IGF-1 (Increlex) 47 5 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Becker Natural History Study Becker Muscular Dystrophy: A Natural History Study to Predict Efficacy of Exon Skipping •What stage is this research? •Where does this study take place? This study is actively recruiting participants. •What is the goal or purpose of this study? This is a natural history study to characterize the Becker muscular dystrophy (Becker) clinical presentation. Investigators will collect information on Becker patients whose in-frame mutations mirror those that would be generated in Duchenne muscular dystrophy (Duchenne) patients treated with skipping of exons 45, 51, or 53. Researchers will correlate specific abnormal dystrophin proteins with the range of clinical outcomes, including physical development, mental development, and quality of life in patients with these specific mutations. Researchers will investigate the observed variability to deepen our understanding of molecular mechanisms relevant to the optimization of exon skipping therapeutic approaches. This study is funded by the National Institutes of Health (NIH). •Who is eligible to participate in this study? To participate in this study you must be a male with Becker, age 4 and above, and have one of the following dystrophin gene deletions where the boundaries of the mutations are confirmed: Exon 45 corresponding inframe mutations: Exon 51 corresponding inframe mutations: Exon 53 corresponding inframe mutations: • • • • • • • • • • • • • • • • • • • • • • • Exon 13-51 Exon 29-51 Exon 43-51 Exon 47-51 Exon 48-51 Exon 49-51 Exon 50-51 Exon 51-52 Exon 10-53 Exon 43-53 Exon 47-53 Exon 48-53 Exon 49-53 Exon 50-53 •What do I have to do if I decide to participate in this study? At each study visit you will have a physical and neurological exam by a study physician, and review your health medication and cardiac history. You will have strength, function, and breathing testing performed by a physical therapist, and you will also complete quality of life questionnaires. At your first study visit you will also have a blood draw and a skin biopsy, and adults will have the option to have a muscle biopsy. 6 •How many visits to the study site are necessary? There will be a total of 4 visits – a baseline evaluation and 3 annual follow-up visits over a 3-year period. •Can any visits be done locally? •Who is funding this study? Exons 44-45 Exon 45-46 Exon 45-47 Exon 45-48 Exon 45-49 Exon 45-51 Exon 45-53 Exon 45-55 Exon 45-59 This study will be run at participating centers of the Cooperative International Neuromuscular Research Group (CINRG) network. The participating CINRG centers include Children’s National Medical Center in Washington, D.C.; the University of Pittsburgh in Pittsburgh, PA; the University of Minnesota in Minneapolis, MN; Ann & Robert H. Lurie Children’s Hospital of Chicago in Chicago, IL; Texas Children’s Hospital in Houston, TX; the University of California, Davis, in Sacramento, CA; and Alberta Children’s Hospital in Calgary, Alberta, Canada. More sites will be added in the future so be sure to check www.ClinicalTrials.gov or the website for the CINRG group: www.cinrgresearch.org for updated site lists. No, they must be done at a participating CINRG center. •Is there any funding to help pay for travel? The study does not provide any funds for travel; however please inquire at each individual site as some CINRG sites may have alternative resources for travel reimbursement or assistance. •Will I get paid for participating in this study? No, you will not be paid for your participation in this study. You will not be charged for additional tests and procedures that are performed only because you are participating in this research. Your responsibility to pay for other medical treatment will not change by your participation in this study. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, there are other benefits, including allowing you to play an active role in your own health care (or that of your child), gaining access to medical specialists that are normally not available to you or your child, and helping others by contributing to the better understanding of Becker. •Where can I learn more about this study? »» You can learn more about this study at www.cinrgresearch.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Clinical Evaluator Outcomes Reliability Study •What stage is this research? This study is actively recruiting Duchenne and Becker muscular dystrophy participants. •What is the goal or purpose of this study? This study outlines structured Clinical Evaluator (CE) testing techniques that are implemented across all sites participating in the Cooperative International Neuromuscular Research Group (CINRG) research studies. The study will determine if the selected techniques are reliable and reproducible across the CINRG network by evaluating the reliability and reproducibility of the measures between CEs. The reliability of these commonly used measurements is fundamental to clinical research, our ability to have confidence in the data we collect, and our ability to draw rational conclusions from the data. •Who is sponsoring this study? This study is sponsored by the Foundation to Eradicate Duchenne (FED). •Who is eligible to participate in this study? Researchers are now recruiting individuals with Duchenne or Becker muscular dystrophy, ages 6 years and older. The diagnosis of Duchenne or Becker muscular dystrophy must be confirmed by a genetic test and/or muscle biopsy. In addition, participants must be able to transfer to a testing table and walk 10 meters without an assistive device. •What do I have to do if I decide to participate in this study? •How many visits to the study site are necessary? Only one visit. •Can the visits be done locally? No, they must be done at a participating CINRG center. •Is there any funding to help pay for travel? The study does not provide any funds for travel; however please inquire at each individual site as some CINRG sites may have alternative resources for travel reimbursement or assistance. •Will I get paid for participating in this study? No, you will not be paid for your participation in this study. You will not be charged for additional tests and procedures that are performed only because you are participating in this research. Your responsibility to pay for other medical treatment will not be changed by your participation in this study. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, there are other benefits, including a full assessment of your physical function and contributing to a study that will benefit muscular dystrophy research. •Where can I learn more about this study? »» You can learn more about this study at www.cinrgresearch.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. You will perform multiple tests that will measure your muscle strength and function. You will also perform breathing tests. You will perform these tests three times with two different physical therapists. •Where does this study take place? This study will be run at 13 participating centers within the CINRG network. The participating CINRG centers may include sites in the US and additional sites in Canada, Argentina, Puerto Rico, Italy, Sweden, India, Israel, and Australia. Please check www.clinicaltrials.gov or the CINRG website www.cinrgresearch.org for a list of participating sites. These websites will be updated as sites are added to the study. Alternatively you may contact the lead Project Manager: Zoë Sund Tel: 202-476-4110 Email: zsund@ childrensnational.org. #CONNECT20 7 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Coenzyme Q10 and Lisinopril Clinical Trial of Coenzyme Q10 and Lisinopril in Muscular Dystrophies •What stage is this research? This clinical trial is actively recruiting participants. •What is the goal or purpose of this study? This is a clinical trial to test a medication used for the heart, called Lisinopril (an angiotensin converting enzyme (ACE) inhibitor) and supplement called Coenzyme Q10, to ameliorate the decline in cardiac muscle functions that occurs in muscular dystrophies. The goal of this study is to determine if Coenzyme Q10 alone, Lisinopril alone, or a combination of Coenzyme Q10 and Lisinopril is more effective at delaying the onset of cardiac symptoms in patients with Duchenne, Becker, or Limb Girdle muscular dystrophy. •Who is funding this study? This study is funded by the Department of Defense (DOD). •Who is eligible to participate in this study? To participate in this study you must have a confirmed genetic diagnosis of Duchenne, Becker, or Limb Girdle muscular dystrophy (certain type 2 only), be 8 years of age or older, and have no clinical cardiac symptoms with a normal left ventricular fractional shortening (>28%) on echocardiogram. You cannot currently be taking Coenzyme Q10, Lisinopril, or beta blockers (a type of heart medication), and you cannot have used these medications in the past for longer than 6 months. •What do I have to do if I decide to participate in this study? First you will have a screening visit. If you are eligible to participate in the study based on the results of your screening visit, you will be randomized to one of four study arms: Arm 1 – CoQ10 alone, Arm 2 – Lisinopril alone, Arm 3 – both CoQ10 and Lisinopril, or Arm 4 – Enhanced standard of care with no study medication. You will then have scheduled study visits, which include a physician exam, strength & breathing testing, spine x-rays, echocardiograms, electrocardiograms, and blood work. •Where does this study take place? This study will be run at select Cooperative International Neuromuscular Research Group (CINRG) network sites and affiliates. This study is currently approved at 9 participating sites: Children’s National Medical Center, Washington, DC; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Carolinas Medical Center, Charlotte, NC; University of Pittsburgh, Pittsburgh, PA; University of Tennessee, Memphis, TN; University of California, Davis, Sacramento, CA; National Center of Neurology and Psychiatry, Tokyo, Japan, Alberta Children’s Hospital, Calgary, 8 Alberta, Canada, and the University of California, Los Angeles, Los Angeles, CA . However, more sites will be added in the future so be sure to check www.clinicaltrials.gov or the website for the CINRG group: www.cinrgresearch.org for updated site lists. •How many visits to the study site are necessary? There are 6-7 visits during the 24 months of the study, which includes screening and months 0.5, 1.5, 6, 12, 18 and 24. •Can any visits be done locally? No, visits must be done at a participating CINRG center. •Is there any funding to help pay for travel? The study does not provide any funds for travel; however please inquire at each individual site as some CINRG sites may have alternative resources for travel reimbursement or assistance. •Will I get paid for participating in this study? No, you will not be paid for your participation in this study. The study site will provide you with the study medication free of charge, should you be placed in an arm involving the use of a study medication. You will not be charged for additional tests and procedures that are performed only because you are participating in this research. Your responsibility to pay for other medical treatment will not be changed by your participation in this study. •Why should I consider participating in this study? One benefit that may result from participation in this clinical trial is a delay in the development of heart problems associated with muscular dystrophy. We are doing this study to find out whether or not people with certain types of muscular dystrophy will do better with lisinopril, CoQ10, or neither. We anticipate that there will be a benefit, but the amount of potential benefit is unknown. There is no greater or lesser benefit anticipated for any of the four randomization groups listed above. Everyone who participates in the study will benefit from more frequent doctors visits and closer medical monitoring. By watching you more closely, we may find problems and treat them earlier than if you were seen less often. •Where can I learn more about this study? »» You can learn more about this study at www.cinrgresearch.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED DP ARF Ultrasound Double-Push Acoustic Radiation Force (DP ARF) Ultrasound for Monitoring Degeneration in Duchenne Muscular Dystrophy •What stage is this research? This study is actively recruiting participants. •What is the goal or purpose of this study? This is a pilot clinical trial to assess the ability of a new ultrasoundbased imaging method, Double-Push Acoustic Radiation Force (DP ARF) ultrasound, to monitor the progression of Duchenne muscular dystrophy. •Who is sponsoring this study? This study is sponsored by the University of North Carolina, Chapel Hill, in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS). •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, a potential indirect benefit may be the satisfaction of being a part of the advancement of medical science to improve monitoring and treatment of Duchenne and the other 30+ types of muscular dystrophies in children and adults. •Where can I learn more about this study? »» You can learn more about this study at www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is eligible to participate in this study? The study population will include 30 boys with Duchenne enrolling at ages 5 to 10 years. To be considered for enrollment, boys must have a clinical onset of Duchenne by age 5, and must have the ability to stand, either alone or with assistance. •What do I have to do if I decide to participate in this study? All boys will be imaged 3 times annually for 4 years. In addition to DP ARF imaging every 4 months, the boys will undergo standard quantitative muscle testing (QMT) and timed function tests (TFT) of time to standing, 6-minute walk, and 30-feet walk. Age at loss of ambulation will also be recorded for each boy. •Where does this study take place? This study takes place at the University of North Carolina, Chapel Hill (UNC-CH). •How many visits to the study site are necessary, and can any visits be done locally? A total of 12 visits – 3 per year for 4 years. All visits must be at UNC-CH. •Is there any funding to help pay for travel? Yes, this study provides reimbursement for air travel (for the patient and an accompanying adult) and car travel (by the mile). Hotel accommodations in Chapel Hill are also provided. •Will I get paid for participating in this study? No, there is no payment for participating, other than the funding to help with travel costs. #CONNECT20 9 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Duchenne Natural History Study Longitudinal Study of the Natural History of Duchenne Muscular Dystrophy •What stage is this research? This study is actively recruiting Duchenne muscular dystrophy and healthy control participants. •What is the goal or purpose of this research? »» The purpose of this study is to establish the largest long-term assessment of people with Duchenne muscular dystrophy (Duchenne). In this study, the investigators associated with the Cooperative International Neuromuscular Research Group (CINRG) will take a detailed look at Duchenne participant’s physical abilities, the medical problems they experience, and how they use health care services. Physical abilities will be compared to a group of healthy controls. »» The second purpose of this study is to find out whether small, normal differences in the genetic makeup of people with Duchenne (called “single nucleotide polymorphisms” or “SNPs”) affect how their disease progresses and relates to muscle strength/size and steroid response. »» The third purpose of this study is to study genetic variations associated with Duchenne. »» The final purpose of this study is to determine whether certain biomarkers are present in people with Duchenne and not in healthy controls. •Who is sponsoring this research? This study is sponsored by the U.S. Department of Education, National Institutes of Health (NIH), and Department of Defense. Parent Project Muscular Dystrophy is funding the study of the New Young Duchenne Cohort. •Who is eligible to participate in this trial? »» Researchers are now recruiting for the New Young Duchenne Muscular Dystrophy Cohort. 100 male Duchenne participants, age 4 – 7 years old, are needed. The diagnosis of Duchenne must be confirmed by genetic test and/or muscle biopsy. »» Researchers are now recruiting for the Healthy Control Cohort. 120 male healthy controls, ages 6-17 years old, are needed. •What to I have to do if I decide to participate in this trial? »» Duchenne Cohort: At each study visit you will have a physical and neurological exam by a study physician, and your health medication will be reviewed. You will have strength, function, and breathing testing performed by a physical therapist, and you and/or your parent/legal guardian will also complete quality of life questionnaires. Optional saliva and/or blood samples will be collected for genetic and/or biomarker (markers that may help us understand more about Duchenne) analysis. 10 »» Healthy Control Cohort: At each study visit you will have strength and function testing completed. Optional blood samples will be collected for biomarker (markers that may help us understand more about Duchenne) analysis. •Where does this study take place? »» This study will be run at 22 participating centers of the Cooperative International Neuromuscular Research Group (CINRG) network. The participating CINRG centers include 12 sites in the US and additional sites in Canada, Argentina, Puerto Rico, Italy, Sweden, India, Israel, and Australia. More sites may be added in the future so be sure to check www.clinicaltrials.gov or the website for the CINRG group: www.cinrgresearch.org for updated site lists. •How many visits to the study site are necessary? There will be up to 12 visits for Duchenne participants. There will be 2 visits for typically developing controls. •Can any visits be done locally? No, they must be done at participating CINRG centers. •Is there any funding to help pay for travel? The study does not provide any funds for travel; however please inquire at each individual site as some CINRG sites may have alternative resources for travel reimbursement or assistance. •Will I get paid for participating in this study? No, you will not be paid for your participation in this study. You will not be charged for additional tests and procedures that are performed only because you are participating in this research. Your responsibility to pay for other medical treatment will not change by your participation in this study. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, there are other benefits, including allowing you to play an active role in your own health care (or that of your child), gaining access to medical specialists that are normally not available to you or your child, and helping others by contributing to the better understanding of Duchenne. •Where can I learn more about this study? »» You can learn more about this study at www.cinrgresearch.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Duchenne Tissue Bank Duchenne Muscular Dystrophy Tissue Bank for Exon Skipping •What stage is this research? This study is actively recruiting Duchenne muscular dystrophy participants. •What is the goal or purpose of this study? Researchers will utilize the Cooperative International Neuromuscular Research Group (CINRG) network to collect and store tissue and blood from patients with Duchenne with specific genetic mutations within the dystrophin gene that could be treated by antisense oligonucleotide (AO) drugs (exon skipping therapies). •Who is sponsoring this study? This study is sponsored by the National Institutes of Health (NIH). •Who is eligible to participate in this study? Researchers are recruiting 60 males with Duchenne, age 4 years and older. Participants must have a known out-of-frame deletion that could be targeted by exon skipping therapies for exons 45, 51, or 53. These include: Mutations eligible for exon 45: Mutations eligible for exon 51: Mutations eligible for exon 53: • • • • • • • • • • • • • • • • • • • • • • • • • • Exon 44 Exon 46 Exon 46-47 Exon 46-48 Exon 46-49 Exon 46-51 Exon 46-53 Exon 46-55 Exon 46-60 Exon 13-50 Exon 29-50 Exon 43-50 Exon 45-50 Exon 47-50 Exon 48-50 Exon 49-50 Exon 50 Exon 52 Exon 52-63 Exon 10-52 Exon 43-52 Exon 45-52 Exon 47-52 Exon 48-52 Exon 49-52 Exon 50-52 •What to I have to do if I decide to participate in this study? A blood and skin sample will be collected from each participant and will be held in a tissue bank at Carolinas Medical Center in Charlotte, NC for future Duchenne research. Hospital in Houston, TX; the University of California, Davis, in Sacramento, CA; Alberta Children’s Hospital in Calgary, Alberta, Canada; the University of Tennessee in Memphis, TN, and Ann & Robert H. Lurie Children’s Hospital of Chicago in Chicago, IL. More sites will be added in the future so be sure to check www. clinicaltrials.gov or the website for the CINRG group: www. cinrgresearch.org for updated site lists. •How many visits to the study site are necessary? Only 1 visit will be needed to collect the blood and skin samples. •Can any visits be done locally? No, they must be done at a participating CINRG center. •Is there any funding to help pay for travel? The study does not provide any funds for travel. •Will I get paid for participating in this study? No, you will not be paid for your participation in this study. You will not be charged for additional tests and procedures that are performed only because you are participating in this research. Your responsibility to pay for other medical treatment will not be changed by your participation in this study. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, there are other benefits, including allowing you to play an active role in your own health care (or that of your child), gaining access to medical specialists that are normally not available to you or your child, and helping others by contributing to the better understanding of Duchenne. •Where can I learn more about this study? »» You can learn more about this study at www.cinrgresearch.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Where does this study take place? This study will be run at select Cooperative International Neuromuscular Research Group (CINRG) network sites and affiliates. The participating CINRG centers include the University of Pittsburgh in Pittsburgh, PA; Johns Hopkins / Kennedy Krieger in Baltimore, MD; Stanford University Medical Center in Stanford, CA; Carolinas Medical Center in Charlotte, NC; Texas Children’s #CONNECT20 11 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED EIM and Ultrasound Electrical Impedance Myography and Ultrasound as Biomarkers of Duchenne •What stage is this research? This study is actively recruiting participants. •What is the goal or purpose of this study? This study is evaluating two new techniques which measure muscle function and monitor disease progression in patients with Duchenne. The first, called electrical impedance myography (EIM), will test nerve and muscle function, and the second, called quantitative ultrasound (QUS), will be used to take images of the muscle. The testing is all pain free. •Who is sponsoring this study? This is a National Institute of Health (NIH) study sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and is being conducted by Boston Children’s Hospital in collaboration with Beth Israel Deaconess Medical Center. •Who is eligible to participate in this study? The study population will include 50 boys with Duchenne, age 2 30 years, as well as 50 healthy male controls, age 2 - 30 years. •Will I get paid for participating in this study, and is there any funding to help pay for travel? Compensation will be provided for each completed study visit in the form of a $30 VISA gift card, and you will also be reimbursed for parking for the entire day, and a $10 meal voucher. Patients and families will not be reimbursed for travel. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a study, there are other benefits, including allowing you to play an active role in your own health care (or that of your child), gaining access to medical specialists that are normally not available to you or your child, and helping others by contributing to the better understanding of Duchenne. •Where can I learn more about this study? »» You can learn more about this study at www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What to I have to do if I decide to participate in this study? »» Children participating in the study will come in for 10 visits over two years. Visits will take place every month at first, then less often for the remaining visits. The tests for the study itself take approximately 2 hours. »» The first test uses an ultrasound machine. Pictures of different muscles are taken with the system, and the pictures are then analyzed mathematically. Each measurement takes only seconds and is entirely painless. »» The second tool is called electrical impedance myography (EIM), which uses a machine to measure how well a tiny electrical current travels through muscle. Investigators will wet the skin with saline, and then place a probe on the skin. Each measurement takes only a few seconds and is painless. »» There are also functional tests done by a physical therapist, which measure muscle strength and endurance. •Where does this study take place? This study takes place at Boston Children’s Hospital. Visits are sometimes also conducted at satellite branches of Boston Children’s Hospital, including the site at Peabody, MA and at Waltham, MA. 12 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Follistatin Gene Transfer Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis •What stage is this research? This Phase 1 trial is enrolling participants by invitation only. •Where is this research being performed and who is funding this research? This research is being led by Dr. Jerry Mendell at Nationwide Children’s Hospital Research Center in Columbus, Ohio. It is being funded by Parent Project Muscular Dystrophy’s GIFTED Program. •What is the goal or purpose of this research? »» Follistatin is a muscle growth-stimulating protein. This research is intended to build upon preliminary studies in mice with muscular dystrophy and in non-human primates which demonstrated that the follistatin gene, when injected into muscles, can cause significant increases in the size of injected muscles and improvements in the strength of injected muscles. If successful, the investigators can potentially prolong a patient’s ability to walk. »» The gene will be carried into the muscle by a virus called adenoassociated virus (AAV). This virus occurs naturally in muscle and does not cause any human disease. •What are the future plans for this research? If this study is successful, the investigators will expand the research to a phase 2 study and will also make plans to test it in patients with Duchenne. •Where can I learn more about this research? »» You can learn more about this research at www.nationwidechildrens.org/center-for-gene-therapy and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is eligible to participate in this study? Again, this study is recruiting patients by invitation only. Adult male Becker patients (>18yo) with a proven mutation of the dystrophin gene and continued ambulation after age 15 years old are being recruited. Participants must have identifiable atrophy of the quadriceps muscle with muscle weakness ≥2 standard deviations below predicted using quantitative muscle testing. This study is also recruiting patients with sproadic inclusion body myositis. •What do participants have to do in this study? Participants with either of these diseases will have shots of the follistatin gene injected directly into their thigh muscle on one or both legs (one time only). One hundred and eighty days following the gene delivery, participants will undergo testing to see if their muscle strength has improved and muscle biopsy to look closely at the muscle to see if the muscle fibers are bigger. Between the time of the gene transfer and the muscle biopsy, participants will be carefully monitored for any side effects of the treatment. This will include an MRI of the thigh muscle before treatment and at day 180 following treatment. Blood and urine tests, as well as physical examination will be done on the participants during the screening visit and several times throughout the study to make sure that there are no side effects from the gene injections. #CONNECT20 13 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED FOR-DMD Finding the optimal steroid treatment for Duchenne muscular dystrophy •What stage is this research? This study is actively recruiting participants. •What is the goal or purpose of the FOR-DMD study? »» This study will look at the benefits and side effects of the three most widely prescribed steroid treatments for Duchenne muscular dystrophy (Duchenne). The type of steroids commonly prescribed for Duchenne are called corticosteroids. Corticosteroids are a type of drug similar to natural hormones produced by the adrenal glands that reduce inflammation and suppress the immune response. They are often prescribed to boys with Duchenne. These steroids may have an effect on stabilizing or even improving muscle strength for a period of time but not all boys respond to treatment. The main steroid that is used is called predniboye. Deflazacort is also used in some countries. These are not “anabolic steroids” which is what athletes use illegally to build up muscle – these do not have an effect in Duchenne. Sometimes they are also referred to as ‘glucocorticoids.’ »» We will compare three different treatment groups: »» Daily predniboye »» Daily deflazacort »» Intermittent predniboye (10 days on / 10 days off). The study is randomised (your child’s treatment group will be decided randomly, as in drawing names from a hat or tossing a coin) and double-blind which means that neither participants nor their doctors will know which group the child is in (until the study is completed). »» All three steroid treatments are commonly used in boys with Duchenne and have been shown to be beneficial. Benefits include an increase in the length of time that the boys can continue to walk, reduction in the development of curvature of the spine, a longer time of adequate breathing, and possibly protection against the development of heart problems. »» However, we do not yet know which steroid treatment has the most benefit and most tolerable side effects. Therefore, this is a trial of present day steroid use which is needed because the practice of prescribing steroids varies a lot across doctors. This means that patients may not be getting the best possible treatment and management of side effects. All boys in this study will be receiving treatment with steroids and will be managed as per the recognized standards of care. •Who is eligible to be in this study? To be in this study your child must have a confirmed diagnosis of Duchenne by genetic test. He must be between 4 and 7 years old and NOT previously treated with steroids except by inhaler or as an ointment. 300 participants are needed, and approximately 96 have enrolled since January. 14 •Where will this study take place? This study will take place in at least 43 muscle clinics in the US, Canada, UK, Germany and Italy and other countries may also be included later. Please visit www.clinicaltrials.gov for a complete list of all study sites. The principal investigators are Dr. R Griggs at the University of Rochester, NY and Prof. K Bushby at Newcastle University, UK. •What will happen during the study? »» If you are interested in the study and your child appears to be eligible, he will be invited to visit the study site for a screening visit. At this appointment the study will be explained to you and your child in detail and some tests will be performed to allow the study doctors to ensure your child meets all the necessary requirements to participate in this study. After the screening period, you and your child will visit the study site at 3 months and then every 6 months after that. There will be a total of around 8-13 visits depending on when your child is enrolled. At each visit your child will be assessed to monitor benefits and side effects of corticosteroids. We hope that many children will be able to find a muscle clinic that is participating in the study reasonably close to where they live and that the study visits will take the place of their routine follow up. »» We expect your child will be in the study for 3-5 years. •Is there any funding to help pay for travel? For participants in the United States and Canada, we are able to reimburse reasonable travel expenses (airfare, mileage, hotel, meals, etc.) incurred to reach the study center closest to the participant’s home. We are able to offer this assistance through a grant provided by the Muscular Dystrophy Association (MDA). After the screening visits, the frequency of clinic visits should not be any more than is usual for follow up in Duchenne. •Will I get paid for participating in this study? No. •Will I have access to the drug once the study has ended? »» Yes, your doctor will discuss treatment options at the end of the study to decide the best steroid treatment plan for your child. »» The only issue is that deflazacort is not currently available in the US and we don’t know if it would be available in the US if the study showed it to be better than the other treatments. We are discussing this with the FDA. Deflazacort is already available in many countries and, in the US, it can be ordered from other countries by physician prescription. #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED •Will participating in this study prevent my child from taking part in other clinical trials? We are aware that trials of other potential new therapies may start during the course of the study. As steroid treatment is part of the normal standard of care in Duchenne we do not believe that being in this study would prevent your child from being in another study later if there were one that he were eligible for. Moreover, although we hope that the majority of children will finish the whole trial, as with any clinical study, you are entitled to withdraw at any time if you no longer wish to participate. •Why should I consider participating in this study? »» While no personal benefit can ever be guaranteed from being in a clinical trial, there are other benefits, including: »» Allowing you to play an active role in Duchenne research »» Access to medical specialists that might not normally be available to your child »» Access to high standard medical care and management in Duchenne »» Contributing to the better understanding of Duchenne and what the best steroid treatment is »» All participants will be getting active drug (there is no placebo group) and will be followed up and managed during the trial according to current standards of care. •What should I do if I decide I want to take part in this study? Please visit www.ClinicalTrials.gov for a complete list of study sites and the study coordinator at each site. Please call or email the study coordinator at the site nearest your home if you would like to participate. You can also contact the FOR-DMD US Project Manager, Kimberly Hart, at telephone 585-275-3767 or email [email protected]. •Who is funding this study? This study is funded by the National Institutes of Health (NINDS). •Where can I learn more about this study? »» You can learn more about this study at www.for-dmd.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 15 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED HT-100 Safety, Tolerability, and Pharmacokinetics of Single & Multiple Doses of HT-100 in DMD •What stage is this research? This trial is actively recruiting participants. •What is the goal or purpose of this research? »» The main purpose of this study is to test the safety and tolerability of different, increasing doses of an experimental medication called HT-100 in boys and young men with Duchenne muscular dystrophy. The study medication, HT-100, is a medicine that may help promote healthy muscle regeneration, diminish inflammation and the resulting damage to muscle, and decrease the scar tissue that forms in the muscles of children with Duchenne. HT-100 does not appear to be mutation-specific, meaning it is potentially applicable to all boys and young men with Duchenne. »» Halo Therapeutics has an approved IND from the FDA allowing the company to conduct this research and has received Orphan Drug status for HT-100 for Duchenne. •Who is funding this research? The drug is being developed for Duchenne by Halo Therapeutics, LLC. This research is funded by the Nash Avery Foundation, Charley’s Fund, Parent Project Muscular Dystrophy, and 14 other Duchenne patient foundations. •Who is eligible to participate in this trial? This trial is open to males with Duchenne, ages 6-20 years old. Ambulatory or non-ambulatory boys can enroll, and participants may be either corticosteroid-naive or on corticosteroid therapy for at least 12 months (stable dose and regimen). Recent, substantial change in use of cardiac medications or medications affecting muscle function and/or significantly compromised cardiorespiratory function would exclude you from this trial. •What to I have to do if I decide to participate in this trial? »» Single and multiple ascending doses of HT-100 will be given to participants. Safety and tolerability will be assessed. Pharmacokinetic sampling, or measurements of the amount of HT-100 in the bloodstream, will also be taken. »» This initial study of safety and tolerability will be followed immediately by a 6-month, open label extension study. All boys and young men who complete the initial study will be eligible to participate in the extension study. 16 •Where does this clinical trial take place? »» There are 5 sites in the US: UC-Davis in Sacramento, CA; Kennedy Krieger Institute in Baltimore, MD; Washington University School of Medicine in St. Louis, MO; Nationwide Children’s Hospital in Columbus, OH; and Cincinnati Children’s Hospital in Cincinnati, OH. •How many visits to the study site are necessary? For the initial study, there are 9 separate visits to the study site, some of which require an overnight stay, and some of which occur over multiple days. For the extension study, there are 4 separate visits to the study site, about 1 every other month. All visits, except the visit at 6 months (which occurs over multiple days), are 1-day visits. •Is there any funding to help pay for travel? Yes, there is some funding available to help pay for travel. In addition, Halo Therapeutics (the sponsor) is making available a travel coordinator to assist families with travel planning. •Will I get paid for participating in this study? No, there is no stipend for participating in this study •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a clinical trial, there are other benefits, including allowing you to play an active role in the health care of your child, gaining access to medical specialists that are normally not available to your child, and helping others by contributing to the better understanding of Duchenne. •Where can I learn more about this research? »» You can learn more at www.halotherapeutics.com and www. ClinicalTrials.gov. »» Patients interested in participating in this trial can email Halo using this address: [email protected] »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Tadalafil A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy •What stage is this research? This Phase 3 clinical trial is actively enrolling participants. •What is the goal or purpose of this research? The main purpose of this study is to determine if tadalafil can slow the decline in walking ability of boys who have Duchenne muscular dystrophy. The study will also assess the safety of tadalafil and any side effects that might be associated with it in boys who have Duchenne. •Where can I learn more about this study? »» Please visit www.lvjjstudy.com or call 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM EST. »» www.clinicaltrials.gov (code NCT01865084) »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is the sponsor of this study? Eli Lilly and Company (www.lilly.com) is the sponsor of this study. •What are the inclusion (enrollment) criteria for this trial? Participants will need to be boys with Duchenne who are between the ages of 7-14 years old and ambulatory. Participants must be on a stable corticosteroid therapy for at least 6 months prior to screening, and must have a left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiogram. Additional details regarding the inclusion and exclusion criteria are posted on www. ClinicalTrials.gov. •What to I have to do if I decide to participate in this trial? Participants will receive study treatment (tadalafil or placebo) for the first 48 weeks of the study, and can then continue into a 48 week extension period during which all participants will receive tadalafil. The primary outcome measure that will be measured at study visits is the 6-minute walk test. •Where does the trial take place? There are currently sites in 16 states in the US, as well as multiple sites in 14 other countries (Asia, Canada, Europe and South America). Please check www.clinicaltrials.gov for a complete list of study sites. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a clinical trial, there are other benefits, including allowing you to play an active role in the health care of your child, gaining access to medical specialists that are normally not available to your child, and helping others by contributing to the better understanding of Duchenne. #CONNECT20 17 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Translarna™ (ataluren) An Investigational New Drug for Nonsense Mutations by PTC Therapeutics •What is the current status of ataluren? »» PTC recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion regarding the company’s application for a conditional marketing authorization of ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) in ambulatory patients aged five years and older. Ataluren will be marketed under the brand name Translarna™, and is the first drug for the underlying cause of Duchenne to receive a positive opinion from the CHMP. Although no equivalent conditional approval program is available in the US, PTC will continue to engage with regulators to determine a path forward for access for all nmDMD patients who may benefit from Translarna. »» PTC Therapeutics is conducting the Ataluren Confirmatory Trial in Duchenne muscular dystrophy (ACT DMD), a Phase 3 trial of the drug in patients with nmDMD. This randomized, double-blind, placebo-controlled trial is designed to confirm the safety and efficacy results seen in its Phase 2b study. The study will enroll 220 participants at approximately 58 sites in North America, South America, Europe, Israel, Asia and Australia. Successful results of this trial will provide the basis for a full approval decision in the EU and the US as well as other countries to follow. »» Studies for nmDMD patients previously enrolled in Translarna trials are ongoing in each of their countries. »» Translarna is also being studied in patients with cystic fibrosis (CF) in the recently opened Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF). •What is nonsense mutation? A nonsense mutation is a premature stop signal in the genetic code that interrupts the production of a protein. Proteins are essential to the proper working of every cell in the body. Nonsense mutations result in incomplete proteins that do not function properly and in turn cause a genetic disorder. For example, in nmDBMD, the muscle protein dystrophin is incomplete and non-functional, leading to muscle wasting and progressive loss of muscle strength. •What is the goal or purpose of this research? Translarna is an investigational new drug that is designed to enable the formation of a functioning protein in a patient with •Who is funding this research? Translarna was discovered and developed by PTC Therapeutics. Its development has been supported by the FDA Office of Orphan Products Development, Parent Project Muscular Dystrophy, the Muscular Dystrophy Association, Cystic Fibrosis Foundation Therapeutics Inc., and the National Center for Research Resources. •When will Translarna be commercially available? Translarna is an investigational new drug that is currently only available through clinical trials. It has received a positive opinion from the CHMP which would normally lead to conditional approval in the EU and certain other European countries within three months. It has not been approved for use by regulatory authorities in any other countries and thus cannot be legally purchased for use by a patient. Based on estimates regarding patient enrollment, initial, top-line data from the Phase 3 clinical trial are expected in mid-2015. If trial results support approval and FDA approves our application, Translarna could be available in the US as early as the second half of 2016. PTC plans to apply for approval in other countries following US approval. Conditional approval in the EU could make it available there as early as 2014, pending country by country final activities that make access possible. •How can I find out if Translarna would benefit my child? Approximately 13% of boys with Duchenne have a nonsense mutation. You should discuss genetic testing with your child’s physician or a genetic counselor. Usually, only a small amount of blood is required to perform the test. The blood sample must be sent to a specialized laboratory that has expertise in Duchenne. Translarna is specifically for patients with a nonsense mutation. It will not benefit patients whose Duchenne is caused by a different mutation, such as a deletion or duplication. •Where can I learn more about Translarna? »» You can learn more about Translarna at www.ptcbio.com. Information about ACT DMD is available on that site as well as on www.clinicaltrials.gov (search term: NCT01826487) and www.DuchenneConnect.org. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. a genetic disorder due to a nonsense mutation. Translarna is taken orally and has the potential to treat the root cause of the disorder by overriding the premature stop signal so that a functional protein can be made. It does not alter a patient’s genetic code or introduce genetic materials into the body. 18 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED CAT1000 Catabasis’ Lead Program for Targeting Inflammation •What stage is this research? Phase 1 studies in adults with CAT-1004 have been completed. A clinical trial in boys with Duchenne is in the planning stages. •Where is this research being done and who is funding this research? This research is being done by Catabasis, a private biopharmaceutical company leveraging pathway pharmacology to develop new compounds for the treatment of rare diseases, including Duchenne muscular dystrophy. The MDA Venture Philanthropy program recently awarded a grant to Catabasis to support preclinical studies in models of Duchenne muscular dystrophy. •Where can I learn more about this research? »» You can learn more about this research at www.catabasispharma.com. »» www.ClinicalTrials.gov will post the clinical trial once it is actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the goal or purpose of this research? CAT-1004 is an anti-inflammatory agent to be given orally, which is in development to target inflammation. Inflammation plays a critical role in the degeneration process in Duchenne, and decreasing inflammation is an approach that could modify the course of Duchenne muscular dystrophy. •What is the current state of this research and what steps need to be completed before moving into a clinical trial? »» Catabasis has recently completed a series of studies in animal models of Duchenne in which CAT-1004 and similar compounds reduced inflammation and improved muscle function. »» Catabasis is planning an initial clinical trial with CAT-1004 in boys with Duchenne. •What is your best estimate for the length of time it will take to move this research into clinical trials? While it is difficult to estimate the exact timing, clinical trials in boys with Duchenne could start in the next year. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. Many complex factors go into determining the right location(s) for a clinical trial. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria would be for a future clinical trial. Since the effects of CAT-1004 would not be limited to certain mutations, CAT-1004 can be tested in boys with all genetic mutations of Duchenne and Becker. #CONNECT20 19 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED DRISAPERSEN Re-dosing program for Duchenne patients who previously participated in the drisapersen clinical studies to skip exon 51 •What kind of program is this? »» Following positive feedback from patients and investigators regarding the willingness and desire of patients to go back on drisapersen and encouraging analyses of its clinical trial data, Prosensa intends to re-dose patients who previously participated in the drisapersen clinical studies (subject to them meeting safety entry criteria). •Where can I learn more? »» You can learn more at www.prosensa.com. »» If you previously participated in a drisapersen clinical program, your investigator at the study site can provide you with more information. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •When will this program start? We remain on track to re-dose the first group of boys in the 3rd quarter of this year. Re-dosing will take a staged approach; patients will resume dosing under new or existing treatment protocols or via an expanded access program. •In which countries will re-dosing start? We plan to initiate dosing in stages, initially this will occur at sites in both North America and Europe, and we are actively working with these sites and investigators to execute these plans. •Could you provide more information about participating sites in North America? »» In the US and Canada, eligible boys are those who completed DEMAND V (DMD114876), those that are currently in the DMD115501 protocol and US/Canadian boys who participated in the DEMAND IV study (DMD114349). »» More detailed information about the re-dosing protocol for the first group of boys in Europe will follow. •Will participation in the re-dosing program require the same number of visits to the sites? Prosensa is investigating the use of home dosing as an option to reduce visits to sites. Home dosing will be implemented where possible, subject to site and the individual’s requirements and applicable health care regulations. •Will participation in the re-dosing program require biopsies to be taken? With the aim of minimizing the burden of participating in the redosing program for patients, no biopsies will be taken. 20 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Exon Skipping for DMD (Sarepta Therapeutics) Exon Skipping by Phosphorodiamidate Morpholino Oligomers (PMO) to produce functional dystrophin protein. •What is exon skipping? Duchenne muscular dystrophy is caused by a genetic mutation or error in the gene that carries instructions for the [production of the] essential muscle protein dystrophin. Exon skipping is a possible way to help the body make working dystrophin protein again. Most mutations that cause Duchenne result in the portion of the protein following the mutation to be made incorrectly. This leads to production of a non-functional dystrophin protein. The idea behind exon skipping is to skip over a section of the gene, called an exon, to enable correct production of the portion of the protein following the mutation. This results in a shorter – but still functional – form of dystrophin. •What PMO-based exon skipping therapies are in development? There are eight investigational exon skipping therapies in different stages of clinical or preclinical (laboratory) testing. Following is a list of the current Sarepta pipeline of exon skipping drug candidates. Exon Skipping Candidate Exon Skip Examples of Potentially Repairable Deletion Mutations Eteplirsen Exon 51 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63 SRP-4053 Exon 53 10-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52 SRP-4045 Exon 45 12-44, 18-44, 44, 46-47, 46-48, 4649, 46-51, 46-53, 46-55 SRP-4044 Exon 44 10-43, 19-43, 30-43, 35-43, 36-43, 40-43, 42-43, 45, 45-54 SRP-4050 Exon 50 51, 51-53, 51-55 SRP-4052 Exon 52 53, 53-55, 53-57, 53-59, 53-60 SRP-4055 Exon 55 47-54, 48-54, 49-54, 50-54, 52-54, 54, 56, 56-62 SRP-4008 Exon 8 3-7, 4-7, 5-7, 6-7 Additional less common genetic mutations that may be amenable to treatment with an exon-skipping therapy may not be listed in the table above. Genetic testing is required to determine if a patient is eligible for exon skipping. Patients and families can speak with their healthcare provider to obtain genetic testing, review test results and learn if they may be a candidate for an exon skipping clinical trial. Through the Decode Duchenne Program administered by PPMD and supported by Sarepta, genetic testing may be available at no charge to eligible patients in the United States who are unable to access testing due to barriers such as cost or lack of insurance coverage. Eligibility criteria can be found by emailing [email protected] or by visiting www.duchenneconnect.org. •What stage is this research? A Phase IIb clinical trial with eteplirsen was completed in 2012. All boys who participated in the initial 24-week placebo-controlled stage of the Phase IIb study are receiving treatment with eteplirsen in a long-term, open-label extension study. Clinical results through 120 weeks – or more than two years – of treatment were recently reported at the American Academy of Neurology Annual Meeting in April 2014. Additional clinical trials of eteplirsen, SRP-4053 and SRP-4045 are planned to begin this year and early next year. •Who is sponsoring this research? Research of eteplirsen and other PMO-based exon skipping therapies in development is led and sponsored by Sarepta Therapeutics, a biopharmaceutical company focused on the discovery and development of novel RNA-based therapeutics for rare diseases. Sarepta has partnered with the Duchenne community to advance exon-skipping technology for more than a decade, and is committed to exploring the potential of this technology to address all of the boys and young men with Duchenne who could potentially benefit from an exon-skipping therapy, including those with rare genetic mutations. •What additional clinical trials are planned? Following is a list of planned clinical trials of eteplirsen, SRP-4053 and SRP-4045. Please note that this information is subject to change. Additional eligibility criteria and outcome measures may apply. (continued on p. 22) #CONNECT20 21 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED (continued from p. 21) •Open-label confirmatory clinical study of eteplirsen »» Study design: open-label historically controlled (no placebo) clinical study. Two cohorts are planned including a treated group of boys with deletion mutations amenable to exon 51 skipping and an untreated group of boys with deletion mutations not amenable to exon 51 skipping. »» Key eligibility criteria: boys aged 7 to 16 years with eligible genotypes who are able to walk a minimum distance and are on a stable corticosteroid regimen. »» Key outcome measures: 6-minute walk test, dystrophin as assessed by muscle biopsy (treated group only), safety and other measures. »» Clinical sites: multiple clinical sites in the United States. »» Timing: dosing planned to begin in the third quarter of 2014. •Open-label clinical study of eteplirsen in patients less than 7 years old »» Study design: open-label (no placebo) clinical study. »» Key eligibility criteria: boys aged 4 to 6 years with deletion mutations amenable to exon 51 skipping. »» Key outcome measures: dystrophin as assessed by muscle biopsy, safety and other measures. »» Clinical sites: multiple clinical sites in the United States. »» Timing: dosing planned to begin in the fourth quarter of 2014. •Open-label clinical study of eteplirsen in patients not able to walk a minimum distance »» Study design: open-label (no placebo) clinical study. »» Key eligibility criteria: boys aged up to 21 years old with deletion mutations amenable to exon 51 skipping who are unable to walk a minimum distance or are non-ambulatory and have stable heart and lung function. »» Key outcome measures: safety and other measures. »» Clinical sites: multiple clinical sites in the United States. »» Timing: dosing planned to begin in the fourth quarter of 2014. •Open-label clinical study of SRP-4053 (Europe only) »» Study design: open-label clinical study, with a placebocontrolled dose-escalation lead-in period. »» Key eligibility criteria: boys aged 6 to 15 years with deletion mutations amenable to exon 53 skipping who are able to walk a minimum distance and are on a stable corticosteroid regimen. »» Key outcome measures: 6-minute walk test, dystrophin as assessed by muscle biopsy, safety, and other measures. »» Clinical sites: multiple clinical sites in the United Kingdom, France and Italy »» Timing: dosing planned to begin in the third quarter of 2014. 22 •Placebo-controlled clinical study of SRP-4053 and SRP-4045 »» Study design: The design of this study is currently in development, and will be confirmed with the U.S. Food and Drug Administration. »» Key eligibility criteria: boys aged 7 to 16 years with deletion mutations amenable to exon 53 or exon 45 skipping who are able to walk a minimum distance and are on a stable corticosteroid regimen. »» Key outcome measures: 6-minute walk test, dystrophin as assessed by muscle biopsy, safety and other measures. »» Clinical sites: multiple clinical sites in North America and Europe. »» Timing: dosing planned to begin in the first quarter of 2015. •Can patients who previously received drisapersen participate in clinical studies of eteplirsen? Patients previously treated with drisapersen may be eligible to participate in eteplirsen clinical studies with a minimum 24-week (6 month) wash-out period and if they meet other study eligibility criteria. •What are the recent results that have been reported from the ongoing Phase IIb extension study of eteplirsen? »» Recently reported results from the Phase IIb clinical study of eteplirsen showed statistically significant and clinically meaningful changes on measures of dystrophin production and walking ability at 48 weeks. In addition, through 120 weeks of treatment with eteplirsen, patients did not report any clinically significant treatment-related adverse events. »» In the study, dystrophin production was assessed by muscle biopsy before starting treatment and twice on treatment. After the last muscle biopsy at week 48, there was a statistically significant increase in dystrophin-positive muscle fibers to 47.0 percent of normal (p≤0.001) among the eight patients who were treated once weekly with either 30 mg/kg or 50 mg/ kg of eteplirsen. The four patients in the placebo/delayedtreatment group, who received a placebo for 24 weeks before initiating treatment with eteplirsen at 30 mg/kg or 50 mg/kg, also demonstrated a statistically significant increase in dystrophinpositive fibers to 38.3 percent of normal (p≤0.009) at week 48, after 24 weeks of treatment. »» Results on endpoints measuring efficacy through 120 weeks – or more than two years of treatment – showed a general stabilization of walking ability in patients who remained evaluable on the 6-minute walk test. Through 120 weeks, evaluable patients treated with 30 mg/kg or 50 mg/kg showed less than a 5 percent decline (13.9 meters) in walking ability from baseline. After experiencing a substantial decline early in the study, the placebo/delayed-treatment group also demonstrated stabilization in walking ability for more than 1.5 years, from #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Week 36 through 120, the period from which meaningful levels of dystrophin were likely produced, with a decline of 9.5 meters over this timeframe. Two patients in the 30 mg/kg group were not evaluable and were excluded from the analysis because they showed rapid disease progression upon enrollment in the study. »» In addition, pulmonary function tests were included in the study as exploratory efficacy endpoints, and results through 120 weeks showed a general stabilization of respiratory function. •Does Sarepta plan to apply for the approval of eteplirsen based on the Phase IIb clinical trial results? Based on guidance from the U.S. Food and Drug Administration (FDA), Sarepta plans to submit a New Drug Application for eteplirsen by the end of 2014. •When might FDA approval of eteplirsen be expected? If the NDA filing for eteplirsen is accepted and granted a 6-month priority review (versus a standard 10 month review), an approval decision is possible in the second half of 2015. • Where can I learn more about clinical studies involving PMO-based exon skipping therapies from Sarepta? »» Information about Sarepta’s clinical trials will be posted on www. ClinicalTrials.gov as it becomes available. »» Additional information is available on Let’s Skip Ahead, an online resource center for the Duchenne community from Sarepta available at www.skipahead.com. Visitors to Let’s Skip Ahead can sign up to receive email updates from Sarepta, including news and information about clinical trials. Information is also available on Sarepta’s corporate website at www.sarepta.com. »» Patients and families can also contact Sarepta at skipahead@ sarepta.com or 855-DMD-SKIP (855-363-7547). #CONNECT20 23 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED ISOFEN 3 A combination drug for the treatment of Duchenne Muscular Dystrophy •What stage is this research? »» This upcoming study will be a phase 2 clinical trial. Isofen3 is a combination of Ibuprofen (a non-steroidal anti-inflammatory agent-NSAID) and isosorbide dinitrate (a drug that releases nitric oxide). Each of these is licensed worldwide for individual use. •What is the goal or purpose of this study? The goal of this study is to determine if the combination of two drugs, Ibuprofen and isosorbide dinitrate, is capable of slowing the progression of Duchenne. In animal studies the drug combination has been shown to help with muscle repair and myogenesis, with reducing inflammation, and with enhancing muscle function. A pilot study in non-ambulant patients with either Becker or Duchenne or Limb-Girdle muscular dystrophy plus two phase I studies in healthy volunteers showed the drug to be safe and tolerable with improvement in some of the measures studied. •Will I get paid for participating in this study? Is there any funding to help with travel? No, this study is on a voluntary basis. Presently there is no funding for travel, but funding is being sought. •Why should I consider participating in this study? While no personal benefit can ever be guaranteed by participation in a clinical trial, there are other benefits, including allowing you to play an active role in your own health care (or that of your child), gaining access to new research treatments before they are widely available and having access to medical specialists that are normally not available to you or your child, and helping others by contributing to the better understanding of Duchenne and Becker. •W here can I learn more? »» You can learn more about this study at www.DuchenneConnect.org and www.ClinicalTrials.org. •Who is funding this study? This study is funded in part by the European Union and there is ongoing fundraising by Duchenne Alliance. •Who is eligible to participate in this study? »» To participate in this study you must be above 6 years with a confirmed diagnosis of Duchenne, non-ambulatory and be able to meet certain heart and respiratory function criteria, with no recurrent headaches. You will need to pass an initial screening visit and meet all inclusion criteria and sign a consent form. •How long will this study last, and will I have access to the drug/treatment once the study has ended? The anticipated length of the study is a total of 42 months with enrollment being 6 months and the study lasting for 36 months. Depending on the results, you may have access to the drug while data is being analyzed and before FDA approval. •Where does this study take place? The study site locations are still being determined. •How many visits to the study site are necessary? There are 14 visits in which you will receive non invasive assessments (except blood draw) of your health status. All visits must be done at a study site, as specific assessment of your muscle function has to be completed by a physiatrist trained in the study procedure. 24 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED PF-06252616 Development of a myostatin inhibitor as a potential anabolic therapy for the muscular dystrophies. •What stage is this research? »» A Phase 1 clinical trial in healthy volunteers is in progress – please see www.ClinicalTrials.gov and search “PF-06252616” for details. The purpose of the study is to determine safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06252616 in healthy subjects. »» A clinical trial of PF-06252616 in boys with Duchenne is in the planning stages and remains dependent upon the final outcome(s) of the phase 1 clinical trial. The current plan is to initiate dosing by the end of this year. •Where can I learn more about PF-06252616? »» The current clinical study is posted on www.ClinicalTrials.gov. Please look for updates later this year for details on the upcoming study in Duchenne. »» Visit Pfizer.com/pipeline, Pfizer’s online database where you learn more about our portfolio of new medicines and find more about our Research and Development efforts around the world. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is PF-06252616? »» PF-06252616 is an experimental monoclonal antibody that, based on the proposed mechanism of action, has the potential to increase muscle mass in patients with evidence of reduced muscle mass. »» Preclinical evidence of increased muscle size and function has been demonstrated in mice and nonhuman primates. »» Evaluation of human safety and evidence of beneficial effects in healthy adults is ongoing. •Who is funding this research? At this time, Pfizer is fully supporting the clinical development of PF-06252616. •What will the inclusion (enrollment) criteria be for future trials? Planning for possible future clinical studies is still in progress and specific inclusion criteria for future clinical studies has not been determined. •Where will Phase 1b / 2 trials take place? Will there be study sites in the US? At this early stage, the current planning is for the clinical trial to be conducted at a small number of selected sites in the US, UK, and Europe. Additionally, all applicable regulatory approvals would need to be obtained in each region prior to any study initiation. •Is Pfizer committed to Duchenne? »» Our investment in Duchenne extends beyond PF-06252616. Although this is our most advanced compound we are actively studying compounds with diverse mechanisms of action and modalities to help Duchenne patients and their families. »» We have been very active in building our internal Duchenne efforts including: recruitment of additional scientists and clinicians with experience of Duchenne, evaluating additional programs for Duchenne, designing clinical trials, and exploring research collaborations. #CONNECT20 25 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED SMT C1100 A Small Molecule Utrophin Upregulator for Duchenne •What stage is this research? A Phase 1b clinical trial in patients with Duchenne completed earlier in 2014 with preliminary results being reported in May 2014. Further patient trials are planned to start later in 2014. •What is the goal or purpose of this research? »» Utrophin is a naturally occurring protein that is similar to dystrophin and scientists have shown that modulating its production can compensate for the missing dystrophin and help to restore healthy muscle function. »» SMT C1100 is a small molecule utrophin modulator that has the potential to benefit all Duchenne patients. This is Summit’s most advanced utrophin modulator with next generation molecules also in development. The approach of utrophin modulation is anticipated to be complementary to other therapeutic approaches currently in development. •Who is funding this research? The research is being supported by investors, the Duchenne community and the UK government. •What will the inclusion (enrollment) criteria be for the upcoming trial? Since reporting of the Preliminary results from the Phase 1b trial the future plans are currently under discussion and the inclusion criteria have not yet been finalized. Further information will be made available in due course. •Where will the trial take place? Will there be study sites in the US? Clinical trials could take place in either Europe or the US or both, and the harmonization program between the FDA and EMA allows for trial data from one region to be used in clinical trial applications in the other. •Where can I learn more about SMT C1100? »» You can learn more at www.summitplc.com. »» www.ClinicalTrials.gov will post the next phase of patient trials as soon as they are recruiting. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the current state of this research? Preliminary results from a Phase 1b clinical trial in boys aged between 5 and 11 years old were reported in May 2014. The study showed SMT C1100 was safe and well tolerated at all doses tested. All the boys had variable blood plasma level of SMT C1100 with only two of the boys achieving levels similar to those of the adult volunteers in the 2012 Phase 1 study. Initial evidence suggests the variability in drug uptake may be due to differences in diet and to other disease-related factors. In addition, in the majority of patients creatine kinase levels were reduced during dosing. Further evaluation of the data from this trial is on-going and it is expected further results will be reported at future scientific meetings. »» Preclinical studies established that SMT C1100: »» Increases utrophin protein in dystrophin deficient muscle cells from Duchenne patients to levels expected to have significant therapeutic benefit »» Significantly increases the amount of utrophin in the mdx mouse model of Duchenne »» Improves whole muscle function in a study with an endpoint similar to the 6 minute walk test »» Reduces muscle degeneration, fibrosis and chronic inflammation 26 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Biglycan A Unique Utrophin Upregulator •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. •Where is this research being done and who is funding this research? This research is taking place at Tivorsan and in the laboratory of Dr. Justin Fallon at Brown University. This work was funded by PPMD’s End Duchenne GAP program. Current funding is coming from private investors in Tivorsan, recently awarded PPMD and MDA foundation grants to Tivorsan, and an NIH grant (“UO1 mechanism”) to Dr. Fallon. •What is the goal or purpose of this research? The goal of this research is to use a protein called recombinant human biglycan (rh-biglycan) to increase utrophin and neuronal NOS (nNOS) at the muscle cell membrane, resulting in reduced muscle damage and improved muscle function. Utrophin is a molecule that is related to dystrophin in structure and form and can “stand in” for dystrophin when present in larger than normal quantities. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. Many complex factors go into determining the right location(s) for a clinical trial. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria would be for a future clinical trial. However, TVN-102 therapy is applicable to all forms of Duchenne, regardless of the underlying mutation. •Where can I learn more about this research? »» You can learn more about this research at www.Tivorsan.com. »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the current state of this research? »» Independent laboratories have reproduced the beneficial effect of rh-biglycan (rhBGN) in mice that lack dystrophin. A reliable method to manufacture the protein has been established and a scalable production process is being optimized. Additional preclinical studies are currently in process. »» An optimized version of rhBGN has been developed and this molecule, called TVN-102, has been designated the lead clinical candidate. »» Tivorsan has initiated discussions with FDA to define its INDenabling preclinical studies and early clinical development plan. •What steps need to be completed before moving into a clinical trial? »» Manufacturing of TVN-102 needs to be scaled-up to produce quantities and purity necessary for use in humans. »» Safety testing must be completed and the pharmacology properties of TVN-102 must be determined. •What is your best estimate for the length of time it will take to move this research into clinical trials? 12-18 months. #CONNECT20 27 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED BMS-986089 Bristol-Myers Squibb’s Candidate for Myostatin Inhibition •What is BMS-986089? BMS-986089 is an investigational protein that binds to myostatin. Myostatin is a protein produced primarily in skeletal muscle cells that prevents muscle cell growth and differentiation. Animals lacking myostatin or animals treated with substances that block the activity of myostatin have significantly larger muscles. •What stage is this research? BMS-986089 is in a Phase 1 clinical trial in healthy volunteers that began in 2014. •Where is this research being done? This research is being done by Bristol-Myers Squibb (BMS). Information regarding ongoing clinical trials can be found on www. ClinicalTrials.gov. •What is the goal or purpose of this research? The primary goal of the Phase 1 study is to assess the safety, tolerability, immunogenicity, drug levels, and drug effects of single and multiple doses BMS-986089 in healthy adult and elderly subjects. •When can we expect to see clinical trials for patients with muscular dystrophy? The timing of a Phase 2 study will depend on the completion of the Phase I studies. Up-to-date information regarding ongoing clinical trials can be found at www.ClinicalTrials.gov. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. BMS will make this information available on www. Clinicaltrials.gov. •Who would be eligible to participate in a clinical trial? It is too early to know what the eligibility criteria will be for a future clinical trial. BMS will make this information available on www. ClinicalTrials.gov. •Where can I learn more about this research? »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. 28 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Carmeseal-MD Carmeseal-MD (Poloxamer 188 NF) •What stage is this research? Our research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. We have completed a pre-IND (Investigational New Drug) meeting with the FDA and plan to start a clinical trial next. •Where is this research being done and who is funding this research? Our pre-clinical development work is conducted by Phrixus Pharmaceuticals in our Ann Arbor laboratories. Our work to date has been funded by the National Institutes of Health (NIH) through SBIR grants, the Biosciences Research and Commercialization Center, as well as, Coalition Duchenne and Duchenne Alliance. Phrixus studies are currently supported by the SMARTT (Science Moving towards Research Translation and Therapy) program at the NIH which is providing regulatory support through RTI International and preclinical studies at SRI International. •What is the goal or purpose of this research? Our goal is to demonstrate that Carmeseal-MD has beneficial effects in patients with Duchenne and Becker muscular dystrophy: An improvement in cardiac and respiratory function via protection of heart muscle and diaphragm. Carmeseal-MD acts as a molecular band-aid by binding to and then sealing microscopic tears in muscle cells caused by the lack of functional dystrophin. This prevents the uncontrolled leakage of calcium which in turn increases the performance of heart muscle and diaphragm and prevents their degeneration. •Where would a clinical trial take place? We are already collaborating with leading research clinicians and have verbal commitments from several to conduct the first trials. High likelihood centers include University of Chicago, IL (Beth McNally, on our SMAB); Nationwide, Columbus, OH (Linda Cripe, on our SMAB); Cincinnati Childrens (John Jefferies and Jeff Towbin, supported our pre-IND meeting); UPMC, Pittsburgh, PA (Jonathan Finder, supported our pre-IND meeting); and University of Michigan, Ann Arbor, MI (Mark Russell). •Who would be eligible to participate in a clinical trial? Carmeseal-MD is expected to be useful for all patients with Duchenne or Becker, regardless of genetic mutation. While inclusion and exclusion criteria still need to be finalized, we expect enrollment of non-ambulatory patients with early cardiac and respiratory dysfunction. This approach maximizes our chances of seeing a positive effect and provides a unique clinical trial opportunity for patients who cannot perform the six-minute walk test. •Where can I learn more about this research? »» Please see www.phrixuspharmaceuticals.com/index.htm, www.ParentProjectMD.org under the Advance Research tab and www.DuchenneConnect.org. •What is the current state of this research? Carmeseal-MD has been shown to be effective in three dystrophic animal models (mdx and mdx/utr double-knock out mice, GRMD dogs) and two models of heart failure (rats with surgically induced heart failure, micro-embolism induced dog heart failure model). Nearly all pre-clinical studies are complete, including three-month GLP toxicology studies in rats and dogs. •What steps need to be completed before moving into a clinical trial? We need to complete enzyme inhibition studies, which are required by the FDA. We also need to prepare and file our IND (pre-IND meeting complete). •What is your best estimate for the length of time it will take to move this research into clinical trials? 3-6 months. #CONNECT20 29 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED DMD: iPS Cell Therapy Duchenne Muscular Dystrophy: iPS Cells and Therapeutic Applications •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. •Where is this research being done and who is funding this research? This research is being done in the lab of Dr. Rita Perlingeiro at the University of Minnesota and is funded by grants from Parent Project Muscular Dystrophy and MDA. •Where can I learn more about this research? »» You can learn more about this research at the website for Dr. Perlingeiro’s lab: http://www.med.umn.edu/lhi/research/ PerlingeiroLab/index.htm »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the goal or purpose of this research? Induced pluripotent stem cells (iPS) are adult cells that have been reprogrammed to an embryonic stem cell-like state. There has been tremendous excitement for the therapeutic potential of iPS cells in treating genetic diseases. Our current research builds on our successful proof-of-principle studies for Duchenne performed with mouse wild-type and dystrophic iPS cells as well as control (healthy) human iPS cells. These studies demonstrate equivalent functional myogenic engraftment to that observed with their embryonic counterparts following their transplantation into dystrophic mice. Our goal now is to apply this technology to iPS cells obtained from patients with Duchenne by establishing methods to genetically correct the disease, and to evaluate the regenerative potential of resulting genetically corrected iPS cells in dystrophic mice. We are also developing a protocol for making iPS cells and their muscle derivative using integration-free methods. •What steps need to be completed before moving into a clinical trial? Safety and efficacy must be established in our pre-clinical work before moving into a clinical trial. •What is your best estimate for the length of time it will take to move this research into clinical trials? 3+ years. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. Many complex factors go into determining the right location(s) for a clinical trial. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria would be for a future clinical trial. 30 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED DT-200 DT-200, a selective androgen receptor modulator (SARM) to improve muscle strength and function in Duchenne Muscular Dystrophy, and other myopathies •What stage is this research? The DT-200 development program has completed 3 initial phase 1 trials in 78 healthy adult volunteers showing the SARM is safe and well tolerated for up to 14 days treatment. Testing in Duchenne has not yet begun. •Where is this research being done and who is funding this research? DT-200 is wholly owned by DART Therapeutics, who are leading the clinical development program. DART is currently seeking funding for the next development step, a 4-week Proof of Concept Clinical (POC) trial. •What is the goal or purpose of this research? DT-200 is a selective androgen receptor modulator (SARM). Selective androgen receptor modulators (SARMs) have been developed to mimic the muscle building effects of androgens (testosterone), without their undesirable side effects. DART hopes that the more precise action of this drug will confer better, longer term safety and tolerability in both adult and pediatric muscle diseases compared to androgens. DT-200 is effective in multiple animal models, including mice that lack dystrophin. Importantly, compared to other SARMs in clinical development, DT-200 shows significantly greater preference for skeletal muscle. Accordingly, DART is developing DT-200 with the objective of improving muscle strength and function in both adult muscle diseases, such as Charcot Marie Tooth disease (CMT) and Facioscapulohumeral Muscular Dystrophy (FSHD), and in pediatric myopathies, such as Duchenne and Spinal Muscle Atrophy (SMA). •What is your best estimate for the length of time it will take to move this research into clinical trials? If the POC trial in healthy adult subjects is positive, DART anticipates initiation of clinical trials in adult and pediatric muscle diseases within six months from the conclusion of the POC trial. •Where would a clinical trial take place? Phase 2 trials would be initiated in both the US and Europe. •Who would be eligible to participate in a clinical trial? It is too early to know what the inclusion criteria would be for a future clinical trial. •Where can I learn more about this research? »» You can learn more about DT-200 (and other DART initiatives) by consulting the DART website at: http://dartrx.com »» www.ClinicalTrials.gov will post all DT-200 clinical trials once they are actively recruiting subjects. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the current state of this research and what steps need to be completed before moving into a clinical trial? Three phase 1 studies with DT-200 were successfully completed in Belgium and Germany, having confirmed the product is safe and well tolerated at the once daily oral dose of 0.5 mg. DART met with the UK Regulatory Agency (MHRA) in May 2013 for scientific advice and input into the design of a Proof of Concept clinical trial. DART plans to initiate this 4-week POC trial in the UK in Q4 2013 in healthy adult volunteers. The main objective of the POC trial is first to evaluate DT-200’s ability to increase mass, strength and function of healthy muscle. It is anticipated the POC trial will take approximately 9 months to complete. #CONNECT20 31 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED GALGT2 Gene Therapy Viral gene transfer for GALGT2 as a surrogate gene therapy for Duchenne •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. However: »» The investigators have completed pre-IND interactions with the FDA, and the study has been favorably reviewed by the NIH Recombinant Advisory Committee. »» IND-enabling toxicology and biodistribution studies have been completed. »» An IND application will be submitted to the NIH in June 2014. •What steps need to be completed before moving into a clinical trial? »» Funding for production of the clinical vector lot (the virus to be delivered to patients) needs to be obtained. »» Funding for a clinical trial must be obtained. (Development and preclinical testing has been funded by the NIH.) •What is your best estimate for the length of time it will take to move this research into clinical trials? 0-6 months (based upon successful funding for the clinical vector lot production). •What is the goal or purpose of this study? »» The goal of this study is to introduce the GALGT2 gene into the body by using a viral vector (an adeno-associated virus, or AAV). Because the virus carries GALGT2 rather than a version of the dystrophin gene, it is a “surrogate” gene therapy. »» GALGT2 encodes the protein GalNAc transferase (beta 1,4 –N-acetylgalactosamine galactosyltransferase). This is an enzyme that transfers a complex sugar molecule onto a few specific proteins, including dystroglycan. »» Usually, GalNAc transferase is found only at the neuromuscular junction (NMJ), where some components of the dystroglycanassociated protein complex are different than elsewhere in muscle. Importantly, at the NMJ, utrophin is present instead of dystrophin. »» In the mdx mouse, viral gene transfer of GALGT2 results in expression of GalNAc transferase across the entire muscle membrane (instead of just at the NMJ), as well as upregulation of utrophin across the entire muscle fiber. »» In the mdx mouse, this expression can correct muscle functional deficits to the same degree as does microdystrophin gene expression. Furthermore, overexpression of GALGT2 corrects muscle pathology in mouse models of other muscular dystrophies, including LGMD2A and congenital muscular dystrophy (MDC1A). »» This AAV viral vector is known not to cause disease. The vector includes a gene promoter that is specifically activated in muscle tissue, so the gene should not be significantly activated in 32 other tissues. The AAV-delivered gene is not integrated into chromosomal DNA. »» Because the GalNAc transferase is already expressed in patients, there should not be any immune response generated to the transferred gene’s protein product. •Who is eligible to participate in this study? The first-in-human gene transfer trial will consist of intramuscular injections into the extensor digitorum brevis (EDB) muscle on the side of the foot in recently non-ambulant patients over the age of 9 years. •What do I have to do if I decide to participate in this study? »» This study involves frequent visits to Nationwide Children’s Hospital (NCH) in Columbus, OH. We anticipate that the study will require 13 visits to NCH over two years. We will be seeking funding to help pay for travel. »» Muscle biopsy will be performed on each EDB muscle. Biopsy of the uninjected muscle will be performed at baseline; biopsy of the injected muscle will be performed at either 6 or 12 weeks after injection. • How long will this study last, and will I have access to the drug/treatment once the study has ended? »» The study will require follow up for two years after injection. »» Patients who participate in the initial intramuscular injection study are unlikely to be eligible for follow up vascular delivery studies, due to the expected development of antibodies to the viral capsid. »» If the treatment were to be approved by the FDA, plasmapheresis to clear anti-AAV antibodies may allow future treatment, although this cannot be guaranteed at present. •Why should I consider participating in this study? »» The initial first-in-human intramuscular injection study is necessary to confirm the expression of the GALGT2 gene in humans, and to assess the safety of this expression. This information is needed to proceed to a future efficacy trial. »» There is no likelihood of personal benefit by participation in this initial clinical trial, but there may be other benefits. These include allowing you or your child to participate in the advancement of a new and promising therapy, and helping others by contributing to the better understanding of Duchenne and Becker. •Where can I learn more about this study? You will be able to learn more about this study at www.DuchenneConnect.org and www.ClinicalTrials.gov, and www.nationwidechildrens.org/center-for-gene-therapy #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Laminin-111 Laminin-111, Integrin and Utrophin as a Potential Therapy for Duchenne Muscular Dystrophy •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. •Where is this research being done and who is funding this research? »» LAM-111 research for the treatment of MDC1A is currently being performed at the University of Nevada, Reno, and Alexion Pharmaceuticals in Connecticut. »» Prothelia’s funding has been primarily through US Government grants. Prothelia has received funding from several advocacy groups including Struggle Against Muscular Dystrophy (SAM), PPMD’s End Duchenne GAP program, and Hope for Gus. The current effort has shifted focus towards the use of LAM-111 for treatment of MDC1A and is being funded by Alexion. •Where would a clinical trial take place? There are several candidate locations including hospitals in Cincinnati (OH), Boston (MA), and Rochester (NY). However, there are many complex factors that go into determining the right location/countries for a clinical trial and further determinations will be made once we approach clinical development. •Where can I learn more about this research? »» www.Prothelia.com »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the goal or purpose of this research? Animal data shows that human laminin-111 upregulates (increases) the molecules integrin and utrophin. Both integrin and utrophin work together to restore lost muscle cell adhesion when dystrophin is missing at the muscle membrane. •What is the current state of this research? This project is in preclinical development with demonstrated effectiveness in the mdx and dyW mouse models of DMD and MDC1A, respectively. Current efforts are focused on MDC1A, though positive clinical data for MDC1A may accelerate clinical development for Duchenne. Further studies in a more severely affected animal model of Duchenne may be required to justify further development of LAM-111 for treatment of Duchenne. •What steps need to be completed before moving into a clinical trial? A scalable process must be constructed that produces sterile recombinant human laminin-111 (rhLAM-111). Prior to any testing of rhLAM-111 in clinical (human) studies, we must ensure it is safe and effective in mouse and large animal models of muscular dystrophy. •What is your best estimate for the length of time it will take to move this research into clinical trials? Uncertain. Current efforts are focused on MDC1A. #CONNECT20 33 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED NBD Peptide Using NF-kB blockers to Decrease Inflammation and Increase Regeneration in Duchenne •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. •Where is this research being done and who is funding this research? This research is being done at Dr. Denis Guttridge’s laboratory at The Ohio State University in conjunction with Theralogics and various academic partners. The work is funded by the NINDS branch of the NIH. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria would be for a future clinical trial. •Where can I learn more about this research? »» You can learn more about Dr. Guttridge’s research at The Ohio State University website: http://biomed.osu.edu »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the goal or purpose of this research? The NF-kB pathway has been shown to be involved in promoting inflammation and compromising muscle function in response to the loss of dystrophin in Duchenne. Dr. Guttridge’s group has used a small molecule called “NBD” to specifically block this pathway. In mice that lack dystrophin, NBD significantly improves the function of breathing muscles and allowed the mice to maintain whole body function. Also, in mice that lack dystrophin and utrophin, the drug significantly improved cardiac function. Skeletal muscle improvements were also observed when NBD was administered to dogs lacking dystrophin. •What is the current state of this research and what steps need to be completed before moving into a clinical trial? »» Discussions have taken place with the FDA in order to submit a pre-Investigational New Drug Application. »» Studies in a large animal model have been completed and a publication reporting the results is pending. »» NBD is being produced on a large scale at a commercial vendor. Non-GLP pharmacology and toxicology testing have been completed. Formal GLP toxicology studies have been planned. •What is your best estimate for the length of time it will take to move this research into clinical trials? At this time, it is too early to estimate when a clinical trial in Duchenne would start. However, preparations are in place to complete the final studies leading to an IND submission. •Where would a clinical trial take place? The Phase 1 safety clinical is planned for Nationwide Hospital, Columbus, Ohio, directed by Dr. Jerry Mendell. For Phase 2, it is too early to know where a clinical will take place and much will depend on the safety profile determined in Phase 1. 34 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED PRO052/PRO055 Exon 52 and 55 Skipping for Duchenne Muscular Dystrophy •What stage is this research? This research is pre-clinical, meaning it has not yet started clinical trials in patients. •What is the goal or purpose of this research? The purpose of this research is to design exon skipping for Duchenne for exons 52 and 55, and to ensure these treatments are both safe and effective. PRO052 and PRO055 may potentially be used in the future as a treatment for Duchenne patients with a mutation that is amenable to skipping exon 52 or exon 55, respectively, in the dystrophin gene. This is applicable to around 4.1% and 2.0% of all Duchenne patients, respectively. •Where can I learn more about this research? »» www.Prosensa.com »» The trials will be posted on www.ClinicalTrials.gov once recruitment begins »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Where is this research being done and who is funding this research? This research is being done at Prosensa Therapeutics. •What steps need to be completed before moving into a clinical trial? The pre-clinical studies are almost completed. These need to conclude with no major safety findings before the preparations can begin for the first clinical trial in study participants. The development of PRO052 and PRO055 is also dependent on the ongoing clinical studies with other similar compounds. •What is your best estimate for the length of time it will take to move this research into clinical trials? It is difficult to estimate when clinical trials will begin recruitment. Once we have more clarity on the path forward for drisapersen (Prosensa’s lead product for Duchenne), we expect to be able to provide an estimate of when trials with PRO052 and PRO055 could start. •What will the inclusion (enrollment) criteria be for the upcoming trials? Participants will need to be boys with Duchenne who have a mutation correctable by skipping exon 52 or 55. Additional details regarding the inclusion and exclusion criteria will be released closer to the trials and will be posted on www.clinicaltrials.gov. •Where would a clinical trial take place? It is too early to know where the trial sites will be located. Many complex factors go into determining locations for a clinical trial. #CONNECT20 35 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED RTC13 Read-Through Compound Development of a drug that corrects nonsense mutations in patients with Duchenne •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. •Where is this research being done and who is funding this research? This research is being done at the University of California Los Angeles (UCLA) and is or has been funded in the past by the Muscular Dystrophy Association (MDA), the National Institute of Health (NIH), and the Department of Defense (DoD). •What is the goal or purpose of this research? We have identified a molecule called RTC13 that can restore a full-length dystrophin protein in skeletal muscles of Duchenne patients affected by nonsense mutations. They are generally caused by single point mutations in the dystrophin gene that lead to the inappropriate presence of specific sequences (UAA, UAG, or UGA) called stop codons. These stop codons cause a premature arrest in the synthesis of the dystrophin protein. As a result, no dystrophin is produced in skeletal muscles and heart. We have recently shown that this drug can restore dystrophin expression in muscles of mdx, a widely used animal model for Duchenne. Our goal is to optimize the dose necessary to achieve therapeutic effects in Duchenne patients and to conduct the safety and toxicology studies required to file an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). It has been estimated that approximately 13% of Duchenne patients could benefit from read-through of nonsense mutations. Importantly, because the drug restores full-length dystrophin, the protein being produced is expected to be fully functional and should be able to halt or at least counteract disease progression. to conduct toxicology and safety studies will require extensive economical resources. As such, effort will be placed on identifying potential funding sources through US government grants and other advocacy groups. •What is your best estimate for the length of time it will take to move this research into clinical trials? 2-3 years. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria would be for a future clinical trial. •Where can I learn more about this research? »» You can learn more about this research at http://bertonilab.neurology.ucla.edu/index.html. »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the current state of this research? Our data demonstrate that RTC13 can efficiently restore dystrophin into muscle of Duchenne models with substantial beneficial effects achieved on muscle function. We are currently optimizing an orally viable formulation of the drug that can be administered to patients as this represents the best option to treat the disorder. We anticipate completing these studies by the end of 2014. •What steps need to be completed before moving into a clinical trial? We have completed proof-of-concept studies in the mdx mouse model for Duchenne. We are now focusing on conducting the toxicology studies needed to demonstrate that the compound is safe to use in children and young adults. The steps necessary 36 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Rycal® ARM210 Using Rycal® ARM210 to Improve Muscle Strength and Function in Duchenne •What stage is this research? This research in Duchenne is late-stage pre-clinical, meaning it has not advanced to clinical trials involving people with Duchenne yet. Plans to advance to clinical trials are underway. In addition, a related compound in development by ARMGO has completed several clinical trials for heart failure and cardiac arrhythmias. Positive activity in patients was demonstrated, validating ARMGO’s novel therapeutic approach. •Where is this research being done and who is funding this research? •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria will be for the clinical trial. •Where can I learn more about this research? »» You can learn more about Rycan ARM210 at ARMGO’s website (http://armgo.com/). »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. This research is being done by ARMGO Pharma, Inc. The Muscular Dystrophy Association recently awarded the company $1 million to develop the compound, Rycal ARM210, for Duchenne. •What is the goal or purpose of this research? ARMGO has identified a new class of small molecule therapeutics (Rycals®) that restore the normal balance of calcium within muscle cells by correcting the activity of a type of channel called the “ryanodine receptor calcium channel complex” (RyR). In mice that lack dystrophin, Rycal® ARM210 corrected a calcium leak occurring through the RyR and improved daily activity and muscle force. The degree of benefit depended on the dose of the compound administered. These studies help establish the rationale for conducting a clinical trial with this compound in Duchenne. •What is the current state of this research and what steps need to be completed before moving into a clinical trial? Formal toxicology studies required by the FDA have now been completed. ARM210 was generally found to be safe and well tolerated. ARMGO plans to file an Investigational New Drug (IND) Application at the end of this year in preparation for beginning a human clinical trial in Duchenne. •What is your best estimate for the length of time it will take to move this research into clinical trials? If an IND is filed by the company at the end of 2014 and is accepted by the FDA, a clinical trial could begin as early as the first quarter of 2015. Initial clinical studies in healthy volunteers to establish safety would then be followed by studies in Duchenne patients. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. Many complex factors go into determining the right location(s) for a clinical trial. #CONNECT20 37 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Spironolactone Using Aldosterone Antagonists to Improve Muscle Strength and Function in Duchenne •What stage is this research? This research in Duchenne is pre-clinical, meaning it has not advanced to clinical trials involving people with Duchenne yet. However, spironolactone is an FDA-approved drug for high blood pressure and end-stage heart failure. •Where is this research being done and who is funding this research? This research is being done at Dr. Jill Rafael-Fortney’s laboratory at The Ohio State University. Parent Project Muscular Dystrophy and CureDuchenne funded initial studies, and now larger federal grants are helping the team to conduct larger studies that will provide enough critical information to design clinical trials. •What is the goal or purpose of this research? Dr. Rafael-Fortney’s laboratory recently observed a profound improvement in a mouse model of Duchenne resulting from treatment with the FDA-approved drugs lisinopril and spironolactone. Muscle strength in skeletal muscles in limbs and those used in respiration was doubled in treated mice compared to untreated mice and function of the heart was also significantly improved. Ongoing muscle damage in skeletal muscles and heart was almost completely prevented. These studies have direct implications for designing clinical trials for the Duchenne patient population. •What is the current state of this research and what steps need to be completed before moving into a clinical trial? •What is your best estimate for the length of time it will take to move this research into clinical trials? Funding for the preclinical studies to compare spironolactone (a non-specific mineralocorticoid antagonist) with eplerenone (a specific mineralocorticoid antagonist) and a clinical trial with primary cardiac outcome measures based on the results of the preclinical study has been obtained. The preclinical study began in July 2013 and all of the results are expected to be analyzed by Fall of 2014, for a clinical trial to start by early 2015. •Where would a clinical trial take place? Dr. Subha Raman at The Ohio State University Wexner Medical Center will be the lead investigator for the trial and UCLA will also be a site for the trial. (See Eplerenone FAQ sheet). •Who would be eligible to participate in a clinical trial? Inclusion criteria will be evaluated by cardiac MRI. •Where can I learn more about this research? »» You can learn more about Dr. Rafael-Fortney’s research at The Ohio State University website (http://medicine.osu.edu/mcbiochem/directory/facultydirectory/jill-a-rafael-fortney/Pages/index.aspx). »» www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. »» A preclinical study with cardiologist collaborator Dr. Subha Raman and physiologist collaborator Dr. Paul Janssen began in July 2013, to compare the cardiac and skeletal muscle improvements in dystrophic mice with spironolactone versus eplerenone. This will be followed by a clinical trial with primary cardiac outcome measures, using whichever drug is more effective in preclinical studies. »» Additional funding is also allowing the researchers to determine the efficacy of each of these drugs on limb and respiratory skeletal muscles and to define the mechanisms of action. Future clinical trials will be planned based on the results of these preclinical outcomes expected by Fall of 2014. 38 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Tamoxifen Using tamoxifen to improve muscle strength in Duchenne and Becker •What stage is this research? This research in Duchenne is pre-clinical, meaning it has not yet advanced to clinical trials involving people yet. Tamoxifen is the generic name for an approved drug (Nolvadex) that is used to treat estrogen-dependent breast cancer. •Where is this research being done and who is funding this research? This research is being done in Dr. Urs Ruegg’s laboratory by Dr. Olivier Dorchies at the University of Geneva using mdx mice, i.e. mice lacking dystrophin. Parent Project Muscular Dystrophy is helping to fund this research. •What is the goal or purpose of this research? »» Drs. Ruegg and Dorchies have shown that tamoxifen can trigger substantial improvements in muscle strength in mdx mice. In fact, low doses (threshold 0.3 mg/kg body weight per day) are effective to improve muscle function. This suggests that the drug acts on a high-affinity target, probably one of the nuclear estrogen receptors, ERa and ERß. Studies are ongoing to investigate the exact mechanism of action using mice deleted of either ERa or ERß and antagonists of these receptors. »» Ultimately, tamoxifen may be part of a “cocktail” along with other treatments that slow or stop the loss of strength in Duchenne or Becker. It is possible that tamoxifen could take the place of prednisone as an alternative with fewer side effects or that lower prednisone doses could be used in combination with tamoxifen. •What is the current state of this research? »» Drs. Ruegg and Dorchies have tested various doses of tamoxifen in both adult and old mice. Benefits of treatment included lower creatine kinase levels, 40% less cardiac fibrosis (scarring) than in untreated mice, and near normal improvements in muscle strength. Although mice are not humans and it is never entirely certain how results will translate, a robust treatment response in mice that lack dystrophin is the gold standard for moving drugs into clinical trials for Duchenne. »» The laboratory of Dr. Dominic Wells at the University of London has recently shown that there is good reproducibility and that the combination of tamoxifen plus prednisolone gives a slightly stronger effect than tamoxifen alone. #CONNECT20 •What steps need to be completed before moving into a clinical trial? »» While current data are encouraging, we don’t yet know if tamoxifen will have the same positive effects in Duchenne and Becker. We need to understand more about how tamoxifen may work in Duchenne. In particular, we need to determine if tamoxifen prevents muscle necrosis and enhances muscle regeneration and how it might interact with cardiac medications, which are also used in Duchenne. »» Noteworthy, the pharmacological profile of tamoxifen is well known; it has also been given as an anti-tumor agent to children and no undesired effects have been noted. •What is your best estimate for the length of time it will take to move this research into clinical trials? There are several different points of view: Some think that it should be tested in dystrophic dogs before a clinical trial, whereas others don’t see the benefit of a canine study, given it is an approved drug. Without a study in dogs, a clinical trial with Duchenne patients may start around the end of 2015, with such a study, 2-3 years later. •Where would a clinical trial take place? It is too early to know where a clinical trial for this research would be located. Many complex factors go into determining the right location(s) for a clinical trial. •Who would be eligible to participate in a clinical trial? Again, it is too early to know what the inclusion criteria will be for the clinical trial. The improvements seen in the mice are very likely not dependent on any particular type of mutation in the dystrophin gene, so tamoxifen is potentially applicable to all boys and young men with Duchenne and Becker and is relatively inexpensive, about USD 1000/year. •Where can I learn more about this research? »» www.ClinicalTrials.gov will post this clinical trial once it is actively recruiting patients. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. 39 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED VBP15 A Novel Delta-9,11 Glucocorticoid Analogue •What stage is this research? This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. We anticipate starting a clinical program later this year. •Where is this research being done and who is funding this research? »» This research is being performed at ReveraGen Biopharma Inc. and Children’s National Medical Center. »» ReveraGen is working through various public-private partnerships to develop VBP15: »» VBP15 is in its third round of milestone driven funding from the MDA Venture Philanthropy (MVP) program. »» Additional funding is provided by the Save Our Sons, NIH TRND, CDMRP Department of Defense, Parent Project Muscular Dystrophy, Foundation to Eradicate Duchenne, and CureDuchenne. •What is the goal or purpose of this research? The goal of this research is to develop a drug (VBP15) that will work as well or better than traditional glucocorticoids (prednisone, deflazacort) but with an improved safety profile compared to these ‘standard of care’ drugs. This will hopefully result in better efficacy (clinical outcomes), and better patient compliance due to improved side effect profile. •What is your best estimate for the length of time it will take to move this research into clinical trials? We anticipate Phase 1 studies to be initiated in Fall 2014. •Where would a clinical trial take place? It is too early to know exactly where a clinical trial would be located, however our Phase 1 trial will be conducted in the US. •Who would be eligible to participate in a clinical trial? We anticipate Phase 1 studies to be performed in normal healthy adult volunteers. Phase 2 studies would likely be open to many Duchenne patients, although it is too early to know what the inclusion criteria would be for a future clinical trial. •Where can I learn more about this research? »» www.reveragen.com »» www.ClinicalTrials.gov will post this trial once it is actively recruiting. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •What is the current state of this research? »» VBP15 has completed the necessary studies to file for IND with the FDA. VBP15 shares many ADME features (ADME – absorption, distribution, metabolism, excretion) with prednisone & other routinely utilized steroids »» Studies in the mdx mouse have shown improvements in function equal to prednisone, yet with reduced side effects. »» Testing in mouse models of other inflammatory indications has shown biological activity equal to or better than prednisone. •What steps need to be completed before moving into a clinical trial? Studies required for IND have been successfully completed and we are currently in the process of writing the IND with a submission expected in 3Q 2014. 40 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED Early Treatment of Cardiomyopathy Early Treatment of Cardiomyopathy with Eplerenone in Duchenne Muscular Dystrophy •What stage is this research? This double-blind, randomized trial has completed enrollment. •What is the goal or purpose of this study? The goal of this study is to determine if a class of medicines called aldosterone antagonists, medicines used for high blood pressure and heart failure, can limit heart muscle damage and preserve heart muscle function in boys with Duchenne. The research team previously showed that in a Duchenne mouse model, aldosterone antagonism in combination with angiotensin converting enzyme (ACE) inhibition limited muscle damage and maintained muscle function. Because of these drugs’ established safety in both children and adults, this study could be initiated soon after completion of the mouse study. •Where can I learn more about this study? »» You can learn more about this study at www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is sponsoring this study? This study is sponsored by BallouSkies with additional support provided by Parent Project Muscular Dystrophy. •Who was eligible to participate in this study? Current enrollment is completed. •What are the participants doing in this study? Participants take either eplerenone or placebo in combination with an ACE inhibitor or angiotensin receptor blocker daily for 12 months. Heart muscle damage and function is being measured using noninvasive cardiac magnetic resonance imaging (MRI), and blood samples are collected periodically. •When will this study be completed? The estimated study completion date is July 2014. •Are there any preliminary results available? No preliminary results are available for this trial. We anticipate being able to present peer-reviewed results by early 2015. •Will there be additional clinical trials in the future, and if so, when? We plan to combine information from ongoing preclinical experiments with the results of this study to design a larger clinical trial that will begin around mid-2015. Stay tuned for eligibility criteria and more information by early 2015. #CONNECT20 41 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED ImagingDMD Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy •What stage is this research? This is an active trial, but enrollment has been completed. •What is the goal or purpose of this study? This study focuses on developing Magnetic Resonance Imaging (MRI) as a tool to monitor disease progression in Duchenne and to serve as an outcome measure for clinical trials. The aim of the study is to determine whether noninvasive MRI outcome measures can replace muscle biopsies in evaluating the effectiveness of new treatments in future clinical trials. •Where can I learn more about this study? »» You can learn more about this study at www.ImagingDMD.org and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is funding this study? This study is funded by the NIH – NIAMS/NINDS. •Who is eligible to participate in this study? Enrollment is complete, but participants in this study are males with Duchenne, ages 5 to 14 years upon entering the study, able to walk independently for at least 100 meters (~length of a football field) without assistive device and climb 4 stairs. Subjects were not excluded based on corticosteroid treatment. Minorities with Duchenne who fit these inclusion criteria are needed in this study. •What are participants doing in this study? MRI and Magnetic Resonance Spectroscopy (MRS) measurements will be performed on the participants’ leg muscles, and muscle strength and functional tests such as walking and climbing four steps will also be performed. Additionally, a small sample of skin cells will be taken from the participants and stored in established tissue banks. •Where does this study take place? This study is recruiting at 3 different cities in the US: University of Florida, Gainesville, FL; Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA; and the Oregon Health and Science University (OHSU) and Shiners Hospital for Children-Portland, Portland, OR. •When will the study be completed? The estimated study completion date is April 2015. •Are there any preliminary results available? This trial is ongoing and no preliminary results are available. 42 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED PRO044 Phase 1/2 Study of PRO044 in Duchenne Muscular Dystrophy •What stage is this research? This phase 1/2a clinical trial has ended. The extension study for participants of this study is planned to start in the second half of 2014. •What was the goal or purpose of this study? •Where can I learn more about this study? »» www.Prosensa.com »» www.ClinicalTrials.gov will post all trials once they are actively recruiting »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. The aim of the study was to identify a suitable dose(s) for further investigation, based on how well PRO044 is tolerated and to provide preliminary evidence of a potentially therapeutic dose, based on dystrophin expression. PRO044 may potentially be used in the future as a treatment for Duchenne patients with a mutation that is amenable to skipping exon 44 in the dystrophin gene. This is applicable to around 6% of all Duchenne patients. • Who was the sponsor of this study and where was the study taking place? Prosensa Therapeutics (www.prosensa.com) was the sponsor of this study. This study took place at four sites in Europe (Belgium, Italy, the Netherlands and Sweden). •Who was eligible to participate in this study? Boys with Duchenne, aged 5-16 years, with a mutation correctable by skipping exon 44. The complete list of inclusion and exclusion criteria can be found at www.clinicaltrials.gov. •Are there any results available? Yes, results of the PRO044 phase 1/2 study were shared at the WMS conference which took place in October 2013. Topline results of this study are that dystrophin restoration was confirmed; dose exposure modelling predicts effective dose range at 6–9 mg/kg intravenously; safety findings of the study are consistent with the known class safety profile; and no drug related serious adverse events were reported. •Will there be additional clinical trials in the future, and if so, when? Further studies with PRO044 await the outcome of the analyses of the drisapersen results (Prosensa’s lead product for Duchenne), since this outcome could influence the study design of future studies with exon skipping products. As soon as we have more clarity, we will provide additional information. •Will any future clinical trials involving PRO044 have a study site in the US? It is Prosensa’s intention to include the US in future clinical trials with PRO044. #CONNECT20 43 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED PRO045 Phase 2b Study of PRO045 in Duchenne Muscular Dystrophy •What stage is this research? The phase 2b dose escalation study is ongoing, but not recruiting participants. The PRO045 study consists of two phases: a dose escalation phase and a confirmatory treatment phase. The confirmatory treatment phase is expected to start in the first half of 2015. • What is the goal or purpose of this study? The aim of the study was to identify a suitable dose(s) for further investigation, based on how well PRO045 is tolerated and to provide preliminary evidence of a potentially therapeutic dose, based on dystrophin expression. PRO045 may potentially be used in the future as a treatment for Duchenne patients with a mutation that is amenable to skipping exon 45 in the dystrophin gene. This is applicable to around 8% of all Duchenne patients. •Will there be additional clinical trials recruiting in the future, and if so, when? The phase 2b dose escalation phase will be followed by a confirmatory treatment phase. This study is expected to start in the first half of 2015, enrolling the participants of the dose escalation phase as well as new participants. It is anticipated that for this study phase the number of trial sites and participating countries will increase including sites in the US. •Where can I learn more about this study? »» www.Prosensa.com »» www.ClinicalTrials.gov will post all trials once they are actively recruiting »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is the sponsor of this study? Prosensa Therapeutics is the sponsor of this study. •Who was eligible to participate in this phase 2b study? Boys with Duchenne, age 5-18 years, with a deletion correctable by skipping exon 45. Participants must be ambulant and must have been receiving a stable dose of glucocorticosteroids for at least 6 months prior to the first PRO045 administration. The complete list of inclusion and exclusion criteria can be found at www.clinicaltrials. gov. •What are participants doing in the phase 2b dose escalation study? Participants receive weekly doses of PRO045 in a number of increasing dose levels, subcutaneously or intravenously. The primary outcome measure is the 6-minute walk test. Additional muscle strength and function tests will be performed. •Where does this study take place? There are currently 6 sites in Europe: one in Belgium, France, Italy, the Netherlands, and two in the UK (London and Newcastle). •When can we expect the results of the phase 2b study? We expect data for this study in the fourth quarter of 2014. 44 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED PRO053 Phase 1/2 study of PRO053 in Duchenne Muscular Dystrophy •What stage is this research? The phase 1/2 dose escalation study is ongoing, but not recruiting participants. The PRO053 study consists of two phases: a dose escalation phase and a confirmatory treatment phase. The confirmatory treatment phase is expected to start in the first half of 2015. • What is the goal or purpose of this study? The aim of the study was to identify a suitable dose(s) for further investigation, based on how well PRO053 is tolerated and to provide preliminary evidence of a potentially therapeutic dose, based on dystrophin expression. PRO053 may potentially be used in the future as a treatment for Duchenne patients with a mutation that is amenable to skipping exon 53 in the dystrophin gene. This is applicable to around 8% of all Duchenne patients. •Will there be additional clinical trials recruiting in the future, and if so, when? The phase 1/2 dose escalation phase will be followed by a confirmatory treatment phase. This study is expected to start in the first half of 2015, enrolling the participants of the dose escalation phase as well as new participants. It is anticipated that for this study phase the number of trial sites and participating countries will increase including sites in the US. •Where can I learn more about this study? »» www.Prosensa.com »» www.ClinicalTrials.gov will post all trials once they are actively recruiting »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. •Who is the sponsor of this study? Prosensa Therapeutics is the sponsor of this study. •Who was eligible to participate in this phase 1/2 study? Boys with Duchenne, age 5-18 years, with a deletion correctable by skipping exon 53. Participants must be ambulant and must have been receiving a stable dose of glucocorticosteroids for at least 6 months prior to the first PRO053 administration. The complete list of inclusion and exclusion criteria can be found at www. clinicaltrials.gov. •What are participants doing in the phase 1/2 dose escalation study? Participants receive weekly injections of PRO053 in a number of increasing dose levels, subcutaneously or intravenously. The primary outcome measure is the 6-minute walk test. Additional muscle strength and function tests will be performed. •Where does this study take place? There are currently 6 sites in Europe: one in Belgium, France, Italy, the Netherlands, and two in the UK (London and Newcastle). •When can we expect the results of the phase 1/2 study? We expect data for this study in the first quarter of 2015. #CONNECT20 45 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED CATENA® Phase 3 Study of Idebenone in Duchenne Muscular Dystrophy (DELOS) •What stage is this research? This trial was completed with 64 randomized and treated patients who were not using concomitant glucocorticoids. •What was the goal or purpose of this study? The primary objective of this study was to assess the efficacy of idebenone (Catena®/ Raxone®) in improving or delaying the loss of respiratory function. Secondary objectives included assessing the efficacy of idebenone in improving or delaying the loss of respiratory function using measures other than those used for the primary endpoint and improving or delaying the loss of muscle strength, motor function, and quality of life in patients with Duchenne. The assessment of safety and tolerability of idebenone was also a secondary objective. •Who was funding this study? This study was funded by Santhera Pharmaceuticals. •Who was eligible to participate in this study? This study was open to males with a diagnosis of Duchenne, between the ages of 10-18 years old. Both ambulatory and nonambulatory patients were eligible. There were no eligibility criteria based on mutation status. •What were participants doing in this study? Participants were randomized to receive either idebenone 900 mg/day (300 mg 3 times a day with meals) or matching placebo for 52 weeks. Patients underwent hospital and home-based respiratory assessments. The primary outcome variable was peak expiratory flow percent predicted (PEF%p) and the primary endpoint was the Change from Baseline to Week 52 in PEF%p as measured by hospital-based spirometry. PEF%p measured using the ASMA-1 device at home was a secondary endpoint. Other respiratory endpoints included Forced Vital Capacity (as FVC%p, a measure of restrictive lung disease predictive of morbidity and mortality in DMD) and Forced Expiratory Volume in 1 Second (as FEV1%p, an additional endpoint for respiratory muscle strength). Muscle and motor strength endpoints included change in muscle strength between Baseline and Week 52 (as measured by hand-held myometry, HHM) and in the Brooke and Vignos scales. Changes in Quality of Life assessment scores and safety and tolerability were also assessed. •When was this study completed? •Are there any preliminary results available? »» For the primary endpoint, Catena®/Raxone® significantly reduced the annual decline in PEF%p by 66% compared to patients taking placebo. The average annual decline in PEF%p was 9.0% for placebo (Baseline: 54.3%; Week 52: 45.3% (n=27), p<0.001) versus 3.1% for Catena®/Raxone® (Baseline PEF%P: 53.1%; Week 52: 50.1% (n=30); p=0.13) for a treatment group difference in change from Baseline to Week 52 of 5.96% (p=0.04). When measured weekly by the patient at home using the hand-held ASMA-1 device (secondary endpoint), Catena®/ Raxone® significantly reduced the annual decline in PEF%p by 80% compared to patients taking placebo. The ASMA-1 device showed a significant 9.0% decline in PEF%p occurred between Baseline and Week 52 in the placebo group (n=31; p<0.001), compared to a non-significant decline of 1.8% in the Catena®/ Raxone® group (n=31; p=0.44), for a treatment group difference in change from Baseline to Week 52 of 7.2% (p=0.03). In FEV1%p, Catena®/Raxone® significantly reduced the annual decline by 78% compared to patients taking placebo. The annual decline in FEV1%p in the placebo group was 10.7% compared to 2.4% in the Catena®/Raxone® group (p=0.03). For FVC%p, also supported a treatment benefit of Catena®/Raxone®. The annual decline in FVC%p was reduced by 37% in Catena®/Raxone®treated patients (9.0% decline in FVC%p in the placebo group versus a 5.7% decline in the Catena/Raxone group; p=0.08). »» No differences were observed between treatment groups in Maximal Inspiratory or Expiratory Pressures or in Peak Cough Flow. »» Catena®/Raxone® was safe and well tolerated. »» Data analysis is still ongoing and other results will be disclosed shortly. »» On the basis of this result, Santhera will approach the FDA and EU Regulatory Authorities for discussions on the most expeditious regulatory pathway to approval. •Will there be additional clinical trials in the future, and if so, when? It is too early to know if additional trials will be required. •Where can I learn more about this study? »» You can learn more about this study at www.santhera.com and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. The last patient visit occurred in January 2014 and the study ended in April 2014. 46 #CONNECT20 ACTIVELY RECRUITING | NOT YET RECRUITING | PRE-CLINICAL | ACTIVE BUT NOT RECRUITING | COMPLETED IGF-I (Increlex) Safety and Efficacy Study of IGF-I in Duchenne Muscular Dystrophy •What stage is this research? This trial has been completed and is no longer recruiting patients. •What was the goal or purpose of this study? The purpose of this study is to determine whether IGF-I (insulinlike growth factor-I) therapy, also known as Increlex, improves or preserves muscle function in Duchenne. The investigators also want to learn if IGF-I can reduce glucocorticoid side effects such as growth failure and insulin resistance. •Who was funding this study? This study was funded by Charley’s Fund, Nash Avery Foundation, Action Duchenne, and Tercica (Subsidiary of Ipsen). •Who was eligible to participate in this study? Participants were males with a diagnosis of Duchenne, age 5 years or older, ambulatory, and who had been on daily glucocorticoid (prednisone or deflazacort) therapy for > 12 months. •What were participants doing in this study? This study involved two groups. Participants in the first group received IGF-I (Increlex) once daily by subcutaneous injection every morning with breakfast for a duration of 6 months, and they also continued to take their glucocorticoid. Participants in the second group only took their glucocorticoid. The study took place at Cincinnati Children’s Hospital Medical Center. •When will this study be completed? The clinical aspects of the study were completed at the end of 2012. The study is currently being written up for publication. •Are there any preliminary results available? The study showed that IGF-I improved height growth and measures of insulin resistance. There was no change (neither improvement nor deterioration) seen in motor function at 6 months of treatment. •Will there be additional clinical trials in the future, and if so, when? No additional IGF-I trials are currently being planned. •Where can I learn more about this study? »» You can learn more about this study at www.tercica.com and www.ClinicalTrials.gov. »» Please check www.DuchenneConnect.org for updates to this FAQ sheet. #CONNECT20 47 NOTES 48 #CONNECT20 NOTES #CONNECT20 49 NOTES 50 #CONNECT20 NOTES #CONNECT20 51 NOTES 52 #CONNECT20 #CONNECT20 401 Hackensack Avenue, 9th Floor Hackensack, NJ 07601 • T. 800.714.5437 EndDuchenne.org