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APL-105 (Trademarked as FRESHKOTE® in the USA and UK) A New Artificial Tear that treats all 3 Layers of the Human Tear Film, has the Highest Oncotic Pressure (65mm/Hg) for ocular surface healing, enhances wettability, is preserved with a proprietary & non-irritating preservative, and is globally patent pending. Developed by the esteemed Dr. Frank J. Holly of the Dry Eye Institute (www.dry-eye-institute.org) and formerly Professor of Ophthalmology and Biochemistry at Harvard University/Schepens Eye Institute and Texas Tech University Medical School. PRODUCT PROFILE SUMMARY OF CLINICAL STUDIES William Trattler, M.D. – Miami, Florida USA o Corneal specialist ophthalmologist/refractive surgeon in large group practice Grant Mason, O.D. – Melbourne, Australia o Optometrist in large private practice David Lamberts, M.D. – Lubbock, Texas USA o Corneal specialist ophthalmologist/lacrimologist and President of Contact Lens Association of Ophthalmologists TLC Vision Toronto, Canada – Dr. Sondra Black – Open evaluation for 6 months in post-refractive dry eye patients Linda Butler, O.D. – Oakhurst, New Jersey USA o Optometrist in large private practice Kazuo Tsubota, M.D. – Tokyo, Japan o Leading Corneal specialist ophthalmologist and Chairman of the largest ophthalmology department in Japanese university setting Post-LASIK Dry Eye Cyber Study – Dry Eye Institute 1 APL-105 Tear Breakup Time, Patient Questionnaire Results & General Observations Bill Trattler, MD Results through October 18th, 2002 APL-105 observations: I have had the opportunity to work with both Dakrina and APL-105 during 2002. I have been even more impressed by the response to this new medication (APL-105) by my patients. In particular, many of my patients had previously used commercially available artificial tears, and noted significant symptom improvement after using APL-105. On my clinical exam, I noticed an improvement in my patient’s corneal surface. As well, the tear break up time improved in almost all of the patients (please see the results on next page). The patient responses on the dry eye questionnaire show that APL-105 provided improvement in their symptoms. Question 1 asked about the severity of burning symptoms. Pre APL-105, the average score was 2.2 – which improved to 1.0 (scale of 1 to 4, with 1 being “My eyes do not feel this way at all” and 4 being “I notice these symptoms all of the time, and it does interfere with my normal activities”). Question 2 asked about a “gritty sensation” of the eye, and the score improved from an average of 2.6 to 1.25 Question 3 asked about the eyes feeling “tired or dry”, and the score improved from an average of 3.0 to 1.25. In summary, patients with significant dry eye problems related to poor tear film quality had significant improvements both subjectively and objectively. I personally feel that this product has been a great treatment for my patients. I am happy to answer any further questions. Objective results on next page. William Trattler, MD Cornea & External Diseases Miami, FL 305-598-2020 ext 1200 http://www.AskLasikDocs.com 2 Tear Breakup Times* for APL-105 Patient # Eye 111 OD OS OD OS OD OS OD OS OD OS 113 114 115 116 First visit (seconds) 9 5 10 8 10 7 4 8 6 8 Second visit (seconds) 10 11 12 11 12 13 11 14 8 12 Third visit (seconds) 12 14 12 14 11 12 12 14 12 12 *TBUT of 10 seconds or lower indicates Dry Eye Syndrome; with 1 being the most severe All of the patients feel better with this new formulation (APL-105), and my overall impression is that this formulation is working well at treating the symptoms of the patients. I have not had any patients have any problems with the medication. The tear breakup times have improved with all of the patients. After checking the first time, I did reapply the product, wait 5 minutes, and recheck the tear break up time. Interestingly, this did not improve the tear-break up time. This suggests that therapeutically this product is helping improve the entire ocular surface, so that perhaps this is a treatment of poor tear film quality rather than just a temporizing measure. Bill Bill Trattler, MD Miami FL http://www.AskPhysicians.com http://www.AskLasikDocs.com 305-598-2020 ext 1200 3 Grant Mason BScOptom MOptom FACBO FCOVD(USA) OPTOMETRIST CONTACT LENS PRACTITIONER PAEDIATRIC OPTOMETRY SPORTS VISION LILYDALE MARKETPLACE 33 HUTCHINSON ST, LILYDALE 3140 PH. 9735 3433 Provider 815523Y AUSTRALIA 22 GLYNNE RD NORTH RINGWOOD, 3134 PH. 9735 3433 Provider 815521B 12th October 2002 Mr J Echols and Dr F Holly Aqueous Pharma USA In ref to: Clinical Trial of APL-105 Dear Joe and Frank, I have had 3 patients complete the 2 week trial to date. Two found that they were better than their prior drop (Bion Tears) and needed to use the drops with reduced frequency. One patient was using the Bion Tears about every 10 minutes (timed by her husband). The APL-105 was only being used every 30-40 minutes and although she was still having some discomfort problems, she felt much better with the APL-105. Both these patients showed an improvement in FBUT from 4 and 7 seconds to 6 and 10 seconds after the 2 weeks. There was also reduced stain with the Lissamine Green. One patient was discontinued after 10 days. She was doing fine for 8 days, but suddenly began to have other, unrelated ocular problems. Her FBUT improved from 2s to 4s and staining was reduced somewhat (she had particularly bad KCS with heavy staining of both corneas and conjunctivae). In light of this being a trial it was decided to resume her prior tear supplement, Polygel, which gave her smeary vision for 20 minutes, but her vision was adequate for 10 minutes until the next instillation of the gel. Her vision for the 10 days of the APL-105 was clear and she reported that she was disappointed that she became symptomatic with other problems after the 8 days, as her vision had not been this clear for over 4 years. At this stage, my impression is that APL-105 is at least as good as Bion Tears, which is the most prescribed drop for dry eye in Australia now; but most likely much better. I have found that the frequency of use is much less than Bion Tears and the tear film appears to be closer to the physiological tears due to the reduction in staining. Comfort and vision certainly are better than with the Bion Tears. As for advanced cases of KCS, my one candidate was fine initially and reported much better vision. 4 Grant Mason BScOptom MOptom FACBO FCOVD(USA) OPTOMETRIST CONTACT LENS PRACTITIONER PAEDIATRIC OPTOMETRY SPORTS VISION LILYDALE MARKETPLACE 33 HUTCHINSON ST, LILYDALE 3140 PH. 9735 3433 Provider 815523Y AUSTRALIA 18th October 2002 Dr F Holly & Mr J Echols Aqueous Pharma USA Dear Frank and Joe, I have just completed my trial study of APL-105. The results have been very good and I have seen noticeable improvement with advanced dry eye patients. 11 patients in total were placed on APL-105, to be used as required. 2 patients discontinued the drops due to discomfort and stinging, but I believe this was due to chemically induced keratitis, as both had severe corneal damage prior to commencement of the study. The 9 remaining patients all reported improved comfort and reduced need to lubricate than with their prior drops or gel. One patient, a moderate KCS sufferer went from drops every ½ to 1 hour to 2-3 drops daily. All 9 patients also showed reduced corneal staining with fluorescein and Lissamine Green; some (3 patients) had total regeneration of the corneal epithelium. Tear break-up time measured both non-invasively and with fluorescein was the same in 4 patients, and improved with 5 patients, although only by 1-3 seconds (which I thought was pretty impressive, especially for a 2 week study). Overall, I was impressed by the results and especially with the improvement in clarity among those using gels for control of the dry eye problems. I would like to thank you for allowing me to be a part of this trial. Yours sincerely, Dr. Grant Mason BScOptom MOptom FACBO FCOVD Melbourne, Australia 5 Clinical Study of a New, Lipid-Containing Artificial Tear, APL-105 The study was designed by and conducted in the Lubbock, Texas clinic of David W. Lamberts, M.D., a corneal specialist ophthalmologist and a well known lacrimologist. The data was tabulated and formatted by Frank J. Holly, Ph.D. of the Dry Eye Institute in Yantis, Texas. Eleven patients are included in the study which lasted four weeks during the fall of 2002. At the end of the second week, the eye drops are crossed over, i.e. the contra-lateral eye then received the test drop between 2 and 4 weeks. APL-105 was furnished by Aqueous Pharma. The control eye drop was Tears Naturale, Alcon Laboratories. Drs. Lamberts and Holly were not compensated for their involvement in this study. This report was written by Dr. Frank J. Holly. The following clinical signs are measured in each eye of each patient at each visit starting on the initial visit: 1. The degree of vital staining by Lissamine green estimated on a scale from 0 – 9. 2. Width of tear meniscus in millimeters. 3. Degree of redness on a scale 0 to 4. 4. Degree of mucus precipitation in the eye on a scale from 0 to 4. The following subjective symptoms are also determined at each visit starting on the initial visit: 1. Degree of burning on a scale between 0 – 4. 2. Degree of dryness on a scale between 0 - 4. 3. Degree of blurred vision on a scale between 0 - 4. 4. Degree of foreign body sensation on a scale between 0 - 4. The frequency of instillation per day is recorded. The following patients were included in the study: Patient #01 61 year old female diagnosed with Sjögren’s syndrome. Patient #02 52 year old female diagnosed with Sjögren’s syndrome. Patient #03 60 year old female diagnosed with Sjögren’s syndrome. Patient #04 66 year old female diagnosed with Sjögren’s syndrome. Patient #05 52 year old female diagnosed with Severe KCS. Patient #06 65 year old female diagnosed with Sjögren’s syndrome. Patient #07 68 year old female diagnosed with Moderately-Severe KCS. Patient #08 54 year old female diagnosed with Severe KCS Patient #09 57 year old female diagnosed with Moderately-Severe KCS. Patient #10 53 year old female diagnosed with Sjögren’s syndrome. Patient #11 50 year old female diagnosed with Sjögren’s syndrome. Results: Eight patients completed the study which means that the test drop was tried in sixteen eyes and the control was also used in sixteen due to the cross-over at two weeks. In half of these eyes, the test drop was used first and after two weeks, the control was used. In the other half of the eyes, the order was reversed. Three more patients partially completed the study. These yielded three more eyes to the study in which the test drops were used, and three eyes in which the control drop was used. Nineteen eyes total for each drop. 6 The ranking shows that in 7 out of 8 parameters APL-105 was superior to Tears Naturale. Only in one parameter (tear meniscus) was APL-105 equal to Tears Naturale. The better performance by APL-105 was shown in the most important clinical parameter: the degree of healing of the corneal epithelium as shown by the decrease in vital staining. 90% of the eyes showed better healing with the test solution and none showed better healing with the control solution. CONCLUSION: Based on this double-blinded, crossover, controlled clinical study it appears that APL-105 is a very effective and long-lasting therapy for the most severe form of KCS, as 8 of the 11 patients were diagnosed with Sjögren’s syndrome and the remaining 3 patients were diagnosed with moderately-severe to severe KCS, thereby substantiating results from 2 previous clinical studies; one by Dr. William Trattler of Miami, Florida and the second by Dr. Grant Mason of Melbourne, Australia. APL-105 is in full compliance with the FDA Ophthalmic Monograph 21CFR§349.12., so is considered as FDA approved. It will be marketed under the brand: FRESHKOTE™ in the US. David W. Lamberts, M.D., Lubbock, Texas Frank J. Holly, Ph.D., Dry Eye Institute, Yantis, Texas February 1, 2003 7 OPEN EVALUATION OF FRESHKOTE™ (APL-105) Linda Butler, O.D. 780 West Park Avenue Oakhurst, NJ 07727 Phone: 732-531-6300 [email protected] Patient #1 30 y/o female KCS - Moderate Patient #2 40 y/o female KCS - Moderate Patient #3 19 y/o female KCS – Mild to Moderate Baseline: #1 TBUT 3 sec. OU, 1+ SPK, 1+ FL stain #2 TBUT 4 sec. OU, 1+ SPK, 1+ FL stain #3 TBUT 6 sec. OU, 1+SPK, 1 + FL stain. Week #1: #1 TBUT 5 sec. OD, 4 sec. OS, 1+ SPK and stain #2 TBUT 6 sec. OU, Trace SPK and stain #3 TBUT 6 sec. OU, 1+SPK and stain Week #2: #1 TBUT 6 sec. OU, no SPK or stain #2 TBUT 8 sec. OU, no SPK or stain #3 TBUT 6 sec. OU, no SPK or stain No adverse effects reported. Patient’s subjective comments were not solicited but all 3 patients felt that the drops were very comfortable and preferred over all previous artificial tears used. TBUT continued to improve in Patients #1 and #2 but remained the same in Patient #3. All 3 patients had no SPK or staining at the end of 2 weeks. Dr. Linda Butler April 18, 2003 8 EVALUATION IN JAPAN In July/August of 2003, FreshKote™ (APL-105) was evaluated by the leading corneal specialist ophthalmologist in Japan, as follows: Kazuo Tsubota, M.D. Professor & Chairman Department of Ophthalmology Tokyo Dental College 5-11-13 Sugano Ichikawa, Chiba 272-8513 JAPAN tel: +81-47-322-0151 fax: +81-47-322-6786 Aqueous Pharma sent 24 bottles of FreshKote to Dr. Tsubota for evaluation in his large corneal clinic and research centre in Tokyo; especially for use in his most difficult dry eye patients. Dr. Tsubota reported back to Aqueous Pharma on 19th August 2003: “I wish to take this opportunity to thank you for you supplying me with the FreshKote dry eye drop treatment. My colleagues and I tried the drops and it seems to be very wonderful”. (specific details of the evaluation have not yet been published by Dr. Tsubota) 9 OPEN CLINICAL TRIAL IN CYBER SPACE ON POST-LASIK PATIENTS WITH REGARD TO DRY EYE MANAGEMENT An unusual clinical study was conducted through cyberspace via the participation of leaders and members of Surgical Eyes Foundation, a web-based organization with the co-operation of the Dry Eye Institute, including the eye care professionals in charge of the recuperating patients, and Aqueous Pharma which made the eye drops available through a sterile compounding pharmacy. This approach excluded haphazard and harmful treatment modalities that they are in vogue in the treatment of post-lasik patients, such as use of ointments, use of antibiotics for sterile inflammation, use of steroids when the inflammation was from the direct result of poor tear film stability, and the too frequent use (flooding the ocular surface) of otherwise benign eye drops, and the discontinuation of highly viscous drops and gels. Depending on the diagnosis of the patients and her symptoms, the proper Aqueous Pharma drop or a combination of such drops was recommended, with APL-105 (FreshKote) the most preferred. Feedback from the patients was solicited and considered in deciding the type of drops suggested and their regimen. After six months of this open study in which more than 200 patients participated, a polling of these patients took place. The participants were asked whether the following statement was “TRUE” or “FALSE” or they were “UNCERTAIN” whether it was true or false. The statement was: “At least some of these (Aqueous Pharma) drops helped my conditions more than other regimen(s) I have tried.” The results are shown on this bar chart. Presented at the Tear Film & Ocular Surface Society Annual Conference 17-19 November 2004, Fajardo, Puerto Rico; by Dr. Frank J. Holly. 80 Percentage of Patients Most of the patients had previously tried every commonly available artificial tear. Efficacy of Aqueous Pharma Drops 76 70 60 50 40 30 20 14 10 10 0 TRUE FALSE UNCERTAIN 10