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Drug Re-Formulation - Creating New Business Opportunities Dr. Alex Nivorozhkin, Chief Operating Officer Amorsa Therapeutics Inc., USA Pharmaceutics & Novel Drug Delivery Systems, March 16-18, 2015, Dubai www.amorsatx.com 1 The Need in Pain Management A Potent Non-Opioid Without the Adverse Effects Morphine has been the gold standard for treating moderate-to-severe pain for nearly 200 years! It’s time for a change: • 16,000 deaths per year due to opioid overdoses • High potential for addiction • Disabling side effects • Tolerance development 2 Why Reformulate Existing Drugs? • Extending life cycle of the product (IP issues) – salt formation, route of administration, proprietary delivery • Improve patient compliance, frequency, ease of administration -depot formulations (CNS) • Serve newly found therapeutics indications -adjusting dose, route of administration, delivery • Improving poor intrinsic physico-chemical properties – Poor bioavailability (due to poor solubility and/or permeability) – TCI reports (2014) identified 30 recently launched drugs with poor bioavailability – BCS Class IV oral drugs sales >$145 B 3 How to Find and Validate a Good Idea? Multistep Iterative Process, You’ll have to Adapt • Talk to the DOCTORS - Unmet medical needs - Capitalize on something already used off-label - Incorporate new formulation into existing practices • Make friends with IP LAWYERS - IP landscape complicated due to years of disclosures and patent activity - Formulation patents are almost always perceived “weaker” than composition of matter (new API) • Set an alliance with PHARMACOLOGISTS – The interest jumps if you have in vivo data – Understanding animal models (efficacy) – • CMC PK/Tox IP Understanding toxicology aspects Introduce your idea to a BUSINESS PERSON – – First pass on commercial potential Interactions with potential investors Docs BD 4 Unmet Medical Need for Pain Management U.S. Market for Opioid Analgesics - $8.3 Billion (2013) Post-Trauma Pain • Opioids are associated with serious side effects including respiratory depression • Military priority for non-opioid treatments Post-Operative Pain • 70 million surgeries each year in the U.S. • >50% report moderate to severe pain Refractory Cancer Pain • Up to 25% of advanced cancer patients have refractory pain – nothing works • No FDA approved treatment for patients 5 5 Unlocking Ketamine’s Potential “The medical community is missing out on one of the best pain drugs there is.” Director, Defense Center for Integrative Pain Management • Ketamine was approved as an anesthetic in 1970 • Recent studies have shown ketamine’s analgesic and antidepressant effects but with undesirable side effects • Majority of therapeutic benefits are due to the conversion of ketamine to norketamine • Amorsa is developing proprietary formulations of novel ketamine analogs designed to: – Deliver the potency of ketamine with fewer adverse effects – Be administered as convenient oral formulations – Offer patients an effective alternative to opioids 6 Ketamine Pharmacology Challenge Human PK Data (3rd party results) Amorsa Solutions •Steady, controlled release formulations designed to limit spikes and improve kinetics •Focus on Norketamine – an active metabolite of KTM-with 2.5x half-life •Selectively deuterated nor-KTM analogs further extend exposure by 50 % (overall ca. 4x vs. KTM) 300 Dose 50 mg Cmax 280 ng/mL Tmax 1.1-1.6 h T1/2 1.1-5.3 h 200 Target Efficacy & Safety Range ng/mL Problems • Spikes in plasma concentration leading to psychomimetic side effects • Short exposure due to fast clearance 100 0 0 2 4 6 Hours 8 10 12 Oral ketamine solution in healthy volunteers 7 Leadership Team & Business Advisors Joe Blanchard Chief Executive Officer • Leadership experience with several early-stage, venture-backed life science firms • Aushon BioSystems, Altus Pharmaceuticals, Genencor, Akzo Nobel, Conoco/DuPont Alex Nivorozhkin, PhD Chief Operating Officer • Expert in drug formulation technologies, synthetic & medicinal chemistry • Boston BioCom, Massachusetts General Hospital, Inotek Pharmaceuticals, Epix Medical Mike Palfreyman, DSc, PhD Chief Scientific Officer • Expert in neuropharmacology & NMDA receptor antagonists • Forum Pharmaceuticals, Anadys Pharmaceuticals, Marion Merrell Dow, Psychiatric Genomics Business Advisors: Lewis Geffen, Esq, Corporate Counsel (Co-Chair of Venture Capital & Emerging Companies Practice, Mintz Levin) Jacob Weintraub, Esq, IP Counsel (Senior Counsel, JWIP, LLC) 8 Scientific & Clinical Advisory Board Michael Palfreyman, DSc, PhD Co-Chairman • Chief Scientific Officer, Amorsa Therapeutics Mihir Kamdar, MD Co-Chairman • • Director, Cancer Pain Clinic at MGH Harvard Medical School Faculty Christopher Gilligan, MD • Chief of Pain Medicine, Beth Israel Deaconess Medical Center Robert Lenox, MD • Professor of Pharmacology and Clinical Neurosciences, University of New England Former Global Head of CNS Drug Discovery, Sanofi Pharmaceuticals • Lt Col (Ret) John Gandy, MD • Member Defense Health Board and Emergency Medicine Physician • Retired Air Force Special Operations Command Emergency Medicine Physician 9 Amorsa’s Drug Development Platform Novel Deuterated Ketamine Analogs Proprietary Formulations Safe & Effective NMDA Receptor Antagonists • Built on known pharmacology • Expedited clinical path possible • Novel analogs expected to deliver improved efficacy and/or safety • Convenient oral tablets • Neuro-attenuating features designed to limit side effects • All FDA approved ingredients • Expected efficacy without the adverse effects • Pipeline of high value applications 10 Formulation Effects on Drug Release Novel hydrogel formulations of ketamine showing varying release profiles (in vitro experiments) 100 K-ER8 80 Release, % Steady release of therapeutically effective concentrations without toxic spikes Established Prototype Formulations K-ER12 60 K-ER24 40 20 In vitro data translates well into in vivo dog model Technology applies to ketamine, norketamine and derivatives including (S)-norketamine-d 0 0 5 10 15 20 25 30 Time, h Prototypical tablets formulated with racemic ketamine 11 Pilot PK Dog Study Using Ketamine-ER24 Tablet Formulation Obtained target plasma drug levels for 24 hours without concentration peaks 200 Target Efficacy & Safety Range ng/mL Confirms a strong in vitro/in vivo correlation 100 Validates our pathway for rapid optimization of future formulations 0 0 5 10 Hours 15 20 25 20 mg ketamine tablets 12 Deuterated (S)-Norketamine Analogs (S)-Norketamine • Previously studied compound with wellcharacterized pharmacological activity • Norketamine, the active metabolite of ketamine • More attractive PK profile than ketamine • S isomer has more potency than R S-Norketamine Deuterium Modification • Targeted modifications to create novel drug candidates • Provides improved pharmacokinetic properties that enhance safety and efficacy (S)-Norketamine-d 13 Preclinical Product Candidates Developing both fast acting and extended release formulations Product Product Candidate Description Planned Target Indications DSN-FA Fast acting formulation containing (S)-Norketamine-d • Acute Trauma Pain • Mass Casualties, Burns DSN-ER12 Extended release 12-hour tablet containing (S)-Norketamine-d • Chronic Pain • Post-Surgical Pain • Refractory Cancer Pain 14 3-Year Drug Development Plan Year 1 Amorsa Product DSN-FA (fast acting) DSN-ER12 (extended release) DSN-FA (fast acting) Indication Acute Trauma Pain Chronic Pain Treatment-Resistant Depression Q1 Q2 Q3 Year 2 Q4 Preclinical Q1 Q2 Q3 Year 3 Q4 Q1 Q2 Q3 Q4 Phase 1a & 1b Phase 2 (healthy volunteers) (thru Year 4) Preclinical Phase 2 Note: Plan does not assume Fast Track designation or modified 505(b)2 path – both are possible pending FDA review 15 Who Dares, Wins Contacts: Alex Nivorozhkin, Ph.D. Chief Operating Officer (617) 921-0114 [email protected] www.amorsatx.com 17