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The Era of Once Weekly Continuous Drug Delivery for Parkinson's

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The Era of Once Weekly Continuous Drug Delivery for Parkinson's The Era of Once Weekly Continuous Drug Delivery for Parkinson’s Disease is Here Randall Moreadith, MD, PhD President and Chief Executive Officer Biotech Showcase JP Morgan 2020 Biotech Showcase 2020 Everything begins with an idea “The treatment of Parkinson’s disease has not changed dramatically in the past 50 years. Patients are invariably treated with L-DOPA to control their symptoms – and patients invariably develop dyskinesia. At Serina we intend to create a paradigm shift in how patients with Parkinson’s disease may be treated.” POZTM - Next Generation in Polymer Technology We are the founding scientists and management that ushered in the first-generation technology - PEG • Proprietary drug delivery technology platform based on poly(2-oxazoline) (POZ™) Dominant IP estate with over 30 issued patents, and 25+ pending Global exclusive license to “click” chemistry from Scripps for POZ-therapeutics (unlimited right to sublicense) Non-immunogenic Does not accumulate in any tissues Is not metabolized Clears entirely by renal filtration • POZ™ provides continuous drug delivery of small molecules when administered via subcutaneous administration Clinically validated – SC injections are safe, very well-tolerated Optimizes safety / efficacy profile of known molecules Extends interval of administration for improved half life and greater patient compliance Creates new IP and extends market exclusivity • Serina’s pipeline of five product candidates target some of the most significant challenges in medicine today 3 How we prepare “polymer therapeutics” Immunothera py • A polymer of POZ is illustrated above with Rotigotine (a potent dopamine agonist) is attached to multiple pendent groups (SER-214) Via a cleavable ester linker (a cleavable linker is one that will release the active drug following cleavage by an enzyme in the blood - butyrylcholinesterase) • If the polymer has an extended profile of circulation in the body The release of the attached drug from the polymer will also be extended = continuous drug delivery 4 Chemical Structures of Pipeline Compounds All have an accessible chemical handle Immunotherapy Buprenorphine Rotigotine Apomorphine Cannabidiol Tetrahydrocannabinol CBD THC • Candidate small molecules must have a “chemical handle” • Linkers are attached to the –OH (creates a stable ester), an azide moiety on the end of the linker allows for permanent “click chemistry” attachment to the pendent alkyne of the polymer backbone • Search known structures (AdisInsight) - thousands of candidate molecules (phenolic hydroxyl, alcohols, carboxylates) 5 Serina Pipeline A CNS-focused pipeline developing high value products for significant markets Drug Candidate Indication Research Preclinical Phase I Phase II Phase III SER-214 Parkinson’s disease (rotigotine) Early SER-214 Restless Leg Syndrome (rotigotine) SER-248 Parkinson’s disease (apomorphine) Advanced SER-227 Post-operative pain (buprenorphine) Opioid use disorder NIH HEAL Initiative SER-228 Refractory epilepsy (cannabidiol) Multiple indications CINV SER-232 Spasticity in MS (tetrahydocannabinol) Autism, Aggression HEAL Initiative – Helping to End Addiction Long-term Why is continuous drug delivery so important in PD ? Continuous delivery of dopaminergic agents invariably improves outcomes 1 Immunotherapy Naïve MPTP-monkeys were divided into two groups Apomorphine rod implant, vs Daily (x 3) apomorphine injections Monkeys that received a rod implant remained ON with NO dyskinesia for 6 months (!) Monkeys that received daily SC injections were transiently ON – and all developed severe dyskinesia within the first two days 1 C Francesco Bibbiani, Lauren C. Costantini, Raj Patel, Thomas N. Chase Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates (2004). 7 (The rod implant causes skin necrosis and is not currently being developed for PD.) The Challenge in Parkinson’s Disease None of the existing drugs used in Parkinson’s provide continuous dopaminergic stimulation L-DOPA remains the most commonly Immunotherapy prescribed drug for Parkinson’s Over 50% of patients will develop dyskinesia within five years of therapy as daily L-DOPA levels are increased Over 90% of patients will develop dyskinesia within ten years of therapy LIDs remains one of the most troubling side effects – and treatment challenges – in Parkinson’s disease What if you could administer a single injection that provided continuous drug delivery – for an entire week ? 8 A Weekly SC Injection of SER-214 Provides continuous drug delivery in monkeys Plasma levels of Released Rotigotine following Cynomolgous macaque monkeys weeklyImmunothera SC injections of SER-214 to Normal Monkeys received a single SC injection of 7.0 mg/kg dose SER-214 weekly for 12 weeks py (male and female; n=10, SD) (this study was the formal 100 toxicology study that supported the IND) In weeks 1/5/9/12 daily plasma 10 rotigotine levels were determined Following a slow rise to Tmax on day 2-3 plasma levels of released 1 rotigotine remained within a week 1 narrow range of ~ 6-8 ng/ml - week 5 without accumulation or accelerated clearance 0.1 week 9 week 12 In a separate study in naïve Plasma concentration (ng/mL) MPTP-monkeys a weekly 0.01 injection of SER-214 fully rescued PD symptoms with no dyskinesia 0 1 2 3 4 5 6 7 liability (data not shown) Time (days) 9 SER-214 - Phase Ia in Stably-treated Parkinson’s Patients Assess safety, tolerability, pharmacokinetics and preliminary efficacy (N=5 per cohort) Establish safety and tolerability of a weekly Cohort Dose of SER-214 (SC) Data injection of SER-214 in Parkinson’s Disease patients Collected A once-weekly SC injection of SER-214 was 0 Single 20 mg Safety, PK safe and very well-tolerated 1 50 mg (beginning of each week for 2 Safety, PK consecutive weeks) Efficacy Establish pharmacokinetics – does a weekly SC injection of SER-214 provide predictable levels of rotigotine within the therapeutic window for relief 2 50 mg (beginning of Week 1) Safety, PK of symptoms ? 100 mg (beginning of Weeks 2 and 3) Efficacy Establish efficacy of SER-214 in providing 50 mg (beginning of Week 1) symptomatic relief of mild motor fluctuations 3 100 mg (beginning of Week 2) Safety, PK Motor portions of UPDRS (Parts II and III) 200 mg (beginning of Weeks 3 and 4) Efficacy constitute the approvable endpoint for all new PD drugs in development 10 A Weekly SC Injection of SER-214 in Parkinson’s Patients Provides continuous drug delivery in stably treated PD patients Immunothera Data from Cohort 3 in the multiple py dose portion of the Phase Ia trial in Parkinson’s disease patients Patients received: an initial subcutaneous dose of 50 mg SER-214 (0.25 mL); 100 mg dose in Week 2 (0.5 mL); and 200 mg in Week 3 and Week 4 (1.0 mL) Plasma levels of released rotigotine are shown for Week 3 (14-21) and Week 4 (21-28) and compared to the 3 mg Neupro patch (UCB published data) 11 A Weekly SC Injection of SER-214 Improves Motor Scores Dose-dependent decline in UPDRS (Part III) Effect of dose on UPDRS part III scores in Parkinson'sImmunotherapy patients following weekly sc of SER-214 (mean for n=5) Data from Cohorts 1,2 and 3 in the multiple dose portion of the Phase Ia trial 2 Dose of SER-214 (mg) 100 200 300 400 0 The predicted change in UPDRS (Part III) at the 400+ -2 mg doses of SER-214 would -4 achieve the approvable 2 endpoint for use of SER-214 -6 linear r =0.88 for the PD indication -8 SER-214 will be developed -10 for patients with early -12 Parkinson’s disease extrapolated UPDRS change from pre-dose from UPDRS change -14 12 POZ-apomorphine Apomorphine has many of the characteristics ideal for POZ • Apomorphine The first dopamine agonist used in the treatment of Parkinson’s disease (1884) Most potent dopamine agonist known (our KOLs call it the “holy grail” of dopamine Rx) Reverse akinesia within minutes Binds with equal affinity as dopamine to receptors that mediate symptomatic relief in PD (D2, D3) Limited bioavailability makes it unsuitable as an oral drug (or any other formulation) Present formulations limited by significant skin irritation through transcutaneous approaches that require daily administration through an insulin infusion set-up, often requiring a skilled healthcare professional to administer • Hypothesis Attachment to POZ should keep the molecule on the polymer until it reaches the blood (no BuChE in the SC compartment 1) – thus avoiding any skin liabilities Upon entry into the vascular compartment the apomorphine is immediately cleaved, providing continuous drug release as long as the polymer circulates 1 Butyrylchonilesterase (BuChE) is synthesized in the liver and secreted into the vascular compartment 13 Apo-Go - Apomorphine Apomorphine is very effective 1 … but the current formulation has significant challenges Patients with advanced PD may have > 6 hours a day of “OFF” time where they are unable to perform routine daily tasks Severe skin reactions Patients use an infusion device to provide continuous delivery of apomorphine ~ 12-16 hours a day Removed at bedtime 1 In July 2018 the only randomized, controlled trial of Apo-Go was published (TOLEDO) showing Nodules daily apomorphine was capable of providing the same reduction in daily OFF time - ~ 2 hrs – as DBS and LCIG. Apo-Go is approved in the EU – not yet approved in the USA. 14 Apo-Go infusion versus POZ-apomorphine No skin reactions at end of a 12-hr infusion of Apo-Go 15 Group I - Apo-Go infusion Significant skin reactions – all monkeys in the Apo-Go group developed abscesses by day three 16 Group 3 – POZ-apomorphine (SER-241) No skin reactions at any time point following injection of POZ-apomorphine 1 17 1 Biopsy of the injection site revealed no evidence of inflammation Apo-Go infusion vs POZ-apomorphine POZ-apomorphine conjugates – provide continuous drug delivery for approximately 7 days P K P r o f i l e o f R e l e a s e d A p o m o r p h i n e a f t e r S C d o s i n g o f A p o m o r p h i n e , S E R - 2 4 0 a n d S E R - 2 4 1 i n F e m a l e M o n k e y s Apo-Go was ( 1 .
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