Alkermes R&D: Differentiated, Patient- Focused and Productive

Transcription

1 Alkermes R&D: Differentiated, Patient- Focused and Productive Richard Pops Chief Executive Officer Alkermes R&D Day July 17, 2013

2 Forward-Looking Statements 2 This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements about our prospects for growth, market share and market evolution, competitive position, intellectual property protection, regulatory agency action, and the anticipated development, timing, data readouts and therapeutic scope and value of our products in clinical development. You should not place undue reliance on these statements. These statements involve risks and uncertainties that could cause actual results to differ materially from those contained in such statements, including, among others: our inability to protect our intellectual property rights and to have sufficient rights to commercialize our products; product competition; clinical trials of our products may be unsuccessful or not initiated or conducted in a timely manner; our products may not show sufficient therapeutic effects or acceptable safety profiles; adverse decisions by regulatory authorities; existing clinical and preclinical data with respect to our products may not be indicative of future clinical or commercial results; unfavorable reimbursement for our products; and our inability to manufacture successfully our products. Additional factors that could cause actual results to differ from those projected in the forward-looking statements are discussed in Alkermes plc s Annual Report on Form 10-K and Form 10-K/A, Quarterly Reports on Form 10-Q and recent Current Reports on Form 8-K, which are available on our website at in the Investors SEC Filings section. These statements are based on our current beliefs and expectations and speak only as of the date of this presentation. We do not undertake any obligation to update any forward-looking statements.

3 Number of Treatments Major Opportunities Exist in Chronic Diseases 3 Biotech's traditional focus Big pharma's traditional focus Schizophrenia Multiple sclerosis Cardiovascular Diabetes Asthma/COPD Cancer (undifferentiated) Depression Cancer (personalized medicine) Pharma's expansion Anemia (severe) Rheumatoid arthritis Substance use disorders Obesity Gaucher's disease Cystic fibrosis Pompe disease Number of Patients Parkinson's Alzheimer's disease disease Source: Ernst & Young Biotechnology Industry Report 2013 and Alkermes. Positions of data points are approximate and intended to be suggestive of relative magnitudes.

4 We Create Valuable New Medicines 4 1. Focus on specific problems patients experience living with chronic disease 2. Identify, at the outset, the general parameters of the value proposition for key stakeholders 3. Build on a foundation of insight derived from known pharmacology and medical practice 4. Embody our discoveries in the form of new, patentable, differentiated medicines 5. Test our medicines in rigorous human clinical trials, asking the most critical questions as early as possible 6. Continuously reevaluate the portfolio as new data emerge

5 What is Valuable? The Hard Questions: 5 Does this represent not just innovation, but useful and important innovation for patients? Does FDA want to approve this drug? Does it address an important unmet medical need? Is it consistent with the current regulatory climate? Are physicians motivated to prescribe this drug? What are the economic realities? Does it make their practice easier or harder? What will payers reaction be? Will they create obstacles to early use or restrict access? Will they require additional data not necessary for FDA approval?

6 New Capabilities Built on a Foundation of Drug Development Experience 6 Advanced Formulations of Existing Medicines New Molecular Entities RISPERDAL CONSTA INVEGA SUSTENNA VIVITROL AMPYRA BYDUREON

7 New Capabilities Built on a Foundation of Drug Development Experience 7 Advanced Formulations of Existing Prodrugs Orthogonal Combinations Single Agents Medicines Aripiprazole Lauroxil ALKS 5461 MMF Prodrugs ALKS 3831 ALKS 7106 RDB 1419

8 Novel Prodrugs 8 New molecular entities (NMEs) capturing the established benefits of blockbuster medicines and improving patient outcomes or experience Aripiprazole lauroxil: A novel, long-acting injectable prodrug of aripiprazole for the treatment of schizophrenia Designed to provide the proven benefits of aripiprazole with a wide range of doses and ready-to-use presentation MMF prodrugs: Novel, oral prodrugs of monomethyl fumarate (MMF) for the treatment of multiple sclerosis (MS) Designed to provide patients with once-daily dosing and reduced GI irritation compared to TECFIDERA (BG-12)

9 Orthogonal 9 In geometry, orthogonal means involving right angles (from Greek ortho, meaning right, and gon, meaning angled). The term has been extended to general use, meaning the characteristic of being independent (relative to something else). It also can mean non-redundant or non-overlapping. vs.

10 Orthogonal Combinations 10 Create new medicines through new insights realized through dual pharmacology ALKS 5461: Combination of a mu-opioid partial agonist (pain, addiction) and a potent mu-opioid antagonist (addiction) for the treatment of depression Insight: Antidepressive properties of an opioid can be decoupled from its addictive properties ALKS 3831: Combination of an atypical antipsychotic and a potent mu-opioid antagonist for the treatment of schizophrenia Insight: Broader spectrum antipsychotic may offer attenuation of weight gain and address dual diagnosis of substance abuse disorder

11 New Single Agents 11 Create NMEs, small molecule or biologic, incorporating the discoveries we have made ALKS 7106: NME for pain Derived from our opioid modulator platform with a unique therapeutic profile, including potent analgesic effects with intrinsically low potential for abuse and overdose death RDB 1419: NBE for cancer Immunomodulator based on IL-2 and its receptors, ideally suited for use in combination with multiple cancer agents and with potential safety and tolerability advantages

12 12 MMF Prodrugs

13 MMF Prodrugs for the Treatment of Multiple Sclerosis 13 Product concept: Novel prodrug of monomethyl fumarate (MMF) with differentiation vs. TECFIDERA (BG-12, dimethyl fumarate, DMF) Approach: Combine proprietary prodrug and formulation technologies to improve dosing regimen and tolerability Potential points of differentiation: Once-daily dosing vs. twice-daily Minimal GI side effects due to less irritability to gastric mucosa Minimal flushing Minimal food effect Forms stable HCl salt and no sublimation of the API

14 TECFIDERA (DMF) Converts to MMF In Vivo Pharmacokinetics After oral administration of TECFIDERA, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of TECFIDERA. Therefore all pharmacokinetic analyses related to TECFIDERA were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. DMF MMF Source: TECFIDERA prescribing information

15 Percent Conversion Innovative Prodrug Approach Enables Efficient Chemical Conversion to MMF RDC 1559 MMF Conversion RDC-1559 MMF Time (min) In vitro analysis shows RDC 1559 converts efficiently to MMF with a half-life of 25 minutes MMF is the only product observed in conversion Appears to have superior conversion over other ester candidates

16 Blood Levels Alkermes Has Strong Capabilities in Oral Controlled-Release 16 TECFIDERA ALKS MMF Prodrug Formulation 1 0 ALKS MMF Prodrug Formulation 2 Time (hr) Source: Alkermes internal modeling for illustration purposes only

17 MMF Prodrugs IP Status 17 Focused IP strategy with patent protection and freedom to operate Composition of matter Filed; would provide protection into 2034 Covers multiple compounds Method of treatment claims filed for MS Oral formulation expertise coupled with prodrug chemistry may yield additional IP protection

18 Current Status 18 Two lead candidates advancing Formulation work focused on QD dosing underway First scale-up completed Toxicology studies to support IND filing underway Plan to file IND and initiate phase 1 study in mid CY 14 Significant de-risking step will provide data on conversion, tolerability, PK and bioavailability

19 19 ALKS 7106

20 The Growing Opioid Crisis 20 most abuse-deterrent technologies developed to date are designed to make product manipulation more difficult or to make abuse of the manipulated product less attractive or rewarding these technologies have not yet proven successful at deterring the most common form of abuse swallowing a number of intact pills or tablets to achieve a feeling of euphoria. For the past year, a team of Wall Street Journal reporters has been investigating the abuse of prescription painkillers, America s No. 1 drug problem. - FDA Guidance for Industry: Abuse-Deterrent Opioids, Evaluation and Labeling, January 2013

21 ALKS 7106: Novel Opioid Modulator for Pain 21 Product concept: Safer, oral opioid analgesic with intrinsically low potential for abuse and overdose death Approach: Novel, potent opioid modulator without abuse-deterrent technology (ADT). Rationally designed for: Specific intrinsic activity at the receptor Rapid entry into the CNS Major points of differentiation: Improved safety profile Ceiling neurotransmitter release predicts low potential for abuse and overdose death Well tolerated in animals at doses far in excess of those required for analgesic action

22 Percent % W e Weight h t B e a Bearing g ALKS 7106: More Potent Than Morphine 22 Inflammatory Pain Model in Rats ALKS A L K 7106 S 7 1(0.1mg/kg) 0 6 m g /k g ) Morphine M o h in(3mg/kg) e m g /k g ) B a s e lin e W e ig h t B e a r in g C F A - In d u c e d W e ig h t B e a r in g D e f ic i t T im e (m in ) ALKS 7106 differentiates from proven opioid analgesic agents Potency: ~30-fold more potent than morphine Early safety assessments demonstrate tolerability well in excess of analgesic dose

23 A v e r a g e N e u r o t r a n s m it t e r R e l e a s e ( p g /s a m p le ) ALKS 7106 Has Ceiling Effect Which Predicts Low Abuse Potential 23 4 A L K S B u p re n o rp h in e 3 M o rp h in e D o s e ( m g /k g ) ALKS 7106: Exhibits a ceiling effect on neurotransmitter release over a broad concentration range

24 ALKS 7106 IP Status 24 Broad IP strategy to protect compounds and methods ALKS 7106 has granted composition of matter protection through 2025 Methods of treating pain applications pending

25 Current Status 25 Extensive in vitro and in vivo characterization completed Further scale-up underway IND-enabling safety studies underway Plan to file IND and initiate clinical studies in mid CY 14 Significant de-risking step will provide data on analgesic effect, abuse potential and tolerability

26 26 ALKS Immunomodulator Program

27 How We Got Here 27 Medifusion : glycosylization of proteins, leading to T ½ extension Protein engineering approaches to improve T ½ Undisclosed candidate Undisclosed candidate RDB 1419 Picasso Undisclosed candidate

28 Alkermes Proprietary Picasso Technology Yields Novel Immunomodulators 28 Product concept: Immunomodulator that enhances tumor-killing T cells Potential points of differentiation: Improved dosing regimen and tolerability profile compared to PROLEUKIN Potential to be complementary to a range of current and emerging cancer therapies

29 PROLEUKIN Effects on Cell Types 29 CD8 + T Cell Intermediate-affinity receptors PROLEUKIN Natural Killer Cell T reg Cell High-affinity receptors Lung Endothelial Cell

30 RDB 1419: Weight of Effect Shifted to Enhance Efficacy 30 CD8 + T Cell Intermediate-affinity receptors RDB 1419 Natural Killer Cell T reg Cell High-affinity receptors Lung Endothelial Cell

31 Severe Limitations With PROLEUKIN Therapy 31 Source: PROLEUKIN prescribing information

32 IL-2 Receptors Exist in Intermediate-Affinity and High-Affinity States Depending on Cell Type 32 IL-2 Intermediate-Affinity Receptors IL-2 High-Affinity Receptors IL-2Ra g c IL-2Rb g c IL-2Rb Expressed on CD8 + T cells and on Natural Killer cells Expressed on regulatory T cells and lung endothelial cells

33 IL-2 Binds to Both Intermediate- and High-Affinity IL-2 Receptors 33 IL-2 Intermediate-Affinity Receptors IL-2 IL-2 High-Affinity Receptors IL-2Ra IL-2 g c IL-2Rb g c IL-2Rb

34 Alkermes Picasso Technology Enables Fusion of IL-2 With IL-2Ra 34 C IL-2Ra IL-2 C N N N- and C-termini of IL-2 are in close proximity Crystal structure of IL-2 bound to IL-2Ra

35 Alkermes Picasso Technology Enables Fusion of IL-2 With IL-2Ra 35 C IL-2Ra IL-2 N C N Circular permutation of IL-2 brings termini close to IL-2Ra N-terminus

36 Alkermes Picasso Technology Enables Fusion of IL-2 With IL-2Ra 36 C IL-2Ra IL-2 Proximal termini allow fusion of circularly permuted IL-2 with IL-2Ra N

37 Alkermes Picasso Technology Enables Fusion of IL-2 With IL-2Ra 37 RDB 1419 C Model of RDB 1419: Fusion of IL-2 with IL-2Ra N

38 RDB 1419 Has Increased Preference for Binding to IL-2 Intermediate-Affinity Receptors 38 IL-2 Intermediate-Affinity Receptors RDB 1419 IL-2Ra IL-2 High-Affinity Receptors RDB 1419 g c IL-2Rb g c IL-2Rb

39 RDB 1419 Exhibits Greater Preference In Vitro for Intermediate-Affinity Receptors vs. PROLEUKIN 39 Activation of Cells Bearing Intermediate-Affinity Receptor 1 Activation of Cells Bearing High-Affinity Receptor 2 x PROLEUKIN (EC 50 = 1.1 nm) RDB 1419 (EC 50 = 0.11 nm) PROLEUKIN (EC 50 = 0.34 nm) RDB 1419 (EC 50 = ~208 nm) x RDB 1419 has greater than 1,000 fold selectivity for intermediateaffinity receptors 1 HH Cell Assay 2 CTLL-2 Cell Assay

40 RDB 1419 Reduces Lung Metastases in B16 Murine Lung Tumor Model 40 Mice were injected with B16F10 tumor cells and two days later were administered RDB 1419 QD for 13 days Dose-Dependent Inhibition of Tumor Growth ns p<0.05 p< % 43% 60%

41 Picasso Technology IP Status 41 Broad patent strategy to protect Picasso platform and individual product candidates Filed patent application on Picasso platform covering methods to engineer targeted fusion proteins to enhance the natural molecular mechanism of action Composition of matter Filed; would protect into 2033

42 Current Status 42 Picasso platform Multiple programs underway Pilot scale facility completed and operational in Wilmington, OH RDB 1419 Scale-up underway Further safety studies in non-human primates IND-enabling activities through CY 14

43 Lower RETURN Higher Expansive Portfolio Designed for Early Clinical Validation 43 Alkermes development focus Traditional biotech focus Lower RISK Higher

44 Lower RETURN Higher Expansive Portfolio Designed for Early Clinical Validation 44 Aripiprazole Lauroxil P 1/2 P 1/2 Alkermes development P2 focus P1 ALKS 5461 P 1/2 Traditional biotech focus ALKS 7106 MMF Prodrugs P2 RDB 1419 P2 Dual Diagnosis ALKS 3831 Lower RISK Higher

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