505(b)(2) Why Now? Ken Phelps. Gemma Casadevall, PhD. President & CEO, Camargo Pharmaceutical Services, LLC. Chief Scientific Officer, Medichem, S.A.

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1 Ken Phelps 505(b)(2) Why Now? President & CEO, Camargo Pharmaceutical Services, LLC Gemma Casadevall, PhD. Chief Scientific Officer, Medichem, S.A.

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3 50 505(b)(2) NDAs Approved Camargo Database

4 $ in billions The Patent / Generics Cliff (Value of product at risk )

5 Generic New Business Strategy Generic Same Drug Product Pharmacy Well-established: Development requirements Cost Profits Competition New Drug What Product? How to sell? Unfamiliar: Development requirements Cost Profits Competition

6 Strategic Drug Development The road to regulatory approval is just one piece of the puzzle. Regulatory Can we convince the agency on what program is necessary? Creative and optimal?

7 Your path What is public? Your development program FDA Requirements for NDA Approval

8 (b)(2) Process 505(b)(2) and the Importance of the Pre-IND Meeting Start Feasibility Pre-IND Stop FDA OK? Pre-IND FDA Meeting Request Submission Package FDA Preliminary Response Pre-IND Meeting On-Site Written Response Only (WRO) Telephonic FDA Final Meeting Minutes 8

9 Maintain the Link Pre-IND NDA 9

10 Exclusivity 505(b)(2) Products without 3-Year Exclusivity that Experienced Generic Competition within the first 3 years 505(b)(2) Products without 3-Year Exclusivity that Experienced Additional Generic Competition after 3 years

11 505(b)(2) Process Preclinical Start FDA OK? Feasibility Pre-IND Phase 1 Phase 2 Phase 3 Stop Formulation Clinical Trial Materials Analytical Methods Regulatory Process Medical Communications NDA Submission 11

12 Strategic Drug Development The road to regulatory approval is just one piece of the puzzle. Regulatory Can we convince the agency on what program is necessary? Creative and optimal? Scientific Can it be done? Reliably and consistently manufactured?

13 Probability of Success by Stage 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Phase 1 to 2 Phase 2 to 3 Phase 3 to NDA Filing NDA Approval Phase 1 to NDA Approval New Molecular Entity 505(b)(2) Source: Clinical Development Success Rates A report by BIO (Biotechnology Innovation Organization), Biomedtracker, and Amplion

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15 Strategic Drug Development The road to regulatory approval is just one piece of the puzzle. Regulatory Can we convince the agency on what program is necessary? Creative and optimal? Scientific Can it be done? Reliably and consistently manufactured? Medical Does the product satisfy an unmet need? Do we understand the practice of medicine?

16 Drug for Which Patient?

17 Limits of Patient Response

18 ~70% of pediatric Rx are off-label GAO, Pediatric Drug Research, May 2001; GAO T.

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21 Target Product Profile

22 Strategic Drug Development The road to regulatory approval is just one piece of the puzzle. Regulatory Can we convince the agency on what program is necessary? Creative and optimal? Scientific Can it be done? Reliably and consistently manufactured? Medical Does the product satisfy an unmet need? Do we understand the practice of medicine? Commercial Is the product commercially viable? How will it be reimbursed?

23 Launch-Aligned Monthly TRx s Recent AED Launches

24 ADHD Market 505(b)(2) Product Launches

25 Product Selection

26 Hands on the project Case study Gemma Casadevall, PhD. CSO Medichem

27 Strategic Development opportunities or challenges? Strength Dosage form Combination product Dosing regimen Formulation Active ingredient Indication Bioinequivalence Rx/OTC switch Route of administration

28 The selection process Task API Synthesis (Enantiomers/ Salts) Formulation Development Options Potential Combination Options Product Selection Criteria questionnaire Medichem-specific process filters List of top 10 APIs Prioritization of top 10 APIs Filtering steps to top 4 APIs Prioritizing of top 4 APIs Agreement on top 2 APIs 2 possible different salts identified 1. Powder/Oral Suspension Currently product an XR do ot c ush o che fo ulatio Pediatric dosing provided in labeling did not meet primary endpoint. Doses above X mg/kg qd have not been studied. 2. Lower strength recommended starting dose not amongst the approved strength 3. Higher strength Dosages above Y mg per day have not been studied. 4 possible fixed dose combinations identified Identification of top API

29 Focus on what you can do and what is feasible PRODUCT Specialty APIs TECHNOLOGY PLATFORMS API Enhanced APIs Multiparticulates Minitabs ODT Oral Sol/Susp. New opportunities Current business FDF Value added medicines Specialty FDFs Smart Polymers Long-acting injectables

30 Action Plan The Need: Markets / competition Technologies Available resources + investments Focus on specific technologies with defined timelines to obtain Value Added Products The Challenge: Dissolved drug (%) The added value: RLD Time (h)

31 Focus on what you can do and what is feasible PRODUCT Specialty APIs TECHNOLOGY PLATFORMS API Enhanced APIs Multiparticulates Minitabs ODT Oral Sol/Susp. New opportunities Current business FDF Value added medicines Specialty FDFs Smart Polymers Long-acting injectables Source. Camargo Blog Jan 2017

32 Focus on what you can do and what is feasible PRODUCT Specialty APIs TECHNOLOGY PLATFORMS Oral Inhalation Topical Injection + IV 2,0% API 1,3% 0,7% 2,6% 2,6% Enhanced APIs 20,4% 7,5% Multiparticulates Minitabs 36,6% ODT Tablet Capsule ODT 15,0% Oral Liquid Ophtalmic Otic Rectal Transdermal 3,9% 11,1% 60,8% 12,9% 22,6% Oral Sol/Susp. Others Nasal Value added medicines Smart Polymers FDF New opportunities Current business Specialty FDFs Long-acting injectables Source. Camargo Blog Jan 2017

33 Improving administration and ease of use for subpatient groups SPRINKLE MULTIPARTICULATE DDS ORAL MULTIPARTICULATE XR SUSPENSIONS ODT/MUPS

34 Multiparticulate Drug Delivery Systems (MDDS) advantages MDDS offer a high degree of flexibility in the design: capsules, tablets (microspheres, coated beads), sachets, suspensions... They can be divided into desired dose strengths without formulation or process changes and/or also can be blended to deliver incompatible active agents simultaneously and/or to provide different release profiles at the same or different sites in the gastrointestinal (GI) tract. They offer a wide range of drug release profile flexibility for single or multiple drug combinations MDDS disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the mucosa by certain irritant drugs, and reduce inter- and intrapatient variability. Provide predictable and consistent gastrointestinal transit and lower chances of undesirable events (e.g., dose dumping, colonic streaming) associated with tablets.

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36 Key points: Biz Case, do your homework! Qualitative assesment Market and Opinion Leader Assessment Portfolio balance Timing Short or long term Resources/ Investments Capability / API Market: US, EU, Regional Quantitative Assesment Feasibility report

37 The internal analysis: Platform vs. Protection PLATFORM APPLICATION/ TYPE OF PRODUCT MARKET PROTECTION ORAL MDDS Pediatrics Prior art ORAL MDDS Geriatrics May be product specific +device ORAL MDDS HPAPI May be product specific INJECTABLES IR Prior art INJECTABLES XR May be product specific INJECTABLES Smart polymers Blue ocean If we have a new polymer

38 A clear regulatory pathway in the US vs EU Will the product be able to sell in both markets? A case by case story Will the product be able to sell for geriatric and paediatric patients?

39 Target Product Profile Description Product X, for oral administration, available as extended-release MDDS (sachet, capsule,...) Product X has been formulated to provide a controlled and predictable release of the drug for once-daily administration. Product X capsules contain specially loaded multipaticulates equivalent to X mg of drug. Indication and Usage Dosage Dosage Form and Strength Administration Product X is indicated for the treatment of: Indication 1 Indication 2 Indication 3 Administer once daily. Dosing of Product X should be individualized. Indication 1: Recommended starting dose is X mg or double, with the highest dose tolerated up to 6 x X mg. Switching from immediate-release to Product X: use the same total daily dose of Product X. Product X Extended-Release MDDS: x mg Product X Capsules: May be swallowed whole. Contents may be mixed in liquid of choice and consumed immediately. Contents may be sprinkled on soft food. The drug/food mixture should be swallowed immediately. Contents may be administered through a nasogastric tube. Product X Sachets: Contents may be mixed in liquid of choice and consumed immediately. Contents may be sprinkled on soft food. The drug/food mixture should be swallowed immediately. Contents may be administered through a nasogastric tube. Example of a Sachet (not actual Product X) Product X X mg

40 Road towards success: PK Studies CMO CRO 10 m 1 m 1 m 6-9 m New candidates proposal

41 A platform enabler process: MPDDS Technology Target Population Advantages Challenges Available drugs Available Geriatrics Pediatrics General (when only tablet available) Can be mixed with semisolid food No risk of aspiration Low appetite Techical difficulties Low Buy or develop Commercial Price Profitability TBD High Buy or develop

42 Conclusions 505(b)(2) pathway is a clear regulatory way to promote innovation with moderate investment vs. NCE Most of the products offer a lower-risk market entry point 505(b)(2) de elop e t oppo tu ities face u i ue challe ges scie tific, egulato y, fi a cial, thus: If we want this investment to be worth we should pay careful attention to: Listen to current patient/market/kol needs Focus on own capabilities Resources/ Investments/technology Keep up ith the Age cy s cu e t thi ki g Face it: e li e i a co sta t cha gi g egulato y e i o e t

43 Summary With 505(b)(2), an experienced partner enables developing and delivering a faster, lower cost, and lower risk program. For weekly drug development insights, subscribe to the Camargo 505(b)(2) blog at: CamargoPharma.com/contact-us/ For more about Medichem, visit Medichem.es/contact/

44 Thanks for your attention