US 505(b)(2) Regulatory Pathway and Strategies

US 505(b)(2) RegulatoryPathway and StrategiesIndustry PerspectivesAAPS Regulatory Sciences Open Forum11/16/2010Ruth Stevens, PhD, MBA

Tale of Two Cliffs• Big Pharma Patents• GenericsLipitorFlomaxSmallPlavixmolecules100 others

Differentiated Products Now Essentially DriveEconomics of US Generics: MylanDuragesicEpiPenPaxil CRDitropan XLPlendilLevothyroxineBystolicRoyaltiesSularBase* EPSTotal EPS (%)Percent incremental contribution to 2008 cash EPS (%)1042 2 1 9Differentiatedproductscontributed**~92% of „08cash EPS271610029*Base EPS includes commodity generics, O-US generics, Matrix**Incremental contributionReference: Ronny Gal, Research Analyst, Sanford C. Bernstein & Co. Presentation atGPhA 2009 Annual Meeting

505(b)(2) ProcessPotential Regulatory Pathways for Drug ProductsUnder DevelopmentAppropriate for drugproducts that are the sameas approved products505(j)ANDAHybrid between an ANDA[505(j)] and a full NDA[505(b)(1)]505(b)(2) NDA‘Full’ Application – Datapredominantly obtained fromstudies conducted by theSponsor505(b)(1) NDA

505(b)(2) RegulationPotential 505(b)(2) Candidates:• Marketed, unapproved (DESI) drug*• PET drugs (FDG F 18, Ammonia N 13, Sodium Fluoride F 18)• Racemates• Known excipients used as active drugs*• New dosage form• Pharmacokinetic alteration• New indication• New combination• Pro-drug of approved drug* May or may not have an RLD

Defining the 505(b)(2) ApplicationA 505(b)(2) application is one for which one or more of the investigationsrelied upon by the applicant for approval "were not conducted by or forthe applicant and for which the applicant has not obtained a right ofreference or use from the person by or for whom the investigationswere conducted" (21 U.S.C. 355(b)(2)).

505(b)(2) NDAReference Listed Drug (RLD)• A drug product that has been previouslyapproved by the FDA• Listed in the Orange Book• Approval documents contain some of theinformation needed for your 505(b)(2)7

Approved Product LabelingDrug SubstanceIndicationSafetyClinicalPharmacologyDDIPharmacokineticsReproductive8

Industry ExamplesHighlighting the Benefits of utilizing the505(b)(2) Regulatory Pathway9

Corporate StrategyThe company applies its KME development model to identify existing drugs or‘known molecular entities’ with established safety profiles which can be developedand clinically differentiated for gastrointestinal indications. The KME developmentmodel allows the company to more quickly establish the efficacy profile of itscandidates for the target gastrointestinal indications.• 505(b)(2) provides the ability to clinically differentiate from other products• Allows for market niche• Not available for ANDA (505(j)) products10

Corporate StrategyMr. Sims: Actually, because we start with drugs already approved by the FDA, we canfile for approval using the 505b2 procedure rather than the full NDA (new drugapplication). Where clinical trials are required for a 505b2 application, the number ofpatients required and length of time needed for those clinical trials are significantly lessthan for a new chemical entity. For example, with ESTRASORB, our Phase 1 trial had14 patients and our Phase 2 and Phase 3 trials required less than 400 patients. As theefficacy and safety of the active ingredients have already been established, thecomplexity of the studies, including the duration, is generally significantly less than foran NDA application. We believe that from the starting point of developing a drug in amicellar nanoparticle to regulatory submission, it should take no more than a three orfour year time frame, which is actually quite fast for this industry. From the point offiling, we would add about another year for FDA review and approval.• Eliminate some of the studies required for a 505(b)(1)(preclinical, extensive safety and efficacy studies)• Significant financial savings• Significant time savings11http://www.novavax.com/images/TWST%200205%20Final.pdf©2005 The Wall Street Transcript, 67 Wall Street, NYC 10005Tel: (212) 952-7400 • Fax: (212) 668-9842 • Website: www.twst.com

Case Study: Colcrys TM - DESI• Colchicine Tablets for treatment of acute gout and familialMediterranean fever (Mutual Pharmaceuticals, NDAs 22-351 and22-352, July 2009)• Colchicine injection removed from the market in February, 2008because of often-fatal toxicity– Mutual showed that this toxicity was due to excessive doseand/or concomitant medications• Approved based only on literature for efficacy for the treatment offamilial Mediterranean fever (FMF) and a single Phase 3 study forthe treatment of acute gout

Case Study: Ulesfia TM - Excipient• 5% benzyl alcohol lotion for treatment of head lice (Sciele Pharma, NDA22-129, April 9, 2009)• Widely-used chemical in cosmetic industry– Never approved as active ingredient so FDA classified it as NME• Development program:– Nonclinical• Literature for repeat dose and genetic toxicology• Literature for in vitro studies demonstrating mechanism of action• 2-year toxicology and carcinogenesis studies from the National Toxicology Program– Clinical Pharmacology/Biopharmaceutics• 2 PK studies (2nd was done because presence of API in the catheter wash wasconfounded results of the 1st study)– Efficacy– Safety• 2 Phase 3 trials, 615 subjects total (240 on treatment)• Relied on its database of 8 studies (2 Phase 3, 3 Phase 2, 2 Phase 1, 1 special safetystudy)• Extensive publication reviewReceived 5 years data exclusivity

Case Study: Cafcit • Caffeine citrate for treatment of apnea of prematurity (MeadJohnson, NDA 20-793, September 21, 1999)• Development Program:– Submitted 1 double-blind trial in 58 preterm infants and 90 literaturearticles• Human PK studies from literature (19 articles)• Drug-drug interactions from literature (71 articles)– No human PK studies conducted in premature infants• Used plasma caffeine levels from subjects in the study and used special software to dopopulation PK analysisReceived orphan drug status (7 years data exclusivity) and expedited review

Pro-Drugs• Fundamental:– Where does the pro-drug become the RLD?–

Case Study: Valacyclovir• Oral tablet for treatment of herpes– Pro-drug of acyclovir– Pro-drug in systemic circulation for about 30 min– Hepatic esterases convert pro-drug to acyclovir– Similar plasma metabolic profile to acyclovir afterconversion

Valacyclovir Regulatory Path• 505(b)(2) NDA as a new molecular entity– Acyclovir is RLD• Can rely on some acyclovir nonclinical & clinical data– Nonclinical studies for NME– Full Phase 1 PK program– Phase 2 dose-ranging– 1 adequate and well-controlled Phase 3 study• 5 Years marketing exclusivity

505(b)(2) Benefits• Able to earn exclusivity– 3 years: clinical studiesessential for approval– 5 years: NCE – old drugsnever approved under an NDA– 7 years: Orphan Drug18

Benefits of 505(b)(2)• Get out of competitive environment of Generics• Regulatory Review Period (10 months)• May be attractive for investors– 505(b)(2) allows for clinical differentiation– Market potential may be greater than generics19

505(b)(2) Risks• Imprecise development costs and timelines– ANDA‟s have few re-do‟s of BE– Recruitment of patients not naive– Uncertain dose (Phase 2)• Unknown competition– Other companies can target the same opportunity20

505(b)(2) Risks• Uncertain market acceptance– Formulary– Sales Force– Doctors– Patients21

505(b)(2) Risks• May not be attractive for investors– “Generics have less risks and better returns”• VC‟s don‟t understand 505(b)(2)• ROI may be lower than 505(b)(1), or a total payoff may belower (double $50MM or $500MM)22

505(b)(2) Risks• Like Generics (505(j)):– must include patent certification(s)– include all relevant patent(s)– subject to the same Paragraph IV challenge andlitigation including a 30-month stay, but it is notgranted a 180-day exclusivity23

Decision to Pursue the 505(b)(2) Regulatory PathwayConsiderations:• Willingness to take educated risks• In-house Expertise• Company Culture• Historical Precedence24

Thank You• Regulatory Sciences Co-Moderators– Michael Bornstein, PhD– Annette Bak, PhD, MBA• Rajneesh Taneja, PhD, RPh