Improving the process of rare disease treatment development “ EMERGING THERAPIES FOR RARE DISEASES ”

2. Improving the process of rare disease treatment development “EMERGING THERAPIES FOR RARE DISEASES” CENTER FOR ORPHAN DISEASE RESEARCH AND THERAPY SYMPOSIUM FRIDAY MAY 2, 2014 Emil D. Kakkis, M.D., Ph.D. President and Founder

3. EveryLife Foundation for Rare Diseases • Dedicated to accelerating biotechnology innovation for rare disease treatments • Advocating practical and scientifically sound change in policy and law to increase the efficiency & predictability of the development process • We believe: • No disease is too rare to deserve treatment • All treatments should be safe & effective • We could be doing more with the science we have

4. Rare disease treatments are being developed but not all rare diseases benefit Successes Challenges • Thousands ultra-rare diseases without approved drugs • Many approved drugs Ceroidlipofuscinoses Methylmalonic acidemia Mannosidosis Mucopolysaccharidosis VII SOLIRIS® (eculizumab) Sanfilippo Syndromes Von Gierke Disease type 1 Orfadin® Galactosialidosis (nitisonone) Propionic acidemia Wolman Disease XENAZINE ® (tetrabenazime) Tablets Glycogen storage disease type IV Isovaleric acidemia Menkes disease Tay Sachs

5. The development process untreated Good Science And then a miracle happens treated

6. Thousands of Rare Diseases Need TreatmentHow can this be done with the current process?Is there really just the valley of death? Lost in Space Wandering in Wilderness Clin-Reg Hell Reimbursement Purgatory Valley of Death IDEA Model POC Tox., IND/CTA Ph. 1 Study Ph2/PH3 NDA Reimbursement 0 Yr 5 Yr 10 Yr 13 Yr 15

7. Development of Treatments for Ultra-Rare Disorders: Challenging Due to Rarity or Difficult Biology • Ultra-rare disorders • Little historical clinical or any other data • Difficult biology such as connective tissue or CNS • Complex irreversible symptoms • Slow variable disease or hard to measure • No valid surrogate measures of disease reversal • Biochemistry or imaging or neurophysiology

8. Ultra-rare Disease Treatments:Few making it through the difficult development processAt only 2-3 approvals per year, it will take >300 years to develop treatments for half of them Ultra-Rare Designations and Approvals # of Designations and Approvals

9. Ultra-rare disease treatment development is difficult but yet the science can be profound • Market sizes are too small for normal investment by industry • Diseases are new to regulatory authorities with little data on history or endpoints • Yet, we have science that can be translated • We can do better

10. Mucopolysaccharidosis I (MPS I)Hurler, Hurler-Scheie and Scheie Syndrome A lysosomal storage disorder • Deficiency of lysosomal enzyme -L-iduronidase • Progressive accumulation of glycosaminoglycans (GAG) • Storage in all tissues • Severe morbidity, early mortality • Rare (est. incidence 1:100,000) Age 5

11. Aldurazyme® (laronidase)A story of success and yet tragedy First laronidase study to treat MPS I untreated treated • Open-label study in 10 patients • Surrogate measures of Storage • Reduction in Liver/spleen size & urine GAG • Similar to Ceredase ® for Gaucher

12. Study 1 was a Resounding Success Liver Size Urine GAG Shoulder Restriction P<0.001 P<0.001 P<0.001 Surrogates and clinical endpoints improved

13. The FDA asked:“What do liver size and urine GAG really mean?” • New questions about validity of the surrogates • After positive study and FDA review group change • Canine MPS I data showing valid relationship to disease • Measures of storage predict tissue storage • No independent human data: surrogates discarded • Open label/heterogeneity: Positive clinical data discarded • Range of motion, sleep apnea, growth rate 1997 1998 1999 2000 DELAYED Program Start 4/97 Start study 12/97 Study End 10/98 File BLA 11/99 Approval May 2000

14. The story continues… Phase 3 Study Positive? Yes and No 6MWT (No patient selection) FVC (Patients selected for <80%) No at p=0.066 Yes with p=0.009 1997 1998 1999 2000 2001 2002 Approval May 2002 Start Phase 3 12/2000 Program Start 4/97 Start study 12/97 Study End 10/98 Pre-BLA 11/99 File BLA 12/2002 DELAYED

15. Phase 3 Study: laronidase increases 6MWT No entry criteria for selection for 6MWT baseline Excess patient heterogeneity complicates data 50 Placebo 40 Aldurazyme 30 20 Wilcoxon p= 0.066* 10 Mean Change, Meters 0 -10 -20 ANCOVA p= 0.039* -30 -40 * Change from Baseline -50 Baseline Week 26

16. Fundamental issues in development • Lack of a predictable process for qualifying a biomarker for use in Accelerated Approval Pathway • Acceptability of alternate study designs and analysis techniques needed for small heterogeneous populations • Lack of expertise in subject matter in regulatory setting

17. Accelerated Approval Accessibility must be improved • Acceptance near impossible for new biomarkers in untreated rare diseases • Need predictable criteria for acceptance for reasonable set of required data that is practical and possible • Greater emphasis on biology and preclinical data • Strong need for changes to study any of the more challenging diseases • Published analysis shows that 3 fold more disease treatments possible for same investment Article at http://www.ojrd.com/content/6/1/49

18. FIRST 16 YEARS:Utilization of Accelerated Approval Pathway for Cancer, HIV and Genetic IndicationsUsage of the Subpart H or E approvals: 64 NDA’s and 9 BLA’s since 1992* Taken from the FDA.gov website table on accelerated approvals http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ucm121597.htm

19. Smart and small changes to acceptance of surrogate endpoints led to real drug Innovation in HIV: 25 new drugs and 4 combinations approved in a 16 year period Small change in regulation: Large effect in innovation Viramune Agenerase Intelence Fortevase Rescriptor Prezista Aptivus Reyataz Selzentry Videx EC Isentress Viracept Crixivan Invirase Retrovir Emtriva Fuzeon Sustiva Kaletra Ziagen Lexiva Viread Norvir Epivir Zerit Hivid Videx 1990 1992 1994 1996 1998 2000 2004 2008 29 drugs in a 16 year period All accelerated approvals New Accelerated Approval Regulations put into Effect

20. Analysis of impact from better access to Accelerated ApprovalThree fold more diseases treated for the same $1Bn investment 36 25 11 36 drugs developed for same 1 billion USD Miyamoto and Kakkis at http://www.ojrd.com/content/6/1/49

21. FDASIA – Great start but not enough • Sec. 901. Enhancement of accelerated patient access to new medical treatments (ULTRA/FAST) • Considerations. – In developing the guidance . . . . the Secretary shall consider . . . . for drugs designated for a rare disease or condition under section 526 of the Federal, Food, Drug, and Cosmetic Act; and • (2)how to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical.” • Sec. 902. Breakthrough therapies • Sec. 903. Consultation with external experts on rare diseases • Sec. 908. Rare pediatric disease priority review voucher incentive program • Sec. 1137. Patient Participation in Medical Product Discussions Still awaiting the final FDA guidance on Accelerated Approval Will it be good enough to help improve access?

22. Successes in FDASIA showed there is momentum for more rare diseases legislation • Patients are motivated & ready to take action • Rep. Upton is actively seeking proposals to improve FDA, spur drug development & innovation

23. CureTheProcess – 2Small policy changes that will dramatically increase the availability rare disease treatments in the next 5-10 years • Specialize:Create more specialized FDA New Drug Review Divisions; give reviewers sufficient time and opportunity to stay connected to the scientific and academic community • Rationalize:Allow for a more scientific rationalized application of the ICH guidelines for safety studies • Incentivize: Create an additional market incentive to encourage industry drug sponsors to repurpose major market drugs for rare diseases

24. We Can Do More with the Science We Already Have The Potential of Drug Repurposing for Rare Diseases • Many patented drugs already developed and approved for common conditions • Might effectively treat rare diseases of same pathway • Quality drugs with high potency and selectivity • A single targeted drug is likely to have multiple therapeutic uses • But rare disease indications will not be developed for patented drugs: Why not?

25. Roadblocks for Repurposing Large Market Drugs for Rare Diseases • The perception of RISK to a billion dollar product is too great to allow any rare disease development • RISKS: Fear that potential adverse effects in clinical trials on very sick patients would risk the product’s market • NO BENEFIT: Adding a few hundred or few thousand rare diseases patients does not increase market revenue enough to justify the costs of repurposing or the potential risk We need a solution to incentivize repurposing of patented drugs

26. Key Benefits of Rare-purposing*that would speed development • Sponsor already exists for the program • Leverages existing expertise of clinical development staff and scientists • Manufacturing and toxicology work complete • Safety is known in humans • Reduced time for development trials & approval • Focus on science, and rare disease clinical studies • Rare-purposed Orphan Drugs will likely cost less than typical orphan products: Drug price set by large market indication * Nickname courtesy of Kay Holcombe, BIO

27. Impact of LegislationSurge in Patented Drug Repurposing Investment in the next 15 years Small change in regulation: Large effect in innovation Small delay in patented drugs becoming generic New label indications granted for Rare Diseases Sponsors invest 100 + new repurposing programs New Orphan Exclusivity Extension Legislation Enacted 2015 2017 2019 2021 2022 2024 2026 2028 2030 • Immediate surge in research investment • New high paying biotech Jobs • Increased tax revenue • Rare Disease patients access to clinical trials 100’s of drugs available for rare disease patients

28. Implementing Policy with ActionUltragenyx Pharmaceutical Inc. • Pipeline of ultra-rare disease drug candidates with lead product in the clinic • Implementing new designs and analyses • Driving the change forward for rare diseases • Pipeline: Four products for five rare diseases • About 80 employees located in Novato, CA

29. MPS VII Sly Syndrome • Deficiency of b-glucuronidase • Same metabolic effect as in MPS I and MPS II • Clinical disease similar to MPS I • Broad spectrum of severity • Severe at birth: hydrops • Prevalence ~100-200 patients • Substantial under-diagnosis

30. Novel Blinded Start Design Proposal • 12 subjects randomized to one of four (A-D) groups • Subjects and observers do not know when subjects cross onto drug Rx • Dosed every other week for 48 weeks. All groups receive a minimum of 24 weeks of 2 mg/kg UX003 therapy

31. Qualification of Total Urinary GAG Excretion as a 1o Endpoint for MPS 7 • Clear genetic pathophysiologic mechanism • Strong predictive value in ERT in MPS models Predictive of clinical efficacy • EMA has accepted as primary endpoint • FDA has not yet at this time

32. Rare disease treatments are comingAn improved process would help • Need better access to accelerated approval • Better biomarker information • Accept study designs/endpoints that accommodate the biological or prevalence challenges • Enhance the expertise at the regulatory agencies • Continue to drive for medical evolution • The first treatment is not the end, just the beginning

33. ekakkis@EveryLifeFoundation.org EveryLife Foundation for Rare Diseases Learn about our efforts and support us at WWW.EveryLifeFoundation.ORG