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No Disease Is Too Rare to Deserve Treatment. Improving the process of rare disease treatment development “EMERGING THERAPIES FOR RARE DISEASES” Emil D.

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Presentation on theme: "No Disease Is Too Rare to Deserve Treatment. Improving the process of rare disease treatment development “EMERGING THERAPIES FOR RARE DISEASES” Emil D."— Presentation transcript:

1 No Disease Is Too Rare to Deserve Treatment

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

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 3

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

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

6 Thousands of Rare Diseases Need Treatment How can this be done with the current process? Is there really just the valley of death? 6 IDEAModel POCTox., IND/CTA Ph. 1 StudyPh2/PH3 NDAReimbursement 0 Yr 5 Yr 10 Yr 13 Yr 15 Valley of Death Wandering in Wilderness Lost in Space Clin-Reg Hell Reimbursement Purgatory

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

8 Ultra-rare Disease Treatments: Few making it through the difficult development process Ultra-rare Disease Treatments: Few making it through the difficult development process At 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 Market sizes are too small for normal investment by industry Diseases are new to regulatory authorities with little data on history or endpoints Diseases are new to regulatory authorities with little data on history or endpoints Yet, we have science that can be translated Yet, we have science that can be translated We can do better We can do better

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

11 No Disease Is Too Rare to Deserve Treatment First laronidase study to treat MPS I Open-label study in 10 patients Surrogate measures of Storage Reduction in Liver/spleen size & urine GAG Similar to Ceredase ® for Gaucher untreated treated Aldurazyme® (laronidase) A story of success and yet tragedy

12 Study 1 was a Resounding Success Liver SizeUrine GAGShoulder Restriction Surrogates and clinical endpoints improved P<0.001

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

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

15 No Disease Is Too Rare to Deserve Treatment Phase 3 Study: laronidase increases 6MWT No entry criteria for selection for 6MWT baseline Excess patient heterogeneity complicates data Baseline Week 26 Mean Change, Meters * Change from Baseline Wilcoxon p= 0.066* ANCOVA p= 0.039* Placebo Aldurazyme

16 Fundamental issues in development Lack of a predictable process for qualifying a biomarker for use in Accelerated Approval Pathway 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 Acceptability of alternate study designs and analysis techniques needed for small heterogeneous populations Lack of expertise in subject matter in regulatory setting 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 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 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 17 Article at

18 FIRST 16 YEARS: Utilization of Accelerated Approval Pathway for Cancer, HIV and Genetic Indications Usage 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 Therapeutic Area Number of Accelerated Approvals Surrogate endpointOther Cancer26 Variety Most pivotal studies without a control group HIV29 CD4 or viral load Combination therapies also approved Other17 Variety PAH, hormones, iron, Crohns, MS, antibiotics Genetic1 Renal pathology Fabrazyme DrugandBiologicApprovalReports/ucm htm 18

19 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 New Accelerated Approval Regulations put into Effect Retrovir Videx Videx EC Crixivan Viracept Sustiva Rescriptor Hivid Fortevase Invirase Norvir Viramune Ziagen Kaletra Epivir Zerit Agenerase Fuzeon Viread Reyataz Emtriva Lexiva Prezista Aptivus Selzentry Intelence Isentress 29 drugs in a 16 year period All accelerated approvals Small change in regulation: Large effect in innovation

20 Analysis of impact from better access to Accelerated Approval Three fold more diseases treated for the same $1Bn investment 36 drugs developed for same 1 billion USD Miyamoto and Kakkis at

21 FDASIA – Great start but not enough Sec Enhancement of accelerated patient access to new medical treatments (ULTRA/FAST) Sec 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 Breakthrough therapies Sec Breakthrough therapies Sec Consultation with external experts on rare diseases Sec Consultation with external experts on rare diseases Sec Rare pediatric disease priority review voucher incentive program Sec Rare pediatric disease priority review voucher incentive program Sec Patient Participation in Medical Product Discussions Sec Patient Participation in Medical Product Discussions Still awaiting the final FDA guidance on Accelerated Approval Will it be good enough to help improve access? 21

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 22

23 CureTheProcess – 2 Small 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 Incentivize: Create an additional market incentive to encourage industry drug sponsors to repurpose major market drugs for rare diseases 23

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? 24

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 25 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 26 * Nickname courtesy of Kay Holcombe, BIO

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

28 Implementing Policy with Action Ultragenyx 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 28

29 MPS VII Sly Syndrome Deficiency of  -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 ~ patients – Substantial under-diagnosis 47

30 Confidential 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 Novel Blinded Start Design Proposal

31 31 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 Qualification of Total Urinary GAG Excretion as a 1 o Endpoint for MPS 7

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

33 No Disease Is Too Rare to Deserve Treatment Learn about our efforts and support us at EveryLife Foundation for Rare Diseases


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