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Emil D. Kakkis, M.D., Ph.D. President and Founder

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2 Emil D. Kakkis, M.D., Ph.D. President and Founder
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 (tetrabenazime) Tablets
Rare disease treatments are being developed but not all rare diseases benefit Successes Challenges Many approved drugs Thousands ultra-rare diseases without approved drugs Ceroid lipofuscinoses Methylmalonic acidemia Mannosidosis Mucopolysaccharidosis VII SOLIRIS® (eculizumab) Sanfilippo Syndromes Von Gierke Disease type 1 Orfadin® (nitisonone) Galactosialidosis Propionic acidemia Wolman Disease XENAZINE ® (tetrabenazime) Tablets Glycogen storage disease type IV Isovaleric acidemia Menkes disease Tay Sachs

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

6 Thousands of Rare Diseases Need Treatment How 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 Yr Yr Yr Yr 15

7 Little historical clinical or any other data
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 Designations and Approvals
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 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) Main message: - underlying cause - disease affects all organ systems and tissues - heterogeneous symptoms - nearly all patients experience severe morbidities and many die between the ages of 10 and 20 Age 5 10

11 First laronidase study to treat MPS I
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 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
FVC (Patients selected for <80%) 6MWT (No patient selection) Yes with p=0.009 No at p=0.066 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 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* -10 10 30 50 -30 -50 -40 -20 20 40 ANCOVA p= 0.039* Placebo Aldurazyme In the double-blind phase, patients receiving placebo showed an increase in the 6MWT distance of nearly 20 m, whereas placebo patients showed a decrease of nearly 20 m. The difference between groups was 38 m, and on the main Intent to Treat analysis, this difference approached statistical significance. Both groups showed a dip at week 4 which we believe was due to loss of a training effect. At baseline, patients underwent 3 6MWT on successive days, but at subsequent time points only 1 6MWT was performed. The week 4 value is closer to the true baseline. In the extension Phase, patients who continued on aldurazyme showed an additional 20 meter increase. The change from baseline, nearly 40 meters, was statistically significant. The placebo crossover patients confirmed the treatment effect as they increased by a similar magnitude as the Aldurazyme patients in the double-blind phase. The difference from Week 26 was significant.

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

18 Number of Accelerated Approvals
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* Therapeutic Area Number of Accelerated Approvals Surrogate endpoint Other Cancer 26 Variety Most pivotal studies without a control group HIV 29 CD4 or viral load Combination therapies also approved 17 PAH, hormones, iron, Crohns, MS, antibiotics Genetic 1 Renal pathology Fabrazyme Taken from the website table on accelerated approvals

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

20 36 drugs developed for same 1 billion USD
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 11 25 36 Miyamoto and Kakkis at

21 FDASIA – Great start but not enough
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 Consultation with external experts on rare diseases Sec Rare pediatric disease priority review voucher incentive program 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?

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 – 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

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

27 100’s of drugs available for rare disease patients
Impact of Legislation Surge in Patented Drug Repurposing Investment in the next 15 years Small change in regulation: Large effect in innovation granted for Rare Diseases New label indications Sponsors invest new repurposing programs Small delay in patented drugs becoming generic Extension Legislation Enacted New Orphan Exclusivity 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 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

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 ~ 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 coming An 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 EveryLife Foundation for Rare Diseases
Learn about our efforts and support us at

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