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 FDA.gov 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