No Disease Is Too Rare to Deserve Treatment
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
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
Rare disease treatments are being
developed but not all rare diseases benefit
Successes
Challenges
• Thousands ultra-rare diseases
without approved drugs
• Many approved drugs
SOLIRIS®
(eculizumab)
Orfadin
(nitisonone)
Ceroid lipofuscinoses
Methylmalonic acidemia
Mannosidosis
Mucopolysaccharidosis VII
Sanfilippo Syndromes
Von Gierke Disease type 1
®
XENAZINE ®
(tetrabenazime) Tablets
Galactosialidosis
Propionic acidemia
Wolman Disease
Glycogen storage disease type IV
Isovaleric acidemia
Menkes disease
Tay Sachs
The development process
Good
Science
And then a miracle happens
untreated
treated
5
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
IDEA
0
Wandering in
Wilderness
Valley of Death
Clin-Reg
Hell
Model POC Tox., IND/CTA Ph. 1 Study Ph2/PH3 NDA
Yr 5
Yr 10
Yr 13
Reimbursement
Purgatory
Reimbursement
Yr 15
6
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
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
30
25
20
15
10
5
Ultra Orphan Designations
Ultra Orphan Approvals
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
0
1997
# of Designations and Approvals
Ultra-Rare Designations and Approvals
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
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
Aldurazyme® (laronidase)
A story of success and yet tragedy
First laronidase study to treat MPS I
• Open-label study in 10 patients
• Surrogate measures of Storage
untreated
• Reduction in Liver/spleen size & urine GAG
• Similar to Ceredase ® for Gaucher
No Disease Is Too Rare to Deserve Treatment
treated
Study 1 was a Resounding Success
Liver Size
Urine GAG
Reduction in Liver Volume During Enzyme Therapy
1
2
3
4
5
6
7
8
9
10
4.4
4.2
4.0
3.8
120 120
100 100
80 80
3.6
3.4
60 60
Normal Adults Normal Children
Percent Body Weight
4.6
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
40 40
20 20
0
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60
Weeks of Therapy
P<0.001
0
0 0
5
5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 45 45 50 50 55 55 60 60
Weeks
Weeks
of of
Treatment
Treatment
P<0.001
Surrogates and clinical
endpoints improved
Degrees of Restriction of Range of Motion From Normal Mean
4.8
70
JOM001
JOM001
HAC002
HAC002
RCD003
RCD003
SSH004
SSH004
SWD005
SWD005
GMD006
GMD006
JAN007
JAN007
NM008
NM008
CEL009
CEL009
BBG010
BBG010
Percent Starting GAG
Percent Starting GAG
5.0
Shoulder Flexion Range of Motion
Mean Degrees of Restriction
Urinary
Urinary
GAG
GAG
Excretion
Excretion
During
During
Enzyme
Enzyme
Therapy
Therapy
5.4
5.2
Shoulder Restriction
Right Shoulder
Left Shoulder
65
60
55
50
45
40
0
10
20
30
Weeks of Therapy
40
P<0.001
50
60
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
Program
Start 4/97
1998
Start study
12/97
1999
Study End
10/98
2000
File BLA
11/99
Approval
May 2000
DELAYED
The story continues…
Phase 3 Study Positive? Yes and No
FVC (Patients selected for <80%)
6MWT (No patient selection)
No at p=0.066
Yes with p=0.009
1997
Program
Start 4/97
1998
Start study
12/97
1999
Study End
10/98
2000
Pre-BLA
11/99
2001
Start Phase 3
12/2000
2002
File BLA
12/2002
Approval
May 2002
DELAYED
Phase 3 Study:
laronidase increases 6MWT
No entry criteria for selection for 6MWT baseline
Excess patient heterogeneity complicates data
Mean Change, Meters
50
40
30
Placebo
Aldurazyme
20
Wilcoxon
p= 0.066*
10
0
-10
-20
-30
* Change from Baseline
-40
ANCOVA
p= 0.039*
-50
No Disease Is Too Rare to Deserve Treatment
Baseline
Week 26
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
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
17
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
Cancer
HIV
Other
Genetic
26
29
17
1
Surrogate endpoint
Other
Variety
Most pivotal studies
without a control group
CD4 or viral load
Combination therapies
also approved
Variety
PAH, hormones, iron,
Crohns, MS, antibiotics
Renal pathology
Fabrazyme
Taken from the FDA.gov website table on accelerated approvals
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
DrugandBiologicApprovalReports/ucm121597.htm
18
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
1990
1992
1994
New Accelerated Approval
Regulations put into Effect
1996
1998
2000
2004
2008
29 drugs in a 16 year period
All accelerated approvals
19
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
36
25
11
Miyamoto and Kakkis at
http://www.ojrd.com/content/6/1/49
20
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?21
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
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
23
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
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
25
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
26
Impact of Legislation
Surge in Patented Drug Repurposing
Investment in the next 15 years
Small change in regulation: Large effect in innovation
2015
•
•
•
•
2017
2019
2021
2022
Immediate surge in research investment
New high paying biotech Jobs
Increased tax revenue
Rare Disease patients access to clinical trials
2024
2026
2028
2030
100’s of drugs available for
rare disease patients 27
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
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
47
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
A
Blinded period
D
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3
48 wk
1 mg/kg
B
placebo
C
placebo
D
placebo
Wk
dose
40 wk
1 mg/kg
32 wk
1 mg/kg
24 wk
Confidential
1 mg/kg
30
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
31
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
32
EveryLife Foundation for
Rare Diseases
Learn about our efforts and support us at
WWW.EveryLifeFoundation.ORG
ekakkis@EveryLifeFoundation.org
No Disease Is Too Rare to Deserve Treatment