no disease is too rare to deserve treatment. improving the process of rare disease treatment...
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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. Kakkis, M.D., Ph.D.President and Founder
CENTER FOR ORPHAN DISEASE RESEARCH AND THERAPY SYMPOSIUM
FRIDAY MAY 2, 2014
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
• Many 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)
Successes Challenges
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The development process
untreated
treated
And then a miracle happensGoodScience
Thousands of Rare Diseases Need TreatmentHow can this be done with the current process?
Is there really just the valley of death?
6
IDEA Model POC Tox., IND/CTA Ph. 1 Study Ph2/PH3 NDA Reimbursement
0 Yr 5 Yr 10 Yr 13 Yr 15
Valley of DeathWandering inWilderness
Lost inSpace
Clin-RegHell
ReimbursementPurgatory
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 processAt only 2-3 approvals per year, it will take >300 years to develop treatments for half of them Ultra-Rare Designations and Approvals
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
0
5
10
15
20
25
30
Ultra Orphan DesignationsUltra Orphan Approvals
# o
f D
es
ign
ati
on
s a
nd
Ap
pro
va
ls
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
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
Study 1 was a Resounding SuccessReduction in Liver Volume During Enzyme Therapy
Weeks of Therapy
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Per
cent
Bod
y W
eigh
t
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
4.4
4.6
4.8
5.0
5.2
5.412345678910
No
rma
l Ch
ildre
nN
orm
al A
du
lts
Urinary GAG Excretion During Enzyme Therapy
Weeks of Treatment0 5 10 15 20 25 30 35 40 45 50 55 60
Per
cent
Sta
rtin
g G
AG
0
20
40
60
80
100
120JOM001 HAC002 RCD003 SSH004 SWD005 GMD006 JAN007 NM008 CEL009 BBG010
Shoulder Flexion Range of MotionMean Degrees of Restriction
Weeks of Therapy0 10 20 30 40 50 60
De
gre
es o
f Re
stri
ctio
n o
f Ra
nge
of M
otio
n F
rom
No
rma
l Mea
n
40
45
50
55
60
65
70
Right Shoulder Left Shoulder
Liver Size Urine GAG Shoulder Restriction
Surrogates and clinical endpoints improved
P<0.001 P<0.001 P<0.001
Urinary GAG Excretion During Enzyme Therapy
Weeks of Treatment0 5 10 15 20 25 30 35 40 45 50 55 60
Per
cent
Sta
rtin
g G
AG
0
20
40
60
80
100
120JOM001 HAC002 RCD003 SSH004 SWD005 GMD006 JAN007 NM008 CEL009 BBG010
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
Start study 12/97
Study End 10/98
Approval May 2000
File BLA11/99
Program Start 4/97 DELAYED
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)
1997 1998 1999 2000 2001 2002
Start study 12/97
Study End 10/98
Approval May 2002
File BLA12/2002
Program Start 4/97
Start Phase 312/2000
Pre-BLA11/99 DELAYED
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
Ch
an
ge,
Mete
rs
* Change from Baseline
Wilcoxonp= 0.066*
-10
10
30
50
-30
-50
-40
-20
0
20
40
ANCOVAp= 0.039*
PlaceboAldurazyme
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
17Article at http://www.ojrd.com/content/6/1/49
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
Therapeutic AreaNumber 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
Other 17 Variety PAH, hormones, iron, Crohns, MS, antibiotics
Genetic 1 Renal pathology Fabrazyme
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ucm121597.htm 18
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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
1990 1992 1994 1996 1998 2000 2004 2008
New Accelerated ApprovalRegulations put into Effect
Retro
vir
Videx
Videx
EC
Crixiva
nVira
cept
Sustiv
a
Rescr
ipto
r
Hivid
Forte
vase
Invir
ase
Norvir
Viram
une
Ziage
n
Kalet
ra
Epivir
Zerit
Agene
rase
Fuzeo
n
Viread
Reyat
az
Emtri
vaLe
xiva
Prezis
ta
Aptivu
sSel
zent
ryIn
tele
nce
Isen
tress
29 drugs in a 16 year periodAll accelerated approvals
Small change in regulation:Large effect in innovation
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
20
11
25
36
Miyamoto and Kakkis at http://www.ojrd.com/content/6/1/49
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 – 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
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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?
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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
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We need a solution to incentivize repurposing of patented drugs
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
Impact of LegislationSurge in Patented Drug Repurposing Investment in the next 15 years
27
2015 2017 2019 2021 2022 2024 2026 2028 2030
New O
rphan
Exc
lusi
vity
Ext
ensi
on Leg
isla
tion E
nacte
d
Spons
ors
inve
st 1
00 +
new
repu
rpos
ing
prog
ram
s Small delay i
n patented drugs
becoming generic
New la
bel in
dica
tions
gran
ted
for R
are
Diseas
es
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
www.ultragenyx.com
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
28
www.ultragenyx.com
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
www.ultragenyx.com Confidential 30
• 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
Novel Blinded Start Design Proposal
Wk 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 54 56 58 60 62 64 66 68 70dose 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 4 1 2 3 4 1 2 3 4
A 48 wk 1 mg/kg 4 mg/kg 2 mg/kg
B placebo 40 wk 1 mg/kg 4 mg/kg 2 mg/kg
C placebo 32 wk 1 mg/kg 4 mg/kg 2 mg/kg
D placebo 24 wk 1 mg/kg 4 mg/kg 2 mg/kg
Blinded period Dose titration period
www.ultragenyx.com 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 1o Endpoint for MPS 7
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
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No Disease Is Too Rare to Deserve Treatment
Learn about our efforts and support us atWWW.EveryLifeFoundation.ORG
EveryLife Foundation for Rare Diseases