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11/14/2011
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TIM COTE MD MPHTIM COTE, MD MPHCMO: NATIONAL ORGNAIZATION FOR RARE DISORDERS (NORD)
PROFESSOR OF REGULATORY PRACTICE: KECK GRADUATE INSTITUTE (KGI)
NORD and KGI
National Organization forOrganization for Rare Diseases
Keck Graduate Institute
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On a personal note…
I will never do that again!again!
Israel stole my heart….
Economic Realities: 1982
Rare diseases = Few pill buyers
1973-1982: 10 new drugs for rare diseases
≈7,000 rare diseases; 25 million people
Congressmen/Senators besieged by parents/caregivers.parents/caregivers.
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Abbey Myer:Grassroots Political Mover
Rare diseases: Individually infrequentIndividually infrequent but collectively common.
“They are like orphans in that they yrequire special care.”---Henry Waxman
The New Deal of the ODA
Get a drug designated with“orphan drug status”drug status Show (with data) that it’s“promising” For treating <200,000 person in the US
Do the clinical trails/get marketing approval.
Receive incentives: Receive incentives: MARKET EXCLUSIVITY Tax credits Fee exemptions
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ODA: A MAJOR SUCCESS
391 Approved Drugsg2,517 Designated
Orphan Drugs2008: 38% of all FDA-
approved NMEs were Orphans
250
vals
The US Orphan Drug Act has been HUGELY SuccessfulThe US Orphan Drug Act has been HUGELY Successful
Number of orphan designations and marketing approvals from 1983-2010
50
100
150
200Orphan Designations
ber o
f Orp
han
Des
igna
tions
or A
ppro
Marketing Approvals
0
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10*
Year
Num
*
* The database is currently being updated to include new marketing approvals for 2010. However, the number of designations for 2010 (192) is accurate.
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The Diseased Populations Served have been VERY Small
Distribution of Orphan Designations and Approvals by Size of Patient Population
100
150
200
250
300
350
400
Nu
mb
er
of
De
sig
na
tio
ns
0
50
0-9 10~19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 100-109
110-119
120-129
130-139
140-149
150-159
160-169
170-179
180-189
190-199
200 &up
US Prevalence (in thousands) of Disease for which Orphan Product Designated
Source: FDA/OOPD, M. Braun et al
Time from Designation to Market Time from Designation to Market ApprovalApproval
0 3
0.1
0.15
0.2
0.25
0.3
Des
ign
atio
ns
Ap
pro
ved
Life table analysis of Progression from Designation to Market
0
0.05
Pro
po
rtio
n o
f D
0 5 10 15 20 25
YEARS
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And all human pathology is targeted by designated orphan drugs*
1%2%2%Oncologic
36%
4%
4%
4%
2%
1%2%2%2%
3%2%
2%
Metabolic
Hematologic-immunologic
Neurologic
Infectious/parasitic
Cardiovascular
Transplantation
Gastrointestinal
Respiratory
Endocrinologic
11%7%7%
6%
5%
4% Endocrinologic
Dermatologic
Ophthalmic
Musculoskeletal
Injury/poisoning
Perinatal
Congenital abnormalities
Others* 2000-2006 Data
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Example: Adagen for ADA
Population: 1:2x105 to 1:1x106
born with homozygous mutationborn with homozygous mutation.
Causes Severe Combined Immunodeficiency
Adagen is one of the first orphan drugs (based on n=12!); enzyme replacement therapyreplacement therapy. Designated in 1984.
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Naglazyme for MS Type VI (Maroteaux-Lamy syndrome) Mucopolysacharridosis,
liposomal storageliposomal storage disorder.
Estimated only 1,100 persons world-wide.
Enzyme replacement can prevent thesecan prevent these changes
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Enzyme Replacement Therapies
Some of the most extraordinarily expensive treatments in the history ofexpensive treatments in the history of mankind (some ≈ $400,000/pt/yr).
FDA does not regulate price.
Radically transformative beneficial to patients lives.
Exclusivity lasts 7 years; knowledge is eternal.
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ExPTPA and Radiogardase for Radiologic Poisonings Two approved therapies
for heavy metalfor heavy metal poisoning, designated as orphans in 2003, 2004.
Chelation for highly-specific indications;specific indications; current zero prevalence.
Example: Eflornithine for African sleeping sickness Extremely rare
disease in the USdisease in the US and Europe
Treatment would be highly personalized, based on travel historyhistory
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Stem cell-based products for rare diseases
21 designations and counting
Most from 2005 on (67%; 12/18)
INDs granted gindicate active research Freeman SN, et. al., Cell Stem Cell, 2010
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Gene therapy products for rare diseases
58 designations 58 designations and counting
Most from 2005 on (59%; 34/58)
Large increase in 2009-2010
Gene Therapy Orphan Designations by Year N=58
02
46
810
1214
1618
20
Des
igna
tions
Many in preclinical or clinical development
Year Interval
WHO HAS DONE THIS?
GARAGE SCIENCE
“BELLYFIRE”
BIG PHARMA Onco
Acquisitions
“Tardy to the Party”y y
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Orphans are Special!
Orphans are special: Science
Transformative, not incrementalincremental
Often 1st therapies for dz.
Effect size and public health imperative speeds approval.
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Orphans are special: Regulatory
Resources: NORD article KGI TMParticle, KGI TMP
FDA Attitude Tx for common dz: PH
threat Tx for rare dz: PH
opportunity
FLEXIBILITY! FLEXIBILITY! Number of clin trials Size of clin trials Design of clin trials
Orphans are special: High Touch!
Patients are paramountparamount
Researchers: All thinkers are thought leaders.
Bandwidth per patient requirements are high
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Orphans are special: High Touch
Patient relations at least as importantleast as important as investor relations.
Enrollment, regulatory, marketing.
Orphans are special: Finances Can be comparitively
small investments. Can yeild high returns
for orphan indications. Revenues relatively
small, ROI relatively large.
Many models: ERT, Pt-sponsored Academicsponsored, Academic Startup, Mid-sized
PharmaKarma: Good things happen: Botox/Epo/Gleevec
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Big Pharma Cultural Impediments
UnlearnTh t it ’t b d That it can’t be done for such little money
That you can’t secure approval with that kind of data.
New learning New learning needed High touch
“Big pharma only knows how toknows how to deliver a gallon of gasoline with a supertanker.”---Trevor Mundel, ex-Novartis now GatesNovartis, now Gates
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Novartis: Ilaris and Muckle-Wells
MWS—only hundreds ofhundreds of patients
Ilaris: IL-1 blocker Lock-key phenom Indication Gout?
N’ t N’s process not scale-able to 6,000 diseases.
Proposal: Think Small
30 years of history demonstrate fewdemonstrate few orphans from large companies.
BUT high success when large corps behind orphan drugs.
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Before Closing--- 3 Practical Matters:
OOPD Grants
Orphan Status Designation
Regulatory Affairs Quickie
FDA/OOPD Grants Program
Only Clinical trials for orphan drugs
$ $400K/yr x 4 yrs
International/Domestic
For$/NFP
30% of completed apps are funded
47 Marketed Products! 47 Marketed Products!
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Orphan Status Designation
What?—The basic regulatory coin. Deceptively easy!!Deceptively easy!!
Why?---Engages you with FDA, Interests investors
Where?---DIY or take an FDA workshop
When?---When you’ve got “promise”; Animal When? When you ve got promise ; Animal model data is fine
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Summary
Orphans drug development is passionate stuffstuff.
Orphans are very different from non orphans.
Gene therapies and stem cell therapies can be “orphan drugs”, offer perhaps the best hope.
With 7,000 diseases, there is an enormous amount of need, new models beckon.
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