Orphan Diseases:A Lif li f Ph ?A Lifeline for Pharma?
Ail Ni l tti PhDAileen Nicoletti, PhDVice President, Defined HealthInsight BriefingOctober 6, 2010
1
Highest Number of Orphan Approvals are For Least Prevalent Diseases
♦ Approval rates (all orphan designations, not adjusted for development stage) are over 20% for products targeting markets with less than 39,000 patients vs. 15% for those with more than 39,000 patients. , p
Page 2Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Nature Reviews Drug Discovery, V9, July 2010 p.519
The Ultra Orphan Attraction
$3 500
Genzyme Orphan FranchiseWW Sales ($M)“It’s almost unanimous that all the Big
Pharmas are paying much more attention to
$2 500
$3,000
$3,500AldurazymeFabrazymeMyozyme
rare diseases than they have in the past,” said Mark Miller, Lilly’s vice president of corporate development, at the time.
$1 500
$2,000
$2,500 Cerezyme“I think people look at the Genzyme model and think that that is a reasonable model to try to emulate.”
♦ Well characterized genetic diseases♦ Straightforward pathways for i i (i ) $500
$1,000
$1,500
intervention (in some cases) ♦ High priced therapies ♦ First to market
$0
$500
2009 2016
Page 3Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
http://www.xconomy.com/boston/2010/07/02/drug‐giant‐eli‐lilly‐buys‐alnara‐pharma‐to‐get‐cystic‐fibrosis‐drug/
The Ultra‐Orphan Reality – Increasingly Competitive
Genzyme Amicusy
ShireNovartis
Shire
PfizerActelionActelion
Biomarin GSKSanofi
Page 4Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Gaucher Disease
1,800Uplyso (Protalix)
Gaucher Disease
• 6 000 7 000 patients in the US
Worldwide Gaucher Drug Sales
1 200
1,400
1,600 Vpriv (Shire)
Zavesca (Actelion)
Cerezyme (Genzyme)
• 6,000‐7,000 patients in the US• 500 Medical Geneticists in US• 4 Companies in the Space• $1.56 Billion WW 2016e Sales
800
1,000
1,200
$US Millions
C i l S i h ilC i l S i h il
Takeaways
400
600• Commercial Success is heavily dependent on being first‐to‐market (so far) o Orphan exclusivity
• Commercial Success is heavily dependent on being first‐to‐market (so far) o Orphan exclusivity
0
200
2000 2002 2004 2006 2008 2010 2012 2014 2016
o Limited switching (?)o Next generation products obtain increasingly smaller niches
o Limited switching (?)o Next generation products obtain increasingly smaller niches
Page 5Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Sales data from Evaluate Pharma, * US & EU5 – based on incidence rate accumulative Types I, II, III = 4/100,000 live births
Fabry Disease
1,400Amigal (Amicus)
Fabry Disease
• 2 500 3 500 patients in US
Worldwide Fabry Drug Sales
1,000
1,200
g ( )
Replagal (Shire)
Fabrazyme (Genzyme)
• 2,500‐3,500 patients in US• 500 Medical Geneticists in US• 3 Companies in the Space• $1.22 Billion WW 2016e Sales
600
800Takeaways
$US Millions
200
400
• Increasingly competitive • New diagnoses drive growth• Entry of new products doesn’t increase growth rate, but
• Increasingly competitive • New diagnoses drive growth• Entry of new products doesn’t increase growth rate, but
0
200
2000 2002 2004 2006 2008 2010 2012 2014 2016
increase growth rate, but parses the market
• Limited number of well defined indications (LSDs getting saturated)
increase growth rate, but parses the market
• Limited number of well defined indications (LSDs getting saturated)
Page 6Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
EvaluatePharma
saturated)saturated)
Competition in Gaucher’s
♦ Technology Overview
Protalix's novel bioreactor plant cell system, based on disposable plastic vials, is the first of its kind.
Plant cell cultures are grown on aqueous media consisting of highly purified water and defined inorganic nutrients g q g g y p gin a completely closed and controlled environment.
The entire process is conducted in a GMP‐approved production suite with optimized temperature, lighting, air and nutrient supplies.
♦ Value Proposition
High output, scalable protein production: Plant‐based systems are capable of producing high quantities of complex proteins at a “dramatically lower cost than mammalian cell culture systems.”
Safety: No known risks of contamination from animal, bacterial, or viral pathogens in a plant based systemor viral pathogens in a plant‐based system.
Protein Assembly and Post‐Translational Modifications: prGCDdoes not require mannose unmasking step required in CHO.Range of Expression. Some proteins which are effectively producedin plant cells can not be made with mammalian and bacterial systems.
♦ prGCD is expected to demonstrate the following characteristics:
more consistent from batch to batch than Cerezyme
longer serum half‐life
Low COGS (25% that of Cerezyme)
Page 7Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Low COGS (25% that of Cerezyme)
Company website
Given Entrenched Position of Cerezyme, What Will Motivate Switching?
♦ There is a high level of physician and patient satisfaction with Cerezyme that gives it a strong foothold on the marketg g
Shire’s compound (velaglucerase) has demonstrated impressive efficacy
Switching studies are ongoing for both h d l dShire and Protalix compounds
♦ Protalix’s prGCD has a longer serum half‐life and potential for monthly dosing, but is being studied on the same q 2 week schedule as Cerezyme in current phase 3 studies.
♦ Protalix claims a much lower COGS with the potential to dramatically reduce pricepotential to dramatically reduce price. Given potential for less frequent dosing, dramatically reduced price at launch seems unlikely.
Page 8Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Graphic from Cowen TA Report, March 2009
Some Orphan Markets Have Become Highly Competitive
Page 9Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Hemophilia Foundation website, Product patient websites
BioMarin Has Acquired Technology to Provide Competitive Advantage
♦ BioMarin acquired Zystor’s glycosylationindependent lysosmal targeting technology in August 2010technology in August 2010.
♦ Potential for more effective and cheaper to manufacture products by avoiding post‐translational modification step.p Accelerated entry into Pompe market
(ZC‐701 projected to be 2 years more advanced than BioMarin’s product which was reported to have manufacturing issues)
Increased targeting to lysosome Potential for reduced cost of goods and
lower dose Potential for greater efficacy
Page 10Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Biomarin and Zystor Company websites, Biocentury.
Where is the Next Ultra‐Orphan Opportunity?
Disease Genzyme Shire Biomarin Actelion OtherGaucher (type 1) Cerezyme Vpriv Zavesca Protalix/Pfizer
Fabry Fabrazyme Replagal
Hunter Elaprase
MPS1 Aldurazyme Aldurazyme
li i lPompe Myozyme Preclinical
MPS VI Nagalzyme
PKU KuvanPEG‐PAL (Ph2)
MerckSerono
LEMS Firdapase
Metachromatic leukodystrophy Preclinical
Sanfilippo A syndrome Preclinical
Global cell leukodystrophy Preclinical Lilly
Neimann Pick Type C Preclinical
MPS IVA Phase 2
Page 11Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Corporate websites, Adis R&D Insight
Where is the Next Ultra‐Orphan Opportunity?
Page 12Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Genzyme’s Future Growth May Be Driven by Non‐Orphan Indications
♦ Genzyme’s marketed products are forecast to increase from $3.7B in 2009 to $6.4B in 2016.
LSD Orphan Franchise growth forecast a 9% annually
l h f ll f $ $ b Oncology growth forecast at 30% annually increasing from $156 in 2009 to over $1B by 2016.
$6,000Synvisc
Sales of Genzyme’s Approved Products ($M)
$4,000
$5,000
Synvisc
Renagel
Thymoglobulin
Mozobil
$2,000
$3,000 Clolar
Leukine
Aldurazyme
b
$0
$1,000
2009 2016
Fabrazyme
Myozyme
Cerezyme
Page 13Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Evaluate Pharma
2009 2016
Actelion Has Expanded Beyond PAH into Other Orphans And Includes Focus on Broader Markets
PAH Genetic Diseases
R&D Focus• Gaucher I• Neimann Pick C• Cystic Fibrosis
R&D Focus• IPF• Systemic Sclerosis (and complications)
Page 14Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Actelion website, press releasas
BioMarin Is Expanding into Other Orphan Diseases
Page 15Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
BioMarin corporate website
Pharma Has Recently Shown Increasing Interest in Orphan Disease Strategy
Page 16Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Bloomberg, Fierce Biotech
Pharma Has Recently Shown Increasing Interest in Orphan Disease Strategy
Page 17Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Orphan Entry or Distressed Asset?
Nasdaq Biotech Index
June 16, 2009“Temporarily shuts plant” “Expects to be fully operational by
d f J l ”
Aug 10, 2009• Discards ~80% of remaining work‐in‐process material
March 24, 2010• Genzyme Announces FDA E f tend of July”
“Current inventories …not sufficient to meet projected global demand.”
• Expects to begin releasing new material… in November and December.
FDA Enforcement Action Regarding Allston Plant
July 31‐ Not fully operationalSept 23, 2009• Plant restart completeDec 1,2009• Shipping begins
Genzyme
Page 18Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Google finance, Genzyme press releases
Orphan Entry Strategy or Bargain Hunting?
Sanofi‐aventis reported 2009 annual sales of $29.5B in 2009. Existing portfolio is forecast to yield $24.3B in 2016 (without accounting for attrition of Phase 3 products).Genzyme’s projected 2016 sales of $6.4B (all from growth of marketed products) will go
Key Products Therapeutic Area 2009 WW Sales Threats/Drivers
Patent expirations begin in 2014, Competition
y p j $ ( g p ) ga long way towards filling revenue gap.
Lantus Diabetes $4,293 Patent expirations begin in 2014, Competition expected from NovoNordisk’s insulin degludec
Lovenox/Clexane Anti‐coagulant $4,241 Patient expired in July, Generic (Sandoz) approved in July.
Pl i C di l $3 346Patent expires in 2011 (US) and 2013 in other major
k t B illi t d d f lPlavix Cardiovascular $3,346 markets. Brillinta recommended for approval.
Taxotere Oncology $3,034 Patent expired in US in May, expires in November in EU.
Avapro Cardiovascular $1,723 Patent expires 2012.
PENTAct‐HIB Vaccines $1,349 Forecast to reach >$2B by 2016
Fluzone Vaccines $867 Forecast ~$1B in 2016
Multaq Cardiovascular $35 Forecast to reach >$2B by 2016
Page 19Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Multaq Cardiovascular $35 Forecast to reach >$2B by 2016
Genzyme’s Fit Goes Beyond Orphan Entry Strategy
Page 20Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Biocentury, September 6, 2010, Genyzme pipeline
Increasing Interest in Orphan Disease is Not Universal
Rank COMPANY Announced Orphan Strategy
1 Pfizer/Wyeth History of growth hormone, Licensed ex‐US rights to Phase 3 LSD and dupuytren’s contracture products in 2009. Acquired FoldRx and created orphan and rare disease group in 2010.
2 Sanofi‐Aventis Limited history in orphan diseases including out‐licensing of products with orphan potential (e.g. HAE product to Jerini). Has bid $18.5B for Genzyme.
3 Novartis
Has product launched for ultra orphan indications (e.g. anti‐IL‐1 mAb for CAPS). Focus include cystic fibrosis, Muckle‐Wells syndrome, Cushing's disease, and others. Historically orphan indications have not been focus of products, but more recently has invested in earlyindications have not been focus of products, but more recently has invested in early development and discovery for TB, spinal cord injury, and muscular dystrophy among others.
4 GlaxoSmithKlineFeb 2010‐ New standalone unit specializing in the development and commercialization of medicines for rare diseases. Builds off TPO , Letairis (ex‐US) and 2009 alliances with Prosensa, nucleic acid based therapies for DMD, and JCR, enzyme replacement therapies for LSD.
Roche has no formal orphan strategy Genentech has a history of biologics for orphan disease5 Roche/Genentech Roche has no formal orphan strategy, Genentech has a history of biologics for orphan disease with 28 orphan designations have been for cancer. Pulmozyme most notable orphan drug.
6 AstraZeneca No orphan strategy. Pipeline recently had one orphan drug for glioblastoma‐ since discontinued.
7 Merck & Co Limited orphan designations (river blindness, JIA, and cancers)
8 Johnson & Johnson No orphan focus, readily utilize orphan designation for relevant indications (cancer, MS, etc.)
9 Lilly
Some recent deal activity in orphan space with acquisition of Alnara (pancreatic enzyme replacement for cystic fibrosis) and academic collaboration for Niemann Pick C. Opportunistic about seeking orphan designation for drugs with potential for secondary indications (e.g. PAH for Cialis)
Page 21Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
DH analysis from various press releases and company publications
indications (e.g. PAH for Cialis)
What is an Orphan Disease Strategy?
Components of an Orphan Strategy:
Commercial model
Regulatory strategyg y gy
Disease area/specialty strategy
Page 22Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
What is an Orphan Disease Strategy?
Components of an Orphan Strategy:
Commercial model
Regulatory strategy
Disease area/specialty strategy
Page 23Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Is Orphan the Logical Next Step in Pharma’s Increased Focus On Specialty Markets?
Benefits to Pharma
Top 20 Pharmaceutical Product Sales by Market Size (millions)
♦ Higher prices
♦ Reduced threat from generic competition (biologics dominant)
♦ Focused call point$100,000
$120,000OrphanSpecialty
♦ Focused call point
♦ Biotech has laid groundwork in science
♦ Biotech weathered the PR storm over the pricing model $60,000
$80,000 PCP
p g
$20,000
$40,000
$0
1990 2000 2009 2016
Page 24Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Evaluate Pharma data, DH analysis
Is Orphan the Logical Next Step in Pharma’s Increased Focus on Biologics?
2009 WW Biologics Sales
Sanofi CEO: We "missed the boat" on biologics Fierce Biotech, Feb 11 2009
Sanofi‐Aventis CEO Chris Viehbacher told the Financial Times that the pharma giant had "missed the boat"
PCP$15.5B15%
Orphan$19.6B18%
when it comes to diversifying into biologics. But he adds that Sanofi has the money it needs to redouble its efforts to strengthen its pipeline.
15%
“We became very attractive to a company like Pfizer, because you cannot be the No. 1 pharmaceutical company in the world and have not yet started in biotech,” Mr. Poussot (Wyeth CEO) said in an
Specialty$71B67%
interview… “You either have to make or buy,” Mr. Tanner said. “In Pfizer’s case, they decided to buy.”
Page 25Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Evaluate Pharma, press releases
Commercial Model Doesn’t Require Pharma Partnerships…
♦ Small call points
♦ Physician relationships and patient advocacy strategies dominate
♦ Pharma’s commercial infrastructure is viewed as unnecessary for products
Pfizer will receive exclusive rights to commercialize XIAFLEX in the 27 member countries of the European Union (EU) and 19 other European and Eurasiantargeting small physician groups and
addressing patients with serious unmet needs.
Union (EU) and 19 other European and Eurasian countries. In addition, Pfizer will be primarily responsible for regulatory activities for XIAFLEX in these countries.
♦ Disease foundations often play pharma’susual role providing funding for clinical trials and providing access to lead investigators and patients for clinical
“What do we need pharmafor? By the time we finish the clinical trials, we know all the patients by name ”
Page 26Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
studies.the patients by name.
Commercial Model Doesn’t Require Pharma Partnerships…Or Does It?
Protalix Chief Executive David Aviezer said his company pursued the Pfizer deal because its first product was approaching regulatory approval and it didn't have the commercial capacity needed to market the drug.
Page 27Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Commercial Model Doesn’t Require Pharma Partnerships…Or Does It?
♦ Mature markets are becoming crowded with undifferentiated players
♦ Science is established and new targets limited
♦ Products may compete on secondary attributes such as convenience or neutralizing antibody formation (e.g. Fabry disease).
$26 7B $5 5B $7 6B $1 6B $1 3B
Remicade
SimponiCimzia
Replagal
Amigal
Vpriv
UplysoZavesca
Helixate
Betaferon/Betaseron
70%80%90%100%
$26.7B $5.5B $7.6B $1.6B $1.3B
Humira
Fabrazyme
Cerezyme
Advate
Kogenate
Helixate
Avonex
Rebif
20%30%40%50%60%
EnbrelAdvateAvonex
0%10%20%
TNF‐a (for Rheumatoid
Arthritis)
IFN‐b (for Multiple Sclerosis)
Factor VIII (for Haemophilia A)
Glucocerebrosidase & Glucosyltransferase
inhibitor
Alpha galactosidase (for Fabry disease)
Page 28Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Evaluate Pharma
(for Gaucher's disease)
What is an Orphan Disease Strategy?
Components of an Orphan Strategy:
Commercial model
Regulatory strategy
Disease area/specialty strategy
Page 29Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Orphan Regulatory Strategy is Not New for Pharma
♦ Early orphan designations sought by Pharma:
Growth hormone Growth hormone
Interferon alpha
Cyclosporin
♦ In many cases (e.g. IFN, CspA), orphan♦ In many cases (e.g. IFN, CspA), orphan indications were not market drivers.
Page 30Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
NRDD
Big Pharma Success with Orphan Designations Appears to Be Improving
Orphan Designations for Products in Development by Big Pharma
16
18
20 Designated/WithdrawnDesignated/ApprovedDesignated
10
12
14
4
6
8
0
2
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Page 31Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2
FDA Orphan Drugs Designation Database, DH analysis
FDA is Attempting to Drive “Repurposing” Strategy for Orphan Diseases
Page 32Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm216147.htmhttp://www.businessweek.com/news/2010‐06‐18/drugmakers‐prodded‐by‐fda‐for‐neglected‐disease‐drugs‐update3‐.html
Pharma Doesn’t Appear Interested in “Repurposing” for Orphan Disease
While Biogen initially pursued Avonex in “several indications” the Cambridge, Massachusetts‐based drugmaker now has no plans to develop it for cutaneous t‐cell lymphoma, said Kate Weiss a company spokeswomanWeiss, a company spokeswoman.“While we’re certainly always open to looking at new indications for all of our drugs, we’re not pursuing that for that indication,” Weiss said today in a phone interview.
J&J decided not to further develop Leustatin in part because there are other drugs available for leukemia, Ernie Knewitz, a spokesman for the company, said today in a telephone interview. J&J is studying products for other types of neglected diseases including the areas of oncology, HIV and hepatitis C, Knewitz said.
Roche is no longer studying Pegasys in cancer, said Kristina Becker, a spokeswoman for the Basel, Switzerland‐based company’s Genentech unit.
Page 33Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm216147.htmhttp://www.businessweek.com/news/2010‐06‐18/drugmakers‐prodded‐by‐fda‐for‐neglected‐disease‐drugs‐update3‐.html
Repurposing Strategy Doesn’t Always Align with Orphan Commercial Model (i.e. High Financial Reward)
Annual Sales of Pfizer’s Sildenafil(WW, millions)
Annual Sales of Biogen Idec’s Avonex(WW, millions)
$2,500
$3,000RevatioViagra
$2,500
$3,000Avonex‐CTCLAvonex‐MS
$1,500
$2,000
$1,500
$2,000
• Prevalence of Stage 2B and
$500
$1,000
$500
$1,000
ghigher CTCL is ~5,400 patients.
• At $24,000/year, 100% penetration is $130M
• Highly competitive market
$0
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
$0
2002
2003
2004
2005
2006
2007
2008
2009
2010
Page 34Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Evaluate Pharma
What is an Orphan Disease Strategy?
Components of an Orphan Strategy:
Commercial model
Regulatory strategy
Disease area/specialty strategy
Page 35Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Orphan Indications Cross All Therapeutic Areas
Sickle Cell DiseaseBeta‐ThalassemiaHemophilia A/BVWDPolycythemia vera
Gaucher SyndromePompe’s DiseaseFabry’s diseaseKrabbe SyndromePolycythemia vera Huntington Chorea
Alzheimer'sALSFAP (TTR)
yTay‐Sachs DiseasesSandhoff DiseaseNiemann PickMucolipidosis IIMucolipidosis III
Hematology
Neurological
Monogenetic Diseases
pMucolipidosis IVHurler SyndromeScheie's DiseaseHunter’s DiseaseSanfilippo Syndrome
Metabolic
MusculoskeletalWolman SyndromeFarber’s DiseaseAustins’ DiseaseCanavan DiseasePKU
Muscular DystrophyCystic FibrosisG t At h
Cardiovascular
Immunological
Criggler‐Najjar Type OTC DeficiencyHemochromatosis
Antitrypsin α‐1 deficiencySCID
Gyrate Atrophy
HypercholesterolemiaHyperlipidemia
Page 36Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Granulomatous DiseaseHereditary Angioedema
Oncology Is the Most Frequent Therapeutic Area for Orphan Designation
US Orphan Designations by Therapeutic Area
European Marketing Authorizations for Orphan Medicines by Therapeutic Area
200250300 Launched
RegisteredPhase 3Phase 2
50100150
Phase 2Phase 1
0
Cancer
CNS
Disease
tabo
licen
sory
logical
ascular
estin
alratory
urinary
keletal
nsplant
tology
C
Infectious D
Met Se
Haem
ato
Cardiova
Gastrointe
Respir
Gen
itou
Musculosk
Tran
Derm
a
Page 37Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
DH analysis based on Adis R&D insight pipeline data showing orphan designation, EMEA report
Orphan Strategy is Similar to Oncology Strategy
WW Sales ($,M) of Oncology Drugs by Regulatory Designation
♦ First mover advantage critical Next generation products tend to require
demonstration of superiority or efficacy in
$6,000
$8,000
$10,000
demonstration of superiority or efficacy in refractory populations to gain approval (and market share)
♦ Science‐driven Identification of mutations is critical to novel
$0
$2,000
$4,000
$ , Identification of mutations is critical to novel targets
♦ Niche pricing drive sales ♦ Biologics dominate
l h i$
♦ Regulatory Pathway not unique Accelerated regulatory pathway for high unmet
need market segments regardless of patient size.
♦ Orphan designation may be greater importance for small molecules (patent expirations). Potential to support greater post‐market label
expansion.
Page 38Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Clin Oncol. 2009 Sep 10;27(26):4398‐405. Epub 2009 Jul 27
Orphan Indication for CNS Diseases Has Not Commanded the Same Level of Pricing
♦ Limited efficacy (mostly symptomatic) combined with significant safety/side effect issues translates into marginal value proposition.
Drug/Class Orphan Indication Price for year of therapy ($US, retail)
Rilutek(riluzole, sanofi‐aventis)
ALS, modest prolongation of survival ~$12,000( , )
Xenazine(tetrabenzaine, Lundbeck/Biovail/Valeant)
Choreiform movements associated with HD
~$30,000
Xyrem(Jazz Pharmaceuticals)
Cataplexy associated with narcolepsy ~$20,000(Jazz Pharmaceuticals)
Sabril(vigabatrin, Ovation/Lundbeck)
Infantile spasms; adult refractory epilepsy
~$20,000
Banzel( fi id Ei i)
Lennox‐Gastaut ~$20,000(rufinamide, Eisai)
Atypical antipsychotics (Abilify, Risperdal)*
Irritability associated with autism ~$10,000
Page 39Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
DH Research
*Also indicated for treatment of schizophrenia and bipolar disorders.
Lundbeck: CNS Orphan Not a Strategy, but Survival
♦ In early 2009, Ludbeck acquired Ovation Pharma for $600 million plus $300 million in potential milestone payments.
♦ The primary driver for the acquisition was to establish a commercial presence in the US and mitigate upcoming patent expiries (Lexapro, 2012 and Ebixa/Namenda, 2015) and a high‐risk development pipeline.
♦ Via this acquisition Lundbeck also gained access to two marketed orphan products, Xenazine(chorea associated with Huntington’s Disease and Sabril for infantile spasms, and a Phase orphan ( g p , pproduct (clobazam for treatment of Lennox‐Gastaut).
Page 40Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Orphan Indication as Entry Into a Broader Patient Population
♦ Companies like Novartis, Roche, Seaside Therapeutics and Neuropharm are targeting Fragile X, an orphan monogenetic disorder, with clinical stage programs focused on the modulation of glutamate or GABA neurotransmitters with hopes that this research will provide insight may extend into other developmental disorders such as autism.developmental disorders such as autism.
Autism Spectrum Disorders
1.5 M (US)Fragile X Syndrome60,000 (US)
1.5 M (US)
CAMBRIDGE, MASS., September 9, 2010—Seaside Therapeutics, Inc. announced today positive data from an open‐label Phase 2 study of STX209, a selective GABA‐B agonist, conducted in patients with autism spectrum disorders (ASD). Earlier in 2010, Seaside announced statistically significant data for this same compound in a Phase 2 study of Fragile X patients.
Page 41Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
Seasidetherapeutics.com
Endocrinology Sales Dominated by PCP and Orphan Markets
• The endocrinology market is fragmented and can overlap with a variety of other specialties including OB Gyn PCP CV
Osteoporosis$3B US marketDiabetes
specialties, including OB‐Gyn, PCP, CV, Oncology, etc.
• It is estimated that only around 10‐15% of drugs prescribed by endocrinologists are
Obesity$200M US market
$20B US market categorized as “endocrinology‐specialist”, with the remainder used by other specialists and PCPs (e.g., diabetes, lipids, etc.)
• Oral anti‐diabetic and osteoporosis drugs are aimed to target PCPs more so then endocrinologists, and therefore are dominated by major pharma
Inborn Errors Metabolism$3B Worldwide sales y j p
• Despite a large potential treatment population and compelling data on the benefits of weight loss, actual treatment of obesity as a disease remains low
$3B Worldwide salesAssuming 60% US = $1.8B
Page 42Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
of obesity as a disease remains low
Source: Evaluate Pharma, Cowen Reports
Endocrinology Specialty Indications
Growth Hormone$1.2B US market
• Growth Hormone products are nearly identical in composition , efficacy and cost, and vary primarily in formulation delivery device and dosing
Testosterone$900M US market
in formulation, delivery device, and dosing frequency
• Testosterone therapy market currently dominated by Androgel (Solvay) with Testim (Auxilium) having
d 20% k h b l
Thyroid Replacement$600M US market
$900M US market around 20% market share by sales.
• Branded synthetic thyroid hormone market is dominated by a few large players (Abbott and King) while generic levothyroxines now constitute $600M US market
Fertility$400M US market
g) g yover 2/3 of the market.
• Fertility is mostly treated by OB‐Gyns/Repro Endos in fertility clinics. Products used in fertility clinics are usually value priced; however this small
AcromegalyAbout $260M US marketAssuming 20% acromegaly of $1.3B in total product sales with 80% carcinoid
clinics are usually value priced; however, this small market can only support a few players.
• Acromegaly market currently dominated by Sandostatin (Novartis) which will be going off‐
Page 43Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
ppatent in the near future.
Source: Evaluate Pharma, Cowen Reports
Endocrinologists Includes Many Orphan Indications
Inborn Errors of MetabolismAmino Acid Metabolism (Med Genet)
Carbohydrate Metabolism (Med Genet)
Lipid/Glucose Metabolism (Med Genet)
Peroxisomes / Organic Aciduria (Med Genet)
Metabolic and Nutritional DisordersDiabetes Mellitus (PC)
Hypoglycemia
Dyslipidemia (PC)
Obesity (PC)
Diseases Related To Bone Metabolism Osteoporosis (PC)
Rickets (Osteomalacia)
Renal Osteodystrophy
Paget’s (Osteitis Deformans)
Mitochondria / Urea Cycle (Med Genet)
Porphyrias (Med Genet)
Adenosine Deaminase deficiency (Med Genet)
Progeria (Med Genet)
Phenylketonuria (Med Genet)
Hyperbilirubinaemia (Med Genet)
Lipodystrophy
Vitamin And Mineral Deficiencies
Vitamin And Mineral Excess
Metabolic Acidosis/Alkalosis
Respiratory Acidosis/Alkalosis
Fructose metabolism disorder
G l b li di d
Osteopetrosis
Fibrous Dysplasia
Hyperostosis
Thyroid Disorders Hyperthyroidism (PC)
Graves’ Disease (PC)Haemochromatosis (Med Genet)
Other Enzyme Deficiencies (Med Genet)
Adrenoleukodystrophy (Med Genet)
Adrenomyeloneuropathy (Med Genet)
Galactose metabolism disorder
Glycogen Storage Disease
Fluid and Electrolyte Imbalance (Nephrol)
Endocrine Gland NeoplasmsAdrenal Cancer (Med Onc)
Thyroid Cancer (Med Onc)
( )
Graves' Ophthalmopathy
Thyroiditis (Hashimoto’s disease)
Euthyroid Sick Syndrome
Thyroid Goiter / Nodules
Pituitary & Growth DisordersHormonal Imbalance DisordersP i P b t (P d)Thyroid Cancer (Med Onc)
Other Endocrine Gland Cancers (Med Onc)
Carcinoid Syndrome (Med Onc)
Multiple Endocrine Neoplasia (Med Onc)
Adrenal DisordersCushing’s Syndrome
Acromegaly, Pituitary Gigantism
Hyperprolactinemia
SIADH (Nephrol)
Diabetes Insipidus
Growth Hormone Deficiency (Ped)
Generalized Hypopituitarism
Precocious Puberty (Ped)
Delayed Puberty (Ped)
Hirsutism
Post‐pubertal Hypogonadism
Hormone Deficiency
Gonaldal Dysgenesis (Turner's Syndrome)
Hyperandrogenism
Parathyroid Disorders Hypoparathyroidism
Hyperaldosteronism
Addison’s Disease
Hypoaldosteronism
Pheochromocytoma
Adrenogenital Syndrome
Secondary Adrenal insufficiency
yp p
Cockayne SyndromeHyperandrogenism
Zollinger‐Ellison syndrome
Hypoactive Sexual Desire Disorder (OB‐Gyn)
Polycystic Ovary Syndrome (OB‐Gyn/PC)Fertility & GynecologyInfertility
Menopause
Page 44Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
HyperparathryoidismCongenital Adrenal Hyperplasia (Ped) Endometriosis
Gastroenterology Also Has Broad Primary Care Overlap
GERD / Peptic Ulcer>$6B US market
• Although the GERD / Peptic Ulcer market contains blockbuster products (most notably Nexium at $2.8B), approximately 80% of revenues are expected to be lost over the next 5 years due to generic erosion and OTC>$6B US market
Ulcerative Colitis$ k
expected to be lost over the next 5 years due to generic erosion and OTC switching of key products.
• While there are a number of therapies currently marketed for UC patients, including front‐line 5‐ASA treatments and biologics, the overall
Crohn’s Disease$1B US market
$1.2B US market
• The Crohn’s market is expected to increase modestly in the near term and is dominated by two major biologics, Remicade and Humira, which combine for over 85% of revenues.
market appears to be poorly served with existing therapies.
Emesis$800M US market
• Although significant revenues are generated from the emesis market, patent expirations of major brands and looming patent cliffs for additional branded products will further erode the market.
• Chronic constipation and associated movement disorders represent a
IBS • The IBS Market is expected to undergo significant growth over the next few years primarily driven by Linaclotide and Xifaxan which expected to
Constipation$400M US market
• Chronic constipation and associated movement disorders represent a large overall market in terms of addressable patients; however, the market is flooded with generic and OTC products.
Page 45Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
$375M US marketfew years, primarily driven by Linaclotide and Xifaxan, which expected to generate combined US revenues exceeding 1.5B by the year 2016.
Source: Evaluate Pharma, Cowen Reports
Significant Near Term Growth in Gastroenterology is Being Driven By Orphan Indications
Antacids/Anti‐ulcerantsGrowth drivers include:Pancreatic Enzymes for CF
GI anti‐inflammatories
Other GI
2009
Pancreatic Enzymes for CFGLP‐2 for Short bowel syndrome
Laxatives
Anti‐emetics
Diet supplements 2009
2016
Anti‐diarrhoeals
Anti‐spasmodics & anti‐cholinergics
Laxatives
Growth driver is Xifaxan – Orphan
0 5,000 10,000 15,000 20,000
Cholagogues
Xifaxan Orphan Approval for Hepatic
Page 46Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
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Orphan Indications Are Also a Key Driver In Respiratory
Bronchodilators
Anti‐leukotrienes
Anti‐histamines
Corticoids
2009
2016
Growth drivers ($1B in growth in 2010‐2016):• Prolastin (alpha 1
Other respiratory
Anti‐cholinergics
Prolastin (alpha 1 antitrypsin (AAT) deficiency)
• Vertex’s CFTR modulator VX 770
Vasodialators (PAH)
Nasal/Throat preps
B2 stimulantsVX‐770
$0 $2,000 $4,000 $6,000 $8,000 $10,000 $12,000
NSAIDs
Vasodialators (PAH)
Page 47Insight Briefing – Orphan Drugs, 06‐Oct‐2010© Defined Health, 2010
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