orphan diseases: a lif li fa lifeline for...

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

Insight 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


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


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


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)


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)


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.


Graphic from Cowen TA Report, March 2009

Some Orphan Markets Have Become Highly Competitive


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


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


Corporate websites, Adis R&D Insight

Where is the Next Ultra‐Orphan Opportunity?


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


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)


Actelion website, press releasas

BioMarin Is Expanding into Other Orphan Diseases


BioMarin corporate website

Pharma Has Recently Shown Increasing Interest in Orphan Disease Strategy


Bloomberg, Fierce Biotech

Pharma Has Recently Shown Increasing Interest in Orphan Disease Strategy


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


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


Multaq Cardiovascular $35 Forecast to reach >$2B by 2016

Genzyme’s Fit Goes Beyond Orphan Entry Strategy


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)


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




Commercial model

Regulatory strategy



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


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.”


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 ”


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.


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)


Evaluate Pharma

(for Gaucher's disease)



Commercial model

Regulatory strategy



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.


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


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


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.


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


Evaluate Pharma



Commercial model

Regulatory strategy



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


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


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.


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


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).


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.


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


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‐


ppatent in the near future.


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


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.


$375M US marketfew years, primarily driven by Linaclotide and Xifaxan, which expected to generate combined US revenues exceeding 1.5B by the year 2016.


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


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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)


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orphan diseases: a lif li fa lifeline for...

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