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© Defined Health, 2014 © Defined Health, 2013
CNS Orphans The Road Less Traveled 7th CNS PARTNERING & DEAL-MAKING GTC Global Technology Company
Ginger S. Johnson, PhD Vice President Defined Health September 18, 2014
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© Defined Health, 2014 2
Our Disclaimer
The information in this presentation has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness.
All expressions of opinion are the responsibility of Defined Health and, though current as of the date of this report, are subject to change.
The contents of this presentation are not meant to be comprehensive, but to encourage a spirited dialogue. Feedback, comments and corrections are welcome.
© Defined Health, 2014
In CNS Broadly, The Balance has Tipped Toward Too Much Risk
• In the context of an increasingly generic standard of care, the commercial risk now associated with many of the CNS (previous) block buster categories (e.g., depression, epilepsy, acute migraine, schizophrenia, ADHD) has become too big for many big and specialty pharma companies.
Generic SoC Novel MOAs Subjective endpoints Placebo response
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© Defined Health, 2014
Orphan Disease: An Opportunity to Balance the Risk in CNS • Those companies who are not ready to give us up on CNS see an
opportunity to balance the risk by targeting orphan diseases.
Orphan Diseases
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© Defined Health, 2014
Defining Orphan/Rare Diseases
• Rare Disease Patient Populations are Defined in Law as:
– USA: <200,000 patients (<6.37 in 10,000, based on US population of 314m)
– EU: <250,000 patients (<5 in 10,000, based on EU population of 506m)
– Japan: <50,000 patients (<4 in 10,000 based on Japan population of 128m)
EvaluatePharma
© Defined Health, 2014
The Orphan Promise
• Development Pros
Potential Fast track, priority review
Tax credits and fee waivers
Grants
Advocacy support
Enthusiastic clinical investigators
Higher than average clinical success rates
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The Orphan Promise: low cost/short timeline development program, friendly regulatory process, pricing flexibility, minimal commercialization costs and market exclusivity.
• Commercialization Pros
7-year market exclusivity
Motivated patients
Advocacy support
Pricing flexibility
Minimal competition
Targeted sales force
© Defined Health, 2014
Orphan Disease: A Multibillion Dollar Category, and Growing • EvaluatePharma finds that the market for orphan drugs, based on the consensus
forecast for the leading 500 pharmaceutical and biotechnology companies, will grow by 7.4% per year (CAGR) between 2012 and 2018 to $127 B.
EvaluatePharma
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© Defined Health, 2014
CNS is Under-Represented (in Number of Products) in the Overall Orphan Market
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NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | APRIL 2012
• Oncology therapeutics dominate orphan drug approvals, accounting for 33% of the marketing authorizations from 2006 to 2011.
• Of the ~60 orphan drug approvals (2006-2011), 17% are for CNS disorders.
Orphan Drug Approvals by Therapeutic Area (2006-2011)
© Defined Health, 2014
The Orphan Pipeline Suggests CNS Could Shine in the Future
0 10 20 30 40 50 60
Rheumatology
Other
Autoimmune
Musculoskeletal
Dermatology
Cardiovascular
Endocrine
Ophthalmology
IEM
Respiratory
Gastrointestinal
Blood
Anti-infectives
CNS
ADIS R&D Insight, EvaluatePharma, Thomson Reuters Cortellis
PIPELINE
Number of agents in clinical development (P1 – Registered)
Neurodegenerative Disease (e.g., MS, ALS, HD) Developmental/Learning Disabilities (e.g., Fragile X) Spinal Cord Injury Intractable/Refractory Epilepsy = High Risk / High Reward
© Defined Health, 2014
However, Traditional CNS Challenges Still Hold for Orphan Diseases
• Disease biology?
• Validated targets?
• Validated biomarkers?
• Definitive diagnosis?
• Time of intervention?
• Trial design?
• Defined clinical endpoints?
• Subjective clinical endpoints?
• Placebo response?
• Outcome measures?
• Well-defined disease burden?
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© Defined Health, 2014
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Cuvposa
Rilutek
Ampyra
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine
Sabril
Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Fabrazyme
Hetlioz
$75,000 - $150,000
© Defined Health, 2014
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Cuvposa
Rilutek
Ampyra
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine
Sabril
Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Hetlioz
$75,000 - $150,000
• MS disease-modifying drugs set the bar.
© Defined Health, 2014
MS Disease Modifying Drugs: Set the Bar and Price
• Disease-modifying MS drugs target a medically relevant subsegment of the overall patient population (relapsing-remitting disease), qualifying them as orphan drugs.
• The target patient population is on the high end of the orphan range. • The value proposition is clear: delay of disease progression. • The $16+ billion dollar MS market (worldwide), dominated by big pharma and
specialty companies, continues to grow at a significant pace, driven by new market entrants and aggressive price hikes (in the US).
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© Defined Health, 2014
Cuvposa
Rilutek
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine
Sabril
Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Hetlioz
$75,000 - $150,000
• Symptomatic MS therapy struggles to establish market access.
Ampyra
© Defined Health, 2014
AMPYRA / FAMPYRA: The Challenge of Establishing Value to All Stakeholders • Ampyra (Acorda/Biogen Idec), an extended-release oral agent that blocks axonal potassium
channels, was approved in the US Jan 2010 with an indication to improve walking in MS patients. • Ex-U.S. rights licensed to Biogen Idec. • After an initial rejection in the EU, the CHMP of the EMA recommended conditional marketing
authorization of Ampyra (Fampyra in Europe) in mid 2011. • In May 2012 Germany’s IQWiG ruled that Fampyra was associated with no incremental benefit. • June 2014, NICE guidelines block access to Fampyra stating “a detailed analysis of the evidence of
costs and benefits led us to conclude it does not currently represent cost effectiveness for the NHS.
http://www.chemanager-online.com/en/news-opinions/headlines/pharma-asks-money-question-earlier-new-drugs;
Ron Cohen, CEO of Acorda Therapeutics regrets not consulting insurers early about its AMPYRA, the first drug to help multiple sclerosis patients walk better. CHEManger Europe Dec. 2011
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© Defined Health, 2014
Cuvposa
Rilutek
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Ampyra
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine
Sabril
Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Hetlioz
$75,000 - $150,000
• Modest benefit limits pricing flexibility.
© Defined Health, 2014
Cuvposa: Value to the Patient
Merz, Inc. Announces the Acquisition of CUVPOSA® (glycopyrrolate) Oral Solution, First and Only FDA-Approved Treatment for Pediatric Chronic Severe Drooling Associated With Neurologic Conditions Aug. 27, 2012
The addition of CUVPOSA® reflects Merz's commitment to neurology "The FDA has classified CUVPOSA® as an orphan drug as sialorrhea is a rare disorder in pediatric patients with neurologic conditions," said Kapil D. Sethi, MD, FRCP, Professor of Neurology and Director of the Movement Disorders Program at Georgia Health Sciences University and Senior Medical Expert of Neurology at Merz Pharmaceuticals, LLC. "Due to the limited treatment options available, sialorrhea is an all-too-often poorly managed condition in pediatric patients suffering from neurologic disorders such as cerebral palsy. CUVPOSA®, the only FDA-approved treatment on the market, is an important advancement in the treatment of chronic severe drooling in children with neurologic disorders."
PR Newswire; FDA News Release 17
• Cuvposa (glycopyrrolate) Oral Solution (Shionogi Pharma); approved by the FDA in July 2010 to treat chronic severe drooling caused by neurologic disorders in children ages 3-16 yrs, a condition that affects QoL and can impact the ability to swallow.
• Glycopyrrolate was approved decades ago to treat peptic ulcers and reduce salivation in patients under anesthesia.
• When used off label, oral tablets had to be crushed to treat drooling in children with neurological disorders. Cuvposa is a cherry flavored oral solution that is easier to administer and provides the optimal dose for each patient.
• In clinical trials, 78% of children on the drug reached clinical improvement in drooling (vs. 19% with placebo).
© Defined Health, 2014
RegenceRx.com
Cuvposa: But Payers Aren’t Buying It
Conclusion (Product Value): Cuvposa brings uncertain clinical value to the treatment of chronic severe drooling, however it may offer some convenience over other options because of dosing flexibility for individual patients, and would preclude the need for tablets to be crushed before administration. Decision: Maintain Cuvposa as non-preferred/non-formulary because there is uncertain evidence for efficacy and there are other less costly formulary options. (Cuvposa is $227-$373 per 30 day Rx; oral glycopyrrolate tables are $79 per Rx).
© Defined Health, 2014
Rilutek: Moderate Value for a Desperate Disease
The New York Times (2004); Rilutek product label 19
Living for Today, Locked in a Paralyzed Body
• Rilutek (riluzole, Sanofi) - only drug indicated for the treatment of amyotrophic lateral sclerosis (ALS), a persistent and progressive disease that causes muscle weakness, disability, and eventual death (typically within 3-5 years of diagnosis).
• Approved in 1995; Two P3 studies showed an average 3 month increase in survival (or time to tracheostomy). Peak sales of ~$200M ww.
• Important component in the treatment of ALS, with solid evidence to support a modest survival benefit.
• However, as the disease progresses, the benefit does not outweigh the cost (or even trouble of taking another pill) to the patient – (an estimated 75% of patients pay less than $50 co-pay per prescription).
ALS patients and their families are forced, on a daily basis, to take stock of the meaning and quality of their lives and to make repeated decisions about how much is too much. Patients with the illness, Dr. Ganzini said, are 25 times as likely to die by doctor-assisted suicide as people with other diseases. Dr. McCluskey, a neurologist in Philadelphia, said that at least 90% of patients with ALS decided to die when they could no longer breathe on their own, although medical science can extend their lives much longer (i.e., tracheostomy).
© Defined Health, 2014
The Next Generation Therapies for ALS • After nearly two decades since the launch of the first drug indicated for ALS
(Rilutek), we are were now poised to have two new therapies for this devastating disease – one a neuroprotective (dexpramipexole), the other addressing muscle strength and function (tirasemtiv).
Rodman & Renshaw Annual Global Investment Conference, Sept. 2012; Company websites
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Mitochondrial Dysfunction
dexpramipexole
Biogen Announces It Will Discontinue
Development of Dexpramipexole January 3, 2013
April 2014 - The BENEFIT-ALS study missed the primary endpoint of mean
change in the ALSFRS-R score. Secondary efficacy endpoints
showed mixed results.
© Defined Health, 2014
Biogen Idec’s Continued Commitment to ALS
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Donald Johns Joins Biogen Idec to Lead ALS Innovation Hub August 26, 2014 Renowned Neurologist to Focus on Accelerating the Company’s Discovery and Development of ALS Therapies – Biogen Idec announced that Donald R. Johns, M.D., has joined the company as vice president, leading Biogen Idec’s amyotrophic lateral sclerosis (ALS) Innovation Hub (ALS iHub). The ALS iHub is a new, cohesive unit dedicated to accelerating the discovery and development of novel therapies for ALS by integrating research with clinical development. … In his role, Dr. Johns leads a group with expertise and unique skill sets that span translational science and technology, neurology research, experimental medicine, clinical development and business development. The ALS iHub seeks to create a new model for developing ALS therapies by incorporating the latest science, technology and advances in clinical trial design. “We are committed to bringing critical therapies to ALS patients as quickly and efficiently as possible. …
© Defined Health, 2014
Cytokinetics Continues to Pursue Effect on Respiratory Function
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Cytokinetics 2014 Annual Stockholders Meeting presentation
Tirasemtiv
• A pre-specified subgroup analyses of BENEFIT-ALS indicates a reduction of decline in Slow Vital Capacity (SVC) on tirasemtiv versus placebo across all subgroups of patients with ALS.
© Defined Health, 2014
Sabril
Cuvposa
Rilutek
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Ampyra
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine
Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Hetlioz
$75,000 - $150,000
• Establishing and building value over time.
© Defined Health, 2014
Xyrem: Building Value, Protection and Price over Time
• Xyrem (sodium oxybate) is the only FDA-approved medication for narcolepsy with cataplexy and excessive daytime sleepiness (EDS). It was approved on July 17, 2002, based on P3 studies which showed a decrease in the number of weekly cataplexy attacks vs placebo by ~50-70% within a month of starting therapy and >90% by one year.
– Sodium oxybate is derived from gamma-hydoroxybutyrate (GHB), a DEA Schedule I controlled substance with a high risk of abuse and diversion.
• Current sales of ~$600 M in 2013; industry analysts project US revenues of over $1B by 2016.
EvaluatePharma 24
Cataplexy, found in 60 -70% of narcoleptics, is characterized by a brief but sudden loss of muscle tone often triggered by intense emotions. Cataplexy can be focal (i.e., drooping of an eyelid or the jaw) or generalized, causing a patient to collapse. Recovery of muscle tone is complete and commonly occurs just as quickly. Cataplexy can gravely affect a patient’s quality of life — resulting in an inability to work or study, strained social relationships, and also serious accidents.
© Defined Health, 2014
Xyrem: Building Value, Protection and Price over Time
• Value – Specified as “treatment standard” (i.e.,
first-line) in the American Academy of Sleep Medicine practice parameters in 2007.
– Restricted access program (Xyrem Success Program); assistance to physicians (e.g., patient education) and patients (e.g., nursing guidance).
– Post-marketing surveillance data showing very low incidence of abuse, misuse, dependence, drug-facilitated sexual assault, overdose, fatalities, and diversion
– Patient assistance program defrays out-of-pocket costs
Jazz Pharmaceuticals website; Brean Murray Carret & Co. Sept. 27, 2012 analyst report; SG Cowen Therapeutic Categories Outlook 25
• Protection – Orphan status – Jazz’s expanded IP covers Xyrem’s restricted
access program (Xyrem Success Program), formulation and method of use
• Price
– With growing value and protection, Jazz has been able to increase the price of Xyrem ~8-fold over the past several yrs; continuing in the double digits.
© Defined Health, 2014
Sabril
Cuvposa
Rilutek
Orphan CNS Today: Range of Price (and Value)
Redbook; DH Analysis
Valu
e Pr
opos
ition
Ampyra
Banzel
Xyrem
MS Disease Modifying
Drugs
Xenazine Acthar
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$5,000 - $20,000 $25,000 - $40,000 $50,000 - $75,000
Average Annual Cost of Therapy (WAC, $USD)
$150,000 - $400,000+
CNS Non-CNS
Hetlioz
$75,000 - $150,000
• The top of the value chain.
© Defined Health, 2014
For Some Disorders, the Value is Apparent in the Consequences of Inadequate Treatment
Company websites; Epilepsy Curr. 2006 May; 6(3): 63–69. 27
© Defined Health, 2014 28
Sabril US Peak Sales
~$125 M
Acthar Gel US Peak Sales
~$1.4 B
The Value of Multiple Indications
EvaluatePharma
• Sabril and Acthar gel both have initial indications for the treatment of infantile spasms. • Sabril is also indicated for the treatment of refractory complex partial seizures. • Acthar gel has 19 label indications.
© Defined Health, 2014
Multiple Indications AND Aggressive Price Increases
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• The recent $5.8 B sale of Questcor to Mallinkrodt was largely driven by the growing sales of Acthar gel in nephrotic syndrome and MS relapse.
EvaluatePharma
Sales of Acthar Gel by Indication
Acthar Gel Cost Per Patient: Price Increases
© Defined Health, 2014
Xenazine: Creating Value Where There Was None
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• Xenazine is the only FDA-approved treatment for chorea associated with Huntington's disease.
• Chorea is the hallmark symptom of HD and affects about 90% of people who have HD, and is characterized by involuntary repetitive, jerky, dance-like movements.
• Peak (2014) sales estimate of just over $280M.
Company websites; EvaluatePharma
© Defined Health, 2014 31
Singer, C. July 2012, Cleveland Clin J of Med, Vol 79, Spp 2; Frank, S.2009, BMC Neurol.18;9:62; www.xenazineusa.com
Xenazine: Creating Value Where There Was None
• Primary endpoint: Chorea was assessed using the Total Maximal Chorea (TMC) score from the UHDRS.
• Secondary endpoints: Clinical Global Impression scale and individual sections of the UHDRS.
• At 80 weeks, reduction in mean TMC score by 4.6 (SD 5.5) UHDRS units (p<0.001).
• Did not impact cognition or global improvement after 2 years of therapy.
The Unified Huntington’s Disease Rating Scale (UHDRS) was developed by the Huntington Study Group as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity.
• Efficacy was established in a 13-week study and open label extension up to 80 weeks.
© Defined Health, 2014 32
Roos. R. 2010. Orphanet J of Rare Diseases 5:40; www.xenazineusa.com
Xenazine: Leaves Plenty of Opportunity to Address Unmet Need
• Troubling side effects: somnolence, dysphagia and increase in Parkinsonian symptoms.
• Black-box warning for increased risk of depression and suicidal thoughts and behavior (in an already highly vulnerable patient population)
• Only addresses one domain of the disease: motor symptoms, and only the chorea type movements.
© Defined Health, 2014 33
A New Member to the CNS Orphan Club
Vanda Pharmaceuticals Investor Presentation
© Defined Health, 2014 34
2014 WAC is $84,231 per year
Does the Value Justify the Price?
© Defined Health, 2014 35
PRIOR AUTHORIZATION POLICY Hetlioz™ (tasimelteon capsules Vanda Pharmaceuticals)
1. Non-24-Hour Sleep Wake Disorder (Non-24), Initial Therapy. Approve for 6 months if the patient
meets all of the following criteria (a, b, c, d, and e): a) The patient is ≥ 18 years of age; AND b) The patient is totally blind with no perception of light; AND c) The medication is prescribed by, or in consultation with, a physician who specializes in the
treatment of sleep disorders; AND d) The diagnosis of Non-24 is confirmed by meeting ONE of the following conditions (i or ii):
i. Assessment of at least one physiologic circadian phase marker (e.g., measurement of urinary melatonin levels, dim light melatonin onset [as measured in blood or saliva], assessment of core body temperature); OR
ii. If assessment of at least one physiologic circadian phase marker cannot be done, the diagnosis must be confirmed by actigraphy performed for ≥ 1 week plus evaluation of sleep logs recorded for ≥ 1 month; AND
e) e) The patient meets both of the conditions below (i and ii): i. The patient has received at least 6 months of continuous therapy (i.e., 6 consecutive
months of daily treatment) with melatonin under the guidance of a physician who specializes in the treatment sleep disorders; AND
ii. The patient did not achieve adequate results with melatonin therapy according to the prescribing physician (e.g., entrainment, clinically meaningful or significant increases in nighttime sleep, clinically meaningful or significant decreases in daytime sleep).
2. Non-24-Hour Sleep Wake Disorder (Non-24), Continuation Therapy. Approve for 12 months if …..
North Caroline State Health Plan
Payers Sit up and Take Notice
© Defined Health, 2014
A Successful CNS Orphan Drug Strikes a Balance …
Market Potential Price
Size of Target Patient Population (s)
Strength of Value Proposition
Market Access
Budget Impact
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© Defined Health, 2014
Characteristics of a Successful CNS Orphan Drugs
– Clinically meaningful value to patient (disease modifying or symptomatic)
• Functional benefit
• Quality of life benefit
• Outcomes
• Pharmacoeconomic benefit
– Value (and price) can be well documented and supported
– Addresses a relatively large orphan population and/or
– Modifies a pathway common to multiple rare disorders
– Associated with motivated patients and active patient advocacy groups (raise awareness, access to patients, drive adoption/market access)
– Has protection beyond patent
– Pays careful attention to payers “budget impact” radar
© Defined Health, 2014 38
Thank you.