Novel Treatments for Orphan Diseases: A Promising Future · Novel Treatments for Orphan Diseases: A...
Transcript of Novel Treatments for Orphan Diseases: A Promising Future · Novel Treatments for Orphan Diseases: A...
Novel Treatments for Orphan Diseases: A Promising Future
September 20th, 2019
Lauren Megargell, Pharm.D.
Director, Clinical Services
Amanda Williams, Pharm.D. Pharmacist, Clinical Market Intelligence
• Define the Food and Drug Administration (FDA) orphan designation
• Identify orphan drugs recently approved and in the near-term
pipeline • Describe disease prevalence and alternative treatment
options
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Learning Objectives
• The presenters for this activity has been required to disclose all relationships with any proprietary entity producing health care goods or services, with the exemption of non-profit or government organizations and non-health care related companies.
• Lauren Megargell, Pharm.D. – PerformRx Employee
• Amanda Williams, Pharm.D. – PerformRx Employee – ApotheCare Services, Managing Partner
Disclosure
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Which of the following drugs is used to treat an orphan disease? A. Botox® (onabotulinumtoxinA) B. Humira® (adalimumab) C. Zolgensma® (onasemnogene abeparvovec-xioi) D. All of the above
Question #1
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Question #2
5
An orphan disease affects less than ________ people in the United States. A. 50,000 B. 100,000 C. 200,000 D. 500,000
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Question #3
6
Which of the following is disease – drug pairings is not correct? A. Tuberculosis – Avapritinib B. Duchenne Muscular Dystrophy – Golodirsen C. Erythropoietic Protoporphyria – Afamelanotide D. Atypical Hemolytic Uremic Syndrome – Ravulizumab-
cwvz
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Background
• Orphan Drug Act of 1983 • Drug to treat or prevent a rare disease (e.g. affecting <
200,000 people in the United States) OR that affects > 200,000 people but is not expected to recover development and marketing costs
• Designation is specific to a unique drug/disease combination • “Orphan” subset – a drug for only a subset of persons with a
particular disease or condition that otherwise affects 200,000 or more people
What is an “Orphan” Designation?
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Societal Impact of Orphan Diseases
• Approximately 7,000 orphan diseases affecting 25-30 million people in the U.S.
• More than half of those afflicted are children • Treatments are available for ~5% of the estimated 7,000
diseases • 80% are genetic in nature • 7.9% of drug spending in the United States is attributed to
orphan indications – 20% of drugs are priced at less than $6,000/year – 1% of drugs are priced in excess of $500,000/year
IQVIA National Sales Perspectives, Jun 2017; FDA Orphan Drugs Database, Feb 2017; IQVIA Institute, Aug 2017
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• Financial incentives – development costs for orphan drugs are LOWER than non-orphan – Tax credits for clinical testing – Research and development grants for clinical trials – Waive User Fee associated with the application (currently $2.5M)
• Extended market exclusivity – New drug – 5 years – Orphan drug – 7 years – Biologic – 12 years
Drug Development Incentives
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• Development process – IND, Phase I-III, NDA/BLA
• Office of Orphan Products Development (OOPD)
Drug Development & Approval Process
• Expedited review pathways – Priority Review – from standard 10 month review to 6 month review – Accelerated Approval – approval based on surrogate endpoint – Breakthrough – for drugs that demonstrate a substantial improvement
compared to currently available therapies – Fast Track – for drugs to treat serious conditions and fill unmet medical
needs
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• Difficulty in identifying and enrolling patients • Multiple sites, including international • Defining and measuring outcomes • Limited sample size means treatment effect needs to be high
to achieve power
Challenges in Orphan Disease Trials
0 2 4 6 8 10 12 14 16 18 20
All new drugs
Orphan drugs
Ultra-orphan drugs
Years
Development Timeframes
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Orphan Drug Approvals By Year
0
10
20
30
40
50
60
70
80
90
100
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Num
ber o
f Uni
que
Drug
/ De
sign
atio
n Ap
prov
als
Year
Orphan Drug Approvals by Year
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Worldwide Sales Forecast
0
200
400
600
800
1000
1200
1400
2019 2020 2021 2022 2023 2024
Sale
s ($b
n)
Year
Worldwide Sales Forecast
Orphan Generic Brand
Market share sales growth 2019 - 2024 ─ Orphan drugs: +25% ─ Brand drugs: -4.3% ─ Generic drugs: -9.7%
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2019 Orphan Drug Approvals
Caplacizumab-yhdp
• Unique Designator: Fast Track • IV, SQ Inhibits the interaction between von Willebrand factor (vWF) and
platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption
• First agent to carry a labeled indication for aTTP • Prevalence is estimated at 3 cases per 1 million adults per year
Drug Approval Date Manufacturer Indication Pricing
CabliviTM (caplacizumab
-yhdp) 02/06/2019 Sanofi
Acquired Thrombotic
Thrombocytopenic Purpura (aTTP)
$277,400/ course
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Onasemnogene Abeparvovec-xioi
Drug Approval Date Manufacturer Indication Pricing
Zolgensma® (onasemnogene
abeparvovec-xioi)
05/24/2019 Novartis AG Spinal
Muscular Atrophy (SMA)
$2.13 million/ dose
• Unique Designators: Breakthrough, Fast Track • Route of Administration: Single dose, IV • Alternative Therapeutic Agents: Spinraza® (nusinersen) • Gene therapy that replaces the survival motor neuron 1 (SMN1) gene, which is
missing or mutated in individuals with SMA • Approved for children under 2 years of age with bi-allelic mutations in the
SMN1 gene • SMA affects approximately 1 in 11,000 babies; about 1 in every 50 Americans is
a genetic carrier
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Pexidartinib
Drug Approval Date Manufacturer Indication Pricing
TuralioTM
(Pexidartinib) 08/09/2019 Daiichi Sankyo Co., Ltd.
Pigmented Villonodular
Synovitis (PVNS)
$19,800/ month
• Unique Designators: Breakthrough • Alternative Therapeutic Agents: None • Route of Administration: Oral • Novel, oral agent that potently inhibits colony stimulating factor-1 receptor (CSF1R) • The first and only approved therapy for PVNS when associated with severe
morbidity or functional limitations, and not amenable to improvement with surgery • Estimated incidence is 11 to 50 cases per million person-years
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Pretomanid
Drug Approval Date Manufacturer Indication Pricing
Pretomanid 08/14/2019 Global Alliance
for TB Drug Development
Tuberculosis (TB) Unknown
• Unique Designators: Fast-Track, Qualified Infectious Disease Product (QIDP) • Alternative Therapeutic Agents: Cycloserine (Seromycin®), Trecator®
(ethionamide), Paser® (p-aminosalicylic acid), Sirturo® (bedaquiline fumarate) • Route of Administration: Oral • Novel class; member of a class of compounds known as nitroimidazooxazines • Part of a new regimen, in combination with bedaquiline and linezolid (B-L-Pa
regimen), for the treatment of extensively drug-resistant (XDR)-TB, treatment intolerant multidrug-resistant (MDR)-TB, and treatment non-responsive MDR-TB
• Incidence in US is less than 25 cases per 100,000 ─8.5% of cases are classified as XDR-TB by World Health Organization ─Only 55% of MDR-TB cases are successfully treated, globally
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Pitolisant
Drug Approval Date Manufacturer Indication Pricing
Wakix® (Pitolisant) 08/14/2019
Harmony Biosciences,
LLC
Excessive Daytime
Sleepiness (EDS) and/or Cataplexy
in Narcolepsy
Unknown
• Unique Designators: Breakthrough, Fast Track • Alternative Therapeutic Agents: Xyrem® (sodium oxybate) • Route of Administration: Oral • Novel mechanism of action; oral potent and highly selective histamine 3 (H₃)
receptor antagonist/inverse agonist • Enhancement of the activity of histaminergic neurons in the brain acts to improve
a patient’s wakefulness and inhibit attacks of cataplexy • Narcolepsy with cataplexy estimated to affect 25 to 50 per 100,000 people
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Entrectinib
Drug Approval Date Manufacturer Indication Pricing
RozlytrekTM
(Entrectinib) 08/15/2019 Roche Holding AG
Neurotrophic Tropomyosin Receptor Kinase (NTRK)
Fusion +, Locally Advanced or Metastatic Solid Tumors Unknown Metastatic, ROS1-Positive
Non-Small Cell Lung Cancer (NSCLC)
• Unique Designators: Breakthrough (NTRK fusion + solid tumors only) • Alternative Therapeutic Agents
─ NTRK fusion + solid tumors: Tyrosine Kinase Inhibitor, Vitrakvi® (larotrectinib) ─ Metastatic, ROS1+ NSCLC: Tyrosine Kinase Inhibitor, Xalkori® (crizotinib)
• Route of Administration: Oral • Alternative therapeutic option to currently available agents • Incidence:
─ NTRK fusion + solid tumors: Unknown ─ Metastatic, ROS1+ NSCLC: 1-2% of NSCLCs have an identifiable ROS1
rearrangement
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Fedratinib
Drug Approval Date Manufacturer Indication Pricing
Inrebic®
(Fedratinib) 08/16/2019 Celgene Myelofibrosis Unknown
• Alternative Therapeutic Agents: Jakafi® (ruxolitinib) • Route of Administration: Oral • Alternative therapeutic option to currently available agents • Janus Associated Kinase 2 (JAK2) selective inhibitor • Estimated prevalence 16,000 to 18,500 patients
Orphan Drugs in the Pipeline
Golodirsen
Drug PDUFA Date Manufacturer Indication Pricing
Golodirsen 08/19/2019 Sarepta
Therapeutics, Inc.
Duchenne Muscular Dystrophy
(DMD)
Unknown
• Unique Designators: Priority Review • Alternative Therapeutic Agents: None
─ Emflaza® (deflazacort) and Exondys 51™ (eteplirsen) carry different DMD indications
• Route of Administration: Intravenous infusion • Uses proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and
exon-skipping technology to skip exon 53 of the DMD gene, which is intended to allow for production of an internally truncated but functional dystrophin protein
• One in approximately every 3,000-5,000 males born worldwide; 8% of DMD patients have genetic mutations subject to exon 53 skipping
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Plasma Purified Human Plasminogen
Drug PDUFA Date Manufacturer Indication Pricing
RyplazimTM (plasma
purified human plasminogen)
08/01/2019–09/30/2019
ProMetic Life Sciences Inc.
Hypoplasmin-ogenemia Unknown
• Unique Designators: Fast Track • Alternative Therapeutic Agents: None • Route of Administration: Intravenous • Novel therapy; plasminogen is a naturally occurring protein • The diagnosis of hypoplasiminogenemia as a prothrombotic disorder is controversial • 1 to 9 cases per million persons
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Nintedanib
Drug PDUFA Date Manufacturer Indication Pricing (Monthly)
Ofev® (nintedanib) 09/19/2019
Boehringer Ingelheim
GmbH
Systemic Sclerosis
Associated Interstitial Lung
Disease (SSc-ILD)
$9,900
• Unique Designators: Fast Track • Alternative Therapeutic Agents: Mycophenolate mofetil (Cellcept®),
cyclophosphamide • Route of Administration: Oral • Currently approved for idiopathic pulmonary fibrosis • Would be the first FDA-approved treatment for SSc-ILD • 108,000 persons in the United States, ~75% of whom have ILD
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Afamelanotide
Drug PDUFA Date Manufacturer Indication Pricing
Scenesse® (afamelanotide) 10/04/2019
Clinuvel Pharmaceuticals
Ltd
Erythropoietic Protoporphyria
(EPP) Unknown
• Unique Designators: Fast Track • Alternative Therapeutic Agents: None • Route of Administration: Intradermal implant; analogue of alpha-Melanocyte
Stimulating Hormone (α-MSH) that stimulates melanocytes to produce and release photoprotective melanin
• The National Institute of Health and Care Excellence (NICE) recommended against reimbursement for afamelanotide, which is approved in the European Union, due to failure to meet health-economic criteria
• Prevalence 1 in 75,000 to 1 in 200,000 persons
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Ravulizumab-cwvz
Drug PDUFA Date Manufacturer Indication Pricing (Monthly)
Ultomiris® (ravulizumab-
cwvz) 10/18/2019 Alexion
Pharmaceuticals
Atypical Hemolytic
Uremic Syndrome
≥$32,000
• Alternative Therapeutic Agents: Soliris® (eculizumab) • Route of Administration: IV • New indication, currently indicated for paroxysmal nocturnal hemoglobinuria
(PNH) ─ PNH also orphan disease, affects 1 to 1.5 persons per million
• Prevalence of 1 to 9 persons per 1 million
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RVT-802
Drug PDUFA Date Manufacturer Indication Pricing
RVT-802 11/22/2019 Enzyvant Therapeutics
Pediatric Congenital
Athymia Unknown
• Unique Designator: Breakthrough, Regenerative Medicine Advanced Therapy (RMAT)
• Alternative Therapeutic Agents: None • Route of Administration: Surgical implant • Novel, tissue-based regenerative therapy which stimulates and facilitates
the production of naïve, immunocompetent T cells in the body • 20 U.S.-born infants annually
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Riluzole
Drug PDUFA Date Manufacturer Indication Pricing
Exservan™ (riluzole) 11/30/2019 Aquestive
Therapeutics
Amyotrophic Lateral
Sclerosis (ALS) Unknown
• Alternative Therapeutic Agents: Riluzole (Rilutek®) oral tablets, TiglutikTM (riluzole) oral suspension
• Route of Administration: Sublingual • Oral film formulation • MOA unknown, has inhibitory effect on glutamate • Prevalence between 2.7 and 7.4 per 100,000 persons
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Avapritinib
Drug PDUFA Date Manufacturer Indication Pricing
Avapritinib 02/14/2020 Blueprint Medicines
Corporation
Gastrointestinal Stromal Tumor
(GIST) Unknown
• Unique Designators: Breakthrough, Fast Track • Alternative Therapeutic Agents: Tyrosine Kinase Inhibitors, Imatinib
(Gleevec®), Sutent® (sunitinib) • Route of Administration: Oral • Oral therapy that inhibits KIT and PDGFRA mutant kinases • Seeking indication for treatment of adult patients with PDGFRA Exon
18 mutant GIST (regardless of prior therapy) and fourth-line GIST • 7-15 cases per million persons per year
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Which of the following drugs is used to treat an orphan disease? A. Botox® (onabotulinumtoxinA) B. Humira® (adalimumab) C. Zolgensma® (onasemnogene abeparvovec-xioi) D. All of the above
32 Copyright © PerformRx, LLC 2019 All Rights Reserved.
Question #1
Which of the following drugs is used to treat an orphan disease? A. Botox® (onabotulinumtoxinA) B. Humira® (adalimumab) C. Zolgensma® (onasemnogene abeparvovec-xioi) D. All of the above
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Question #1
An orphan disease affects less than ________ people in the United States. A. 50,000 B. 100,000 C. 200,000 D. 500,000
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Question #2
An orphan disease affects less than ________ people in the United States. A. 50,000 B. 100,000 C. 200,000 D. 500,000
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Question #2
Which of the following is disease – drug pairings is not correct? A. Tuberculosis – Avapritinib B. Duchenne Muscular Dystrophy – Golodirsen C. Erythropoietic Protoporphyria – Afamelanotide D. Atypical Hemolytic Uremic Syndrome – Ravulizumab-cwvz
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Question #3
Which of the following is disease – drug pairings is not correct? A. Tuberculosis – Avapritinib B. Duchenne Muscular Dystrophy – Golodirsen C. Erythropoietic Protoporphyria – Afamelanotide D. Atypical Hemolytic Uremic Syndrome – Ravulizumab-cwvz
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Question #3
1. Developing Products for Rare Diseases & Conditions. U.S Food & Drug Administration. Available at: https://www.fda.gov/industry/developing-products-rare-diseases-conditions
2. Search Orphan Drug Designations and Approvals. U.S Food & Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm
3. ClinicalTrials.gov. U.S. National Institutes of Health. Available at: https://clinicaltrials.gov/ 4. Manufacturer Press Releases and Websites. 5. UpToDate. Wolters Kluwer. Available at: http://www.uptodate.com/ 6. Medicine Use and Spending in the U.S.: A Review of 2018 and Outlook to 2023. IQVIA Institute for Human Data Science.
May 2019. 7. Orphan Drugs in the United States. IQVIA Institute for Human Data Science. October 2018. 8. The portal for rare diseases and orphan drugs. Orpha.net. Available at: https://www.orpha.net/consor/cgi-bin/index.php 9. Estimating the clinical cost of drug development for orphan versus non-orphan drugs. Orphanet Journal of Rare Diseases.
Available at: https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0990-4#Tab4 10. Pomeranz K, Urquhart L. Orphan Drug Report 2019. EvaluatePharma. Available at: https://info.evaluate.com/rs/607-YGS-
364/images/EvaluatePharma%20Orphan%20Drug%20Report%202019.pdf?mkt_tok=eyJpIjoiWWpVMk1UVmtNRFpqT0dFeiIsInQiOiIrcmZ3QjNwamZWWVwvZ1ZkcU5XS2E3Rk5oNXA5MXZJVUVCRitMQXpQd0sxMGJPU0JhdGRWbVJQQkZrc0xZNDNPSXRNM09wMGh2OEFXNXFNN1wvb1plT
11. Lin JJ, Shaw AT. Recent Advances in Targeting ROS1 in Lung Cancer. J Thorac Oncol. 2017 Nov; 12(11): 1611–1625. 12. Shanley M. New Data Reinforces Difficulty in Orphan Drug Development. MD Magazine. May 2018. Available at:
https://www.mdmag.com/medical-news/new-data-reinforces-difficulty-orphan-drug-development 13. Growth in rare disease R&D is challenging development strategy and execution. Tufts Center for the Study of Drug
Development Impact Report. 2019 Jul/Aug; 21(4). Available at: https://static1.squarespace.com/static/5a9eb0c8e2ccd1158288d8dc/t/5d2490ae0072ee0001a1a198/1562677423360/summary_julyaugust_2019.pdf
14. Patent-to-launch time for orphan drugs is 2.3 years longer vs. other drugs. Tufts Center for the Study of Drug Development Impact Report. 2018 May/Jun; 20(3). Available at: https://static1.squarespace.com/static/5a9eb0c8e2ccd1158288d8dc/t/5af455f9352f53cd2156399e/1525962233431/summary_mayjune18.pdf
15. Mezher, M. Study: Patent Term Restoration Extends Drug Patents by About 3 Years. Regulatory Focus. February 2019. Available at: https://www.raps.org/news-and-articles/news-articles/2019/2/study-patent-term-restoration-extends-drug-patent
References
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Questions?