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

2 Copyright © PerformRx, LLC 2019 All Rights Reserved.

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


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


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

Copyright © PerformRx, LLC 2019 All Rights Reserved.

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

Copyright © PerformRx, LLC 2019 All Rights Reserved.

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?


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


• 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


• 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


• 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


Orphan Drug Approvals By Year

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2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

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Orphan Drug Approvals by Year


Worldwide Sales Forecast

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200

400

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1000

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1400

2019 2020 2021 2022 2023 2024

Sale

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Worldwide Sales Forecast

Orphan Generic Brand

Market share sales growth 2019 - 2024 ─ Orphan drugs: +25% ─ Brand drugs: -4.3% ─ Generic drugs: -9.7%


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


Onasemnogene Abeparvovec-xioi


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


Pexidartinib


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


Pretomanid


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


Pitolisant


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


Entrectinib


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


Fedratinib


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


Plasma Purified Human Plasminogen


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


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


Afamelanotide


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


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


RVT-802


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


Riluzole


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


Avapritinib


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




Question #1



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


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


Questions?

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