Drug Repositioning: Extracting Added Value from Prior R&D Investments

InsIght Pharma rePorts 250 First Avenue • Suite 300 • Needham, MA 02494 • 781-972-5444 • InsightPharmareports.comA division of Cambridge Healthtech Institute

Drug repositioning has become a matter of intense interest during the past few years. It is an approach to drug development that calls for reinvestigation of candidates that did not succeed in advanced clinical trials (for reasons other than safety) for potential use in other therapeutic indications.

Expert Intel l igence for Better Decis ions

Insight Pharma Reports July 2010

Author: Hermann A.M. Mucke, Ph.D.

Discussed in this Report: • Intellectualpropertycoverage

for new uses of known drugs

• Toolsetsforidentifying repositioning opportunities and business strategies

• Applicablelegalframeworks and regulatory timelines for repositioned drugs

• Casestudiesofcompound repositioning and approaches taken

• Activitiesofselectedkey companies in the drug repositioning business

• Financialaspectsandeconomic potential of drug repositioning

Drug repositioning is also known as drug repurposing, reprofiling, or retasking. In “on-target repurposing,” a drug’s known pharmacological mechanism is applied to a different therapeutic indication than that for which it was initially developed. Even more innovative is “off-target repurposing,” which looks for pharmacological mechanisms that have not yet been described for a known molecule. In either case, having previously failed during clinical development is not a criterion for repositioning; the avenue is equally open to drugs that are or have been marketed.

Drug repurposing can have very different commercial implications. These will depend on where the drug comes from, how much accessible data exist, and how well the repurposer can exploit the new value chain created by a successfully repurposed drug. This will to a large extent depend on what sort of intellectual property can be secured for the drug’s new use, as examined in Chapter 2 of Drug Repositioning: Extracting Value from Prior R&D Investments. The repurposer fights an uphill battle against examiners who will scrutinize the prior art for“obviousness,” i.e., any public facts that can be construed to have anticipated the new medical use of a known drug.

Together with expert knowledge in pharmacology, state-of-the-art genomic, proteomic, animal model, and bioinformatics technologies are employed to identify repurposing opportunities and business strategies. These more technology-oriented aspects are discussed in Chapter 3, followed by an outline of the regulatory environment for repurposing in Chapter 4. Here, we discuss the applicable legal framework and show that while repurposing can remove the initial 1–1.5 years of preclinical and Phase I development time (the

latter only if no new formulation has to be developed and tested), the later stages of the regulatory review process for repurposed drugs are the same as with new chemical entities. Chapter 5 discusses exemplary cases of drug repositioning and the approaches taken, depending on the intended goal.

Therapeutic Field

Molecular or Pathway Target

Different On-Target Repurposing

(Medium Novelty)

Off-Target Repurposing

(High Novelty)

Same Use Extension

(Not Repurposing)

Off-Target Repurposing

(RareCases)

Same Different

Drug repurposing has become a new business segment for the life science services industry. Chapter 6 profiles selected key companies that offer platform-based services to identify repurposing opportunities. For the decade ahead to 2020, we predict that cutting-edge repurposing technology will see increasing integration as a standard process of resource utilization, de-risking and acceleration of drug development. In this chapter we also discuss the internal repurposing efforts of Pfizer, Novartis, and Eli Lilly and how these programs tie into their overall development strategies. Drug Repositioning: Extracting Added Value from Prior R&D Investments concludes with a discussion of the financial aspects, considering the benefits of repurposing for larger, smaller, and startup companies.

About the AuthorHermann A.M. Mucke, Ph.D., spent 17 years in academia and industry before he founded H.M. Pharma Consultancy (www.hmpharmacon.com) in 2000 to become an independent pharmaceutical consultant, analyst, and science author. His last industry position was Vice President R&D in a European pharmaceutical company, which he helped to take public on the Frankfurt Stock Exchange in 1999. Since then, Dr. Mucke, who holds a Ph.D. in biochemistry from the University of Vienna (Austria), has become a consultant and advisory board member for several European and American pharmaceutical companies and a regular reviewer of drugs and patents for Thomson Current Drugs and Ashley Publications. Dr. Mucke is based in Vienna.

Toorderareport,e-mailrlaraia@healthtech.com,callRoseLaRaiaat781-972-5444,ororderon-lineatInsightPharmaReports.com

Overview

Use Extensions vs. On- and Off-Target Repurposing

Source:H.M.PharmaConsultancy

Chapter 1 INTRODUCTION: A SECOND LIFE FOR DRUGS AND DRUG CANDIDATES1.1. Targets and Agents: Approaching the

Limits1.2. Human Physiology as a Network of

Interdependencies1.3. Leveraging Drug Repurposing To Turn

the Tables on Pipeline Erosion1.4. Finding Another Disease To Treat: On-

Target and Off-Target

Chapter 2 DRUG REPOSITIONING AND INTELLECTUAL PROPERTY2.1. Considerations Regarding the

Patentability Criteria2.2. Searching Prior Art to Assess

Repurposing Opportunities2.3. Searching for Intellectual Property Gaps2.4. Data Support: An Indispensable

Requirement for Second Use Patenting2.5. Case Study: Developer Actelion Claims Bosentan for Ovarian Cancer

Chapter 3 THE STRATEGIC CONCEPT, THE SCIENCE, AND THE TOOLS OF THE THERAPEUTIC SWITCH3.1. What Strategic Considerations Make a

Compound a Repositioning Candidate?3.2. Identification of Repurposing

OpportunitiesKnow the ScienceKnow the ResourcesHypothesis-Driven Approaches3.3. Targeted High-Throughput Screening

and Inverse High-Content ScreeningPhenotypic Screening: Parameter-Free High-

Content ScreeningMultiplexing Animal Tests3.4. Putting Informatics to WorkCase Study for Gene Expression: VVP808Case Study for Virtual Screening and In Silico

Docking: SOSA and EntacaponeCase Study for Systems Biology: OptimataData Mining and Ligand-Similarity

ApproachesNew Opportunities Through Grid Computing?3.5. Repurposing Aided By Drug

Reformulation and New Forms of Delivery

3.6. Repurposing for Biodefense: A Strategy Outside of the Mainstream

Chapter 4 REPOSITIONED DRUGS AND REGULATORY AUTHORITIES4.1. The FDA’s 505(b)(2) New Drug

Application4.2. The EMEA “Hybrid Application”

Chapter 5 EXAMPLES OF DRUG REPURPOSING5.1. Successfully Repositioned Compounds

That Were Never Marketed For Their Original Development Targets or Were Withdrawn From the Market

Pfizer’s Sildenafil: From Failed Antihypertensive, to Lifestyle Drug, to Orphan Disease

Thalidomide: A Colossal Tragedy and a New Beginning

Azidothymidine: A Cancer Drug Candidate Repurposed as an HIV Therapeutic and Vice Versa

5.2. Drugs That Were Moderately Successful and Were (Or Are Being) Repurposed

Galantamine: Transformed Into an Alzheimer’s Drug, With More Perspectives

Cicletanine: An Antihypertensive for Pulmonary Hypertension…And Diabetes?

Ropinirole and Pramipexole: Parkinson’s Drugs for Restless Leg Syndrome

Benzbromarone: A Potentially Problematic Gout Drug Applied To MRSA Infections

Clioquinol: An Old Antiprotozoal As a Lead Compound for Neuroprotection

Astemizole: A Problematic Antihistamine with Significant Alternative Perspectives

5.3. Successful Primary-Use Drugs in Repurposing Scenarios

Milnacipran and Duloxetine: Two Antidepressants Now Approved for Fibromyalgia

Finasteride: From Prostate to Hair LossImatinib for Diabetes and Rheumatoid

Arthritis5.4. Failed, and Failed Again…Perhaps For the

Wrong ReasonsMCI-225: From Psychiatry Drug Candidate, to

Gastrointestinal and Urinary Tract Agent

Chapter 6 COMPANIES IN THE DRUG REPURPOSING BUSINESS6.1. Business Models Centered On Drug

Repurposing: Different From Those for Discovery?

6.2. The Small, Drug-Repurposing SpecialistsSosei Group Corp.CombinatoRx, Inc.Ore Pharmaceutical Holdings, Inc.Biovista, Inc.Melior Discovery, Inc.Numedicus Ltd.Vifor Pharma/Galenica GroupAureus PharmaHorizon Discovery Ltd.Tangent Reprofiling Ltd.Anaxomics Biotech SL

SOM Biotech SLSWITCHBIOTECH LLCCelentyx Ltd.Almac Group Ltd.6.3. “Big Pharma” and Drug RepositioningPfizer NovartisEli Lilly6.4. Public Efforts to Facilitate Drug

Repurposing

Chapter 7THE ECONOMIC POTENTIAL OF DRUG REPURPOSING7.1. Cost Savings of Repurposing In

Discovery and Development7.2. Acceleration of Drug Development: Time

Equals Sales7.3. The Benefits of De-Risking7.4. The Repurposing Service Provider’s

Perspective7.5. Summary and Outlook

ReferencesCompany Index with Web Addresses

FIGURESFigure 1.1. On- vs. Off-Target Repurposing

Contextualized in Three Dimensions: Chemical, Mechanistic, Therapeutic

Figure 2.1. Intellectual Property Protection in On- and Off-Target Repurposing Scenarios

Figure 3.1. Strategies for Repurposing Marketed Drugs vs. Non-Marketed Drug Candidates

Figure 4.1. Regulatory Pathways for Drug Repurposing: Marketed vs. Shelved/Withdrawn Drugs

TABLESTable 1.1. Use Extensions vs. On- and Off-

Target RepurposingTable 4.1. Regulatory Timelines for a

Repurposed Drug vs. a New Chemical Entity (NCE)

Table 5.1. Global Sales (US$ Millions) for Propecia vs. Proscar, 2003–2009

Table 6.1. International PCT Patent Disclosures From Ore Pharmaceuticals

Table 6.2. International PCT Patent Disclosures From Biovista, Inc.

Table 6.3. International PCT Patent Disclosures From Melior Discovery

Table 6.4. International PCT Patent Disclosures From Vifor

Table of Contents

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