Therapeutic Drug Repurposing, Repositioning and Rescue
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Drug Discovery Therapeutic Drug Repurposing, Repositioning and Rescue Part III: market exclusivity using Intellectual Property and regulatory pathways There is a growing consensus that Drug Repurposing, Repositioning and Rescue (DRPx) can impact the prescription drug industry for all concerned stakeholders. In part this is due to the fact that the pharmaceutical industry now accrues ~25% of its annual revenues from DRPx products. The DRPx approach appears to offer solutions to a myriad of problems that the industry faces. However, a major perceived hurd le in the successful execution and further uptake of DRPx concerns the Intellectual Property (IP) and regulatory labyrinth associated with such efforts. In this paper we discuss the exclusivity issues of a repurposed drug when using a combination of Intellectual Property and Regulatory pathways. By Dr Stephen rug Repurposing, Repositioning and impact on the revenue stream of the pharmaceuti- Naylor, David M. Rescue (DRPx) emerged in the early cal sector has created a flurry of new activity and Kauppi and Judge M. D1990s as a viable alternative to conven- interest in DRPx. For example a new journal dedi- Schonfeld tional Drug Discovery and Development cated to DRPx entitled Drug Repurposing, (DDD)1,2. DRPx initiatives and endeavours cur- Repositioning & Rescue has recently been rently play an increasing role in the DDD efforts of launched5, a book on the subject published3, a the pharmaceutical industry. It is estimated that the series of annual conferences inaugerated6 and a DRPx process accounts for more than 30% of new workshop proceedings sponsored by the USA drugs and vaccines approved by the US FDA in Institute of Medicine was published last year7. In recent years3. In addition Aris Persidis, President addition Cures Within Reach has just launched its and Co-Founder of BioVista, has estimated that web-based DRPx networking platform Repurposed, Repositioned and Rescued Drugs ‘CureAccelerator’8, and HM Pharma has recently (RRRDxs) now generate ~25% of annual revenue introduced a new, DRPx ‘Discontinued Drug and for the pharmaceutical industry4. This growing Candidate Database’9. 62 Drug Discovery World Summer 2015 Drug Discovery Much of this activity has been perpetrated by dedicated DRPx non-profit and small biotechnolo- gy companies. During the past 20-25 years at least 67 DRPx non-profit and companies have been cre- ated. In that time period 11 of those companies were acquired for a total acquisition cost of $2.38 billion. Currently there are at least 38 companies engaged in active DRPx efforts, and ~65% of them are focused on developing robust RRRDx pipelines and marketing approved drugs2.The advantages that accrue from DRPx efforts are even more com- pelling when considering the market potential of a RRRDx. Such RRRDx price points are determined by the same market forces as a conventional DDD drug, and include drug safety and efficacy differen- tiation, market need, patient acceptance, market- ing strategy and IP position10. Thus a RRRDx has the same possibility to achieve blockbuster status as a de novo derived drug. We have highlighted this phenomenon previously by compiling a ‘Top 10’ list of current mini-blockbuster (~$0.5 billion/year in sales) and blockbuster (>$1 billion/year in sales) RRRDxs2. This compendium of RRRDxs includes this paper focus on USA-driven processes, but Figure 1 Evista, Gemzar, Proscar, Propecia, Revlimid, many of the general IP and regulatory issues are Comparison of the IP and Revatio, Rituxan, Tecfidera, Thalomid, and somewhat similar in other major global pharma- regulatory processes in de 2 novo DDD versus DRPx Viagra . It is noteworthy that all the drugs listed ceutical regions such as Europe, Japan and China. A. DDD were developed and are sold by large pharma or B. DRPx large biotech companies. The Top 10 mini-block- De Novo DDD & DRPx busters and blockbusters have produced a total of De Novo DDD is a well described, defined and ~$12.89 billion in peak annual sales alone. Thus it regulated process11. The initial discovery phase is is not surprising to learn that DRPx constitutes both costly, time consuming and fraught with anywhere from 10-50% of current R&D spending, dead-end efforts. Paul and co-workers have esti- and is a determinant factor in the life cycle man- mated that the cost and cycle-time for the discov- agement of pharm aceutical products2. ery process in order to successfully launch a single The numerous benefits of DRPx are clear and drug is $674 million and 5.5 years respectively12. well documented1-3,7. DRPx can result in new Identification of a ‘Lead Candidate’ typically sales and market opportunities for shelved or results in a whirl of IP filing activity on behalf of abandoned compounds/drugs. Plus additional the pharmaceutical company. The lead candidate is investigation and exploration can reveal major then subjected to in vitro cellular and animal test- new mechanisms of action relative to new target ing to determine its absorption, distribution, disease indications that may also lead to metabolism, excretion and toxicity (ADMET) pro- Intellectual Property (IP) claims. Such efforts can file. Paul has suggested that this ‘Pre-Clinical’ also extend the life of current, marketed drugs by phase costs on average $150 millon and takes determining new indications and/or formulations. approximately one year to complete in order to This includes all the component parts of the DRPx ensure a single candidate gets to market12. discovery process, IP and regulatory issues pertain- Successful completion of the pre-clinical phase ing to the clinical trials and the most suitable busi- then necessitates the filing of an Investigational ness models10. In particular RRRDx market exclu- New Drug Application (IND) with the FDA. The sivity is of paramount importance and can be ade- completed IND is required in order to administer a quately achieved by a combination of thoughtful IP drug or biologic agent to patients in human clinical and regulatory strat egy efforts executed via an trials. The drug candidate is evaluated in humans appropriate business model. This third and final via a series of clinical trials (Phase I-III) as outlined paper in the series discusses these issues and in section 505(b)(1) of the US Federal Food, Drug describes various approaches to achieve market and Cosmetic Act of 1938. After successful com- exclusivity. The primary descriptions discussed in pletion of the clinical trials the drug candidate is Drug Discovery World Summer 2015 63 Drug Discovery subject to a New Drug Application (NDA) or Pre-Clinical phase only requires a demonstration “iologic License Application (BLA) depending on of efficacy for the new indication in either a crell o whether the compound is a chemical or biological animal model system. Assuming that the lead can- entity. It should be noted that some biologics are didate exhibits efficacy for the new indication then also simultaneously regulated under the US Federal an IND is filed with the FDA. The major difference Public Health Service Act of 1944, but this is out- is that a RRRDx is subject to the 505(b)(2) side the scope of this article. Finally upon NDA or process, which allows information from previous BLA approval, the New Molecular Entity (NME), studies to be used in the evaluation of the drug can- or New Biologica l Entity (NBE) is allowed to enter didate. Hence the lead candidate can typically the marketplace and be prescribed and sold to enter the clinical trials process after Phase I, nor- patients/consumers. A somewhat similar process is mally at Phase IIa. In the case of biologics, since required by regulatory agencies in other countries the DRPx process is so new, the regulatory and this is discussed below. All this is captured and approval is via a different route for many biolog- summarised for the DDD process under FDA reg- ics. Under the Biologics Price Competition and ulatory guidelines in Figure 1a. Innovation Act (2010) a biosimilar (or biologic for The DRPx process is remarkably similar to that a new indication) is evaluated using the 351(K) described above for DDD, and is encapsulated in process. In either case successful clinical trials lead Figure 1b. However, the discovery stage is signifi- to either an NDA or BLA and the repurposed cantly truncated since both computational biology drug/biologic ente rs the market. and phenotypic screening tools provide rapid plat- There are numerous differences when comparing form approaches1,13. Since the lead candidate has DDD to DRPx and in all cases affords benefits to most likely been subjected to safety and toxicolog- the RRRDx over the de novo derived drug. This is ical evaluation for the original indication, then the all summarised in Table 1. For example Paul has 64 Drug Discovery World Summer 2015 Drug Discovery suggested that the cost of bringing a de novo drug Table 1: Comparative analysis metrics of de novo DDD versus DRPx DDD to market is $1.778 billion12. We estimate that the a Annual sales cost of launching a RRRDx is approximately $300 million, a saving of ~85%1,2. In a similar manner, de novo DDD DRPx DDD the time and risk of bringing a RRRDx to market is also significantly reduced when compared to a de Time (Years) 13.5 6.5 novo derived drug. The differential financial analy- Cost (US $) 1.78 billion 300 million sis of DDD compared with DRPx is even starker. The Net Present Value (NPV), at an estimated 10% Risk (%) cost of capital, of a de novo drug, with calculated annual market sales of $300 million, is negative Discovery success < 5 100 $795 million and an Internal Rate of Return (IRR) of negative 3.2%. In contrast a $300 million Phase II to Launch 10 25 RRRDx has a NPV of a healthy $280 million with Phase III to launch 50 65 an IRR of 15.0%.