Drug repositioning – a key tool in the drug development arsenal

Drug development pipelines have been a major indicator of the health of the pharmaceutical industry itslef. However if we look at recent trends, the simple truth is that many company pipelines are drying up and most are not growing at the desired pace. A second indicator which is the "return per dollar spent in the lab", has itself been steadily decreasing. In response to these, pharmaceuticals have been trying tactics such as “light reformulations” of drugs that extend patent protection and company buyouts that instantly grow their pipelines with new drugs and compounds. These tactics however are by necessity short lived since regulatory bodies and the patent office, under increasing pressure from the public and generics companies, are beginning to tighten their criteria and we will eventually begin to run out of companies that are worthwhile to buy.

To take the example of intellectual property protection, in the next 5-10 years approximately 300 drugs from every major Pharma will suffer from patent expirations and loss of exclusivity (LoE). “The immediate danger facing [Big Pharma 1] is the…expiration of … patent rights ... Generic companies will stage a run on at least 14 [Big Pharma 1] patents — and 70% of its sales — over the next five years; [Big Pharma 1, 2 and 3] are staring down the barrel of similar patent expirations.” (Wall Street Journal Editorial, January 28, 2009).

Enter drug repositioning, the process of applying an existing drug or compound to a new indication. Drug repositioning (a.k.a drug re-tasking and drug repurposing) holds significant promise, not only because it saves significant amounts of cost, it also promises to cut down the development period for a marketable drug by 15-20%. The promise is such that certain major Pharma companies are directing 50% or more of their pipeline effort to new uses of existing drugs. For example, at the Analyst Day of 5 March 2008, Pfizer indicated that 50-60% of its Phase II to Phase III transitions would be existing drugs in new indications.

Drug repositioning is not a new idea. It has been happening since the early 1990s, mostly though as a serendipitous process. In recent years however a number of companies have developed tools to make the process more systematic. Most use mathematical or other models that by necessity make certain assumptions and may omit seemingly unrelated but probably relevant knowledge. They also tend to focus on the benefit side of the equation i.e. finding the new application for the compound or drug. Some companies such as Biovista however, go a step further by simultaneously addressing the risk side of the equation, namely the adverse effects profile, making for much more balanced predictions of the clinical outcome of the repositioned drug.

Biovista’s Solution
Biovista systematically screens for biologically plausible new indications for existing drugs that can be patented, thus securing expanded market rights, and also reducing threats from drug class followers or generics. Biovista’s solution revolves around its proprietary Clinical Outcome Search Space of over 8,000 indications and 8,000 AE’s, which is screened by over 12,000 marketed or generic drugs to find mode of action (MoA) matches. By starting with existing drugs, meaning mature chemistries about which a very big efficacy/safety knowledge set already exists, Biovista’s development starting point is at least 3 years ahead of typical target validation and hit screening programs. There are two major applications for Biovista’s solution:

1  Drug Repositioning: Biovista systematically screens for alternative uses of existing drugs ahead of prior art. In addition, it screens for plausible combinations of drugs that may enhance the ability of a drug to meet its end point.
2  Drug De-Risking: Biovista can identify with a high degree of accuracy what the rare or unusual (AEs) could be associated with a drug, a target, or a drug combination, prior to clinical trials. It can also help identify AEs for a specific patient group (e.g., Asian, pediatric or geriatric), and can help distinguish effects that are due to the drug or the disease. Biovista combines systematic repositioning with simultaneous drug de-risking to improve the Benefit/Risk ratio of the drugs in its portfolio, or those of its partners.

Impact for the Pharma Industry
Biovista's clinical outcome platform represents a major new tool that promises to impact the industry in the following ways:
1  Save time and money in developing safer drugs for more indications than initially screened for. It may also help reduce the risks of withdrawals because of lack of efficacy.
2  Streamline the application process by helping avoid surprises with the FDA that could result in Clinical Hold or, worse, withdrawal. Most such events happen because the Benefit/Risk value of the drug was not fully explored or explained.
3  Help maximize a drug’s asset value. By finding more indications where a drug can be safely used, the investment in development is better leveraged than if the drug was marketed in just one disease.
4  Help gain time and competitive space. By finding new uses of drugs prior to any public citations, a major competitive advantage is secured. By filing the new patents, Biovista offers two major benefits for Pharma:
    ⁃  An offense strategy – by expanding drug uses and opening up  new markets
    ⁃  A defense strategy – by protecting itself against drug class followers, competitors or generics from encroaching into its space with their own drugs.

Validation of Biovista’s Technology
As with any modeling resource, it is essential to have as accurate an assessment as possible of its predictive and other performance capabilities so as to deploy it only in those circumstances where it is shown to deliver meaningful results. In a blinded study  (manuscript submitted for publication), Biovista accurately predicted an average of 70% of the AEs presented in over 50 clinical trials at the annual meeting of the American Association of Clinical Oncologists (ASCO 2007), with data from 1997 and before. Predictive performance actually varied from 80%+ to 60% over a predictive window of from 3 to 8 years. In September 2008, the Biovista platform was put to good use by Cempra who de-risked drugs of interest and explored their potential for additional indications.

Technology, Workflow and Timeline
Biovista’s proprietary technology works by first describing in very deep terms how a disease, a drug , a target or an AE work, which is known as MoA analysis. It then compares the MoA’s of over 12,000 marketed drugs against the MoA’s of over 8,000 diseases and 8,000 AEs for matches. Once a match is found, then the new disease IP for the drug is filed and experiments are initiated with service providers. It takes Biovista 30-45 days to de-risk and reposition a drug, including full biological plausibility and the outline of the clinical development plan. This rapid timeline is a major advantage for Biovista and its partners, since the Biovista drugs are essentially ready to enter Phase IIa clinical trials in a very short period of time and carrying a unique time, accuracy, lack of bias and cost advantage.

It typically takes the industry an average of 10 years and about $1billion to develop a drug for a disease. The Biovista approach uses the untapped medical potential of already existing drugs to short-cut this process, and deliver drugs in clinical trials in 1-2 years, instead of 5, and for $3-5MM per Phase II start, instead of $50 million. Given that the value of a drug after successful Phase II clinical trials can exceed $200MM, it becomes clear that in the current industry climate, approaches such as these make a lot of sense.

The Biovista  platform is already being used to create IP and develop a pipeline
Casting a strong vote of confidence in its technology, Biovista has initiated its own multi-million drug repositioning effort in several indications, where the drugs meet three major criteria:
  a  they display significant biological plausibility as disease modifying potential therapies for the new indications,
  b  they have a superior safety profile to drugs used as current standards of care, and
  c  there is no prior art in the patent or scientific literature linking them to the new indications.

Currently, Biovista has initiated animal model proof of concept studies in multiple sclerosis, macular degeneration and epilepsy, with oncology, diabetes, obesity and cardiovascular disorder studies starting later in 2009. Biovista has filed five patents to date covering 12 drugs in MS, AMD and epilepsy, with others in process.