"One of the things you learn from years of dealing with drug people, is that you can turn your back on a person, but never turn your back on a drug."

                    - Raoul Duke, Fear and Loathing in Las Vegas

"In the field of observation, chance favors only the prepared mind."

                    - Louis Pasteur

The above quotes allude to the growing realization that new opportunities exist for many "old" drugs, but sophisticated knowledge management platforms will be needed to properly identify these drug repositioning opportunities.

Amid the "fear and loathing" accompanying the numerous reports of the drug development pipeline drying-up, the biopharmaceutical industry is warmly embracing the drug repositioning model as an efficient and expedited mechanism to fuel their clinical development programs with "old" drugs that have newly appreciated indications.  At the recent Drug Repositioning Conference held in San Francisco, CA on July 13-14, 2011, industry experts convened to share their insights from their own drug repositioning experiences, to discuss the impact drug repositioning has had on the drug development landscape, and to assess new directions for the field.

The concept of drug repositioning (or repurposing) is not new.  In the past, serendipitous observations played a principle role in identifying novel uses for approved drugs already on the market for other indications, noted Pankaj Agarwal, Director of Computational Biology, Molecular Discovery & Development at GlaxoSmithKline.  Aspirin serves as a classic example.

What is new however is that biopharmas, including Merck Serono, AstraZeneca and GSK, all of whom were represented at this conference, are now placing a premium on leveraging their prior research and development (R&D) investments to rescue stalled clinical-stage compounds by re-investigating their efficacy for treating alternative new indications.

Given the high attrition rate of experimental drugs, drug repositioning offers a "solution for speedy re-introduction of compounds back into the pipeline," commented Natalia Novac, Associate Manager, R&D Knowledge Management Operational Excellence at Merck Serono.  While Novac commented that Serono's original repurposing business model had focused on Phase 3 clinical compounds, they now realize that they need to start earlier, after a drug passes Phase I safety and toxicity testing, to plan for secondary indications.  Others in the audience advocated preparing even earlier, at the preclinical stage in the product lifecycle, a practice adopted at Pfizer, to identify potential alternative indications that could be used either as a back-up, if efficacy testing for the primary indication fails, or as a repositioning strategy.

Some in the audience challenged the notion that only drugs that have passed Phase I harbor future value for repurposed use, indicating that a drug that failed its initial Phase I study when delivered at a high dose could be safely delivered at a much lower dose that fell within the therapeutic window for the treatment of an alternative indication.  Taken together, these divergent criteria argue the utility of broadening eligibility to include all clinical compounds (and perhaps even preclinical compounds) under consideration for repositioning.

Knowledge Management: Pillar of the Drug Repurposing Approach

Nowadays, biopharma is not leaving these hidden, yet potentially golden, repositioning opportunities up to chance alone.  There is a concerted effort within biopharma to capture and organize the vast amounts of existing public and proprietary data into rich knowledge networks of biological pathways and disease targets.

Merck Serono, AstraZeneca, and GSK are all heavily investing in various Knowledge Management platforms.  Speakers mentioned a host of existing automated technology platforms that review texts (i.e.: publications, abstracts, clinical case reports, etc.), extract entities (i.e.: proteins X and Y) and build relationships between entities (i.e.: protein X activates protein Y) to create biological knowledge networks. These networks could be overlaid onto disease specific network maps to facilitate identification of key, possibly novel, disease targets.  This type of approach could also be used to identify the relevant indication(s) based on their drug's established mechanism of action.

In addition to fully automated platforms, organizations such as Thomas Reuters offer MetaMiner Partnerships to "bring the highly specialized expertise in manual curation and disease map development to create new pathways quickly" for its clients.  In a collaborative move, Reuters launched a new consortium in July 2011 to map the bioprocesses for all FDA drugs approved in the last three years.

Spotlight on AstraZeneca's high-investment foray into drug repurposing

AstraZeneca's aptly named New Opportunities group has been tasked with finding new opportunities for existing compounds in areas that the company is currently not working in.  Regenerative medicine is one such new area, remarked Nick Brown, Associate Director of Informatics for AstraZeneca's New Opportunities group. Orphan diseases were also considered attractive gateway indications, suggesting that ALS could be within AstraZeneca's sights if the right opportunity were to be identified.

AstraZeneca is going further than most when building their Knowledge Management Platforms.  As Brown explained, his group is in the process of bringing together over 2000 proprietary internal databases from across AstraZeneca's global reach.  He admittedly faces a huge standardization challenge, but makes the point that these disparate databases contain tons of valuable proprietary information about their own drugs that remain relatively inaccessible.  Brown strongly believes that re-capturing this propriety information "hidden away" will reveal novel and lucrative repurposing opportunities for AstraZeneca. Brown has also developed a rich Asset Repositioning Matrix that has already led to the identification of new disease targets and indications, as well as, potential collaborators and key opinion leaders.

The 20-member group functions as a virtual R&D with a budget comparable to one of AstraZeneca's therapeutic areas, underscoring their confidence in and commitment to the repurposing strategy.  Formation and funding of this group also emphasizes AstraZeneca's belief, also expressed frequently by other conference attendees, that factoring human data into the knowledge maps is "huge". Given the size of AstraZeneca's investment and commitment it was interesting that the primary focus to date for this group had been on late stage Phase II or III compounds in clinical development, suggesting that a considerable amount of Phase I and pre-clinical information still remained untapped.

The value proposition behind the drug repositioning approach is obvious: generate new revenue streams by leveraging prior capital- and resource-intensive investments and in so doing offer patients better treatments.  While the opportunities are vast, there are several important limitations, including issues of commercialization, patentability, freedom of use, and the regulatory path to approval, to name just a few. Not to fear - speakers including commercialization expert David Cavalla, regulatory expert Ken Phelps, and patent attorney Kevin McLaren, discussed a slew of strategies to work through these vital issues.  Further discussion of these issues can be found here and here.

So given the buzz generated at this conference, my question is: can ALS drug development benefit from a drug repositioning approach?

One way I thought about this was in terms of speed.  The critical need for expedited drug development for ALS is underscored by the aggressive and merciless progression of disease resulting in death typically within three years after diagnosis.  Clinical development of a repurposed drug could significantly shorten the traditional drug development timeline and bring an efficacious drug to patients faster and, in so doing, offer access to more ALS patients.

Ok, so yes, repositioning saves time, but is it relevant to ALS?  As noted by speaker Chris Lipinski, Scientific Advisor at Melior Discovery, 30% of clinical compounds have new uses and (strikingly) 90% of these new uses are on-target.  These findings indicate that rather than finding new molecular targets for old drugs, we are discovering the relevance of these druggable targets in new indications, implying that there are major gaps and flaws in our fundamental understanding of disease biology. 

Final thought: As our understanding of ALS biology deepens and disease targets are further validated, a drug repurposing approach could be a valuable complement to traditional ALS drug discovery efforts. 

So who's with me?

- Sheila Menzies, PhD, Scientific Program Officer at Prize4Life