Oct. 10, 2007 | Call it what you will, extracting value from well-studied compounds that bind an interesting drug target, have drug-like characteristics, and offer an attractive safety and pharmacokinetic profile, but, for whatever reason, were not effective in patients, is a lesson in pharmaceutical recycling.
Such terminated chemical entities have failed in clinical studies and are gathering dust on a refrigerator shelf or taking up freezer space. But despite being abandoned, there is intrinsic value in the resources invested in their creation and characterization, the intellectual property (IP) assets they represent, and their potential worth as a source of revenue, whether for out-licensing or as the seed of a future development program or partnering opportunity yet to be conceived.
As pharma productivity lags and truly novel, safe, and effective drugs emerge at a snail’s pace, companies are increasingly willing to scavenge through the pharma equivalent of Grandma’s attic to search for hidden treasure. What has become commonly known as drug repositioning is sometimes referred to by the more utilitarian term of drug repurposing, or perhaps, reprofiling. Nix the fancy terms, though, and this effort to reposition corporate assets is nothing more than resource recycling, however with a high tech twist.
In 2005, Gene Logic saw the potential for establishing a viable business model around drug repositioning as a niche, value-added activity and built in a creative risk/benefit sharing mechanism. Two years later, with eight pharma partners on board — including Roche, Organon, Pfizer, and recently inked deals with Merck Serono and Solvay — the company views the repurposing of its corporate focus as a successful work in progress. Says Bethany Mancilla, VP of business development and licensing, “We believe the long-term value for Gene Logic lies in drug repositioning.” As part of a move toward pharmaceutical development, “We are looking at a number of strategic alternatives that will leverage the value of our genomics business.”
Looking back, Marcel van Duin, executive director and head of pharmacology at Organon, attributes the rise of interest in drug repositioning to two main factors: the emergence of enabling technology platforms capable of rapidly evaluating drug properties and demonstrating their efficacy in various models; and the recognition of potential value in compounds that failed for reasons other than toxicity.
Drug repositioning is an opportunity to “drive serendipity,” says van Duin. There is a history of successful repositioning — Pfizer’s Viagra and Rogaine, for example — that demonstrates that this serendipity exists. Exposing compounds to the full range of technology platforms can drive this process, “but you have to be realistic, it will not dramatically change the numbers of new chemical entities in development.”
Early on, Gene Logic applied its core genomics and in silico platforms to identify targets for drug screening. These efforts produced the company’s toxicogenomics initiative and BioExpress and ASCENTA databases, which have captured transcription profiles of drugs targets in more than 430 disease contexts. During this period, Gene Logic was accumulating a knowledge base of how different compound classes and individual molecules affect therapeutic targets across tissue types. The subsequent acquisition of in vivo imaging technology, in vitro pathway-based assays, and methodologies for a directed form of metabolomics from Millennium Pharmaceuticals, combined with Gene Logic’s bioinformatics capabilities, led to what Mancilla describes as a natural convergence of the companies’ business models toward offering a “third route [internal discovery and in-licensing being the first two] for pharma companies to build their late-stage pipelines and improve productivity.”
Broadening the Model
Aspreva Pharmaceuticals, from its outset, distinguished itself from other drug repositioning companies by targeting approved or late-stage drugs and searching for value-added alternative indications outside the initial strategic focus. As Michael Hayden, co-founder of Aspreva, told Bio•IT World in 2005: ‘We won’t cost you a cent. We’ll take the drug, and we’ll share the upside. You focus on the primary market; we’ll take care of everything else.”
Aspreva acquired the rights to develop Roche’s transplantation drug CellCept (mycophenolate mofetil) in all autoimmune disease indications in 2003, and this program has been at the core of Aspreva’s growth. However, the company recently announced a reorganization to focus on core activities that could drive long-term growth, along with a 25% reduction in staff. The announcement followed the June release of preliminary Phase III results showing that CellCept was not superior in efficacy to cyclophosphamide for the treatment of lupus nephritis.
“The philosophy of identifying novel applications is still at the core of Aspreva, but we are changing our tack in terms of how we might access drug candidates,” says Noel Hall, co-founder, president, and director. “The company is now also evaluating more traditional approaches to identifying drug candidates,” with in-licensing at the forefront of that strategic shift.
In light of Pfizer’s history of identifying alternative indications for some of its most successful compounds and the high rate of drug candidate failures at the Phase II clinical trial stage, Donald Frail, head, global indications discovery unit, at Pfizer Global Research and Development, believes that the industry as a whole is exploring the value of alternative indications too late in the lifecycle of a compound.
“There is an opportunity to look much earlier,” says Frail, and Pfizer has launched an internal, dedicated research group, “to explore systematically the biology/mechanism of compounds in disease models across multiple indications.” Not calling it a drug repositioning initiative, as it includes compounds still in development, Frail prefers “indications discovery.”
“I have a bias that drives our strategy,” Frail explains. “The most likely identification of an alternative indication will not be through an off-target effect, but rather an on-target effect affecting a biology in another target tissue.” One aspect of technology development that could facilitate the search for new indications is in the area of clinical informatics. “A key question, for example, is how to capture physicians observations, whether on marketed compounds or those in clinical trials,” — observations of an activity or change in physiologic response that would not be considered an adverse event, and would therefore not require reporting, but that might signal a novel mechanism of action and a beneficial response, says Frail.
Tools for Reuse
Key technology providers have bought into the concept. Melior Discovery applies its theraTRACE indications discovery platform to the systematic analysis of a single compound in multiple in vivo disease models. The company’s lead compound MLR-1023 was originally developed to treat ulcers and is now in development for type II diabetes.
Sosei targets its Drug Reprofiling Platforms in two directions — to develop new uses for marketed drugs and drug templates and for compounds that have stalled in Phase II. Several are in Phase II development in new indications including chronic obstructive pulmonary disease, cancer pain, and fibromyalgia.
KineMed leverages its repertoire of in vivo pathway-based assays to identify compounds that modulate the kinetics of select metabolic pathways. KineMed has established partnerships in the areas of atherosclerosis, diabetes, osteoarthritis, neurogenesis, and neurodegeneration with companies including Bayer, Merck, Merck Serono, Organon, and Roche.
Gene Logic says publicly that of the more than 70 drug candidates entered into its Phase R drug-repositioning program, it has found a potential new therapeutic use for 25-33% of them. GL1001, acquired from Millennium and repositioned to treat inflammatory bowel disease has completed in vivo proof-of-concept testing. Gene Logic is seeking a clinical development partner for the drug.
Thomas Barnes, now senior VP of discovery at Gene Logic, admits that when he was part of the Millennium start-up group, their first presentation of the drug repositioning strategy to venture capitalists was met with skepticism on multiple levels. Could the company identify new indications of value? Could it extract desirable molecules from pharma? Could it structure agreements based on milestones and royalties needed to fuel the business model? And could it convince pharma to assume the risk of taking an abandoned molecule back into development?
“Pharma has learned so well and is accepting the value proposition so much that now we have to compete with their own internal [repositioning] efforts,” says Barnes. Outside the United States, Gene Logic found that before it could even try to persuade companies to consider drug repositioning it had to help them “understand the concept that when you kill a molecule it is not necessarily dead.”
Two facets of Gene Logic’s strategy deserve particular attention. First is its proactive approach. It scours databases for compounds left by the roadside that it deems suitable for its repositioning program. It then approaches a pharmaceutical company with a list of compounds of interest and asks whether they are available.
Second is its risk-sharing business model, in which, “we give the partner the first bite of the apple,” as Mancilla describes it. Partners may opt to resurrect a compound and reestablish an internal development program focused on the new target or indication, with Gene Logic sharing in any future success.
“If a partner remains uncertain about a compound’s potential once a new indication or therapeutic target has been validated, we may decide to work with the partner to pursue additional testing and further de-risk the program for pharma, explains Stephen Donahue, senior VP of clinical development at Gene Logic. If the partner declines the opportunity, Gene Logic has the option to move the validated compound forward, in which case the company would likewise share any future gains with its partner.
At the heart of a drug repositioning agreement are “drugs that failed in a well-behaved way,” says Barnes. They pass through early stage safety trials untarnished, with no significant adverse effects, and either falter in efficacy studies or are discontinued due to reasons unrelated to clinical development, such as budgetary issues, duplicative/parallel programs, or portfolio deprioritization.
Gene Logic asks two things of its partners: provide five grams of material for each compound and reveal the real reason for termination. These discussions may begin to stray into areas of corporate sensitivity regarding intellectual property, strategic planning, and ongoing in-house and collaborative programs.
Organon’s van Duin explains that it is not easy to retrieve historical data from discontinued projects. “There is no VP of failed compounds,” he says.
Revisiting and assessing data that were once the focus of intense interest may require information known only by the people who oversaw those projects. Companies need to decide whether to reprise a molecule based on a re-exploration of why the compound was killed in the first place and its predicted or potential new value in relation to the company’s current internal development, partnering, and licensing philosophy.
Perhaps one of the most sensitive aspects of collaborative drug repurposing is the act of releasing a pharmaceutical compound to another company for evaluation, especially compounds with a relatively lengthy history of investment, development, and testing. Strategic assets are prized and protected and, as a rule, pharma does not readily share intellectual property, knowledge, or compounds.
But if greater sharing of knowledge and molecules between drug development partners and niche technology providers can bring more new drugs to market and improve productivity, then those barriers may weaken.
Likewise, if drugs that have already received significant investment for proof-of-concept studies, toxicology and pharmacokinetic profiling, and safety testing in humans can be repositioned and successfully commercialized for a different indication or, in concert with efforts toward personalized medicine, for use in a defined patient population, then discontinued and stalled compounds will have the potential to be revenue producers and partnering vehicles.
Regardless of what you call it, more companies are open to the idea of exploring more broadly the potential of proprietary molecules before relegating them to the developmental dustbin.
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