CMR Technology Watch: CombinatoRx and Synergistic Drug Combinations

11 August 2003 00:00  [Source: ICB Americas]

Who would have predicted that combining a drug for pneumonia with a powerful antipsychotic would yield a promising candidate for the treatment of cancer? And yet that is what a team of researchers at Boston-based CombinatoRx Inc. have done. Described in the June 24 Proceedings of the National Academy of Sciences, their discovery is not a fluke but the result of a systematic effort to identify synergistic combinations of known drugs with novel patterns of activity.

Founded in 2000 by researchers from Harvard and the Massachusetts Institute of Technology (MIT), the company has already identified at least a dozen lead compounds, several of which are in Phase I clinical trials.

Investors are convinced. The latest round of venture financing, which ended in the summer of 2002, brought CombinatoRx $40 million, putting total capitalization at $58 million. In recognition of the achievement, president and CEO Alexis Borisy was two months ago named Ernst & Young New England Entrepreneur of the Year in the category of biopharmaceuticals.

Drug companies are also coming on board. In April 2002, CombinatoRx announced a research collaboration with Sosei Co. Ltd., a Tokyo-based biopharmaceutical company, to discover new combination drugs and validate new indications in a broad range of disease areas. Sosei expects the collaboration to significantly advance its Drug Reprofiling Platform (DRP), which is reevaluating hundreds of Japanese compounds not being developed or actively marketed in Japan for reasons other than toxicity.

"Not only are we able to uncover new uses for the DRP compounds as single agents, but we are also able to discover combination drugs in which our DRP ingredients demonstrate a novel benefit in combination," said Shinichi Tamura, Sosei CEO, at the time of the announcement.

The company has several other undisclosed alliances as well.

Combination drugs famously demonstrated their potential with the success of HIV cocktails discovered in the late 1990s. They have made more recent headlines as well: In June, Pfizer announced the results of Phase II trials for the treatment of drug-resistant malaria using Zithromax and chloroquine. Pfizer scientists found that 28 days after taking chloroquine, only 31 percent of the patients treated were free of symptoms. For Zithromax, the number was 38 percent. When the two drugs were taken together, however, the success rate rose spectacularly to 96 percent-far in excess of any simple additive effect. Phase III trials are being planned.

Impressive as this result may be, combining the two was a reasonable hunch. Both drugs are antibiotics, and chloroquine has been a standard treatment against malaria for 30 years..

CombinatoRx, on the other hand, has made a mission of finding odd but efficacious combinations. "Physicians mix drugs all the time and find beneficial effects, but they have looked at less than 1 percent of potential combinations," says Alexis Borisy, president and CEO of CombinatoRx. "We have created the capability to look at the rest and have identified many entirely novel and non-obvious combinations which are now moving into clinical testing."

Systems biology is the theoretical heart of CombinatoRx's approach. Traditional drug discovery programs take a fairly direct approach aimed at finding molecules to modify a single gene or protein. In many diseases, however, the cellular signaling networks at their root contain redundant and self-buffering pathways, so that modulating a single pathway cannot achieve the desired effect. Similarly, when several cell types are involved, influencing only one may be insufficient. The complexity of such systems prevents any single "magic bullet" from effectively interfering with the disease process.

While the biological premise for systems biology is sound, finding combinations that affect networks can be quite challenging. The numbers grow exponentially; a library of just 2,000 molecules, for instance, will form 1,999,000 paired combinations.

CombinatoRx addresses these problems by using high-throughput screening against cell-based phenotypic disease assays. A custom-designed informatics backbone identifies synergistic effects, and the combinations responsible are further profiled to determine their mechanism of action and product suitability. The libraries are comprised of known active pharmaceutical ingredients, which have the advantages of recognized pharmacology and toxicity profiles, established safety in humans and proven manufacturing and formulation feasibility.

Several examples appear in the June PNAS paper. In total, over 120,000 different pairs were screened for synergistic effects in inhibiting growth of fluconazole-resistant Candida albicans; enhancing the activity of fluconazole in fluconazole-resistant C. albicans; cytokine modulation in primary human blood cells; and inhibiting the proliferation of cancer cells.

Notable results include the discovery that combination of the fungistatic agent fluconazole with the urinary tract analgesic phenazopyridine (PAP) yields a fungicide that does not significantly affect human cells. PAP itself has only modest antifungal activity, a fact never before reported. Further studies showed that the two compounds together affect membrane pump activity, though neither agent on its own has such an effect.

The researchers also found that the pairing of the glucocorticoid dexamethasone and the antiplatelet agent dipyridamole effectively prevents the production of tumor necrosis factor-alpha in primary human blood cells. Both agents individually show TNF-alpha suppresive effects, but their combined action in vitro has never been described, the authors note, and the current understanding of their modes of action would not have supported a prediction of the observed interaction effect.

In their studies of cancer cells, the group found that pairing the antipsychotic chlorpromazine (Thorazine) with the antiprotozoal pentamidine (neither of which alone showed substantial activity) prevented the growth of lung carcinoma cells not only in vitro, but also in vivo, in a human tumor xenograft assay in mice. The paper's authors observe that the combination was even more effective than the anticancer drug paclitaxel, at concentrations of the two drugs that correspond to clinically achievable plasma concentrations. Further, the mice exhibited no loss of body weight nor any of the visible behavior changes typically found in mice treated with standard chemotherapeutics.

Additional work is being done to determine whether these and other combinations uncovered by the study will succeed in humans, but there is no question that combination high-throughput screening (cHTS) has been validated as a discovery technology. "This method enables us to unlock an enormous set of potential therapeutic combinations that, left to traditional methodology, may have never been discovered," says Brent Stockwell, a co-author of the paper, member of CombinatoRx's advisory board and fellow at MIT's Whitehead Institute.

Even combinations that do not make it to market can nevertheless have great usefulness in studying the cellular pathways at the root of disease, he adds. "Our screening approach is complementary to other methods for exploring biological systems and protein networks and may be useful for studying the underlying biological pathways responsible for disease. New drug combinations can be used as probes to study how changes in disease networks impact disease outcomes in model systems such as mice."

-Clay Boswell

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