Small but mighty

LAUSANNE, Switzerland—Debiopharm and cancer drug firmAscenta Therapeutics have reached an exclusive license agreement for thedevelopment and commercialization of Ascenta's Phase I stage candidate AT-406.

AT-406 is an orally available small molecule that isdesigned to neutralize major inhibitors of apoptosis. AT-406 was discovered inthe laboratory of Dr. Shaomeng Wang at the University of Michigan. Clinicaltrials with AT-101 are ongoing in the United States and Europe. Phase Iand Phase II trials evaluating AT-101 as single-agent therapy have alreadydemonstrated cytoreductive activity in several cancers, including chroniclymphocytic leukemia, non-Hodgkin lymphoma and prostate cancer. Phase II trialsevaluating AT-101 in combination with chemotherapy and/or radiotherapy havealso been carried out in a number of cancers including hormone-refractoryprostate cancer, non-small cell lung cancer, B-cell malignancies, small celllung cancer, glioma and esophageal cancer.

Debiopharm will designate the molecule Debio 1143. Themolecule is designed to block the activity of a number of IAPs including XIAP,c-IAP1, c-IAP2 and ML-IAP.

Dr. Rolland-Yves Mauvernay, president and founder ofDebiopharm, says it should be possible to combine Debio 1143 with otherpro-apoptotic agents, which could potentially bring huge benefits to patients byenhancing the efficiency of the treatment.

Evasion of apoptosis is a hallmark of cancer, enablingcancer cells to live indefinitely and grow uncontrollably. Most current cancertherapies, including chemotherapeutic agents, radiation and immunotherapy, workby inducing apoptosis. However, because of molecular alterations in theapoptotic pathways, many cancer cells are resistant or develop resistance tothese agents. A promising new direction for drug development involves targetingapoptotic pathways directly to induce cell death and/or restore sensitivity toother treatments.

According to Maurice Wagner, director of corporate affairsand communications for Debiopharm Group, the timeline to develop thesmall-molecule IAP inhibitor may be hard to gauge at this stage, as Phase Iclinical trials have yet to be completed.

"In any event, we will proceed as quickly as we can, whilstobserving all safety standards," he says. "As is our business model, we willnot commercialize the drug ourselves, but license it out in due time to acompany that can sell and market it internationally. The out-licensing partnerwill be selected at a later stage."

Looking forward, Wagner says as the company proceeds withdevelopment, it will set objectives to reach.

"We will in particular design carefully clinical studies incancers with high medical needs," he explains. "Our success will depend uponwhether we can reach our objectives. In the short term, successes might be related to preclinical synergisticactivity of Debio 1143 and other anti-cancer agents, and most importantly,obtaining encouraging clinical data from the ongoing Phase I study. Thelong-term success will depend upon our finding a good combination in theclinics, such as a combination that will prove therapeutically superior to thestandard of care."

According to Wagner, the company has worked with Ascenta inthe past few years, but this is the first time that the two companies haveentered into a partnership with each other.

Wagner says there were two factors that led Debiopharm totarget Ascenta as a collaborator for this effort: "We saw the expertise ofAscenta in the field of apoptosis, and the quality of the relationship that wecould establish with the Ascenta team," he says.

Mel Sorensen, president and CEO of Ascenta, says Debiopharmproved to be an attractive collaborator because of its commitment to andexpertise in the development of medicines to help cancer patients.