Synta's elesclomol fails Phase III melanoma trial
This article was originally published in Scrip
Synta Pharmaceuticals has suspended the closely watched Phase III melanoma trial of its promising novel drug elesclomol (STA-4783) – its lead candidate which it was developing with GlaxoSmithKline – after an independent data monitoring committee (DMC) identified serious safety concerns, including more deaths in the experimental arm compared with the control chemotherapy arm.
Shares in Synta, which inked a deal worth up to $1.01 billion with GlaxoSmithKline in October 2007, fell 79% on Nasdaq on February 27th after the news was announced. DrSafi Bahcall, Synta's chief executive, called it a "stunningly disappointing day" for the company and the patients and physicians who had participated in the trial.
The 630-patient international Phase III SYMMETRY trial enrolled patients with metastatic melanoma who had not received prior chemotherapy but who may have already been treated with non-chemotherapeutic agents such as biologics. Patients were randomised to elesclomol plus paclitaxel chemotherapy or paclitaxel alone.
"We are enormously disappointed for melanoma patients, particularly because there are so few treatment options available. We will be working hard over the next several weeks to analyse and better understand the results from this trial," said Dr Eric Jacobson, Synta's chief medical officer. Metastatic melanoma has proven to be one of the most difficult tumours to treat, with many drugs having failed and poor median survival that is generally less than one year with standard chemotherapy.
"We will present detailed results in an appropriate scientific venue as soon as a full analysis has been completed. In the interim, we will be in discussions with our collaborator, GSK, about the future development of elesclomol," said Dr Bahcall. No decisions have been made yet about the elesclomol programme, he said, but ongoing clinical trials of the product, including a Phase I/II trial in prostate cancer, have been suspended pending further analysis of the results of the melanoma trial.
The Phase III result came as a complete shock, Dr Bahcall added. "There is nothing short of a train falling on my head that could have surprised me more than what we found out yesterday," he said during a conference call. "Many questions are raised by these data which came as complete surprise to us.What could explain such dramatic difference between this study and our prior study?Did post study treatment effects contribute to the imbalance in survival?What drove the unexpected increase in adverse events?" He said the company did not yet have answers but would be working hard over the next weeks to learn more.
As recently as December, the DMC had conducted an interim futility analysis and recommended the trial continue. Neither at the December meeting nor at previous meetings did it notify Synta of serious safety concerns, the company said.
Even after the recent February meeting with the DMC, the company does not have a lot of detail about the cause of increased deaths in the experimental arm, said Dr Jacobson. "We haven't had a chance to fully analyse data and understand what the safety signals are." Synta was unable to comment on whether the imbalance in deaths was due to safety or efficacy.
The efficacy analysis of the trial is continuing as well. Although there was a trend towards improved progression-free survival (PFS) – the trial's primary endpoint – it was unlikely to meet significance, Dr Jacobson said. Overall survival data are still immature.
The Phase III results are particularly unexpected after the promising Phase IIb data. In the 81-patient randomised trial, which convinced GSK to strike a deal for the compound, there was a significant improvement in PFS (the primary endpoint) for the drug in combination with paclitaxel compared with paclitaxel alone. Although overall survival was not an endpoint in the trial, survival in the experimental arm was improved compared with chemotherapy in historical trials (scripnews.com, October 16th, 2007).
Synta has not yet disclosed the target of its drug. However, the company has said that it is in a new class of agents called oxidative stress inducers, which work by increasing the amount of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide in cells, which leads to programmed cell death via the intrinsic mitochondrial apoptotic pathway. Existing chemotherapy drugs, including paclitaxel, may lead to an increase in ROS, but in most cases this is a consequence rather than a cause of apoptosis, Synta said. This is a significant difference because ROS increase is non-toxic to normal cells, while the primary mechanisms by which cytotoxic chemotherapy work are often toxic to both cancer and normal cells.
While all cells have some low level of ROS, cancer cells naturally operate with a higher level relative to normal cells. Elesclomol only kills tumour cells because it induces additional stress that pushes cancer cells, but not healthy cells, over the critical threshold, Synta says. ROS inducers include arsenic trioxide, a marketed cancer drug, and Pharmacyclics' investigational candidate Xcytrin (motexafin gadolinium) which was recently discontinued for its lead oncology indication after the FDA issued a non-approvable letter.
If elesclomol is discontinued, Synta plans to focus on advancing its Hsp90 inhibitor, STA-9090, which is in two Phase I dose escalation studies in solid tumours. It expects data by the end of the year. Although many companies are developing Hsp90 inhibitors, Synta says that its compound has shown higher potency and a better safety profile in preclinical models than many of the others. It also has another drug, apilimod, in Phase IIa development for rheumatoid arthritis.
Dr Bahcall said that the company has "more than enough cash to develop the next set of programmes to clinical proof-of-concept". On its third quarter 2008 earnings call, Synta said that it expected to end the year with between $65 million and $70 million in cash and receivables. Synta also recently concluded an agreement with Roche for the development of the Synta CRACM (Calcium Release-Activated Calcium Modulator) programme for the treatment of inflammatory and autoimmune diseases, and which provided an up-front payment of $16 million in cash as well as committed research funding of $9 million over the next two years and full preclinical and clinical cost reimbursement. Synta also recently announced that had achieved a milestone related to the development of elesclomol, earning an additional $10 million payment from GSK.