Synta Readying 2 Key Lung Cancer Trials

Synta Pharmaceuticals (NASDAQ:SNTA) is gearing up to begin two key clinical trials in non-small cell lung cancer (NSCLC) with its two novel compounds – ganetespib and elesclomol – that are being closely watched by potential Big Pharma partners.

“Both are differentiated from anything else that’s out there,” CEO Dr. Safi Bahcall says in an exclusive interview with

Ganetespib is a potent, second-generation inhibitor of heat shock protein 90 (Hsp90), a well known cancer target. Hsp90 is a molecular chaperone required for the proper activation of many cancer-promoting proteins and is recognized as a key facilitator of cancer cell growth and survival. “It is one of the highest priority cancer targets because of its critical role across multiple cancer indications and in promoting resistance to chemotherapy as well targeted therapies,” he adds.

At a meeting of the International Association for the Study of Lung Cancer in February, Synta presented positive preliminary Phase 2 clinical data for ganetespib in treating NSCLC. In 33 patients with stage 3b/4 lung cancer, three had durable objective responses, ten had lesion tumor shrinkage, and 22 achieved lesion stabilization.

In a recent report, Roth Capital Partners analyst Andrew Vaino said ganetespib is the “most promising current Hsp90 inhibitor” in development and is poised to be the first second-generation Hsp90 inhibitor to make it to a Phase 3 clinical study. “While the preliminary data presented are early-stage … that 66% of patients experienced lesion stabilization shows, to us, a strong sign of activity.”

Ganetespib’s “safety appears remarkable,” Mr. Vaino added, with diarrhea, fatigue and nausea being the most common adverse events. Several multinational drug companies have stopped work on their second-generation Hsp90 inhibitors after patients experienced retina damage, which hasn’t been a problem for the more than 350 patients treated to date with ganetespib.

Dr. Bahcall says Synta is targeting lung cancer, because “we have seen convincing evidence of clinical activity in lung cancer.” He adds, “We have seen a number of patients who failed to respond to standard therapies, show definitive responses after receiving ganetespib.”

In addition to Synta’s focus on NSCLC, ganetespib is currently being evaluated in a broad range of investigator-sponsored cancer clinical studies, including NSCLC, breast, prostrate, pancreatic, colorectal, gastric, small cell lung, ocular melanoma, liver, gastrointestinal stromal tumors and hematologic cancers. “While these other trials are still quite early stage, we are seeing interesting signs of activity in gastric and breast cancer,” he adds.

Synta plans to begin a pivotal two-stage Phase 2b/3 clinical trial in the current quarter, treating second-line advanced NSCLC patients with ganetespib in combination with the chemotherapy, docetaxel. Preliminary results from the Phase 2b portion are expected either at the end of 2011 or the first quarter of 2012.

The Phase 2b portion of the trial, which will enroll about 240 patients, is designed to assess progression-free survival and safety and identify if there are any special subpopulations of patients that get the most benefit from the drug.

The Phase 3 portion of the trial will enroll some 500 patients, with overall survival as the likely primary endpoint. It will start in the early part of next year, with interim data available by the end of 2012 and final data the following year.

Dr. Bahcall says Synta also has seen encouraging data that radiation therapy can be more effective with ganetespib. He says, “Ganetespib inhibits some of the known repair mechanisms that are activated when cancer cells are irradiated. By suppressing these repair mechanism, ganetespib appears to enhance the activity of this type of treatment.” He adds that the company is considering another trial this year to examine the drug’s benefit with radiation therapy.

“The partnering interest we’re seeing for the ganetespib program is based on three things: the clear evidence that the compound is clinically active; that it has an unusually well tolerated safety profile for an active systemic therapy; and of course, the very large potential markets being addressed – multiple cancer indications, with very high unmet needs,” Dr. Bahcall says.

He is confident the company will conclude one or more partnerships this year. “We have four promising programs, each of which are in active partnering discussions. The discussions around ganetespib are moving along well, but we’ve seen good interest in each of these programs. The number of independent programs increases our confidence that we’ll identify one or more partnerships that we will want to enter into by the end of the year, whether it is for ganetespib or one of the others.”

Last month, at the American Association for Cancer Research (AACR) annual meeting, Synta outlined additional research findings for ganetespib and updated the mechanism that its elesclomol drug uses to target cancer cell metabolism.

“Elesclomol works very differently than conventional chemotherapies or ‘targeted’ therapies which inhibit various cell signaling factors. Elesclomol targets the energy source – the power plant – of cancer cells: the mitochondria,” Dr. Bahcall says.

Citing the drug’s novel approach, he acknowledges that it has taken some time to understand why the drug worked in certain patients and not in others.

“Over the past year, our scientists have discovered that there is a marker that can differentiate between patients in which elesclomol is likely to be active and those in which it is not. That marker ties to the mechanism of action – the marker is a reflection of just how much a cancer cell is relying on the mitochondria for energy,” he explains. “Essentially, our drug targets active mitochondria, which requires oxygen. When cells have active mitochondria burning oxygen, treatment with elesclomol kills the cell; when cells do not have enough oxygen for active mitochondria, elesclomol doesn’t work. The marker our scientists identified is a way to measure, in the blood, to what extent cancer cells have active mitochondria.”

Using a running analogy, he points out that there are two types of running state: the aerobic, or jogging state, in which there is enough oxygen available for normal energy production in muscle cells; and the anaerobic, or sprinting state, in which cells rapidly exhaust available oxygen supply. There is a marker in the blood of the anaerobic sprinting state – the lactic acid buildup, which you feel as muscle burn. That’s analogous to what happens in cancer cells, he says. “Cancer cells in the jogging regime are killed by elesclomol, and the cancer cells in the anaerobic or sprinting regime are not killed. The biomarker we use to distinguish between the two is the analog of lactic acid build-up in runners.”

Dr. Bahcall says Synta has looked at the randomized trials that it ran with elesclomol and found clinical activity in patients who were in an aerobic state, the “joggers”. There was no clinical activity in the anaerobic state, the “sprinters”.

“This finding is exciting to all of us, because it represents a new type of drug and a new way of identifying just those patients who are likely to benefit,” he adds. “Targeting cancer cell metabolism in this way is an entirely novel approach to treating cancer, distinct from chemotherapy or cell signaling inhibition. Cancer metabolism is emerging now as one of the most exciting areas in cancer research.”

Investigator-sponsored clinical trials of elesclomol in acute myeloid leukemia and ovarian cancer are currently underway, and Synta expects to initiate a Phase 2 trial of elesclomol in non-small cell lung cancer by mid-year, he says, adding that research is continuing on several other cancer types, because the compound applies to many different cancers. “And that becomes very significant,” Dr. Bahcall adds.

While Synta’s inflammation program is still in the research stage, it includes drug candidates designed to inhibit the production of cytokines interleukin-12 and interleukin-23 and compounds that modulate the calcium-signaling pathway in immune cells that drive inflammatory responses in rheumatoid arthritis, psoriasis and inflammatory bowel disease.

“Essentially, what we’re developing are oral drugs that can suppress key proteins that drive inflammation,” Dr. Bahcall says. That compares with anti-inflammatory drugs like Remicade and Embrel, which are injected. “Our goal is to improve the activity and reduce the toxicities compared to currently available treatments. Most currently available therapies are either too toxic to be broadly used, or not sufficiently targeted to modify any more than just the symptoms of serious inflammatory or autoimmune disorders – for example, the aspirin class. While the injectable biologics are potent, pills which could achieve the same activity would be much more convenient for patients and might be able to avoid some of the other side effects associated with treatment with injectable biologics.” Synta hopes its compounds will move into the clinic sometime next year to begin Phase 1 human studies.

Pointing out that Synta has cash to finance its operations into 2012, he contends the company is in a “nice position, because we have significant investor interest, as seen by the quality and numbers of investors that participated in our most recent financing, as well as significant interest from partners, all of which create additional sources of capital that can extend our cash runway, as needed.”

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

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