Synta Pharmaceuticals Announces Presentation of Preliminary Results of Phase 3 SYMMETRY Trial of Elesclomol in Metastatic Melanoma at ASCO 2009

- Trend towards improvement seen in primary PFS endpoint, does not achieve significance

- A significant PFS improvement was achieved for patients with normal LDH, a pre-specified exploratory analysis

- Mature survival data expected by end of 2009 or early 2010

LEXINGTON, Mass.--(BUSINESS WIRE)--May 30, 2009 - Synta Pharmaceuticals Corp. (NASDAQ: SNTA), a biopharmaceutical company focused on discovering, developing, and commercializing small molecule drugs to treat severe medical conditions, today announced the preliminary results of the Phase 3 SYMMETRYSM trial of elesclomol in combination with paclitaxel in metastatic melanoma. The results are the subject of an oral presentation by Steven O'Day, M.D., Chief of Research and Director of the Melanoma Program, The Angeles Clinic and Research Institute, at the Annual Meeting of the American Society of Clinical Oncology. The SYMMETRY trial and other trials for elesclomol were suspended in February 2009 after a meeting of an independent Data Monitoring Committee for the SYMMETRY trial observed an imbalance in deaths in favor of the control (paclitaxel alone) arm.

“There is an enormous unmet need and lack of treatment options for patients with metastatic melanoma. It is disappointing to all of us that the primary endpoint of the SYMMETRY trial, progression free survival (PFS), while showing a trend towards benefit, did not achieve statistical significance in the full patient population, particularly given the positive results from the prior, double-blind, randomized, controlled Phase 2b trial,” said Dr. O'Day. “A statistically significant PFS improvement was achieved, however, in the normal LDH population, which constituted just over 2/3 of total evaluable patients in this trial. The preliminary safety analysis shows that both the combination and control arms were well tolerated with generally comparable adverse event profiles. The imbalance in deaths observed between the two arms to date cannot be explained by organ-specific toxicities attributable to elesclomol. More mature survival data will be needed to understand the safety profile more fully.”

SYMMETRY Primary Endpoint Preliminary Results

Database lock and final analysis for the primary endpoint of the trial, PFS, are expected in Q3 2009. Preliminary results for PFS, in the full intent-to-treat (ITT) population, consisting of the 621 patients who were evaluable by April 2009 out of 651 total enrolled patients, were presented today:

PFS, ITT population

 


 
Elesclomol + Paclitaxel

(N=309)

 


 
Paclitaxel

        (N=312)        

 


 
Events 170 192
Median (months; 95% C.I.) 3.4 (2.6 – 3.6) 1.9 (1.9 - 2.9)
Hazard ratio (95% C.I., p-value)

 


 
0.84 (0.64 – 1.04), p=0.111

These results show a trend towards improvement in PFS, which did not achieve statistical significance (p=0.111; stratified log-rank test).

Patients in the SYMMETRY trial were stratified prospectively for level of LDH (lactate dehydrogenase), a known prognostic factor in melanoma; M-grade (degree of disease metastasis); and prior treatment history. Results of pre-specified exploratory analyses with respect to these variables showed a correlation between activity of elesclomol and level of LDH:

PFS, ITT population,

normal LDH

 


 
Elesclomol + Paclitaxel

(N=209, 68%)

 


 
Paclitaxel

        (N=215, 69%)       

 


 
Events 99 124
Median (months; 95% C.I.) 3.7 (3.5 – 5.4) 2.1 (1.9 – 3.5)
Hazard ratio (95% C.I., p-value)

 


 
0.72 (0.55 – 0.94), p=0.015
PFS, ITT population,

elevated LDH

 


 
Elesclomol + Paclitaxel

(N=100, 32%)

 


 
Paclitaxel

        (N=97, 31%)        

 


 
Events 71 68
Median (months; 95% C.I.) 1.8 (1.7 – 2.0) 1.9 (1.8 - 2.5)
Hazard ratio (95% C.I., p-value)

 


 
1.11 (0.78 – 1.59), p=0.556

Medians are calculated using Kaplan-Meier methodology. Cox proportional hazards modeling was used to generate hazard ratios. Normal LDH was defined as less than 1x ULN (the upper limit of normal, 234 U/L); elevated LDH was defined as greater than or equal to 1x ULN and less than 2x ULN. Patients with LDH greater than 2x ULN were excluded from the trial.

“We were disappointed that the primary endpoint in the Phase 3 SYMMETRY trial was not achieved,” said Eric Jacobson, M.D., Chief Medical Officer of Synta Pharmaceuticals. “The observation, however, that the combination of elesclomol plus paclitaxel improved PFS in a large subpopulation of patients with this difficult to treat disease is encouraging. The experience and insights that we have gained and will continue to gain from the SYMMETRY trial will be very important as we evaluate potential paths forward for this first-in-class program.”

“I want to thank the patients, their families, and all the healthcare professionals around the world who worked so closely with us to conduct this trial with such a high level of quality, efficiency, and attention to detail,” said Safi R. Bahcall, Ph.D., Chief Executive Officer of Synta. “While we wish results from this study would have rapidly led to a new option for patients with metastatic melanoma, that is not the case. We are encouraged by the signs of clinical activity, and are strongly committed to more fully understanding the underlying science, which could inform the selection of patients for future trials.”

Additional Preliminary Results

Adverse events of all NCI CTC Grades 1-4 occurring in >10% of patients were, in the ELPAC vs PAC alone arm respectively, alopecia (40% vs 40%), fatigue (39% vs 38%), nausea (31% vs 25%), diarrhea (25% vs 22%) and constipation (18% vs 18%), cough (15% vs 13%), headache (14% vs 14%), asthenia (13% vs 9%), rash (13% vs 11%), peripheral neuropathy (13% vs 12%), vomiting (12% vs 9%), and pyrexia (10% vs 7%).

Moderate to severe adverse events, those of NCI CTC Grade 3-4, were, in the ELPAC vs PAC alone arm respectively, fatigue (3.6% vs <1%), peripheral neuropathy (2% vs 1.3%), alopecia (1.6% vs 1.9%), vomiting (1.3% vs 1.3%), diarrhea (1.3% vs 0%); nausea, headache and asthenia (<1% vs <1%); and constipation, cough, rash and pyrexia (<1% vs 0%).

Overall Survival (OS) data are not yet mature; measures of significance of the relative mortality risk between the two arms are still evolving. No organ specific toxicities have been identified which would explain the imbalance in deaths observed in the interim DMC analysis. Survival data are expected to mature by end of 2009 or early 2010.

Although no patients are currently receiving study treatment, patients are continuing to be followed for assessment of survival.

The complete oral presentation will be available at the ASCO website at www.asco.org.

SYMMETRY Trial Design

The SYMMETRY trial enrolled patients with stage IV metastatic melanoma who had not received prior chemotherapy but who may have already been treated with non-chemotherapeutic agents such as biologics. The blinded, randomized, controlled study, conducted at approximately 160 centers in 15 countries. Patients were randomized (1:1) to elesclomol (213 mg/m2) plus paclitaxel (80 mg/m2) or paclitaxel alone (80 mg/m2) and receive three weekly treatments and one week without treatment per each four week cycle. If tolerated, treatment continued until disease progression. Patients were stratified according to LDH levels, M-grade status and prior treatment history. Responses were assessed using standard RECIST criteria at baseline and at a minimum every other cycle, with radiology scans being assessed by independent, blinded, reviewers at a central site. The primary endpoint of the study was progression-free survival; overall survival and tumor response rate were secondary endpoints. The trial enrolled a total of 651 patients and 621 patients were evaluable as of April 2009.

About Elesclomol

Elesclomol is a first in class oxidative stress inducer that triggers apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high levels of reactive oxygen species, or oxidative stress. Elesclomol is believed to act by increasing the level of oxidative stress in cancer cells even further, beyond sustainable levels, inducing apoptosis. This mechanism of action, called oxidative stress induction, represents a novel way of selectively targeting and killing cancer cells.

In a double-blind, randomized, controlled Phase 2b clinical trial in 81 patients with stage IV metastatic melanoma, elesclomol in combination with paclitaxel met the primary endpoint, doubling the median time patients survived without their disease progressing, compared to paclitaxel alone (p = 0.035). The most common adverse events in the elesclomol plus paclitaxel group included fatigue, alopecia, constipation, nausea, hypoaesthesia, arthralgia, insomnia, diarrhea, and anemia.

In October 2007, Synta and GSK entered into a collaboration agreement for elesclomol. Under the terms of the agreement, the companies will jointly develop and commercialize elesclomol in the U.S. and GSK will have exclusive responsibility for development and commercialization of elesclomol outside the U.S.

About Oxidative Stress

Elesclomol increases the generation of reactive oxygen species (ROS) such as oxygen radicals in cells. These ROS cause signaling leading to an increase in pro-apoptotic factors, a decrease in anti-apoptotic factors, and ultimately to the initiation of programmed cell death via the mitochondrial apoptosis pathway. By elevating ROS and altering the balance of apoptotic signaling factors, elesclomol sensitizes cancer cells to conventional anti-cancer agents that cause cell death through the mitochondrial apoptosis pathway.

Normal, non-cancer cells typically have very low levels of ROS and have a high antioxidant capacity. In contrast, cancer cells generally have much higher levels of ROS and exist in a state of oxidative stress, leaving them vulnerable to any further increases in ROS.

About Metastatic Melanoma

Melanoma, the most deadly form of skin cancer, arises from melanocytes, the pigment-producing cells of the skin. According to the American Cancer Society, melanoma accounts for approximately five percent of all skin cancers but causes about 75% of all skin cancer-related deaths. An estimated 60,000 people will be diagnosed and nearly 8,200 people will die from melanoma this year in the U.S. alone. If diagnosed and surgically removed while localized in the outermost skin layer, melanoma is potentially curable; however, for patients with metastatic disease the prognosis is poor, with limited available treatments and an expected survival of only six to nine months. The incidence of melanoma has increased more rapidly than any other cancer during the past ten years.

About Synta Pharmaceuticals

Synta Pharmaceuticals Corp. is a biopharmaceutical company focused on discovering, developing, and commercializing small molecule drugs to extend and enhance the lives of patients with severe medical conditions, including cancer and chronic inflammatory diseases. Synta has a unique chemical compound library, an integrated discovery engine, and a diverse pipeline of clinical- and preclinical-stage drug candidates with distinct mechanisms of action and novel chemical structures. All Synta drug candidates were invented by Synta scientists using our compound library and discovery capabilities. For more information, please visit www.syntapharma.com.

Safe Harbor Statement

This media release may contain forward-looking statements about Synta Pharmaceuticals Corp. Such forward-looking statements can be identified by the use of forward-looking terminology such as "will", "would", "should", "expects", "anticipates", "intends", "plans", "believes", "may", "estimates", "predicts", "projects", or similar expressions intended to identify forward-looking statements. Such statements, including statements relating to the timing, developments and progress of our clinical and preclinical programs, reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such forward-looking statements, including those described in "Risk Factors" of our Form 10-K for the year ended December 31, 2008 as filed with the Securities and Exchange Commission. Synta undertakes no obligation to publicly update forward-looking statements, whether because of new information, future events or otherwise, except as required by law.

Contact: Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7979
or
Synta Pharmaceuticals Corp.
Aurora Krause, 781-541-7125

Posted: June 2009

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