Synta Pharmaceuticals Announces Updated Elesclomol SYMMETRY(SM) Data Presented at Melanoma XIII
"The data from the SYMMETRY trial presented at the Perspectives in Melanoma XIII Conference shows an important connection between patients' baseline level of LDH (lactate dehydrogenase), an established biomarker in melanoma, and treatment outcome with elesclomol," said Dr. O'Day. "Patients with low and normal baseline levels of LDH showed an improvement in progression free survival (PFS), the primary endpoint of the study. The OS (overall survival) data for these groups are still highly censored and evolving; no difference has been observed to date between the treatment and control arms. In contrast, patients with high baseline level of LDH showed no PFS benefit and a decreased survival time relative to the control arm. These results, along with the results of other recent randomized clinical trials, suggest that baseline LDH status may evolve from a prognostic factor for the disease to a potentially predictive factor for treatment. This could pave the way for a more personalized approach to treating this disease that considers markers such as LDH in determining an optimal approach to therapy."
"We believe there are three emerging findings from the SYMMETRY trial that are important for the future of the elesclomol program," said Vojo Vukovic, M.D., Ph.D., Senior Vice President and Chief Medical Officer, Synta Pharmaceuticals. "First, there are clear signs of clinical benefit in the normal LDH population. In this patient group, which represents 68% of the trial population, the PFS endpoint was achieved. Second, any potential adverse effect on survival in favor of the control arm appears to be restricted to the high LDH patient population. Finally, and importantly in considering development of elesclomol beyond melanoma, there were no substantial differences in Grade 3 or 4 toxicities between the two arms of the trial, consistent with safety findings from prior trials, indicating that elesclomol was well tolerated."
"Additional survival data, as well as a further understanding of the interaction between oxidative stress induction and LDH level, will be important for determining the future of the program," continued Dr. Vukovic. "Both the elesclomol oxidative stress mechanism and LDH relate to metabolic pathways. Together with our academic collaborators we are actively investigating the connection between the two, and expect to present initial results at scientific meetings later this year. We expect to present SYMMETRY survival data with 12 months minimum follow-up, and announce further decisions related to the future of the elesclomol program, in the first half of 2010."
SYMMETRY Results Presented at Melanoma XIII
Updated results for PFS, OS, response rate, and safety were presented, including prespecified exploratory analyses of the effects of baseline LDH levels on treatment outcomes. The complete presentation can be found at http://www.syntapharma.com/Documents/SYMMETRYPIM13.pdf.
Progression Free Survival
Updated progression free survival data showed no substantial changes from results presented May 30 this year at the American Society for Clinical Oncology meeting. Results for the overall Intent to Treat (ITT) population presented at the Melanoma XIII meeting showed a trend in favor of elesclomol in combination with paclitaxel as compared to paclitaxel alone (3.4 vs. 1.9 months, HR=0.88, p=0.188). The normal LDH population, 68% of patients, experienced a significant improvement in median PFS (3.6 vs. 2.1 months, HR=0.76, p=0.027). In contrast, the high LDH population, 32% of patients, showed no benefit (1.8 vs. 1.9 months, HR=1.10, p=0.549).
Response Rate
The Overall Response Rate (complete response plus partial response) was measured based on RECIST objective tumor response criteria for those patients with at least one follow-up assessment. Overall Response Rates for ELPAC vs. PAC were 7.4% vs. 4.4% for all randomized patients (N=595, p=0.121); 8.4% vs. 3.9% for the normal LDH population (N=407, p=0.065); and 5.3% vs. 5.4% for the high LDH population (N=188, p=1.00). Of the responders, two were complete responses, which occurred in the ELPAC arm in the normal LDH population; all other responses were partial responses.
Overall Survival
Survival results presented represent a minimum of six months follow-up since study termination on February 26, 2009. This data set shows a 55% censoring rate, indicating that results are not yet mature and may change. The hazard ratio in the full patient population (ITT analysis) is 1.17 (95% C.I. 0.93-1.48, p=0.173). The hazard ratio in the high LDH population (LDHgreater-than or equal to 1x ULN) is 1.49 (1.05-2.11); in the normal LDH population (LDH<1x ULN) is 0.99 (0.72-1.36); and in the low LDH population (LDHless-than or equal to 0.8x ULN) is 0.88 (0.58-1.34).
At time of study termination in February 2009, 63% of randomized patients were off treatment. As a sensitivity analysis to explore the effect of study termination, the subgroup of patients enrolled before November 1, 2008 (N=422), which had the opportunity to receive a minimum of four cycles of treatment, was examined. 83% of this population was off treatment at the time of study termination. Results from this analysis were presented at the meeting and showed that differential impact of baseline LDH levels on overall survival outcomes persisted, with high LDH patients performing most poorly and low LDH patients performing most favorably.
Safety
Elesclomol was well-tolerated in the SYMMETRY trial and most observed adverse events were NCI CTC (National Cancer Institute Common Toxicity Criteria) Grade 1 or 2. The most common Grade 3 or higher adverse events in the treatment arm (elesclomol plus paclitaxel) compared to the control arm (paclitaxel alone) were neutropenia (6.8% vs. 2.5%), fatigue (4% vs. 1.2%), anemia (2.2% vs. 1.8%), dyspnea (2.2% vs. 1.8%), alopecia (1.9% vs. 2.8%), peripheral neuropathy (1.9% vs. 1.2%), vomiting (1.9% vs. 1.5%), and infusion related reaction (1.9% vs. 2.2%).
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, was 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 received 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 eight weeks, 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 SYMMETRY trial and other trials for elesclomol were suspended in February 2009 following a meeting of an independent Data Monitoring Committee for the SYMMETRY trial in which an imbalance in deaths in favor of the control (paclitaxel alone) arm was observed.
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.
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 can both trigger apoptosis and enhance the sensitivity of cancer cells to certain conventional anti-cancer agents.
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.
SOURCE: Synta Pharmaceuticals Corp.
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125
