Synta’s Newest Phase II Results Could Reshape Ganetespib’s Pivotal Data, But Some Analysts Remain Skeptical
This article was originally published in The Pink Sheet Daily
Executive Summary
Synta provided one-year follow up data for its Phase IIb/III trial testing ganetespib in NSCLC, and revealed some protocol changes which it believes will de-risk the Phase III design. Analysts on the third quarter earnings call by and large bought into the story, but some skepticism remains.
Synta Pharmaceuticals Corp. management delivered an upbeat assessment of one-year follow up data for its Phase IIb/III GALAXY-1 trial testing its lead oncology candidate ganetespib, a heat shock protein 90 (HSP90) inhibitor, in second-line non-small-cell lung cancer.
Although survival data were not as robust as were reported in a June update, most analysts on and off a Nov. 4 conference call apparently felt they warranted continuation to a pivotal trial.
While Synta surely wanted to present the updated Phase II data in a positive light, the company is also aiming to persuade the Street that it has identified and addressed design issues in GALAXY-1 that might have compromised a subsequent pivotal trial. Synta is currently enrolling the Phase III GALAXY-2 study of ganetespib. With the termination in late September of Infinity Pharmaceuticals Inc.’s retaspimycin in NSCLC, Synta’s most advanced competitor in the HSP90 race has called it quits. Retaspimycin had earlier failed in a Phase III trial in gastrointestinal stromal tumors (GIST) (Also see "Patient Deaths Stop Infinity Pharma’s Phase III HSP90 Trial In Cancer" - Pink Sheet, 15 Apr, 2009.).
The HSP90 class continues to intrigue the oncology community as a promising mechanism that works through several cancer pathways and is involved in the function of numerous client proteins including proteins involved in “oncogene addiction” (e.g,, ALK, HER2, mutant BRAF and EGFR), proteins involved in resistance to chemotherapy (e.g., ATR, BCL2, BRCA 1/2, CDK1/4), proteins involved in angiogenesis (HIF-1 alpha, VEGFR, PDFGR), and proteins involved in metastasis (e.g., MET, RAF, AKT, IGF-1R) (Also see "Synta’s Ganetespib Could Break The Hsp90i Curse" - Pink Sheet, 3 Jun, 2013.).
However, the failure of retaspimycin raises scrutiny of the class and poses the perennial question often asked in the wake of a clinical failure of a novel mechanism: Is it compound-specific or target class-specific?
A Positive Spin, An Optimized Design
Chief Medical Officer Vojo Vukovic said that data from the one-year follow-up post enrollment completion, with just over 65% of survival events recorded, has helped to de-risk the Phase III trial by identifying “the best patient population and ways to optimize the operational plan” for GALAXY-2.
Specifically, based on the biopharma’s increased confidence in ganetespib’s activity, Synta plans to add about 200 patients to bring the final GALAXY-2 patient count to 700. The typical per-patient cost in a cancer trial is $30,000 to $40,000. The added patient cost will come out of Synta’s cash hoard of $53 million, which it expects to fund operations into the second quarter of 2014. The additional patients will also drive an expansion in study sites, both academic and community.
Additionally, the company will no longer enroll patients from Russia and Ukraine. Those sites apparently enrolled healthier patients into the docetaxel-alone arm who received more chemotherapy on study than had been anticipated, prolonging their survival. “Median survival in the East was closer to nine or ten months and the hazard ratio [was] less mature there,” said CEO Safi Bahcall. “Because they live so long, there is relatively less follow-up.”
So while there was a median survival of six months and a hazard ratio of about 0.5 in the West, the median survival at the Russian and Ukrainian study sites was longer, and the hazard ratio was in the 0.8-0.9 range. Synta’s internal projections estimate the hazard ratio for GALAXY-2 to be in the 0.6-0.7 range.
“We are aware of many that have failed the transition from Phase II to Phase III because of the operational risks of expanding to many untested sites and countries,” said Vukovic. With the new operational plan, Lexington, Mass.-based Synta expects 75% of sites in GALAXY-2 to be in Western countries.
Synta is hoping that the expanded population will decrease risk from imbalances or statistical fluctuations, and that the shift away from Russian and Ukrainian patients will improve the chances of ganetespib succeeding in GALAXY-2. Management does not expect to have to submit formal protocol amendments for the expanded study population or the shift to Western study sites.
The company is also hoping that these amendments to the trial will explain the drop in survival from 4.3 months to 3.3 months seen between June (10.7 months for ganetespib plus docetaxel vs. 6.4 months in the docetaxel-alone group) and late October (10.7 months vs. 7.4 months), and allay investor concerns. When the update was first revealed at the World Conference on Lung Cancer held in Sydney, Australia on October 28th, Synta’s stock dipped 20% to close at $5.40. It has moved steadily downward since then, and closed at $4.11 Nov. 4.
Jim Birchenough of BMO Capital Markets wrote in a Nov. 4 note that the extended timelines and additional cost would strain Synta’s cash; he lowered his price target and wondered if the time and cash crunch would compromise the biopharm’s ability to maximize potential deal economics.
Other Noteworthy Developments
In September, Synta unveiled its HSP90 inhibitor drug conjugate platform (HDC). The technology, to link a targeting moiety (HSP90 inhibitor) to a payload (anticancer agent), is reminiscent of Endocyte Inc.’s small molecule drug conjugation technology (SMDC) which links a folate-receptor targeting ligand to a chemo payload (Also see "Endocyte Targets Folate Receptor Cancers, Devising Innovative Route To Market" - Pink Sheet, 5 Sep, 2011.). The rationale is that because tumors retain HSP90 inhibitors, it will result in higher concentration and longer duration of active payload drug inside cancer cells.
Bahcall said the company has received lots of positive feedback about the platform from potential pharma partners. He also said that HDCs would use traditional chemotherapeutic agents such as taxanes and platinums, but also new investigational agents including MEK, PI3K and CDK inhibitors. “We are in preclinical development now,” he added. “We hope to file an IND within the next 12 to 14 months.
In July 2013, Synta announced preliminary results of the ENCHANT-1 Phase II trial evaluating ganetespib monotherapy in HER2-positive or triple-negative breast cancer. Of the five HER2-positive patients, two achieved objective tumor response and two achieved stable disease during 12 weeks of treatment. Of ten TNBC patients, two achieved objective tumor response and three achieved stable disease. One TNBC patient diagnosed with inoperable disease at time of enrollment showed a complete clinical response at week 12, and was restaged to operable disease.