Assistant Managing Editor

Emerging patient safety concerns sent shares of Synta Pharmaceuticals Corp. and Amicus Therapeutics Inc. plunging Friday, as Synta halted development of its late-stage melanoma drug elesclomol due to a higher-than-expected death rate and Amicus suspended a Phase II trial of Pompe disease drug AT2220 after two patients suffered adverse events.

The news was much worse for Lexington, Mass.-based Synta, which had most of its value tied to elesclomol, an oxidative stress inducer that just finished enrollment earlier this month in the 630-patient Phase III SYMMETRY trial aimed at testing the drug in combination with paclitaxel in Stage IV metastatic melanoma. Investors bailed on the stock Friday. Trading at 25 times the normal volume, shares (NASDAQ:SNTA) nosedived $5.03, or 79 percent, to close at $1.36.

The troubling safety data were surprising given the successful Phase IIb study in 2007, which was designed with similar treatment combination, dosage and administration schedule as the SYMMETRY trial, as well as the fact that only two months ago the study's independent data monitoring committee recommended that the trial continue as planned following a safety analysis. Yet the DMC returned to company executives last week to report serious safety concerns, including an apparent imbalance in the number of deaths in the elesclomol treatment arm.

"Words cannot possibly express my disappointment," said Synta President and CEO Safi Bahcall, who told investors during a conference call that further review of the data only confirmed the DMC's findings. "While there was some benefit in the primary endpoint [of progression-free survival], it did not reach statistical significance. The secondary endpoints are not supportive, and the safety concerns are serious."

The company said the data still are under review and was not able to provide details regarding what might have contributed to the reported deaths and other safety issues. Nevertheless, the outlook for elesclomol is bleak, at best.

Analyst Simos Simeonidis, of Rodman & Renshaw, wrote in a research note it might be possible, "theoretically," that further analysis could provide an explanation that would allow for further development. But "based on current information, we believe elesclomol's development is finished, at the very least, for the foreseeable future." He added that the drug always had been a high-risk program, partly because the melanoma space has stymied nearly every drug tested in that indication. Previous failures in that indication have included Canvaxin, an immunotherapy from now-defunct CancerVax Corp., and kinase inhibitor Nexavar (sorafenib, Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals). Genta Inc.'s Genasense (oblimersen sodium) also faltered in Phase III, though the Berkeley Heights, N.J.-based firm has started another Phase III trial in melanoma, hoping the use of a biomarker will improve its chances of success. (See BioWorld Today, Aug. 22, 2007.)

After reviewing the initial elesclomol data, Synta decided to suspend not only the SYMMETRY trial, but all other ongoing studies of the drug, such as a Phase I/II trial in combination with docetaxel in metastatic hormone-refractory prostate cancer. Additional trials had been planned in different cancer indications this year, but now are unlikely to go forward.

Elesclomol is partnered with London-based GlaxoSmithKline plc in a potential $1 billion deal signed in 2007. Bahcall told investors that GSK concurs with Synta's decision to suspend development but declined to comment further on the status of the partnership until the company's earnings report later this month. (See BioWorld Today, Oct. 11, 2007.)

But he maintained that Synta remains in a strong financial position. The firm posted a cash balance of $83 million as of Sept. 30, and added another $15 million in a milestone payment from GSK in December. Late last year, the firm also entered a preclinical collaboration with Basel, Switzerland-based F. Hoffmann-La Roche Ltd. to develop calcium release-activated calcium modulator channels, and that deal came with a $25 million up-front payment, which includes $9 million paid out in research funding over two years. (See BioWorld Today, Jan. 5, 2009.)

Synta has "more than enough cash to develop our next set of programs to clinical proof of concept," Bahcall said.

After elesclomol, the company's pipeline includes apilimod, a small-molecule inhibitor if interleukin-12 and IL-23, which is in a Phase IIa rheumatoid arthritis trial, and STA-9090, a small-molecule heat-shock protein 90 inhibitor. That compound is in Phase I trials with data expected later this year.

Synta has not yet disclosed any actions for restructuring and preserving cash, though Bahcall acknowledged that this "will be a tough time for us as a company." He later added, "We'll be working night and day to come back from this."

Amicus' Pompe Disease Drug on Hold

With two other midstage programs in full swing, Cranbury, N.J.-based Amicus had a bit of a buffer to Friday's news of a clinical hold on a Phase II trial of AT 2220 (1-deoxynojirimycin HCl) in adults in Pompe disease.

The company's shares (NASDAQ:FOLD), which traded as low at $6.26 in the morning, rebounded somewhat to close Friday at $8.06, down $1.45, or 15.3 percent.

Amicus, which initiated the Phase II study in June, reported that two patients in the study experienced "self-reported adverse events" that were categorized as serious and probably treatment-related by site investigators. The company suspended further enrollment and received verbal notice of a clinical hold from the FDA. Amicus plans to evaluate all available data. Then it will work with the agency to amend the study protocol and "get the trial back on track as quickly as possible," John F. Crowley, the firm's president and CEO, stated in a press release. The study is designed to enroll 18 patients diagnosed with Pompe disease, a disorder caused by an inherited mutation of the alpha-glucosidase enzyme.

Currently available treatments for that orphan indication include enzyme replacement therapies, such as Cambridge, Mass.-based Genzyme Corp.'s Myozyme (alglucosidase alfa), but Amicus' approach aims to restore enzyme function. The study's primary objective is to evaluate safety and tolerability at different dosing levels over a 12-week period, though it also is expected to explore the effect of treatment on acid alpha glucosidase activity and on glycogen levels in various cells and tissues. Additional measurements will look at preliminary assessments of pulmonary and skeletal muscle function.

Amicus does not expect the AT2220 clinical hold to have any impact on ongoing Phase II studies of Amigal (migalastat hydrochloride) in Fabry's disease and Plicera (afegostat tartrate) in Gaucher's disease.