Threshold for success

SOUTH SAN FRANCISCO, Calif.—California biotechnology company Threshold Pharmaceuticals Inc., announced in July that it will initiate an international Phase 2 trial of its investigational hypoxia-activated prodrug TH-302. The randomized, double-blind, placebo controlled trial will evaluate a 400 mg/m² dose of TH-302 in combination with full-dose pemetrexed in advanced non-squamous non-small cell lung cancer (NSCLC) compared to the combination of pemetrexed and placebo as second-line therapy in 440 patients. The trial will measure overall survival as the primary endpoint, with secondary endpoints including safety and an assessment of antitumor activity as determined by progression-free survival and objective response rate.

TH-302 is Threshold's lead compound that targets tumor hypoxia, the low-oxygen condition found in the microenvironments of most solid tumors as well as the bone marrows of some hematologic malignancies. As a prodrug, TH-302 is activated only under hypoxic conditions commonly found in the tumor microenvironment. The compound kills tumor cells by releasing bromo isophosphoramide mustard (Br-IPM), a potent DNA alkylating agent that interferes with the transcription of DNA to make essential proteins, and that renders cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect.” 

“Independent studies have demonstrated the presence of hypoxia in tumors from patients with NSCLC, which supports the rationale for evaluating a hypoxia-activated prodrug, such as TH-302, in this setting,” says Dr. Laura Hansen, senior director of corporate communications for Threshold Pharmaceuticals.

The ability to target cancer cells in hypoxic areas of the tumor microenvironment provides two vital advantages. First, the compound offers the potential to target the types of tumor cells most closely associated with cancer progression and resistance to traditional therapies.

“Tumor cells residing in hypoxic areas ... are associated with tumor progression, metastasis, resistance to radiotherapy and standard chemotherapy and ultimately treatment failure,” says Hansen. “Hypoxic tumor cells are often not affected by many commonly used cytotoxics, including intercalating agents, tubulin inhibitors, anti-metabolites and classical alkylating and alkylator-type agents, as well as large molecules such as antibodies.”

The second major advantage could be a potential reduction of systemic toxicity compared to cytotoxic chemotherapies. Because of the compound's preferential activation in the targeted hypoxic regions of solid tumors, TH-302 may be less likely to damage healthy cells elsewhere in the body, as commonly occurs with other forms of cancer therapy. In earlier Phase 1/2 trials, the most common adverse events following combination therapy of TH-302 and pemetrexed were fatigue, anemia, stomatitis and nausea.

In a completed Phase 1/2 trial that also evaluated TH-302 in combination with full-dose pemetrexed in a smaller subset of patients with relapsed/refractory non-squamous NSCLC, median progression-free survival (PFS) was seven months and median overall survival was 14.9 months, both of which represent about a 50-percent improvement over historical survival rates for non-squamous NSCLC patients receiving second-line chemotherapy.

“The early results from a limited number of patients treated with TH-302 and pemetrexed are encouraging: six of 15 patients (40 percent) showed a partial response as their best response, and median PFS was seven months,” says Hansen. “From historical reports of Phase 3 trials conducted in the second-line setting of NSCLC, one would expect about a 12-percent response in non-squamous NSCLC patients treated with pemetrexed alone and median PFS of about three months.”

“TH-302 ... has shown encouraging anti-tumor activity across a wide range of cancers in investigational trials, and we are excited about evaluating TH-302 in combination with pemetrexed as potential second-line treatment for patients with non-squamous NSCLC,” said Dr. Jonathan Goldman, director of clinical trials in thoracic oncology at UCLA Hematology & Oncology, in a media release. Goldman is the principal investigator of the ongoing trial.

TH-302 has been evaluated in more than 1,000 patients to date in a variety of indications, both as monotherapy and in combination with chemotherapy and antiangiogenic agents. The compound is currently the subject of two large Phase 3 trials: one for advanced soft-tissue sarcoma and another for advanced pancreatic cancer.

Threshold has a global license and co-development agreement for TH-302 with international pharmaceutical and chemical company Merck KGaA of Darmstadt, Germany. The agreement, announced in February 2012, grants Merck KGaA global commercialization rights to TH-302, and gives Threshold an option to co-commercialize in the United States. Threshold retains primary responsibility for developing TH-302 in the United States in the soft-tissue sarcoma indication; Threshold and Merck KGaA plan to jointly develop TH-302 in all other cancer indications being pursued, with Merck KGaA agreeing to pay 70 percent of the worldwide development costs for the compound. So far, under the terms of the agreement, Merck has paid Threshold $110 million in upfront and milestone payments, with Threshold standing to earn up to $440 million in additional potential milestone payments.

The success in clinical trials thus far of TH-302 and its potential to revolutionize treatment of hypoxic tumors—coupled with Threshold's robust pipeline, strong balance sheet and commercialization partnership with Merck KGaA—has led some financial analysts to speculate that Threshold's stock may be severely undervalued at its current price of around $4.20 per share. Forbes analysts, in a September 2013 article by contributor Bryan Rich, gave the company's stock a target price of $13.50 per share, listing it among biotech stocks it saw with potential to triple in value. Analyst Dr. Tony Schwartz echoed this optimism in investment research publication Seeking Alpha following the announcement of Threshold's latest Phase 2 trial, giving the stock a 12-month price target of $9.50, but noting the risks involved in a small-cap biotechnology company like Threshold, suggesting that these predictions of aggressive stock price growth are mainly predicated on TH-302's continued success in clinical trials and ultimate approval.