BioCentury: Hypoxic Depth Charge

• Product Development - Hypoxic Depth Charge - Threshold Pharmaceuticals has preliminary Phase I/II data showing that its TH-302 hypoxia-activated prodrug (HAP) could kill cells in hypoxic regions of tumors where chemotherapy doesn't reach.
From BioCentury - http://www.biocentury.com
 
By Aaron Bouchie
Senior Writer

Traditional chemotherapeutics kill rapidly dividing solid tumor cells that are close to the vasculature, where oxygen levels are normal. However, they do not penetrate deep into the hypoxic compartment of tumors where oxygen levels are low. This leaves residual cells that have been shown to acquire mutations that enable them to develop drug resistance and to metastasize.
A number of companies are developing compounds that target these hypoxic areas. Last Sunday, Threshold Pharmaceuticals Inc. disclosed preliminary data from two Phase I/II trials suggesting that its TH-302 hypoxia-activated prodrug (HAP) will complement chemotherapy.
Study 402 looked at TH-302 in combination with Gemzar gemcitabine from Eli Lilly and Co., Taxotere docetaxel from sanofi-aventis Group or Lilly’s Alimta pemetrexed in patients with advanced solid tumors. Study 403 looked at TH-302 plus doxorubicin in patients with soft tissue sarcoma.
Combined data from 33 evaluable patients in the dose-escalation Phase I portions of the trials showed that TH-302 plus the chemotherapies resulted in partial responses in 9 patients (27%) and stable disease in 17 (52%). Although the data are from a small number of patients, CMO John Curd told BioCentury the company is seeing activity that is higher than standard of care chemotherapy.
For example, in a head-to-head Phase III trial of Taxotere vs. Alimta as secondline therapy in patients with non-small cell lung cancer (NSCLC), response rates (complete responses plus PRs) were 8.3% and 8.5%, respectively. In Study 402, secondlineTH-302 plus either drug resulted in a PR in 3 of 6 NSCLC patients.
“Even though it’s only six patients, you would expect only one or maybe two responses,” Curd said. “If it were five responses out of 10 patients then we would feel more comfortable, so we need more numbers there.”
The company saw PRs in 2 of 4 softtissue carcinoma patients, as well as in 1 of 3 ovarian cancer patients, 1 of 2 esophageal cancer patients, 1 of 2 pancreatic cancer patients and in the single anal cancer patient. “It’s an impressive hint, that’s what it is. A lot more activity than what one would expect over chemo alone,” Curd said.
So far, the company isn’t seeing any safety issues with the combinations. The hematological adverse event profile for the combinations is what would be expected from cytotoxic chemotherapy alone, according to Curd. TH-302 did result in more severe skin and mucosal toxicities. “We expected that because the skin is highly hypoxic, but we think they’re manageable,” he said. The company is considering how to control the skin irritations.
TH-302 also showed efficacy as monotherapy in a Phase I trial, Study 401, resulting in stable disease or better in 18 of 31 patients, including PRs in a third-line SCLC patient and a second-line metastatic melanoma patient. That study was expanded to include up to 90 patients to assess efficacy in lung cancer and melanoma. Of the first three evaluable patients in the expansion, there were two PRs — one in a fourth-line SCLC patient and one in a second-line metastatic melanoma patient. The maximum tolerated dose of TH-301 as a monotherapy was 575 mg/m2 in  Study 401, data from which were presented last Saturday at the American Society of Clinical Oncology meeting in Orlando.
Curd expects to complete the doseescalation part of Study 402 this summer and of Study 403 in late summer or fall. “As soon as we confirm the MTD then we can start enrolling the Phase II portion with that dose,” he said.
Using HAPs to target hypoxic regions of tumors is not a new idea. The theory is that the inactive, stable HAPs would travel deep into a tumor — far from oxygenproviding capillaries — and then activate when the environment reaches a certain level of hypoxia. The HAP would thus kill a tumor from the inside-out, complementing traditional chemotherapies that kill cells close to capillaries. The first HAP in the clinic was tirapazamine, which sanofiaventis returned to SRI International in 2007 after the compound failed Phase III trials in NSCLC and head and neck cancer.
National Cancer Institute-sponsored Phase III studies to treat cervical cancer are ongoing. Curd said tirapazamine has three flaws, which Threshold tried to avoid when designing TH-302. First, tirapazamine is activated when oxygen concentrations reach about 1.5%, which is before it gets to the most hypoxic portions (0.5%) of the tumor. This leaves a relatively narrow therapeutic index because tirapazamine undergoes activation in tissues with more modest hypoxia, like the retina. According to Curd, TH-302 has a chemical sensor for the level of oxygen in the tissue, and is activated when oxygen concentrations drop below 0.6%. “It’s like a depth charge, which you can set for when you want it to go off,” he said. “We’ve done exactly the same thing so that it has to be very deep hypoxia.”
Another problem with tirapazamine, Curd said, is that it is metabolically inactivated by DT-diaphorase (DTD), a liver enzyme. This results in the need for higher dosing, he said, which conflicts with the molecule’s narrow therapeutic index. Threshold engineered TH-302 so that it would be inert to the normal metabolic machinery. Third, he said, tirapazamine kills only the cell in which it is activated. TH-302 has a half-life of about 10 minutes after activation, so it is able to diffuse and kill additional tumor cells.
The other HAP in clinical trials is Proacta Inc.’s PR-104, which is in Phase II testing to treat NSCLC in combination with Taxotere and to treat advanced hepatocellular carcinoma incombination with Nexavar sorafenib from Bayer AG and Onyx Pharmaceuticals Inc. Novacea Inc. had been developing AQ4N, a HAP of the topoisomerase II inhibitor AQ4. The compound was in a Phase Ib/IIa trial to treat glioblastoma multiforme (GBM), but the company stopped development in 2008 to conserve cash. It returned rights to BTG plc in January before completing a reverse merger with  Transcept Pharmaceuticals Inc. BTG told BioCentury it is no longer developing AQ4N