Threshold Pharmaceuticals' Partner Merck KGaA, Darmstadt, Germany, Receives FDA Fast Track Designation for Evofosfamide for the Treatment of Patients Living With Advanced Pancreatic Cancer

SOUTH SAN FRANCISCO, CA--Threshold Pharmaceuticals, Inc. (NASDAQTHLD) today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company's partner Merck KGaA, Darmstadt, Germany, for the development of evofosfamide (previously known as TH-302), administered in combination with gemcitabine, for the treatment of previously untreated patients with metastatic or locally advanced unresectable pancreatic cancer. This is the second Fast Track designation for evofosfamide, the first having been granted to Threshold in November 2014 for the development of evofosfamide in combination with doxorubicin for the treatment of patients with advanced soft tissue sarcoma. Threshold and Merck KGaA, Darmstadt, Germany, are collaborating on the development of evofosfamide, an investigational compound currently in Phase 3 clinical trials.

"We are pleased that evofosfamide has been granted Fast Track status for the treatment of patients living with pancreatic cancer," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "Evofosfamide is currently being studied in two pivotal Phase 3 clinical trials: one in patients with advanced soft tissue sarcoma and the other in patients with advanced pancreatic cancer. Based on current projections, we expect that the number of protocol-specified events for the pivotal Phase 3 trials of evofosfamide may be reached in the second half of 2015, with the results of the primary efficacy analyses to be available shortly thereafter."

"Merck KGaA, Darmstadt, Germany, is focused on discovering and developing innovative new therapeutic options for cancers that are particularly difficult to treat," said Luciano Rossetti, Head of Global Research and Development for the biopharmaceutical business of Merck KGaA, Darmstadt, Germany. "Many patients with pancreatic cancer present with advanced, inoperable tumors, and there are limited treatment options currently available for them. The Fast Track designation for evofosfamide in pancreatic cancer, which is currently being studied in the MAESTRO Phase 3 study, will help to facilitate the timely development of this high-priority program for Merck KGaA, Darmstadt, Germany."

The FDA established the Fast Track designation process to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening conditions that demonstrate the potential to address unmet medical needs.

About the Phase 3 Trials of Evofosfamide
In December 2012, Merck KGaA, Darmstadt, Germany, initiated the global pivotal Phase 3 MAESTRO clinical trial assessing the efficacy and safety of evofosfamide in combination with gemcitabine in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. MAESTRO stands for evofosfamide in the treatment of MetastAtic or unrESectable pancreaTic adenocaRcinOma. The MAESTRO trial is a randomized, placebo-controlled, international, multi-center, double-blind Phase 3 clinical trial of evofosfamide plus gemcitabine compared with placebo plus gemcitabine. The primary efficacy endpoint is overall survival; the secondary endpoints include efficacy measured by progression-free survival, overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. Patients were randomized to either gemcitabine 1000 mg/m2 plus placebo or to receive evofosfamide 340 mg/m2 administered intravenously with gemcitabine 1000 mg/m2 on Days 1, 8, and 15 of each 28-day cycle. The trial completed target enrollment of 660 patients in October 2015.

In partnership with the Sarcoma Alliance for Research through Collaboration (SARC), Threshold is conducting an international, randomized pivotal Phase 3 clinical trial designed to investigate the efficacy and safety of evofosfamide in combination with doxorubicin, compared with doxorubicin alone, in previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma. The primary endpoint of the trial is overall survival. Secondary endpoints include progression-free survival, overall response rate, pharmacokinetics and safety. Patients were randomized to either doxorubicin alone or to receive evofosfamide 300 mg/m2 administered intravenously on Days 1 and 8 with doxorubicin 75 mg/m2 on Day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive evofosfamide according to the same dosing schedule, 300 mg/m2 Days 1 and 8 of each 21-day cycle until progression or undesirable side effects. The trial completed target enrollment of 620 patients in December 2013.

About Pancreatic Cancer 
In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer in the United States and an estimated 40,560 people will die of this disease.1 Ranked as the 12th most common cancer worldwide, it is the 7th most common cause of cancer-related death, accounting for 4% of deaths.1With 93-95% of patients dying from their disease within 5 years, pancreatic cancer has a low survival rate.2,3 There has been little improvement seen in the survival of patients with this disease over the past 30 years4 and there remain limited treatment options for pancreatic cancer.5 Surgery remains the only curative approach for pancreatic cancer;5 however, many patients (80-85%) present with advanced, inoperable disease.6 For this large group of patients ineligible for surgery, the aim of treatment is prolongation of survival and palliation of symptoms.7

About Soft Tissue Sarcoma
Soft tissue sarcomas are a group of aggressive cancers that form in the soft tissues of the body (e.g., muscles, tendons, fat, blood vessels, lymph vessels, nerves, and tissue around joints) for which currently there are limited treatment options. Tumors may develop at any site, but manifest most often in the extremities and metastasize most often to the lungs and liver. In 2015, it is estimated that there will be 11,930 new cases of soft tissue sarcoma in the United States, and an estimated 4,870 people will die from this disease.7 Chemotherapy is the standard treatment for metastatic or unresectable soft tissue sarcoma. First-line palliative chemotherapy may be beneficial to nearly 50% of patients with advanced soft tissue sarcoma;8 however, prognosis for patients with advanced higher-grade disease is poor with historical median overall survival of 8 to 12 months after developing metastatic disease.9

About Evofosfamide
Evofosfamide (previously known as TH-302), an investigational hypoxia-activated prodrug, is designed to be activated under tumor hypoxic conditions, a hallmark of many cancers. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood supply as a result of aberrant vasculature. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.

Evofosfamide is currently under evaluation in two Phase 3 trials: one in combination with doxorubicin versus doxorubicin alone in patients with locally advanced unresectable or metastatic soft tissue sarcoma (STS), and the other in combination with gemcitabine versus gemcitabine and placebo in patients with locally advanced unresectable or metastatic pancreatic cancer (the MAESTRO trial). Both Phase 3 trials are being conducted under Special Protocol Assessment (SPA) agreements with the FDA. The FDA and the European Commission have granted evofosfamide Orphan Drug Designation for the treatment of STS and pancreatic cancer. The FDA has also granted Fast Track designation for evofosfamide for both STS and pancreatic cancer. Evofosfamide is also being investigated in a Phase 2 trial designed to support registration for the treatment of non-squamous non-small cell lung cancer, and in earlier-stage clinical trials of other solid tumors and hematological malignancies.

Threshold has a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize in the U.S.

About Threshold Pharmaceuticals 
Threshold Pharmaceuticals, Inc. is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in the microenvironments of most solid tumors as well as the bone marrows of some patients with hematologic malignancies. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (www.thresholdpharm.com).

Forward-Looking Statements
Except for statements of historical fact, the statements in this press release are forward-looking statements, including all statements regarding the potential benefits of Fast Track designation for evofosfamide, including with respect to such designation facilitating the timely development of evofosfamide; the anticipated timing of protocol-specified events and the availability of the results of the primary efficacy analyses from, the evofosfamide Phase 3 STS clinical trial and the MAESTRO trial; the potential for Threshold's ongoing evofosfamide Phase 2 clinical trial to support registration for the treatment of patients with non-squamous non-small cell lung cancer; and the potential therapeutic uses and benefits of evofosfamide to treat patients with advanced STS, advanced pancreatic cancer, non-small cell lung cancer and other cancers. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to: the risk that the Fast Track designation for evofosfamide may not lead to timely development of evofosfamide and may not lead to an expedited regulatory review or approval process, and such designation also does not increase the likelihood that evofosfamide will receive regulatory approval; the ability of Threshold and Merck KGaA, Darmstadt, Germany, to enroll or complete evofosfamide clinical trials, including the ability of Threshold and Merck KGaA, Darmstadt, Germany, to complete the ongoing Phase 3 clinical trials of evofosfamide in the expected timeframe or at all; the risk that because the timing of the availability of primary efficacy data from the ongoing Phase 3 clinical trials of evofosfamide is driven by the number of events in each trial, which neither Threshold nor Merck KGaA, Darmstadt, Germany, controls, Threshold cannot predict with certainty when the primary efficacy data from either Phase 3 clinical trial will be available; Threshold's dependence on its collaborative relationship with Merck KGaA, Darmstadt, Germany, including its dependence on decisions by Merck KGaA, Darmstadt, Germany, regarding the amount and timing of resource expenditures for the development of evofosfamide and the risk of potential disagreements with Merck KGaA, Darmstadt, Germany, regarding the commencement of additional clinical trials or milestone payments; the difficulty and uncertainty of pharmaceutical product development, including the time and expense required to conduct clinical trials and analyze data, and the uncertainty of clinical success and regulatory approval; the risk that later trials, including the Phase 3 clinical trials of evofosfamide, may not confirm the results of earlier trials; the risks that the design of, or data collected from, the ongoing Phase 3 clinical trials of evofosfamide may be inadequate to demonstrate safety and efficacy, or otherwise may be insufficient to support any regulatory approvals, and that despite the potential benefits of the SPA agreements with the FDA, significant uncertainty remains regarding the regulatory approval process for evofosfamide and that evofosfamide may not receive any marketing approvals in a timely manner or at all; issues arising in the regulatory process and the results of such clinical trials (including product safety issues and efficacy results); dependence of Threshold and Merck KGaA, Darmstadt, Germany, on single source suppliers for evofosfamide, including the risk that these single source suppliers may be unable to meet clinical supply demands for evofosfamide which could significantly delay the development of evofosfamide; and Threshold's need for and the availability of resources to develop evofosfamide and to support Threshold's operations. Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Quarterly Report on Form 10-Q, which has been filed with the Securities and Exchange Commission on April 30, 2015 and is available from the SEC's website (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors". We undertake no duty to update any forward-looking statement made in this news release.

References

1. National Cancer Institute. SEER Stat Fact Sheets: Pancreas. Available at:http://seer.cancer.gov/statfacts/html/pancreas.html Accessed: May 2015. 
2. EUROCARE-4 database on cancer survival in Europe. Long-term survival expectations of cancer patients in Europe in 2000-2002. Available at: http://www.eurocare.it/Results/tabid/79/Default.aspxAccessed: May 2015. 
3. Siegel R, et al. CA Cancer J Clin 2012;62(1):10-29. 
4. Malik NK, et al. J Gastrointest Oncol 2012;3(4):326-34. 
5. Loc WS, et al. World J Gastroenterol 2014;20(40):14717-25. 
6. Seufferlein T, et al. Ann Oncol 2012;23(Suppl 7):vii33-40. 
7. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015. 
8. Karavasilis V, et al. Cancer 2008;112:1585-1591. 
9. Riedel RF, et al. Cancer 2012;118:1474-1485.

Contact:
Contact
Laura Hansen, Ph.D.
Senior Director, Corporate Communications 
Phone: 650-474-8206 
E-mail: [email protected]

 

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