SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

May 31, 2015 09:00 ET

Threshold Pharmaceuticals Presents Encouraging Preliminary Phase 2 Data in Multiple Myeloma at ASCO

CHICAGO, IL--(Marketwired - May 31, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced new preliminary data from the Phase 2 component of an ongoing Phase 1/2 trial of evofosfamide (an investigational compound formerly known as TH-302) in combination with the proteasome inhibitor Velcade® (bortezomib) and low-dose dexamethasone ("EBorD") in patients with relapsed/refractory multiple myeloma. A clinical benefit rate of 29% (one complete response, two partial responses, and one minimal response) was observed in patients treated at the recommended Phase 2 dose of evofosfamide (340 mg/m2) in EBorD. Objective responses were observed in heavily pretreated patients (median of 8 prior systemic therapy regimens) including prior treatment with bortezomib (median of 3 prior bortezomib-containing regimens). Evofosfamide, an investigational hypoxia-activated prodrug currently in Phase 3 clinical trials in locally advanced or metastatic pancreatic cancer and advanced soft tissue sarcoma, is being developed in collaboration with Merck KGaA, Darmstadt, Germany. The data are being presented today at American Society of Clinical Oncology (ASCO) meeting in Chicago, Illinois (Abstract #8579).

"New treatment options are greatly needed for patients with multiple myeloma whose disease has progressed despite having received multiple previous therapies," said Tillman Pearce, M.D., Chief Medical Officer of Threshold. "Research suggests that hypoxia may play an important role in treatment resistance in multiple myeloma and supports the investigation of hypoxia-activated therapeutics in patients with relapsed/refractory multiple myeloma. As such, we are encouraged by the initial responses observed with EBorD therapy, particularly given that the patients in our trial had already received multiple types of treatment prior to enrollment including a median of 3 prior bortezomib-containing regimens."

"While the two pivotal Phase 3 trials of evofosfamide in patients with advanced soft tissue sarcoma and advanced pancreatic cancer remain our top priority, we are actively investigating evofosfamide in other cancers where hypoxia is implicated, preclinical data are supportive, and there is a high unmet medical need for new treatment options," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "We are encouraged by results seen to date suggesting activity of evofosfamide plus dexamethasone with or without bortezomib in patients with treatment-resistant multiple myeloma and are working with clinical experts in the field to help determine the most viable clinical and regulatory paths forward."

The ongoing Phase 1/2 trial is investigating evofosfamide and dexamethasone with or without bortezomib with respect to safety and tolerability, dose-limiting toxicities and the maximum-tolerated dose of evofosfamide, and preliminary efficacy in patients with relapsed/refractory multiple myeloma. The recommended Phase 2 dose of evofosfamide in EBorD was previously established at 340 mg/m2.1 A total of 25 patients with relapsed/refractory multiple myeloma have been enrolled in the EBorD component of the study as of May 1, 2015. At the ASCO meeting, preliminary safety and efficacy analyses were presented from 18 patients who initiated therapy prior to December 1, 2014, with presented analyses reflecting data in the clinical database as of May 2015.

Key preliminary data from EBorD dosing cohorts presented at ASCO include:

Preliminary assessment of safety and tolerability

Preliminary safety and tolerability results from the 18 patients included in the ASCO presentation support further investigation of evofosfamide in patients with relapsed/refractory multiple myeloma. The most common Grade 3/4 hematological adverse events were thrombocytopenia (reported in 11 patients), anemia (reported in 6 patients), and neutropenia (reported in 4 patients). Nausea (reported in 8 patients; one Grade 3/4) and fatigue (reported in 7 patients; one Grade 3/4) were the most common non-hematological adverse events. Eleven serious adverse events (SAEs) were reported in 9 patients. The only SAE occurring in more than one patient were two events of colitis. Neither event was considered related to evofosfamide. Five SAEs were considered as related to evofosfamide: bronchiolitis, melena, pneumonia, thrombocytopenia and viral infection. Skin toxicity and mucosal toxicities were not dose limiting. Rash was reported in five patients; stomatitis, skin lesion, pruritus and skin hyperpigmentation were each reported in one patient; none of these were Grade 3 or higher. No patients discontinued treatment due to an adverse event. There were no deaths related to study drug.

Preliminary assessment of clinical activity

Preliminary results from the 18 patients included in the ASCO presentation suggested anti-myeloma activity of EBorD therapy. According to modified International Myeloma Working Group (IMWG) criteria,2,3 responses included one complete response (CR), two partial responses (PRs), one minimal response (MR) and eleven stable disease (SD) assessments; three patients had progressive disease (PD). The patients with the CR and PRs had all previously undergone autologous transplantations and had received prior current standard treatment including IMiDs (a class of immunomodulators), proteasome inhibitors (including bortezomib), dexamethasone, and at least one conventional alkylating agent.

About Multiple Myeloma

Multiple myeloma, a hematologic cancer resulting from abnormal plasma cells typically found in the bone marrow, affects nearly 230,000 people worldwide with approximately 114,000 new cases diagnosed per year.4 An estimated 96,000 people in the U.S. are living with, or in remission from, multiple myeloma.5 The number of new cases that will be diagnosed in the U.S. in 2015 is estimated to be almost 27,000, and the estimated number of deaths is approximately 11,000.6

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 the development of 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 microenvironments of most solid tumors as well as the bone marrows of some 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 statements regarding the potential therapeutic uses and benefits of evofosfamide, including as a potential new treatment option in cancers where hypoxia is implicated, and statements related to potential clinical and regulatory paths forward for, and the future investigation of, EBorD therapy in patients with relapsed/refractory multiple myeloma. 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 ability of Threshold and Merck KGaA, Darmstadt, Germany, to enroll or complete evofosfamide clinical trials; 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; issues arising in the regulatory or manufacturing process and the results of such clinical trials (including safety issues and efficacy results); the risk that the final data from the ongoing Phase 1/2 trial of evofosfamide in EBorD may be materially different from the preliminary data that Threshold has reported, particularly as patient treatment and enrollment continues and additional and updated patient data becomes available; the 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; 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; and Threshold's need for and the availability of resources to develop its drug candidates 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. Laubach JP, et al. A Phase 1/2 trial of TH-302 and dexamethasone without or with bortezomib (TBorD) in patients with relapsed/refractory multiple myeloma. Blood 2014 124:2142.
2. Durie B, et al. International uniform response criteria for multiple myeloma. Leukemia 1-7, 2006.
3. Rajkumar SV, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117: 4691-4695, 2010.
4. International Agency for Research on Cancer, GLOBOCAN 2012 database. Available at http://globocan.iarc.fr/. Accessed May 25, 2015.
5. Leukemia & Lymphoma Society. Facts 2014-2015. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf
6. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015.

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