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Partner : Merck KGaA

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Threshold Pharmaceuticals' Partner Merck KGaA, Darmstadt, Germany, Receives FDA Fast Track Designation for Evofosfamide for the Treatment of Patients Living With Advanced Pancreatic Cancer
Marks Second FDA Fast Track Designation for Evofosfamide, an Investigational Compound Currently in Phase 3 Clinical Trials
SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 05/12/15 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) 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.
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Source: press release, 5/12/15. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=912471

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Threshold Pharmaceuticals Reports First Quarter 2015 Financial and Operational Results

SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 04/30/15 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today reported financial results for the first quarter 2015. Revenue for the first quarter ended March 31, 2015 was $3.7 million. The operating loss for the first quarter ended March 31, 2015 was $9.6 million. The net loss for the first quarter ended March 31, 2015 was $11.2 million, which included the operating loss of $9.6 million and non-cash expense of $1.5 million related to the changes in fair value of the Company's outstanding warrants and was classified as other income (expense). As of March 31, 2015, Threshold had $83.1 million in cash, cash equivalents and marketable securities, with no debt outstanding.

"Our two pivotal clinical trials with evofosfamide remain on track," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "Based on current projections, we expect that the number of protocol-specified events for the pivotal Phase 3 trials of evofosfamide in patients with advanced soft tissue sarcoma as well as in patients with advanced pancreatic cancer (MAESTRO) may be reached in the second half of 2015, with the results of the primary efficacy analyses to be available shortly thereafter. We look forward to providing clinical updates on earlier-stage programs with evofosfamide at upcoming medical meetings. In addition, we are pleased with the level of interest in our first data presentation on TH-4000, our proprietary hypoxia-activated epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), at the recent AACR annual meeting. We are looking forward to initiating two Phase 2 clinical trials of TH-4000 this year, the first in patients with EGFR-positive, T790M-negative non-small cell lung cancer and the second in patients with head and neck cancer."
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Source: press release, 4/30/15. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=909758

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November 3, 2014

Threshold Pharmaceuticals' Partner Merck KGaA, Darmstadt, Germany, Completes Target Enrollment in the TH-302 Phase 3 MAESTRO Study in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma

SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 11/03/14 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD), today announced that Threshold's partner Merck KGaA, Darmstadt, Germany, through its biopharmaceutical division, has completed target enrollment of 660 patients in the global Phase 3 MAESTRO (MetastAtic or unrESectable pancreaTic adenocarcinoma) study assessing the efficacy and safety of TH-302 in combination with gemcitabine in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. Threshold has a global license and co-development agreement with Merck KGaA, Darmstadt, Germany for TH-302, which includes an option for Threshold to co-commercialize in the U.S.

"The MAESTRO trial of TH-302 for patients with advanced pancreatic cancer is the second of two pivotal Phase 3 trials of TH-302 to complete enrollment, the first being our trial for previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "We are pleased to have completed enrollment in both trials. We anticipate conducting the primary analysis of overall survival for our Phase 3 trial in patients with advanced soft tissue sarcoma in the first quarter of 2016 and having top-line data for MAESTRO in 2016."

MAESTRO is a randomized, placebo-controlled, international, multi-center, double-blind Phase 3 trial of TH-302 plus gemcitabine compared with placebo plus gemcitabine. The primary efficacy endpoint is overall survival; the secondary endpoints include efficacy measured by progression-free survival (PFS), overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. The study is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). The study design was also discussed with the European Medicines Agency (EMA) during a scientific advice procedure.
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Source: press release, 11/03/14. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=879765

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Threshold Pharmaceuticals Announces Initiation of TH-302 Phase 3 MAESTRO Study in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma
Threshold Earns a $30 Million Milestone Payment From Merck KGaA

SOUTH SAN FRANCISCO, CA -- (Marketwire) -- 01/25/13 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that Threshold's partner Merck KGaA, Darmstadt, Germany, through its division Merck Serono, initiated the global Phase 3 MAESTRO study assessing the efficacy and safety of investigational hypoxia-targeted drug TH-302 in combination with gemcitabine in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. The initiation of the Phase 3 MAESTRO study resulted in Threshold earning a $30 million milestone payment from Merck KGaA pursuant to the terms of Threshold's license and co-development agreement with Merck KGaA, which includes an option for Threshold to co-commercialize in the U.S. MAESTRO stands for TH-302 in the treatment of MetastAtic or unrESectable pancreaTic adenocaRcinOma.

MAESTRO is a randomized, placebo-controlled, international, multi-center, double-blind Phase 3 trial of TH-302 plus gemcitabine compared with placebo plus gemcitabine and is expected to enroll 660 patients. The primary efficacy endpoint is overall survival; the secondary endpoints include efficacy measured by progression-free survival (PFS), overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. The study is being conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). An SPA is a review conducted by the FDA on a clinical trial that will form the primary basis of an efficacy claim in a marketing application. The FDA provided written agreement that the design and planned analysis of this study could adequately address objectives in support of a regulatory submission. However, the determination for drug approval by the FDA is made after a complete review of a marketing application and is based on the entire data in the application. The study design was discussed with the FDA also at an End of Phase 2 meeting and with the European Medicines Agency (EMA) during a scientific advice procedure.
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Source: press release, 1/25/13. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=735750

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Threshold Pharmaceuticals Announces Agreement With U.S. FDA on a Special Protocol Assessment for Planned Phase 3 Trial of TH-302 in Combination With Gemcitabine in Advanced Pancreatic Cancer

SOUTH SAN FRANCISCO, CA -- (Marketwire) -- 10/16/12 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that the U.S. Food and Drug Administration (FDA) has reached agreement with the U.S. affiliate of Merck KGaA, Darmstadt, Germany, Threshold's partner for the development and commercialization of TH-302, covering a Special Protocol Assessment (SPA) for a Phase 3 randomized trial of TH-302 in patients with metastatic or locally advanced unresectable pancreatic cancer. The trial is designed to evaluate the efficacy and safety of TH-302 in combination with gemcitabine compared with gemcitabine therapy alone. Pursuant to Threshold's license and co-development agreement with Merck, Merck will be responsible for conducting the Phase 3 study under the SPA.

A Special Protocol Assessment (SPA) is a written agreement with the FDA that documents FDA's agreement that the design and planned analysis of a study can adequately address objectives in support of a regulatory submission. However, FDA's determinations for marketing application approval are made after a complete review of a marketing application and are based on the entire data in the application.

"In light of the evolving landscape for the first-line treatment of patients with advanced pancreatic cancer, we are pleased with the FDA's agreement that the design and planned analysis of this study adequately address the objectives necessary to support a regulatory submission," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "Given that the Phase 2 clinical trial met its primary endpoint, which was presented earlier this year at the annual AACR and ESMO medical meetings, we and our partner Merck are looking forward to further investigating TH-302 in a Phase 3 study in patients living with this extremely difficult to treat cancer."
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Source: press release, 10/16/12. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=713686

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MAESTRO - A Randomized, Double-Blind, Phase III Study of the Efficacy and Safety of Gemcitabine in Combination With TH-302 Compared With Gemcitabine in Combination With Placebo in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma
Estimated Enrollment: 660
Study Start Date: December 2012
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01746979?term=TH-302&rank=10

Compound/DeviceSpecialtyIndicationCompound ClassTarget
TH-302 Pancreatic Ca.OncologyPancreatic cancerAlkylating agent (prodrug)DNA

Mechanism of action: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole phosphoramidate conjugate with potential antineoplastic activity. The 2-nitroimidazole moiety of hypoxia-activated prodrug TH-302 acts as a hypoxic trigger, releasing the DNA-alkylating dibromo isophosphoramide mustard moiety within hypoxic regions of tumors. Normoxic tissues may be spared due to the hypoxia-specific activity of this agent, potentially reducing systemic toxicity.

Phase of Development: III

Event Type: Data: Phase III trial results

Dates: 2015-10-01 - 2015-12-31

Results:

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Threshold Pharmaceuticals Highlights Multiple Presentations at the 2016 ASCO Annual Meeting
Presentation of additional subset data from Phase 3 MAESTRO trial of evofosfamide in pancreatic cancer demonstrates meaningful improvement in overall survival in patients from Asia; risk of death reduced by almost 50 percent
CHICAGO, June 06, 2016 (GLOBE NEWSWIRE) -- Threshold Pharmaceuticals, Inc. (NASDAQ:THLD) today announced multiple presentations on clinical trials on its hypoxia-activated prodrugs, evofosfamide and tarloxotinib at the American Society of Clinical Oncology (ASCO) Annual Meeting being held June 3 through 7, 2016 in Chicago, Ill.

Today, Threshold presented additional data from its analysis of the randomized, double-blind Phase 3 MAESTRO clinical trial of evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma conducted by Merck KGaA. A meaningful improvement in overall survival was reported for the subgroup of 123 Asian patients enrolled at Japanese and South Korean sites in which the risk of death was reduced by 48 percent for patients on the treatment arm compared to patients on the control arm with an associated stratified hazard ratio of 0.52 (95% CI: 0.32 - 0.85). The patients from Asia also had significant improvements in PFS, objective response rates, and reductions in the pancreatic cancer biomarker, CA19-9 (abstract 4007). As previously reported in January 2016, the primary efficacy endpoint of this study of overall survival narrowly missed statistical significance based on specified intent-to-treat analysis while showing improvements in secondary efficacy endpoints of progression-free survival (PFS) and response.

On June 4, 2016, the following posters were displayed:

Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide and Pemetrexed in Second Line Advanced Non-Squamous Non-Small Cell Lung Cancer. Csoszi et al. (abstract 9075).

As reported in January 2016, the study was stopped early based on a futility analysis of overall survival conducted by the study Data and Safety Monitoring Board (DSMB). The study enrolled 265 patients of a planned 440 patients. The response rate with evofosfamide plus pemetrexed was 18.0 percent and significantly higher compared to 8.1 percent with placebo plus pemetrexed. The median PFS with evofosfamide plus pemetrexed was 4.5 months (95% CI: 4.0 to 6.4 months) and significantly higher compared to 2.9 (95% CI: 2.6 to 4.1) months with placebo plus pemetrexed. Hematologic toxicity was greater in the evofosfamide plus pemetrexed arm, while non-hematologic toxicity was similar across treatment arms. No new safety signals were identified.

Evofosfamide combined with gemcitabine/nab-paclitaxel in patients with previously untreated locally advanced or metastatic pancreatic adenocarcinoma (PAC): results of a phase I trial. Borad et al. (abstract 4114).

Nineteen patients were treated for a median of 6 cycles. The maximum tolerated dose of evofosfamide was established at 340 mg/m2 in combination with 800 mg/m2 gemcitabine and 100 mg/m2 nab-paclitaxel. No new safety signals were identified with myelosuppression being the primary dose limiting toxicity. The best response rate was 53 percent and the confirmed response rate was 37 percent.

Two additional trials-in-progress posters were also displayed:

A Phase 2 Study of Tarloxotinib Bromide (TRLX) in Patients with Recurrant or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) or Skin (SCCS).
Rischin et al. (abstract TPS6105)

A Phase 2 Study (NCT02454842) of Tarloxotinib Bromide (TH-4000) in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI.
Liu et al. (abstract TPS9100)

Copies of the posters may be obtained from Threshold's website, www.thresholdpharm.com, under Scientific Publications.
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Source: press release, 6/06/16. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=974408

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Threshold Pharmaceuticals Announces Its Two Phase 3 Studies Evaluating Evofosfamide Did Not Meet Primary Endpoints
Studies of Evofosfamide Combined With Chemotherapy in Advanced Pancreatic Cancer (MAESTRO) and Advanced Soft Tissue Sarcoma (TH-CR-406/SARC021) Did Not Meet Primary Endpoints of Improving Overall Survival With Statistical Significance
SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 12/07/15 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced the outcomes of two Phase 3 cancer studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide (previously known as TH-302), an investigational hypoxia-activated prodrug, which is being evaluated for first-line treatment of advanced pancreatic adenocarcinoma and advanced soft tissue sarcoma, in combination with chemotherapy. The Phase 3 studies are being conducted under Threshold's collaboration with Merck KGaA, Darmstadt, Germany.

In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 - 1.01; p=0.0589).

In the Phase 3 TH-CR-406/SARC021 study being conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 - 1.29).

Patient safety was monitored in MAESTRO and TH-CR-406/SARC021 by independent data monitoring committees throughout the conduct of each study. No new clinically significant safety findings were observed.

Detailed results from both studies will be submitted for presentation at upcoming international scientific meetings and for publication in peer-reviewed journals. Threshold will not be pursing further development of evofosfamide in soft tissue sarcoma and pancreatic cancer.

"We are surprised and disappointed that these studies did not show that evofosfamide could extend the lives of patients with these two difficult-to-treat diseases," said Barry Selick, Ph.D., Chief Executive Officer at Threshold. "Threshold has been pursuing evofosfamide for over ten years in collaboration with world-class scientists and investigators throughout the world. While we believe there remains substantial data to support the role of hypoxia in cancer treatment resistance, we are deeply frustrated with our inability in these trials to impact that in a meaningful way. I would like to thank all of the patients and their families, and the physicians, nurses, and support staff who participated in these studies."

Conference Call and Webcast
At 8:30 a.m. Eastern Time on Monday December 7, 2015, Threshold's management will host a conference call and a simultaneous webcast. The webcast can be accessed on the company's website in the Investors/Webcasts section http://investor.thresholdpharm.com/events.cfm. Alternatively, please call 1- (888) 767-9745 (U.S) or (440) 996-5547 (international). The conference ID number is 99761325. The webcast will be archived on Threshold's website for at least 30 days.
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Source: press release, 12/07/15. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=945765

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