Threshold Pharmaceuticals Announces Interim Results from Tarloxotinib Program and its Plans to Focus on Evofosfamide and Earl...
September 29 2016 - 6:04PM
Threshold Pharmaceuticals, Inc. (Nasdaq:THLD), a clinical-stage
biopharmaceutical company specializing in the development of novel
pharmaceutical products and technologies for the treatment of
cancer, today announced interim data from its two Phase 2
proof-of-concept clinical trials of tarloxotinib and outlined its
plans to focus company resources on the more clinically-advanced
evofosfamide program as well as an earlier-stage anticancer
candidate, TH-3424.
"While the response observed in our squamous cell carcinoma of
the skin study with tarloxotinib was encouraging, the overall
results from the two studies didn't meet the activity thresholds
required to move forward the molecule forward despite the promising
results seen in preclinical translational studies,” said Barry
Selick, Ph.D., Chief Executive Officer of Threshold. "As a result,
we are making no further investment in this program. Instead, we
plan to build on the efforts of our collaborator, Dr. Michael
Curran of The University of Texas MD Anderson Cancer Center, to
demonstrate the potential therapeutic value of adding evofosfamide
to immune checkpoint inhibition, to continue to pursue discussions
with Japanese regulatory authorities regarding potential
registration pathways for evofosfamide, and to advance TH-3424
through IND-enabling toxicology studies with the goal of reaching
the clinic in 2017. We plan to provide additional operational
guidance in the fourth quarter of 2016."
About the Tarloxotinib Program Tarloxotinib
bromide (the International Nonproprietary Name, previously known as
TH-4000), or "tarloxotinib", is a prodrug designed to selectively
release a covalent (irreversible) EGFR tyrosine kinase inhibitor
under severe hypoxia, a feature of many solid tumors. The
interim results from the two Phase 2 proof-of-concept clinical
trials evaluating the efficacy and safety of tarloxotinib are
outlined below. Both clinical trials utilized a Simon two-stage
design to ensure adequate efficacy as measured by tumor response to
justify continued enrollment. Tumor response was evaluated at
baseline and every eight weeks using the Response Evaluation
Criteria in Solid Tumors (RECIST). As a result, and taking into
consideration the totality of the clinical data with tarloxotinib,
enrollment in both Phase 2 clinical trials and further development
of tarloxotinib will be discontinued.
Tarloxotinib in patients with recurrent or metastatic squamous
cell carcinoma of the head and neck (SCCHN) or skin (SCCS)
(TH-CR-602):
- In the first stage of the SCCS arm of the trial, a confirmed
partial response was observed in 1 of 7 patients. According
to the study design, the response rate was sufficient to expand the
trial to evaluate additional patients.
- However, of the 22 SCCHN patients who were assessed, although 8
achieved stable disease, none achieved a confirmed partial
response.
Tarloxotinib in patients with EGFR-mutant, T790M-negative,
advanced non-small cell lung cancer (NSCLC) (TH-CR-601):
- In the first stage of the trial, a response rate greater than
or equal to 4 out of 19 patients was the threshold for expansion
and continuation of the trial. Per protocol response is
defined as tumor shrinkage (a partial or complete response).
- Although 7 of 21 assessed patients achieved stable disease, no
patients achieved a confirmed partial response.
Threshold licensed exclusive worldwide rights to tarloxotinib
from the University of Auckland, New Zealand, in September
2014.
About the Evofosfamide Program Evofosfamide
(previously known as TH-302) is an investigational
hypoxia-activated prodrug of a bis-alkylating agent that is
preferentially activated under severe hypoxic tumor conditions, a
feature of many solid tumors. On December 6, 2015, the Company
announced the outcomes of two Phase 3 studies (MAESTRO and
TH-CR-406/SARC021) of evofosfamide stating that neither study met
its primary endpoint. However, the Phase 3 trial (MAESTRO)
data demonstrated meaningful improvement in overall survival in a
subgroup of 116 patients from Japan, in which the risk of
death was reduced by 48 percent for patients on the treatment arm
compared to patients on the control arm. In addition, translational
data evaluating the role of hypoxia in mediating treatment
resistance to cancer immunotherapy conducted at The University of
Texas MD Anderson Cancer Center suggests that evofosfamide may play
a role in improving the efficacy of “checkpoint antibodies” such as
ipilumimab. The Company’s evofosfamide efforts are as follows:
- Plan to initiate a Phase I clinical trial with four disease
specific expansions of evofosfamide in combination with immune
checkpoint antibodies in collaboration with researchers and
clinicians at The University of Texas MD Anderson Cancer
Center.
- Pursue discussions with Japanese regulatory authorities
regarding potential registration pathways for evofosfamide for
treatment of pancreatic cancer.
About the TH-3424 Program TH-3424 is the
Company’s new, small-molecule drug candidate, discovered at
Threshold, being evaluated for the potential treatment of
hepatocellular (liver) cancer (HCC), castrate resistant prostate
cancer (CRPC), T-cell acute lymphoblastic leukemias (T-ALL), and
other cancers expressing high levels of aldo-keto reductase family
1 member C3 (AKR1C3). Tumors overexpressing AKR1C3 can be resistant
to radiation therapy and chemotherapy. TH-3424 is a prodrug that
selectively releases a potent DNA cross-linking agent in the
presence of AKR1C3. Preliminary nonclinical toxicology
studies suggested an adequate therapeutic index that the Company
believes warrants continued development as follows:
- Continue to conduct Investigational New Drug (IND)-enabling
toxicology studies of TH-3424 in collaboration with Ascenta
Pharmaceuticals, Ltd.
A comprehensive summary of TH-3424’s preclinical profile
including biochemical, in vitro cell-based, and in vivo
animal-based characterization of its pharmacological properties was
presented at the 2016 Annual Meeting of the American Association
for Cancer Research (AACR) in April 2016. Copies of the
poster are available at the Company’s website at:
http://www.thresholdpharm.com/scientific_publications.
As a result of the Company’s focus on evofosfamide and TH-3424,
Stewart M. Kroll, the Company's Chief Operating Officer, and the
members of the biostatistics and data management group will be
departing the company. Kristen Quigley, Executive Director of
Clinical Operations at Threshold, will retain leadership of all
clinical trial operational responsibilities. The Company estimates
that it will incur a one-time charge in the fourth quarter of
approximately $0.9 million related to the reduction in
headcount, including severance, benefits and related costs. This
charge is expected to include approximately $300,000 of non-cash
expense related to the extension of the post-termination exercise
period for the outstanding vested stock options for the affected
employees. About Threshold Pharmaceuticals
Threshold is a clinical-stage biopharmaceutical company focused on
the discovery and development of drugs and diagnostic agents
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 the Company’s website. Forward-Looking
StatementsExcept for statements of historical fact, the
statements in this press release are forward-looking statements,
including all statements regarding the therapeutic potential of
evofosfamide and TH-3424; Threshold’s plans to focus its resources
on evofosfamide and TH-3424; anticipated development activities
related to evofosfamide and TH-3424, and the anticipated timing
thereof; Threshold’s plans to continue to pursue discussions
regarding potential registration pathways for evofosfamide in
Japan, and the potential for evofosfamide to be approved for
marketing in Japan; and Threshold’s estimates of the total and
non-cash charges it expects to occur in connection with the
reduction in employees, and the anticipated timing thereof. 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 difficulty and uncertainty of pharmaceutical
product development, including the risks that the design of, or
data collected from, the planned Phase I clinical trial of
evofosfamide with immune checkpoint inhibitors may be inadequate to
demonstrate safety or sufficient efficacy, or otherwise may be
insufficient to support any further development of evofosfamide,
and that Threshold’s toxicology studies of TH-3424 may not
demonstrate sufficient safety to support an investigational new
drug application and to further the development of TH-3424 into the
clinic; the uncertain and time-consuming regulatory approval
process, including the risk that data from the completed MAESTRO
clinical trial will not be sufficient to support the approval of
evofosfamide for the treatment of patients with pancreatic cancer
in Japan; Threshold's need for and the availability of resources to
develop evofosfamide and TH-3424 and to support Threshold's
operations, including the risks that Threshold’s
currently-available resources may be insufficient to further
current development plans for evofosfamide and TH-3424 and that
Threshold will otherwise need to raise substantial additional
capital in order to advance the clinical development of
evofosfamide and TH-3424; the risks that Threshold could determine
to abandon the development of evofosfamide and TH-3424 as a result
of inadequate resources, negative or inconclusive clinical trial or
toxicology study results, the failure to obtain regulatory approval
of evofosfamide in Japan, or otherwise; and risks related to
Threshold’s ability to implement the reduction in employees as
currently anticipated, the impact of such reduction on Threshold’s
business and unanticipated charges not currently contemplated that
may occur as a result of such reduction. 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 August 1,
2016 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.
Contact:
Denise Powell
denise@redhousecomms.com
510.703.9491
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