On January 11, 2016 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported an update on its evofosfamide program including that Threshold and Merck KGaA, Darmstadt, Germany have agreed upon key terms for the licensing back of all rights to evofosfamide to Threshold (Filing, 8-K, Threshold Pharmaceuticals, JAN 11, 2016, View Source [SID:1234508731]). The companies have a global license and co-development agreement for evofosfamide, an investigational hypoxia-activated prodrug for the treatment of cancer, which was discovered and initially developed by Threshold.

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The decision to return rights to evofosfamide to Threshold follows the unblinding of two Phase 3 clinical trials of evofosfamide (TH-CR-406 and MAESTRO) and a previously unplanned, subsequent interim futility analysis of a Phase 2 clinical trial of evofosfamide in patients with non-squamous non-small cell lung cancer (n-s NSCLC). As previously announced, both Phase 3 trials failed to meet the primary endpoint of demonstrating a statistically significant improvement in overall survival. The results of the MAESTRO trial will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Gastrointestinal Cancers Symposium during an oral presentation session scheduled to begin at 2:00 p.m. Pacific Time on Friday, January 22, 2016 (Abstract #193).

Following the topline results from the two Phase 3 clinical trials, Threshold and Merck KGaA, Darmstadt, Germany decided to unblind the Phase 2 clinical trial in n-s NSCLC and conduct an interim futility analysis. The Phase 2 trial was designed to enroll 440 patients with advanced n-s NSCLC. A total of 265 patients were enrolled and 112 events (deaths) were reported at the time of the interim analysis. An independent Data Safety Monitoring Board conducted the analysis and concluded that the trial is unlikely to reach its primary endpoint of improving overall survival with statistical significance. As a result, further enrollment in this trial will be closed. Additional findings from the interim analysis indicated that evofosfamide plus pemetrexed demonstrated longer progression-free survival (PFS) associated with a reduction in the risk of progression or death by approximately 30%. No new safety findings were reported. Data for this trial will be finalized and results presented at a future medical meeting.

"We are pleased to have agreed to key terms for the licensing back of all rights to evofosfamide to Threshold and we will share our plans for the future development of evofosfamide once our ongoing analyses of the data from the recently unblinded clinical trials are complete," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "In parallel, we continue to focus on prosecuting two Phase 2 clinical trials of tarloxotinib, our hypoxia-activated EGFR tyrosine kinase inhibitor, and to assess other strategic options for the company."

About Evofosfamide

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. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic. Threshold previously announced the outcomes of two Phase 3 studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide stating that neither study met its primary endpoint. The related news release dated December 7, 2015, can be accessed on the company’s website in the Investors/News Releases section View Source


About Tarloxotinib Bromide

Tarloxotinib bromide (the proposed International Nonproprietary Name), 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. Accordingly, tarloxotinib has the potential to effectively shut down aberrant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the systemic side effects associated with currently available EGFR tyrosine kinase inhibitors. Tarloxotinib is currently being evaluated in two Phase 2 proof-of-concept trials: one for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR tyrosine kinase inhibitor, and the other for patients with recurrent or metastatic squamous cell carcinomas of the head and neck or skin. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.

On January 11, 2016 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations and a primary focus in Hematology and Oncology and Servier Canada Inc., an affiliate of Servier a research-oriented pharmaceutical company which is pioneering new therapies primarily for cancer and cardiovascular diseases, reported the signing of a strategic partnership (Filing, 8-K, Spectrum Pharmaceuticals, JAN 11, 2016, View Source [SID:1234508730]).

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As part of this partnership, Spectrum will grant the exclusive rights to develop and commercialize in Canada a franchise of four Spectrum hemato-oncology drugs: Zevalin (ibritumomab tiuxetan) Injection for intravenous use, Folotyn(pralatrexate injection), Beleodaq (belinostat) for Injection and Marqibo (vinCRIStine sulfate LIPOSOME injection) for intravenous infusion. Spectrum will receive $6 million in upfront payments, plus development milestone payments and royalties based on net product sales.

"We are pleased to announce this strategic partnership with Servier, a leading company in Canada," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "This deal allows us to continue to focus on our core priorities including SPI-2012, Poziotinib, Apaziquone and Evomela. This year we plan to initiate two key trials with drugs that target blockbuster markets and we are looking forward to hearing from the FDA on two of our NDA submissions. We believe that our pipeline has never been as strong as it is today, and we continue to focus on executing on our key priorities."

"This strategic partnership between Spectrum Pharmaceuticals and Servier Canada will contribute to consolidate our global strategy in Oncology. Our ambition is to become a benchmark player in this field," said Frédéric Sesini, Executive Vice-President International Operations of Groupe Servier. "We are fully committed in providing Canadian patients with innovative treatment options. With this key partnership, Servier Canada Oncology will start operating and will work to make these treatments available soon," underlined Frederic Fasano, Chief Executive Officer of Servier Canada Inc.

On January 11, 2016 Sanofi and Innate Pharma reported that they have entered into a research collaboration and licensing agreement to apply Innate Pharma’s new proprietary technology to the development of innovative bispecific antibody formats engaging natural killer (NK) cells to kill tumor cells through the activating receptor NKp46 (Press release, Innate Pharma, JAN 11, 2016, View Source [SID:1234508722]).

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Sanofi and Innate Pharma will work together on the generation and evaluation of up to two bispecific NK cell engagers, using technology from Innate Pharma and Sanofi’s proprietary bispecific antibody format as well as tumor targets. Under the terms of the licence agreement, Sanofi will be responsible for the development, manufacturing and commercialization of products resulting from the research collaboration. Innate Pharma will be eligible to up to €400m in development and commercial milestone payments as well as royalties on net sales.

"Over the past year, Sanofi has launched strategic corporate collaborations in the field of immuno-oncology that exemplify our commitment to open innovation in R&D and have the potential to transform the treatment of cancer," said Gary Nabel, Chief Scientific Officer, Sanofi. "Working with Innate Pharma, we seek to create new bispecific antibodies that will focus the immune system to kill cancer cells by engaging natural killer cells."

"There is a lot of excitement around bispecifics in immuno-oncology. By building on our knowledge of the activating receptor NKp46, we have generated a technology to specifically induce tumor killing by NK cells. This new technology platform is complementary to our innovative portfolio of first-in-class antibodies targeting immune checkpoints. We intend to use it for our internal portfolio expansion, as well as through non-exclusive agreements with other companies, such as in this agreement with Sanofi", said Nicolai Wagtmann, Chief Scientific Officer of Innate Pharma.

NKp46 is an activating receptor expressed on all natural killer cells. It is the most specific marker of human NK cells and plays a major role in their tumor cell recognition. NKp46-bispecific NK cell engagers bind with one arm to an antigen at the surface of tumor cells, and with another arm to the NKp46 receptor on NK cells. This leads to activation and specific tumor-killing by NK cells, an immune cell population representing a significant proportion of all cytotoxic lymphocytes in the body.

On January 11, 2016 Incyte Corporation (Nasdaq:INCY) and AstraZeneca (NYSE:AZN) reported a new collaboration to evaluate the efficacy and safety of Incyte’s Janus-associated kinase (JAK) 1 inhibitor, INCB39110, in combination with AstraZeneca’s next generation epidermal growth factor receptor (EGFR) inhibitor, Tagrisso (osimertinib) (Press release, Incyte, JAN 11, 2016, View Source [SID:1234508720]). The combination will be assessed as a second-line treatment for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), who have been treated with a first generation EGFR tyrosine kinase inhibitor (TKI) and subsequently developed the T790M resistance mutation.

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There is increasing evidence that signaling through the JAK-STAT (signal transducer and activator of transcription) pathway could be a contributing factor in resistance to EGFR TKI treatment in patients with EGFR mutation NSCLC. Blocking both JAK and EGFR activity may therefore offer an improved targeted treatment benefit in some patients.

Under the terms of the agreement, AstraZeneca and Incyte will collaborate on a Phase 1/2 study, to be conducted by Incyte. The Phase 1 part of the trial is expected to establish a recommended dose regimen for the combination of INCB39110 and Tagrisso while the Phase 2 part of the study will assess the safety and efficacy profile. Results from the study will be used to determine whether further clinical development of this combination is warranted.

"The expansion of our research collaboration with AstraZeneca will allow us to further our understanding of these two compounds and explore their potential synergies both of which support our goal of delivering innovative medicines that will benefit patients with cancer or other diseases," said Rich Levy, MD, Chief Drug Development Officer, Incyte. "We look forward to adding to our ongoing clinical research for INCB39110 and exploring the potential of this combination."

"We are pleased to be building on our existing relationship with Incyte and exploring a potentially exciting combination for lung cancer patients who have developed a resistance to first generation EGFR inhibitor treatment," said Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca. "This collaboration allows us to explore further ways in which Tagrisso, our first-in-class T790M-directed tyrosine kinase inhibitor, can help meet urgent unmet patient need, following its accelerated approval in the U.S. and the recent positive CHMP opinion, recommending approval in Europe."

This agreement builds on an existing collaboration between the two companies, announced in May 2014, to explore AstraZeneca’s anti-PD-L1 immune checkpoint inhibitor, durvalumab, in combination with Incyte’s oral indoleamine dioxygenase-1 (IDO1) inhibitor, epacadostat (INCB24360).

About INCB39110
INCB39110 is an orally bioavailable, isoform-selective inhibitor of Janus-associated kinase 1 (JAK1). JAK1 activity is believed to play an important role in both autoimmune and oncologic diseases. JAK1 forms heterodimeric complexes with JAK2, JAK3 or TYK2 and functions as an immunomodulatory and inflammatory signalling kinase. Selective JAK1 inhibition prevents STAT signaling downstream of a number of cytokines, including IL-6, IL-10 and interferon-gamma. Consistent with the dominant role for JAK1 in mediating heterodimeric JAK/STAT signaling, JAK1 inhibition has been shown to result in equivalent efficacy compared to balanced JAK1/JAK2 modulation in a variety of preclinical solid and liquid tumor models. INCB39110 will be investigated in clinical trials as monotherapy in graft versus host disease (GvHD) and in several combination-based therapeutic regimens, including with PI3Kδ (INCB50465), IDO1 (epacadostat) and EGFR (Tagrisso) inhibitors.

About Tagrisso (osimertinib)
Tagrisso (osimertinib) is the only approved medicine indicated for adult patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer. This indication is approved under the FDA’s accelerated approval process based on tumour response rate and duration of response (DoR). Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M-positive, locally advanced, or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, and in combination with other compounds.

Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.

On January 11, 2016 Incyte Corporation (Nasdaq: INCY) reported significant and rapid progress in its continued transformation into a leading global biopharmaceutical company (Press release, Incyte, JAN 11, 2016, View Source [SID:1234508719]). With two new programs expected to enter the clinic in the coming months, Incyte will have 13 development molecules in pivotal and proof-of-concept trials across a variety of oncology and non-oncology indications, illustrating the power of Incyte’s drug discovery and development engine.

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"We are experiencing a revolution in the way cancer is treated, and Incyte is at the forefront of innovation in drug discovery," said Hervé Hoppenot, President and Chief Executive Officer, Incyte. "Our rich portfolio of small molecules and biologics places us in a unique position. We have significant optionality to investigate these candidates alone as well as in combination as we continue our mission to deliver medicines that will positively impact the lives of patients with cancer and other diseases."

Presentation Highlights

JAK Inhibitors
The Phase 3 JANUS 1 trial of ruxolitinib, a JAK1 / JAK2 inhibitor, in second line metastatic pancreatic cancer is now fully recruited, with results expected in 2016. The primary endpoint of JANUS 1 is overall survival. Two Phase 2 trials of ruxolitinib, in colorectal and breast cancer, are now fully recruited, with overall survival data expected from both in 2016.

Incyte has two selective JAK1 inhibitors in clinical development, INCB39110 and INCB52793. A clinical collaboration has been initiated to investigate the safety and efficacy of the combination of INCB39110 with AstraZeneca’s next generation EGFR inhibitor Tagrisso (osimertinib)* in patients with EGFRm non-small cell lung cancer with the T790M mutation. Incyte’s second JAK1 selective inhibitor, INCB52793, is in a dose escalation study in patients with advanced malignancies. INCB52793 has shown synergistic efficacy in combination with standard of care in preclinical models of multiple myeloma.

Building upon positive, published third-party data of ruxolitinib from an investigator-sponsored trial in graft versus host disease (GVHD), a proof-of-concept trial of INCB39110 for the treatment of patients with GVHD has begun.

Each of the four pivotal trials of baricitinib, a JAK1 / JAK2 inhibitor licensed by Incyte to Eli Lilly and Company, met the primary endpoint in patients with rheumatoid arthritis. Lilly is finalizing the submissions of a New Drug Application (NDA) to the FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency. Both will trigger milestone payments from Lilly to Incyte.

IDO1 Inhibitor
The ECHO (Epacadostat Clinical development in Hematology and Oncology) program has been designed to investigate combinations of Incyte’s IDO1 inhibitor, epacadostat, across the full cycle of anti-tumor immunity, including with checkpoint blockade, vaccines and other modulators of the tumor immune response.

The Phase 3 ECHO-301 study evaluating the combination of epacadostat with the anti-PD-1 antibody Keytruda (pembrolizumab)* for the first-line treatment of patients with advanced or metastatic melanoma is expected to begin in the first half of 2016. Recruitment has also begun into the eight tumor-specific cohorts of ECHO-202, the Phase 2 trial of epacadostat in combination with pembrolizumab.

Incyte is conducting three additional Phase 1/2 clinical trials of epacadostat in combination with immune checkpoint inhibitors. ECHO-204, in combination with Bristol-Myers Squibb’s PD-1 inhibitor, Opdivo (nivolumab)*, has opened seven tumor specific cohorts, and ECHO-203 with AstraZeneca/MedImmune’s investigational PD-L1 inhibitor, durvalumab, has opened six tumor specific cohorts. ECHO-110, a trial in combination with Roche/Genentech’s investigational PD-L1 inhibitor, atezolizumab, in patients with NSCLC is ongoing.

Selected Portfolio Updates
Incyte’s PI3Kδ inhibitor clinical development program is focused on INCB50465, based on the molecule’s potential lack of hepatotoxicity and improved potency compared to approved PI3Kδ inhibitors and compared to Incyte’s PI3Kδ inhibitor INCB40093. A Phase 1/2 trial of INCB50465, both as monotherapy and in combination with INCB39110, is already underway in multiple B-cell malignancies. Clinical activities of INCB40093 are being closed.

Incyte is also pursuing a series of clinical studies to investigate the safety and efficacy of several therapeutic doublets. These include a clinical trial of Incyte’s JAK1 inhibitor, INCB39110, in combination with either its IDO1 inhibitor, epacadostat, or its PI3Kδ inhibitor, INCB50465, as well as a trial of Merck’s anti-PD-1 antibody, pembrolizumab, in combination with either Incyte’s PI3Kδ inhibitor, INCB50465, or its JAK1 inhibitor, INCB39110.

Two new compounds are expected to enter Incyte’s clinical development portfolio in the first half of 2016. INCB59872, a potent and selective LSD1 inhibitor, is expected to enter clinical trials in patients with advanced malignancies in the coming months. INCAGN1876, an anti-GITR agonist antibody that is part of the ongoing discovery alliance with Agenus, Inc, is expected to enter clinical trials for the treatment of patients with advanced cancer during the first half of 2016. Incyte’s alliance with Agenus has recently been expanded to include a total of 7 therapeutic targets, with options for additional expansion.

Corporate Update
In January 2016, Michael Morrisey joined Incyte Europe Sàrl and the Incyte Executive Management team as Corporate Senior Vice President and Head of Global Technical Operations. Michael has extensive manufacturing experience and has excelled in building manufacturing organizations, most recently as Corporate Vice President, Head of International Technical Operations at Celgene International.

Webcast Information
A presentation made by Incyte at the 34th Annual J.P. Morgan Healthcare Conference will be webcast live today at 1:30pm PT / 4:30pm ET and can be accessed within the Investors section of www.incyte.com under Events and Presentations. Investors interested in listening to the live webcast should log on before the start time in order to download any software required. The slide deck and a replay of the presentation will also be made available following the presentation.