On November 20, 2014 Blueprint Medicines disclosed a new drug discovery program targeting cancers with RET fusions and predicted resistance mutations (Press release, Blueprint Medicines, NOV 20, 2014, View Source [SID:1234508104]). The announcement was made during an oral presentation at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, on Blueprint Medicines’ discovery of several novel kinase fusions implicated in cancer and identification of several new cancer indications for known kinase fusions.
"One of the greatest challenges in treating cancer is addressing cancer cells’ ability to become resistant to therapy. Our new drug discovery program uniquely addresses both the activated wild-type form of RET and its predicted resistance mutations, enabling us to potentially develop a transformative therapy for cancer patients with RET fusions," said Christoph Lengauer, PhD, MBA, Chief Scientific Officer of Blueprint Medicines. "With the unveiling of this program, we add another proof point for the productivity of Blueprint Medicines’ team and the differentiation of its kinase-focused drug discovery platform, which combines an innovative target discovery engine with a first-of-its-kind fully-annotated chemical library."
Using proprietary computational tools and techniques, Blueprint Medicines’ scientists identified RET fusions in four of 20 cancer types analyzed, including thyroid, lung, breast and colon cancers, providing a strong rationale for the development of a novel RET inhibitor across multiple patient populations. The identification of RET fusions in colon and breast cancers was one of the novel findings in the research. Combining genomics with structural and cell biology, Blueprint Medicines’ scientists were able to predict future resistance mutations of RET inhibitors currently in clinical studies. Blueprint Medicines’ drug discovery is ongoing.
Blueprint Medicines’ new RET inhibitor program adds to the Company’s existing pipeline, consisting of BLU-285, the first known selective inhibitor of KIT Exon 17 for patients with systemic mastocytosis and gastrointestinal stromal tumors (GIST), and BLU-554, the first known selective FGFR4 inhibitor for patients with hepatocellular carcinoma (HCC). Blueprint Medicines expects to initiate clinical trials for its KIT and FGFR4 programs in 2015.
Fusion genes (or fusions) are known to contribute to the development of cancers. A fusion gene is formed from the abnormal association of two normally separated genes, as a result of a translocation or other chromosomal rearrangements. Fusion genes are proven cancer drug targets, and a number of approved and exploratory drugs target kinase fusions.

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On November 19, 2014 Sunesis Pharmaceuticals reported the online publication of results from the Company’s Phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia (AML) in the November 7, 2014 Ahead of Print issue of Haematologica (Press release Sunesis, NOV 19, 2014, View Source;p=RssLanding&cat=news&id=1991012 [SID:1234500984]). The article, titled "A Phase 1b/2 study of combination vosaroxin and cytarabine in patients with relapsed or refractory acute myeloid leukemia," is available online at View Source

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"Acute myeloid leukemia is a complex, genetically heterogeneous cancer for which there has been no advancement in drug treatment in over 40 years," stated Dr. Jeffrey Lancet, Senior Member and Professor of Oncologic Sciences at the H. Lee Moffitt Cancer Center, Tampa, Florida and lead author of the publication. "In this study, we see that vosaroxin, in combination with cytarabine, is active and well tolerated. These results were mirrored in the Phase 3 VALOR trial, which demonstrated clinically meaningful outcomes supported by encouraging response rates and a manageable safety profile.

The Phase 1b/2 study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed or refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m2 on days 1, 4) were given in combination with cytarabine on 1 of 2 schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m2 per day on days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m2 per day on days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. The maximum tolerated dose for schedule A was vosaroxin 80 mg/m2 (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis); the maximum tolerated dose was not reached for schedule B (recommended phase 2 dose: 90 mg/m2).

The median age in the study was 60 years, and patients had received as many as 6 prior cycles of therapy. Furthermore, most patients (89%) had intermediate or unfavorable cytogenetic risk status. The most common treatment-emergent nonhematologic adverse events of any grade were diarrhea, hypokalemia, nausea, and stomatitis. In the efficacy population, (all first relapsed or primary refractory patients treated with vosaroxin 80-90 mg/m2; n=69), the complete remission (CR) and combined CR rates (CR or CR with incomplete blood count recovery) were 25% and 28%, respectively. Thirty-day all-cause mortality was 2.5% among all patients treated at 80-90 mg/m2. Based upon these results, the phase 3 VALOR trial of vosaroxin plus cytarabine was initiated in patients with first relapsed or refractory acute myeloid leukemia.

"The results published in Haematologica online were the foundation for the VALOR trial, among the largest studies ever conducted in the relapsed or refractory AML setting," said Adam Craig, Chief Medical Officer of Sunesis. "Based on the outcome of VALOR, we plan to submit a Marketing Authorization Application for vosaroxin and look forward to discussing the data with the U.S. Food and Drug Administration. We also look forward to building upon these and other data for vosaroxin in AML through investigator-sponsored studies."

On November 19, 2014 BIND Therapeutics reported positive results from its ongoing Phase 2 study of BIND-014 in non-small cell lung cancer (NSCLC), demonstrating it has met the primary objective in the once every three weeks (Q3W) arm as measured by overall response rate (ORR) (Press release BIND Therapeutics, NOV 19, 2014, View Source [SID:1234500985]). The data demonstrate that BIND-014 is well-tolerated with clinically meaningful anti-tumor activity at a lower dose than conventional docetaxel in patients with advanced or metastatic NSCLC. BIND-014 also demonstrates promising anti-tumor activity in patients with tumors expressing KRAS mutations (mutated Kirsten ras oncogene homolog). KRAS mutations in NSCLC are generally associated with poor response to currently available drug therapy regimens, including docetaxel. An additional signal was observed in patients with squamous cell carcinomas, a major NSCLC subtype poorly served by existing available therapies. These data were presented at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

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"We believe the activity and tolerability of BIND-014 demonstrated in this study suggest meaningful differentiation from the historical docetaxel experience, in both the broader NSCLC patient population and in two important groups of patients with high unmet medical need," said Hagop Youssoufian, M.D., M.Sc., Chief Medical Officer, BIND Therapeutics. "Furthermore, as the first product candidate from our Medicinal Nanoengineering platform to enter the clinic, we believe that the increased efficacy and reduced toxicity at a lower dose compared to historical docetaxel experience suggests that Accurins are successful in targeting the therapeutic payload to the tumor. Based on these positive results, we plan to conduct additional global, multicenter Phase 2 studies to confirm and expand the dataset on BIND-014 and to define an expeditious regulatory path for BIND-014."

The Q3W dosing arm of the open label, multicenter, Phase 2 study enrolled 40 patients with advanced metastatic NSCLC who were treated with 60 mg/m2 of BIND-014 on Day 1 of a 21-day cycle and achieved the following preliminary results:

Five patients (13%, N=40) achieved a partial response with a median duration of response of 5.2 months and median progression free survival (PFS) of 2.7 months. There was one unconfirmed partial response that was not included in the analysis per RECIST v1.1.
Nine patients were enrolled with a confirmed KRAS mutation and two of those nine experienced an objective response (22%); median PFS in patients with KRAS mutant tumors was 2.7 months.
In patients with squamous cell carcinoma (n=9) there were no confirmed objective responses; however, median PFS in patients with squamous cell carcinoma was 2.8 months. Prolonged ( > 4 cycles) disease control was also noted in six of nine (66%) patients with squamous histology.
Preliminary median overall survival was 6.2 months for all patients treated, 9.6 months in patients with KRAS mutant tumors and 11.1 months in patients with squamous cell carcinoma.
Twenty-one of 40 patients received four or more cycles of therapy, attesting to the tolerability of BIND-014. Consistent with previous results, neutropenia, anemia, neuropathy, and alopecia, commonly observed with docetaxel, were significantly reduced with BIND-014.

"Data from this open label study suggest the potential for BIND-014 superiority over docetaxel in the treatment of NSCLC patients," said Ronald B. Natale, M.D., Medical Director of the Clinical Lung Cancer Program at the Women’s Guild Lung Institute and investigator for the Phase 2 trial of BIND-014 in NSCLC. "Furthermore, BIND-014 demonstrated intriguing activity in patients with KRAS mutated lung cancers, a group of patients who have historically been unresponsive to standard treatment with docetaxel. This initial experience with BIND-014 provides a glimpse into a new way to selectively target NSCLC tumors, an area of cancer with high unmet need."

BIND plans to initiate global, multicenter Phase 2 studies of BIND-014 in patients with KRAS mutant NSCLC and in patients with NSCLC of squamous histology who have progressed on prior therapy. These studies aim to assess overall survival and additional endpoints to position BIND-014 for subsequent registration studies.

Based on the promising results of the Q3W arm presented today and the more patient-friendly once every three week dosing schedule, combined with the absence of a confirmed partial response in the first 22 patients enrolled on the Q1W schedule, the company will not continue enrollment on the weekly dosing schedule.

Data from the Phase 2 study will be included in a presentation by BIND CEO Scott Minick at the Stifel Nicolaus Weisel Healthcare Conference in New York at 8:35 a.m. EST today. Interested parties may access a live webcast of the presentation by visiting the BIND Therapeutics website at www.bindtherapeutics.com. The webcast will be archived on the BIND Therapeutics website following the event for one week.

On November 18, 2014 Teva Pharmaceutical Industries reported the commercial availability of a liquid formulation of TREANDA (bendamustine HCI) Injection (Press release Teva, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990616 [SID:1234500981]). This new liquid formulation removes the step of reconstituting lyophilized powder with sterile water prior to adding the required dose of medicine to the infusion bag and administering to a patient. By eliminating the need for reconstitution, preparation time for healthcare professionals is reduced.

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"TREANDA continues to play a valuable role in the treatment of patients with CLL or indolent B-cell NHL that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen," said Paul Rittman, Vice President and General Manager, Teva Oncology. "With the new liquid formulation of TREANDA, we are not only building on the legacy of this important product, but also furthering Teva’s commitment to continuously improving our medicines."

On November 18, 2014 Agios Pharmaceuticals reported the first reported safety and clinical activity for AG-120 from the ongoing Phase 1 dose escalation study in patients with IDH1-mutant positive advanced hematologic malignancies, including acute myeloid leukemia (AML) (Press release Agios Pharmaceuticals, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990940 [SID:1234500982]). Agios has exclusive U.S. development and commercial rights to AG-120, a first-in-class, oral, selective, potent inhibitor of the mutant IDH1 enzyme. Daniel Pollyea, M.D., clinical investigator at the University of Colorado School of Medicine, will present the data in a late-breaking oral presentation today at the 26th Annual EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics being held in Barcelona, Spain. The company will webcast an investor conference call from the symposium at 10:00 a.m. EST (4:00 p.m. CET) on Wednesday, November 19, 2014.

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As of October 17, 2014, the ongoing Phase 1 trial for AG-120 had enrolled 17 patients with a documented IDH1 mutation whose cancer relapsed or failed to respond (refractory) to at least one prior treatment regimen. At the time of the data cut, 14 patients with relapsed and/or refractory AML were evaluable; three patients recently initiated therapy and were not evaluable.

The initial data showed investigator assessed objective responses in seven out of 14 evaluable patients, including four complete remissions, with responses observed across the four dose levels tested, and early evidence of durability. One additional patient remains stable on study. AG-120 was well tolerated, with the majority of adverse events reported as mild to moderate. The maximum tolerated dose has not yet been reached. One patient had a dose limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 after AG-120 dose reduction according to treatment protocol. This patient is in complete remission and remains on AG-120. AG-120 showed favorable drug exposure and pharmacokinetics at all doses tested and also substantially reduced plasma levels of the oncometabolite 2-hydroxyglutarate (2HG), which is produced by the mutant IDH1 protein, to the level observed in healthy volunteers. The mechanism of response is consistent with differentiation, as evidenced by the maturation of the leukemic cells into infection fighting white blood cells, or neutrophils. Based on these findings, the company plans to initiate multiple expansion cohorts in the first half of 2015.

"These data show very promising evidence of clinical activity for AG-120 in AML patients with an IDH1 mutation," said Chris Bowden, M.D., chief medical officer of Agios Pharmaceuticals. "Together with the data we reported from our ongoing Phase 1 study of AG-221 in advanced hematologic cancers, our lead investigational medicine and an IDH2-mutant inhibitor, we believe IDH inhibitors could potentially change the treatment paradigm for AML patients with these mutations. We look forward to moving rapidly into multiple expansion cohorts in the first half of 2015 to further characterize the potential of AG-120."

"We are highly encouraged to see the early favorable safety profile and clinical activity of AG-120, which includes four patients who achieved complete remission," said Dr. Pollyea. "For the first time in decades, we have the potential to offer certain AML patients an improved targeted treatment for this fatal disease that has historically had limited treatment options. I am hopeful that in the future we clinicians will be able to offer well tolerated and highly effective targeted therapies for our patients who have AML harboring an IDH mutation."

Patients in the ongoing Phase 1 trial have advanced AML whose cancer was refractory to available medical treatments or relapsed after treatment. The primary objectives of the Phase 1 trial are to determine the maximum tolerated dose (MTD) and the recommended dose for further study of AG-120. Secondary objectives include characterization of the safety profile, pharmacokinetics, pharmacodynamics and early anti-tumor activity. The trial uses an open-label, dose escalating design. Patients have been enrolled to date in four cohorts of AG-120 administered at 100 mg twice a day, 300 mg once a day, 500 mg once a day and 800 mg once a day. The median age of these patients is 73 (range 42-87).