On February 15, 2020 Oncoceutics, Inc. reported the outlicense of the rights to the company’s lead compound, ONC201, for Japan to Ohara Pharmaceutical Co., Ltd (Press release, Oncoceutics, FEB 15, 2019, View Source [SID1234558361]). In addition, Ohara will receive a right of first refusal on the license of ONC201 for additional areas, including most of Asia and West Africa, and a right of first refusal for the company’s next generation compound, ONC206, in these territories.

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In return for the license and future rights, Ohara will make a multi-part payment to Oncoceutics including upfront payments, milestone payments, payment for purchase of the drug for re-sale, and royalties. In addition, Ohara will make a significant equity investment into Oncoceutics. Ohara will also be responsible for the execution of clinical trials required to obtain Marketing Authorization in Japan and the commercialization of ONC201 in the Japanese market.

ONC201 is a novel small molecule with a unique mechanism of action that has demonstrated anti-cancer activity and safety in preclinical models and in several ongoing clinical trials, including clinical trials in adult and pediatric patents with high-grade gliomas. The trials focus on gliomas that harbor a H3 K27M mutation that can be identified by immunohistochemistry or gene sequencing, including the FDA-approved companion diagnostic FoundationOne CDx. H3 K27M-mutant glioma is a molecularly-defined disease with a dismal prognosis.

Oncoceutics’ clinical trials are being carried out at numerous leading cancer centers across the United States, including: Massachusetts General Hospital, Dana Farber Cancer Institute, NYU Langone, MD Anderson Cancer Center, Levine Cancer Institute, Miami Cancer Institute, University of California San Francisco, and the University of Michigan. In addition, Emory University, University California Los Angeles, Columbia University and several other institutions are in the process of joining the program. Recently, the FDA granted Fast Track Designation to ONC201 for the Treatment of Adult Recurrent H3 K27M-mutant High-Grade Glioma.

"We are delighted to be partnering with Ohara Pharmaceutical Co., Ltd. whose mission and focus set them apart in the Japanese market and make them the ideal collaborators to bring ONC201 to Japanese patients with H3 K27M-mutant gliomas and other indications," said Wolfgang Oster, MD, PhD, Chief Executive Officer and Chairman of Oncoceutics. "This agreement sets the stage for developing ONC201 towards entry into global markets and providing a therapeutic option to patients in Japan who are affected by a serious disease. Oncoceutics will work closely with Ohara to expand the use of ONC201 into other cancers that are similarly responsive to the pathways engaged by ONC201. We are thrilled by the shared vision between the two companies to introduce a truly novel therapeutic paradigm to a broad selection of tumors that abuse dopamine signaling to promote their growth."

"We are excited to be working with the exceptional team at Oncoceutics to bring this novel medicine and medical concept to Japan for patients with cancer for whom there are no other options," said Seiji Ohara, President of Ohara Pharmaceuticals., Ltd. "The introduction of new treatment paradigms have often led to breakthroughs in diseases that have no therapeutic standards. The anticipated market entry for ONC201 in Japanese pediatric and adult oncology patients is consistent with Ohara’s strategy to challenge and address unmet medical needs. We are excited with the opportunity of the two companies to collaborate and develop ONC201 to address a broad selection of cancers responsive to ONC201."

On February 15, 2019 Bayer reported that it has exercised its option, under a change-in-control clause in the collaboration agreement with Loxo Oncology, to obtain the exclusive licensing rights for the global development and commercialization, for Vitrakvi (larotrectinib) and BAY 2731954 (LOXO-195) (Press release, Bayer, FEB 15, 2019, View Source [SID1234549944]). Both compounds are being developed globally for the treatment of adult and pediatric patients with advanced solid tumors harboring NTRK gene fusions. The option was triggered by the acquisition of Loxo Oncology by Eli Lilly and Company, which became effective today. As a result of this exercise, the joint co-promotion agreement in the U.S. between Bayer and Loxo Oncology is being converted to full commercialization in the U.S. by Bayer.

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"Bayer is dedicated to improving the lives of cancer patients, and precision oncology is a promising area that has the potential to redefine the way cancer patients are treated. Our collaboration with Loxo Oncology was an important milestone and with the opportunity to exercise our option on Vitrakvi and BAY 2731954, we are taking the next step in our efforts to advance the future of cancer care and strengthen our leadership in this field," said Robert LaCaze, Member of the Executive Committee of Bayer’s Pharmaceuticals Division and Head of the Oncology Strategic Business Unit at Bayer. "With the first-ever approved TRK inhibitor with activity against TRKA, TRKB and TRKC, Vitrakvi, and BAY 2731954 progressing through clinical development, we have two compounds in our precision oncology portfolio and we are committed to expanding this portfolio by bringing forward highly differentiated and promising additional projects."

In November 2017, Bayer and Loxo Oncology entered into a global collaboration for the joint development and commercialization of the TRK inhibitors Vitrakvi and BAY 2731954 (LOXO-195). Following the change of control, Bayer will be solely responsible for the global development and commercialization of both Vitrakvi and BAY 2731954. Bayer is already leading ex-U.S. regulatory activities, and worldwide commercial activities. When the new exclusive licensing arrangement takes effect, the co-promotion in the U.S. will be converted into an exclusive commercialization by Bayer and the sharing of commercial costs and profits on a 50/50 basis for the U.S. market will be replaced by royalties to be paid by Bayer. Bayer will continue to pay royalties on future net sales outside the U.S.

In addition, in connection with Bayer’s exercise of the option, certain licenses granted by Loxo Oncology to Bayer will become exclusive following anti-trust clearance in the U.S.

About Vitrakvi (larotrectinib) and BAY 2731954
Vitrakvi is an oral TRK inhibitor for the treatment of adult and pediatric patients with solid tumors with an NTRK gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Research suggests that the NTRK genes can become abnormally fused to other genes, producing a TRK fusion protein that can act as an oncogenic driver, leading to cancer cell growth and survival.

BAY 2731954 is an oral investigational new drug in clinical development rationally designed for the treatment of patients with cancers that have acquired resistance to initial TRK therapy. In July 2017, a multi-center Phase I/II trial in patients with TRK fusion cancers who have progressed while receiving another TRK inhibitor or are intolerant to another TRK inhibitor was initiated.

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless of where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).

Important Safety Information

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were:
increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.

On February 15, 2019 Nektar Therapeutics presented the corporate presentation (Presentation, Nektar Therapeutics, FEB 15, 2019, View Source [SID1234533358]).

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On February 15, 2019 Decipher Biosciences (formerly GenomeDx), a leader in the field of urologic cancer genomics, reported a research collaboration with Dendreon Pharmaceuticals, a commercial-stage biopharmaceutical company and pioneer in the development of immunotherapy, to apply genomic tumor profiling using the Decipher assay and GRID software to identify prostate cancer patients on active surveillance who may benefit most from treatment with sipuleucel-T. PROVENGE (sipuleucel-T) was the first U.S. Food and Drug Administration (FDA)-approved immunotherapy made from a patient’s own immune cells (Press release, GenomeDX BiosciencesInc, FEB 15, 2019, View Source [SID1234533357]).

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"We are pleased to work with Dendreon on this important research collaboration, which we believe will help accelerate the discovery and development of genomic solutions to aid in the treatment and management of prostate cancer," said Elai Davicioni, PhD, chief scientific officer of Decipher Biosciences. "Leveraging Decipher, GRID and machine learning to uncover novel predictors of treatment response will help realize our mutual goal of personalizing therapy for patients with prostate cancer."

As part of the agreement, Dendreon will provide Decipher Biosciences with tumor samples from its Phase 3 ProVent trial (NCT03686683), which will evaluate the effectiveness of sipuleucel-T in reducing disease progression in men with prostate cancer on active surveillance. Decipher Biosciences will use its whole transcriptome Decipher assay to assess the biological behavior of a patient’s tumor and its GRID software and database to evaluate gene expression signatures that may be associated with sipuleucel-T response.

"More than 50,000 men choose active surveillance every year1, which includes regular monitoring to ensure the cancer is not growing or spreading, over more serious treatment options that can negatively impact quality of life," said Bruce A. Brown, M.D., chief medical officer at Dendreon. "It is our hypothesis that treating patients on AS with sipuleucel-T immunotherapy will enable more of them to stay in the AS cohort longer, perhaps indefinitely."

About Decipher Cancer Classifier Tests and GRID

Decipher prostate and bladder cancer classifiers are clinical, commercially available oncology tests that provide a genomic assessment of tumor aggressiveness for individual patients. Decipher Biopsy is indicated for men with localized prostate cancer at diagnosis, Decipher RP is indicated for men after prostate removal surgery, and Decipher Bladder is indicated for patients being considered for neoadjuvant chemotherapy prior to bladder removal surgery. The Decipher tests are used by physicians to stratify patients into more accurate risk groups than determined by traditional diagnostic tools and to help determine which patients may be more likely to benefit from additional treatment.

The Decipher tests are derived from the Decipher Genomics Resource Information Database (GRID). GRID contains the genomic profiles of tens of thousands of tumors from patients with urological cancers, and is believed by Decipher Biosciences to be the largest shared genomic expression database in urologic cancer as well as one of the world’s largest global RNA expression databases using cloud-based analytics. Each tumor analyzed with a Decipher test adds new data to the GRID database, which is compiled into a Decipher GRID Profile that may reveal additional biological characteristics of the tumor for ongoing research purposes. Going beyond risk stratification, Decipher and GRID make genomic information accessible for researchers to predict responses to therapy better and to guide treatment more precisely. In addition, GRID is a platform for interactive research collaboration, and may enable more rapid discovery, development, commercialization and adoption of new genomic solutions for key clinical questions in cancer treatment.

On February 15, 2019 CStone Pharmaceuticals ("CStone") reported that the National Medical Products Administration (NMPA) recently approved a Phase III clinical trial in China for its partnered drug candidate avapritinib as a third-line treatment against KIT-driven gastrointestinal stromal tumors (GIST) (Press release, CStone Pharmaceauticals, FEB 15, 2019, View Source [SID1234533356]).

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The study will be part of the global VOYAGER Phase III trial comparing avapritinib against the current standard of care regorafenib in GIST patients who have previously received imatinib and one or two additional tyrosine kinase inhibitors (TKIs). The study is designed to evaluate avapritinib’s safety and efficacy, with progression-free survival as the primary efficacy endpoint.

GIST, which is classed as a rare disease, is a form of sarcoma usually found in the walls of the stomach or the small intestine, and is typically diagnosed between the ages of 50 and 80. The most common forms of GIST are linked to mutations that lead to over-activation of the KIT or PDGFRα tyrosine kinases, resulting in deregulated cell growth. Approximately 90% of GIST cases are linked to mutations of KIT or PDGFRα.

According to data from the NAVIGATOR Phase I clinical trial reported as of October 15, 2018, avapritinib was administered to 109 fourth-line or later GIST patients at doses of 300mg or 400mg.

Within that population, 1 patient achieved complete response and there were 21 partial response (ORR[1] of 20%); stable disease was reported in 72 patients (DCR[2] of 66%); 60% of patients had tumor reductions; and mDOR[3] was 7.3 months.
Of 23 third/fourth-line GIST patients not previously treated with regorafenib, 78% experienced tumor reductions, while 6 achieved partial response (ORR of 26%), 13 achieved stable disease (DCR of 83%), and the mDOR was 10.2 months.
In 56 patients with PDGFRα D842V-driven GIST, tumor reduction was observed in 98% of patients, with 5 complete response and 42 partial response (ORR of 84%). The 12-month DoR was 76.3%, and the 12-month progression free survival rate was 81.3%.
Dr. Frank Jiang, chairman and CEO of CStone, commented: "Avapritinib is a first-in-class precision medicine drug that has been awarded Breakthrough Therapy Designation by the U.S. FDA due to its outstanding clinical efficacy. Current available clinical data already demonstrated the drug’s great potential for advanced GIST patients. CStone is delighted to be able to introduce this product to Chinese patients via our partnership with Blueprint Medicines, and we look forward to generating positive clinical data in China."

CStone’s Chief Medical Officer Dr. Jason Yang noted: "Avapritinib is the only inhibitor of KIT and PDGFRα D842V mutant kinases under clinical development in China at present. We aim to advance the Phase III VOYAGER study for avapritinib rapidly to benefit Chinese patients with KIT-mutated GIST. We are also planning trials of avapritinib for the treatment of earlier lines of GIST and systemic mastocytosis. In addition, we will consider exploring the potential of combination therapy with CStone’s IO backbone assets."

About avapritinib

Avapritinib is an orally available, potent and highly selective inhibitor of KIT and PDGFRα. Preclinical data have shown that avapritinib is active across a broad spectrum of KIT and PDGFRα mutations, including KIT D816V, PDGFRα D842V and KIT exon 17 mutations, for which there are limited or no effective treatment options. Blueprint Medicines is initially developing avapritinib, an investigational medicine, as a treatment for patients with advanced GIST and advanced systemic mastocytosis (ASM).

In June 2017, avapritinib received Breakthrough Therapy from the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation. Previously, the FDA awarded avapritinib orphan drug and fast-track designation. In addition, the molecule has also been granted orphan drug status by the European Commission.

At the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting, data from the Phase I EXPLORER clinical trial was published showing that avapritinib produced sustained clinical response in patients with ASM, and the therapeutic effect was found to deepen over time regardless of disease subtype, previous treatment, or initial dose.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Greater China.