On August 24, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported the U.S. Food & Drug Administration (FDA) has granted Breakthrough Therapy Designation to cabozantinib, Exelixis’ lead compound, as a potential treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy (Press release, Exelixis, AUG 24, 2015, View Source [SID:1234507324]). Created in 2012, FDA’s Breakthrough Therapy Designation expedites the development and review of drugs that are intended to treat serious or life-threatening diseases, and for which preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Drugs that receive Breakthrough Therapy Designation may benefit from involvement of FDA senior managers in the review process, potential rolling submission and/or Priority Review of a sponsor’s New Drug Application (NDA), and other benefits.

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"Receiving Breakthrough Therapy Designation is an important regulatory achievement for cabozantinib in renal cell carcinoma," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "Following the positive top-line results announced in July and a productive dialogue with the FDA, Exelixis believes we can expedite our regulatory timelines and complete the cabozantinib NDA submission in advanced RCC prior to the end of 2015. We look forward to working closely with the FDA during the submission and review process, keeping in mind our ultimate goal of bringing a new therapeutic option to the renal cell carcinoma community as soon as possible."

Cabozantinib received Breakthrough Therapy Designation based on the results of METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in patients with RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI). In top-line results announced in July 2015, METEOR met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for cabozantinib as compared to everolimus in the first 375 patients randomized as determined by an independent radiology review committee. Cabozantinib reduced the rate of disease progression or death by 42 percent compared to everolimus (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.45-0.75, p<0.0001).

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. A distinct tablet formulation of cabozantinib is under investigation for advanced renal cell carcinoma and other types of cancer. COMETRIQ is not indicated for patients with advanced RCC or any other form of the disease.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the United States.1 Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Treatments for advanced RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon) until the introduction of targeted therapies into the RCC setting a decade ago. In the second and later-line setting, which encompasses approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two therapies have been approved for the treatment of patients who have received prior VEGF receptor TKIs. However, despite the availability of several therapeutic options, currently approved agents have shown little differentiation in terms of efficacy and have demonstrated only modest PFS benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET, and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype, and reduced overall survival.6 Up-regulation of MET in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL, and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ (cabozantinib capsules) is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.

Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.

On August 24, 2015 Epizyme, Inc. (NASDAQ:EPZM), a clinical stage biopharmaceutical company creating novel epigenetic therapies for patients with cancer, reported the U.S. Food and Drug Administration (FDA) has accepted the company’s investigational new drug (IND) application for tazemetostat for the treatment of adults and pediatric patients with INI1-negative tumors or synovial sarcoma (Press release, Epizyme, AUG 24, 2015, View Source [SID:1234507322]). In the second half of 2015, Epizyme plans to initiate a multi-center phase 2 study in adults and a multi-center phase 1 study in children to evaluate tazemetostat in patients with relapsed or refractory INI1-negative tumors or synovial sarcoma.

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"Patients with INI1-negative tumors have a life-threatening disease and few treatment options. Our development approach reflects Epizyme’s strategy for aggressively advancing tazemetostat for indications with high unmet need," said Peter Ho, M.D., Ph.D., Chief Development Officer. "These clinical studies and our IND enable the expansion of our clinical development program, as we aim to establish tazemetostat’s benefit globally in multiple therapeutic areas where it has shown promise in early research."

"We believe the treatment of INI1-negative tumors offers an opportunity for us to establish a strong clinical profile for tazemetostat in multiple patient populations and reinforces Epizyme’s leadership position in the field of targeted epigenetic therapeutics," added Robert Gould, Ph.D., President and Chief Executive Officer. "These new registration-supporting studies in INI1-negative tumors and synovial sarcoma will complement our ongoing 5-arm phase 2 study of tazemetostat in non-Hodgkin lymphoma, which is actively enrolling patients."

INI1 is a critical component of the SWI/SNF regulatory complex, a chromatin remodeler that acts in opposition to EZH2. INI1-negative tumors have altered SWI/SNF function, resulting in aberrant and oncogenic EZH2 activity. This activity can be targeted by small molecule inhibitors of EZH2 such as tazemetostat. INI1-negative tumors are generally aggressive and are poorly served by current treatments. For example, current treatment of MRT, a well-studied INI1-negative tumor, consists of surgery, chemotherapy and radiation therapy, which are associated with limited efficacy and significant treatment-related morbidity. The annual incidence of patients with INI1-negative tumors and synovial sarcoma in major markets, including the U.S., E.U. and Japan, is approximately 2,400.1

The adult phase 2 multicenter study will enroll up to 90 patients in three cohorts. The first cohort will be comprised of patients with malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK) and atypical teratoid / rhabdoid tumor (ATRT). The second cohort will be comprised of patients with other INI1-negative tumors including epithelial sarcoma, epithelioid malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, and renal medullary carcinoma. The third cohort will be comprised of patients with synovial sarcoma. Dosing in all three cohorts will be at the recommended phase 2 dose of 800 mg twice per day (BID) with a tablet formulation, which Epizyme is also using in its ongoing phase 2 trial in non-Hodgkin lymphoma. The primary endpoint is overall response rate (ORR) for patients with INI1-negative tumors and progression-free survival (PFS) for patients with synovial sarcoma. Secondary endpoints include duration of response, overall survival (OS), PFS for patients with INI1-negative tumors, safety and pharmacokinetics (PK).

The pediatric phase 1 multicenter study will enroll approximately 40 patients in a dose escalation design, followed by dose expansion, with an oral suspension of tazemetostat. The study will enroll subjects with INI1-negative tumors or synovial sarcoma. INI1-negative tumors include MRT, ATRT, RTK, and other INI1-negative tumors as previously described. The primary endpoint of study is safety with the objective of establishing the recommended phase 2 dose in pediatric patients. Secondary endpoints include PK, ORR, duration of response, PFS and OS.

Epizyme will present a clinical update for the phase 1 portion of the ongoing phase 1/2 trial of tazemetostat at ESMO (Free ESMO Whitepaper)’s European Cancer Conference on September 26, 2015. This update will include safety data from the entire cohort and efficacy data from patients with solid tumors including INI1-negative tumors.

About EZH2 in Cancer

EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include non-Hodgkin lymphomas, INI1-negative cancers such as malignant rhabdoid tumors, epithelioid sarcomas, and a range of other solid tumors including synovial sarcoma.

About the Tazemetostat Clinical Program

In addition to the aforementioned studies in patients with INI1-negative tumors and synovial sarcoma, Epizyme is evaluating tazemetostat in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and solid tumors in a phase 1/2 study. The dose escalation and dose expansion cohorts from the ongoing phase 1 part of the study are fully enrolled.

The phase 2 NHL study is the phase 2 portion of the phase 1/2 study. This trial is a five-arm, multi-center, international study that will assess the safety and activity of tazemetostat in patients with relapsed or refractory non-Hodgkin lymphoma. The study will enroll up to 30 patients in each arm, prospectively stratified for EZH2 mutation status and cell-of-origin, assuming each arm of the study achieves its primary response rate goal in its first stage. The five study arms are enrolling relapsed/refractory patients with:

Germinal center DLBCL with mutant EZH2
Germinal center DLBCL with wild-type EZH2
Follicular lymphoma with mutant EZH2
Follicular lymphoma with wild-type EZH2
Non-germinal center DLBCL
The Company also plans to initiate additional clinical evaluations of tazemetostat, including a combination with R-CHOP in patients with DLBCL, and a combination with a B-cell signaling agent or other emerging targeted therapies for B-cell lymphomas.

About Tazemetostat

Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-negative tumors or synovial sarcoma. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for compound EPZ-6438.

Additional information about the ongoing phase 1/2 program, including clinical trial information, may be found here: View Source

On August 24, 2015 Medivation, Inc. (Nasdaq:MDVN) and BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) reported that they have entered into an asset purchase agreement under which Medivation will acquire all worldwide rights to talazoparib (formerly referred to as BMN 673), a highly-potent, orally-available poly ADP ribose polymerase (PARP) inhibitor currently in a Phase 3 study for the treatment of patients with deleterious germline BRCA 1 or BRCA 2 mutations and locally advanced and/or metastatic breast cancer (Press release, BioMarin, AUG 24, 2015, View Source [SID:1234507320]).

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Under the agreement, Medivation will be responsible for all research, development, regulatory and commercialization activities for all indications on a global basis.

"Acquiring all worldwide rights to talazoparib provides Medivation with a transformational opportunity to diversify and expand our proprietary portfolio and global oncology franchise. PARP inhibitors are an exciting class of oncology therapeutics that have been associated with promising activity across multiple tumor types, including breast and prostate cancer. These latter two disease indications are areas in which Medivation has proven expertise and development capabilities and in the case of prostate cancer, an established and successful commercial presence," said David Hung, M.D., President and Chief Executive Officer of Medivation. "Talazoparib’s potential to act alone or augment the effects of a wide array of tumor DNA-damaging oncology therapies and its high potency and level of activity in various cancers make talazoparib a great strategic fit for Medivation’s oncology portfolio, building on existing strengths as well as potentially allowing Medivation to expand into new oncology indications."

"We believe that Medivation is an outstanding company to drive the future development of talazoparib and ensure it reaches its full therapeutic potential," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin. "Medivation’s expertise and track record in oncology clinical development and commercialization has been well demonstrated by the Company’s success to date. Placing talazoparib in their capable hands allows us to optimize our portfolio and focus our resources on established areas of expertise – developing novel products to treat rare and ultra-rare genetic diseases."

Under the terms of the agreement, Medivation will pay BioMarin $410 million upfront, up to an additional $160 million upon the achievement of regulatory and sales-based milestones and mid-single digit royalties for talazoparib. At the closing of the transaction, Medivation will assume all financial obligations associated with the development and commercialization of talazoparib.

The closing of the transaction is conditioned on the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. The transaction is anticipated to close in 2015.

About Talazoparib

Talazoparib is a highly-potent, orally available PARP inhibitor, a class of molecules that has shown clinical activity against cancers involving defects in DNA repair, under investigation for the treatment of certain cancers.

Talazoparib is currently in the Phase 3 EMBRACA trial in patients with germline BRCA mutated breast cancer. The pivotal study is a two-arm study randomizing patients with germline BRCA mutated locally advanced and/or metastatic breast cancer 2:1 to talazoparib or the protocol-specified physicians’ choice of chemotherapy. Patients may have received no more than two prior chemotherapy regimens for metastatic disease. The primary objective of the study is to compare progression-free survival of patients treated with monotherapy talazoparib relative to those treated with protocol-specified physicians’ choice single-agent chemotherapy. Radiographic progression will be determined by blinded independent central radiology review. Talazoparib is also being studied in a single arm Phase 2 ABRAZO trial evaluating overall response rates in patients with germline BRCA mutated breast cancer, and in multiple investigator-sponsored trials across multiple tumor types.

On August 24, 2015 AstraZeneca reported that it has entered into a clinical trial collaboration with Peregrine Pharmaceuticals, Inc. to evaluate the safety and efficacy of Peregrine’s investigational phosphatidylserine (PS)-signalling pathway inhibitor, bavituximab, in combination with AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab (MEDI4736) (Press release, AstraZeneca, AUG 24, 2015, View Source;astrazeneca-and-peregrine-pharmaceuticals-to-collab [SID:1234507319]). The planned Phase I/Ib trial will evaluate the safety and efficacy of bavituximab in combination with durvalumab in multiple solid tumours.

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AstraZeneca and Peregrine will collaborate on a non-exclusive basis, to evaluate the combination of bavituximab and durvalumab with chemotherapy as a potential treatment in various solid tumours. The Phase I part of the trial is expected to establish a recommended dose regimen for the combination and the Phase Ib part of the trial will assess the safety and efficacy of the investigational combination. The initial trial will be conducted by Peregrine.

Bavituximab and durvalumab are investigational immunotherapies with different mechanisms that assist the body’s immune system in fighting cancer. Bavituximab targets and modulates the activity of phosphatidylserine, a highly immune-suppressive molecule expressed broadly on the surface of cells in the tumour microenvironment. The treatment increases activated T-cells in tumours and fights cancer by reversing the immunosuppressive environment that many tumours establish in order to proliferate. Durvalumab is a monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. Preclinical data have demonstrated that by combining the enhanced T-cell mediated anti-tumour activity of bavituximab with checkpoint inhibitors like PD-L1 antibodies, the ability of tumour-specific T-cells to continue attacking the tumor is prolonged.

Robert Iannone, Head of Immuno-Oncology, Global Medicines Development, at AstraZeneca said: "We believe that combination therapy in immuno-oncology has the potential to be a novel and highly effective approach to treating cancer. Our partnership with Peregrine provides the opportunity to explore an exciting, novel combination that could deliver important clinical benefit to patients across a range of cancers."

Steven W. King, President and Chief Executive Officer of Peregrine said: " Data generated to date have shown significant potential for combining bavituximab with agents targeting the PD-1/PDL-1 pathway and we’re excited to further explore this approach in studies with durvalumab. AstraZeneca, with its biologics arm MedImmune, is a recognised leader in the immuno-oncology field and this collaboration will play a key role as we continue to fully explore the potential of bavituximab in combination immunotherapies for a variety of clinical applications."

NOTES TO EDITORS

About Bavituximab

Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognise and fight tumours. Bavituximab, the lead compound in Peregrine’s immuno-oncology development programme, blocks PS to remove this immunosuppressive signal and sends an alternate immune activating signal. Targeting PS with bavituximab has been shown to shift the functions of immune cells in tumours, resulting in robust anti-tumour immune responses.

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. Durvalumab blocks these signals, countering the tumour’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer.