On December 5, 2017 Clovis Oncology (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for rucaparib and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of April 6, 2018 (Press release, Clovis Oncology, DEC 5, 2017, View Source;p=RssLanding&cat=news&id=2321248 [SID1234522390]). In October, Clovis completed its sNDA submission for rucaparib as maintenance treatment in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are platinum sensitive, and in a complete or partial response to platinum-based chemotherapy. The Company is seeking approval for use of rucaparib for this indication regardless of a patient’s BRCA mutation status.

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"We are pleased that we continue to make significant progress toward our goal of delivering rucaparib to a much broader population of women with advanced ovarian cancer," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We are particularly encouraged by the FDA’s decision to grant priority review to the application, which may allow us to make rucaparib available to these women in a more expeditious manner."

A priority review designation is granted to proposed medicines that the FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. Priority designation shortens the review period from the standard ten months to six months from the acceptance of the NDA.

The rucaparib sNDA was submitted to the FDA in October 2017 and is based on data from the phase 3 ARIEL3 clinical trial. ARIEL3 is a double-blind, placebo-controlled trial of rucaparib that enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner: 1) BRCA mutant 2) HRD-positive; and, finally, 3) the intent-to-treat population, or all patients treated in ARIEL3.

Clovis announced positive topline results from the ARIEL3 clinical trial in June 2017. Additional data from the trial were presented at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Conference in Madrid, Spain,1 and subsequently published in The Lancet.2

Clovis intends to file a variation to the Marketing Authorization Application (MAA) in Europe in early 2018 for the maintenance indication, contingent on a potential approval in Europe for the ovarian cancer treatment indication.

About the ARIEL3 Clinical Trial

The ARIEL3 pivotal study of rucaparib is a confirmatory randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a complete or partial response to platinum-based chemotherapy. The study enrolled 564 patients with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. To be eligible for the study, participants had to have received at least two prior platinum-based treatment regimens, been sensitive to the penultimate platinum regimen, and achieved a complete or partial response to their most recent platinum-based regimen. There were no genomic selection criteria for this study. Trial participants were randomized 2:1 to receive 600 milligrams of rucaparib twice daily (BID) or placebo.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in ovarian cancer as well as several additional solid tumor indications. During the fourth quarter of 2016, the Marketing Authorization Application (MAA) submission in Europe for rucaparib in an ovarian cancer treatment indication was submitted and accepted for review. A CHMP opinion is expected in late 2017. In October 2017, Clovis Oncology submitted a supplemental New Drug Application (sNDA) in the U.S. for a second line or later maintenance treatment indication in ovarian cancer based on the ARIEL3 data. In early 2018, Clovis plans to file a variation to the MAA in Europe for the maintenance treatment indication contingent on a potential approval for the ovarian cancer treatment indication. Studies open for enrollment or under consideration include ovarian, prostate, breast, gastroesophageal, pancreatic, lung and bladder cancers. Clovis holds worldwide rights for rucaparib.

About Rubraca (rucaparib)

Rubraca is a PARP inhibitor indicated in the U.S. as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. The indication for Rubraca is approved under the FDA’s accelerated approval program based on objective response rate and duration of response, and is based on results from two multicenter, single-arm, open-label clinical trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Please visit rubraca.com for more information.

About Ovarian Cancer

According to the American Cancer Society, more than 22,400 women will be diagnosed with ovarian cancer in the U.S. in 2017. There are often no clearly identifiable initial symptoms, and in an estimated 80 to 85 percent of ovarian cancer cases, the cancer has spread to other parts of the body before a person is diagnosed and can be treated. Ovarian cancer ranks fifth in cancer deaths and causes more deaths than any other cancer of the female reproductive system.

On December 5, 2017 MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported the closing of the global collaboration and license agreement with Incyte Corporation for MGA012, an anti-PD-1 monoclonal antibody (Press release, MacroGenics, DEC 5, 2017, View Source [SID1234522392]). The agreement was announced on October 25, 2017.

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Under the terms of the agreement, MacroGenics will receive an upfront payment of $150 million, while Incyte receives worldwide rights to develop and commercialize MGA012 in all indications. MacroGenics is eligible to receive up to $420 million in potential development and regulatory milestones, and up to $330 million in potential commercial milestones. If MGA012 is approved and commercialized, MacroGenics would be eligible to receive royalties, tiered from 15 percent to 24 percent, on future sales of MGA012 by Incyte.

After a pre-defined transition period, Incyte will lead global development of MGA012. MacroGenics retains the right to develop its own pipeline assets in combination with MGA012, with Incyte commercializing MGA012 and MacroGenics commercializing its asset(s), if any such potential combinations are approved.

In addition, MacroGenics retains the right to manufacture a portion of both companies’ global clinical and commercial supply needs of MGA012. MacroGenics intends to utilize its commercial-scale GMP facility, which is expected to be fully operational in 2018.

On December 5, 2017 Janssen Research & Development, LLC (Janssen) reported that the Phase 3 iNNOVATE (PCYC-1127) study evaluating IMBRUVICA (ibrutinib) in combination with rituximab (RITUXAN) in relapsed/refractory and treatment-naïve patients with Waldenström’s macroglobulinemia (WM) successfully met its primary endpoint of progression-free survival (PFS) (Press release, Johnson & Johnson, DEC 5, 2017, View Source [SID1234522391]). An Independent Data Monitoring Committee (IDMC) recommended unblinding iNNOVATE based on efficacy results observed in the pre-specified interim analysis. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

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"It is gratifying to see that patients with Waldenström’s macroglobulinemia – a rare, difficult-to-treat form of blood cancer – have achieved this magnitude of benefit with the IMBRUVICA combination with rituximab as compared to rituximab alone in either the relapsed/refractory or newly diagnosed setting," said Craig Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs, Janssen Oncology. "Since the approval of IMBRUVICA in 2013 for Waldenström’s, we have added to the body of evidence and patient experience, by conducting this randomized Phase 3 trial and confirming IMBRUVICA’s clinical benefit first seen in the relapsed/refractory setting and now demonstrated with earlier use in the treatment journey for the WM patient."

Janssen and Pharmacyclics will share and discuss the unblinded data from the study with health authorities around the world. IMBRUVICA received FDA approval in WM in January 2015.

About iNNOVATE
iNNOVATE is a Pharmacyclics-sponsored, randomized, placebo-controlled, double-blind, Phase 3 study, which is evaluating IMBRUVICA (ibrutinib) in combination with rituximab, and placebo in combination with rituximab in 150 patients with relapsed/refractory and treatment-naïve Waldenström’s macroglobulinemia (WM). In the study, patients were randomized to receive intravenous rituximab 375 mg/m2 once weekly for four consecutive weeks, followed by a second four-weekly rituximab course following a three-month interval. All patients received either IMBRUVICA 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The primary endpoint is progression-free survival, with secondary objectives including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment, overall survival, and number of participants with adverse events as a measure of safety and tolerability within each treatment arm. WM is a form of non-Hodgkin’s lymphoma and is a rare disease, with an incidence rate of about three cases per million per year in the U.S. Roughly 1,000 to 1,500 people are diagnosed with WM each year in the U.S.1

About IMBRUVICA
IMBRUVICA (ibrutinib) was one of the first therapies to receive U.S. approval after having received the FDA’s Breakthrough Therapy Designation.2 IMBRUVICA works by blocking a specific protein called Bruton’s tyrosine kinase (BTK). The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.3 IMBRUVICA targets and blocks BTK, inhibiting the survival and spread of cancer cells, and impacting signaling associated with other serious conditions. Worldwide, IMBRUVICA was used to treat more than 90,000 patients to date. For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA
INDICATIONS
IMBRUVICA is indicated to treat adults with2

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) patients who have received at least one prior therapy
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Marginal zone lymphoma (MZL) patients who require systemic therapy and have received at least one prior anti-CD20-based therapy
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Chronic Graft-Versus-Host Disease (cGVHD) patients who failed one or more lines of systemic therapy
IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%), muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%), and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On December 5, 2017 Mateon Therapeutics, Inc. (OTCQX:MATN), a biopharmaceutical company developing investigational drugs for the treatment of orphan oncology indications, reported new preliminary data in a mouse model of colon cancer indicating that reductions in tumor volume after treatment with CA4P and anti-CTLA-4 combination therapy are associated with an enhanced immune response (Press release, Mateon Therapeutics, DEC 5, 2017, View Source [SID1234522393]). CA4P induces immediate, rapid and extensive tumor cell necrosis which can stimulate the immune system, while antibodies to CTLA-4 stimulate the immune system through a different mechanism, by blocking immunosuppression (which is the same mechanism used by the approved drug marketed under the trade name Yervoy).

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"We are excited about the possibility of using CA4P to improve patient responses to checkpoint inhibitors, which have shown significant but nevertheless limited therapeutic benefits as monotherapy," said William D. Schwieterman, M.D., President and CEO of Mateon Therapeutics. "While the direct clinical benefits of CA4P alone as an anti-cancer agent are limited, these initial data indicate the promise of this agent to stimulate the immune system and enhance the efficacy of checkpoint inhibitors – an exciting and rapidly emerging field of oncology where our unique approach may offer a distinct advantage."

Mateon previously reported data from a CT-26 colon cancer animal model showing that combination treatment with CA4P and anti-CTLA-4 causes large reductions in tumor volume and statistically significant improvements in survival when compared to anti-CTLA-4 alone, CA4P alone, or vehicle control. Similar anti-tumor effects were observed when this combination was studied in an EMT-6 mammary tumor animal model. The CT-26 model was repeated for the studies reported today, again showing large reductions in tumor volume with combination therapy. This repeat study also captured additional data on immune response, with preliminary data showing increases in the median number of tumor-associated white blood cells (WBC’s) (69.2K vs. 39.0K vs. 16.7K for CA4P plus anti-CTLA-4, anti-CTLA-4 alone and vehicle control, respectively), T cells (5.2K vs. 1.6K vs. 1.8K), and effector cytotoxic CD8+ T Cells (2.0K vs. 0.8K vs. 0.5K), indicating a heightened immunologic response to the tumor in the presence of the two-drug combination. Importantly, treatment with both CA4P and anti-CTLA-4 generally maintains an elevated tumor-associated median effector T cell/regulatory T cell ratio, which also indicates a heightened immune response. Work to further characterize the immune response seen with the combination is ongoing.

On December 5, 2017 Oncolytics Biotech Inc. (TSX: ONC) (OTCQX: ONCYF) (Oncolytics or the Company), a biotech company developing REOLYSIN, also known as pelareorep, an intravenously delivered immuno-oncolytic virus that activates the innate and adaptive immune systems to turn ‘cold’ tumors ‘hot’, reported that the company has received a favorable Final Advice Letter from the European Medicines Agency (EMA) (Press release, Oncolytics Biotech, DEC 5, 2017, View Source [SID1234522394]). The Letter refers to the proposed use of pelareorep in combination with paclitaxel, for the treatment of hormone receptor positive, HER2 receptor negative (HR+/HER2-) metastatic breast cancer patients in a pivotal phase 3 registration study and suggests that a single 400-patient study may be acceptable to form the basis of a Marketing Authorization Application (MAA) in Europe.

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"The EMA’s feedback and Final Advice Letter are very much inline with the feedback and advice we received from the FDA in September and adds to the support we have for our proposed target patient population of HR positive/HER2 negative metastatic breast cancer patients for the registration study," said Dr. Matt Coffey, President and CEO of Oncolytics Biotech. "Our statistically significant and clinically compelling overall survival data, Fast Track designation and clear guidance from the FDA and EMA allow us to focus on the completion of the adaptive study design that will include approximately four hundred patients with a pre-determined interim analysis at two hundred patients. Furthermore, the EMA provided guidance that if the study achieves its primary endpoint, it may form the basis of a Marketing Authorization Application for commercialization in Europe. The design of the study, feedback from both the FDA and EMA and our recently announced partnership with Adlai Nortye will also drive our ongoing partnering process."

Oncolytics’ proposed target population for its phase 3 study of pelareorep is patients with HR+/HER2- mBC, which represents approximately 73 percent of metastatic breast cancer cases that have limited treatment options that offer survival benefit. Details of the pivotal phase 3 registration study will be made available following evaluation and completion of discussions with clinical advisors and potentially partners.

About Metastatic Breast Cancer
Metastatic breast cancer, also known as advanced or Stage 4 breast cancer, has spread to other parts of the body. Most commonly the lungs, liver, bones or brain. The disease affects over 154,000 women in the United States and according to the American Cancer Society, has a five-year survival rate of just 22 percent. Significantly lower than stage 3, with a five-year relative survival rate of 72 percent and stage 2, with a five-year survival rate over 90 percent.

About REOLYSIN/Pelareorep
REOLYSIN, also known as pelareorep, is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers.