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Loxo Oncology Announces FDA Orphan Drug Designation Granted to LOXO-101 for Treatment of Soft Tissue Sarcoma

On September 2, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company focused on the discovery, development, and commercialization of targeted cancer therapies, reported that the United States Food and Drug Administration (FDA) has granted the company orphan drug designation for LOXO-101 for treatment of patients with soft tissue sarcoma (Press release, Loxo Oncology, SEP 2, 2015, View Source [SID:1234507381]).

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Soft tissue sarcomas are cancers of the body’s connective or supportive tissues, such as cartilage, fat, muscle, fibrous tissue, and blood vessels. The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the United States. Orphan drug designation provides to Loxo certain benefits, including market exclusivity upon regulatory approval if received, exemption of FDA application fees and tax credits for qualified clinical trials.

About LOXO-101

LOXO-101 is a potent, oral, selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules. The TRK family (TRKA, TRKB, and TRKC) has been implicated in diverse tumor types such as lung cancer, head and neck cancer, melanoma, colorectal cancer, sarcoma, and breast cancer. LOXO-101 was built specifically to inhibit TRK and is currently the only selective TRK inhibitor in clinical development. LOXO-101 is currently being evaluated in a Phase 1 dose escalation trial for patients with advanced solid tumors.

Incyte Announces Global License Agreement with Jiangsu Hengrui Medicine for SHR-1210, an Investigational Anti-PD-1 Monoclonal Antibody

On September 2, 2015 Incyte Corporation (Nasdaq: INCY) reported a global license and collaboration agreement with Jiangsu Hengrui Medicine Co., Ltd. for the development and commercialization of SHR-1210, an investigational anti-PD-1 monoclonal antibody (Press release, Incyte, SEP 2, 2015, View Source [SID:1234507380]).

Under the agreement, Incyte will have the exclusive development and commercialization rights to SHR-1210 worldwide, with the exception of Mainland China, Hong Kong, Macau, and Taiwan. SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months.

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"The addition of this anti-PD-1 candidate to our early stage portfolio reinforces our commitment to cancer patients and further diversifies our clinical development programs," stated Hervé Hoppenot, President and Chief Executive Officer of Incyte. "We continue to make excellent progress in the multiple clinical trials underway across our existing portfolio, including our strategic collaborations."

Piaoyang Sun, Chairman of the Board of Hengrui, added, "Both Incyte and Hengrui are dedicated to cancer immunotherapy and are investigating several relevant biological targets in the area. The addition of SHR-1210 is an excellent fit to Incyte’s oncology portfolio, and we are pleased to see Incyte’s commitment to this PD-1 program. Combining the expertise and resources of both companies can accelerate the development of SHR-1210."

Terms of the Agreement

Under the terms of the agreement, Incyte will acquire development and commercialization rights to SHR-1210 worldwide, with the exception of Mainland China, Hong Kong, Macau, and Taiwan, in exchange for an upfront payment of $25 million. The terms also include potential milestone payments of up to $770 million to Hengrui, consisting of $90 million for regulatory approval milestones, $530 million for commercial performance milestones, and $150 million based on clinical superiority. The terms also include tiered royalties to Hengrui on net sales of SHR-1210 in Incyte territories. Under the Agreement, Incyte and Hengrui will assume all financial obligations associated with the development and commercialization of SHR-1210 in their respective territories.

About Anti-PD-1 Monoclonal Antibodies

Monoclonal antibodies targeting PD-1 enhance anti-tumoral immunity and are being developed for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand. Inhibition of the interaction between PD-1 and PD-L1, known as immune checkpoint blockade, can enhance T-cell responses and mediate preclinical antitumor activity.1

For this transaction, Incyte was advised by Morgan Lewis, and Hengrui was advised by Wilson Sonsini Goodrich & Rosati.

EISAI CLEARS ALL-CASE SURVEILLANCE CONDITION FOR APPROVAL OF ANTICANCER DRUG GLIADEL(R) 7.7MG IMPLANT

On September 2, 2015 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has received notification from Japan’s Ministry of Health, Labour and Welfare (MHLW) to the effect that the "all-case surveillance" survey condition required for approval of Gliadel 7.7mg Implant (carmustine, "Gliadel") has been lifted (Press release, Eisai, SEP 2, 2015, View Source [SID:1234507378]).

In September 2012, the MHLW approved Gliadel indicated for malignant glioma with the following condition for approval: "Because of the very limited number of subjects treated in the Japanese clinical trials, the applicant is required to conduct all-case drug use-results survey until data from a certain number of patients are accumulated after market launch, in order to identify the background information of patients treated with the product and collect safety and efficacy data on the product in the early post-marketing period, and thereby take necessary measures to ensure proper use of the product."

The MHLW lifted this condition for approval after evaluating safety and efficacy data submitted by Eisai from patients with malignant glioma (558 cases for safety analysis, 536 cases for efficacy analysis). According to the results of the evaluation, the MHLW determined that the conditions for approval have been met.

Gliadel is the only sustained-release formulation approved for intracranial implantation in Japan. Each wafer contains the nitrosourea alkylating agent carmustine distributed in a biodegradable polymer matrix. Implanting the agent into the brain following surgical removal of malignant glioma allows for direct delivery of chemotherapy to the tumor site, allowing the agent to be used prior to initiating radiation, chemotherapy and other standard therapies. Gliadel is manufactured and distributed by Eisai, and the product is co-promoted by Eisai and Nobelpharma Co., Ltd.

Eisai will continue to promote and provide information on the proper use of Gliadel while making further contributions to improve the quality of life of patients.

DelMar Pharmaceuticals Announces Expansion of VAL-083 Development Program to Include Ovarian Cancer

On September 2, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it will present an abstract entitled, "A Comparison of the Mechanisms and Cytotoxic Activity of Dianhydrogalactitol (VAL-083) to Cisplatin in Ovarian Tumor Models Harboring Wild-type and Mutant p53," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Conference being held October 17-20, 2015 in Orlando, FL (Press release, DelMar Pharmaceuticals, SEP 2, 2015, View Source [SID:1234507377]).

The presentation will summarize VAL-083’s potential as a new treatment for ovarian cancer in the context of DelMar’s recent research and historical data from prior NCI-sponsored clinical trials.

"These data have been developed in collaboration with researchers at MD Anderson Cancer Center and are aligned with our business model to leverage historical clinical proof-of-concept with modern biological data to solve modern unmet medical needs in the treatment of cancer," said Jeffrey Bacha, DelMar’s president and CEO.

DelMar Pharmaceuticals is currently conducting a Phase II clinical trial with VAL-083 for the treatment of refractory glioblastoma multiforme (GBM). Interim data from this trial presented at the American Association of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting demonstrated a promising dose-response trend in patients with recurrent GBM. DelMar will present the next update of its GBM program at the 2nd International Symposium on Clinical and Basic Research in Glioblastoma, being held September 9-12, 2015 in Toledo, Spain.

The Company has also announced plans to initiate clinical development with VAL-083 in non-small cell lung cancer (NSCLC), which will be funded through DelMar’s collaboration with Guangxi Wuzhou Pharmaceutical (Group) Co. Ltd. Details of this trial will be presented at the 16th World Conference on Lung Cancer being held September 7 – 9 in Denver, Colorado.

About VAL-083

VAL-083 is a "first-in-class", small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated safety and efficacy in treating a number of cancers including lung, brain, cervical, ovarian tumors and leukemia. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer and has received orphan drug designation in Europe and the U.S. for the treatment of gliomas.

DelMar is currently studying VAL-083 in a multi-center Phase I/II clinical trial for patients with refractory glioblastoma multiforme (GBM) in accordance with the protocol that has been filed with the U.S. Food and Drug Administration (FDA) at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO). As a potential treatment for glioblastoma, VAL-083’s mechanism of action appears to be unaffected by the expression of MGMT, a DNA repair enzyme that is implicated chemotherapy resistance and poor outcomes following front-line treatment with Temodar (temozolomide).

U.S. Food and Drug Administration Accepts Supplemental Biologics License Application for Opdivo (nivolumab) in Previously Treated Non-Squamous Non-Small Cell Lung Cancer Patients

On September 2, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the supplemental Biologics License Application (sBLA) for Opdivo for the treatment of previously treated patients with non-squamous (NSQ) non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, SEP 2, 2015, View Source [SID:1234507376]).

This sBLA seeks to expand the current indication for Opdivo in patients with previously treated squamous (SQ) NSCLC. The projected FDA action date is January 2, 2016.

The agency has also granted this application priority review, and Opdivo Breakthrough Therapy Designation for this indication, underscoring the need for new treatments for this patient population, where currently a significant unmet medical need remains. According to the FDA, the criteria for Breakthrough Therapy Designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

"We are pleased with this important step forward in the FDA’s consideration to expand the use of Opdivo to include non-squamous non-small cell lung cancer patients, as well as the Breakthrough Therapy Designation," said Michael Giordano, senior vice president, head of Development, Oncology, Bristol-Myers Squibb. "From its inception, our clinical development program for Opdivo in lung cancer has been based on our deep scientific expertise and always with the goal of helping patients achieve gains in survival. We look forward to working with the FDA to make this treatment option available to more patients."

The submission is based on CheckMate -057, a Phase 3 study that evaluated the survival of patients with NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The positive results of a separate study, Checkmate -017, formed the basis of the current lung cancer indication; study -017 evaluated the survival of patients with SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. In both studies Opdivo demonstrated an overall survival benefit.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year according the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC, the five-year survival rate drops to two percent.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) as a monotherapy in two cancer indications. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the FDA granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).