On August 30, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical development-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported the completion of patient enrollment in the Phase 2 "PINNACLE" clinical trial of tarextumab (anti-Notch2/3, OMP-59R5) for the treatment of small cell lung cancer (SCLC) (Press release, OncoMed, AUG 30, 2016, View Source [SID:1234514798]). The PINNACLE study enrolled 145 patients with extensive-stage SCLC who had not received prior treatment. Topline data from the Phase 2 trial are expected to be reported at the end of 2016 or in early 2017.

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"Our PINNACLE Phase 2 trial accrued patients more quickly than anticipated and we would like to thank the patients, their families, caregivers and the participating investigators and study site personnel for their participation. Small cell lung cancer is a difficult to treat cancer and unfortunately most patients survive a year or less. New and improved treatment options are needed for these patients," said Jakob Dupont, M.D., Chief Medical Officer of OncoMed. "In a Phase 1b dose-escalating trial of tarextumab in small cell lung cancer we observed that patients who received standard-of-care chemotherapy in combination with tarextumab near or at the selected Phase 2 dose appeared to have deeper anti-tumor responses and improved survival outcomes, particularly in tumors that were high in certain Notch pathway genes. We look forward to seeing if these observations are maintained in our Phase 2 trial and anticipate reporting data from PINNACLE at the end of 2016 or in early 2017."

Patients enrolled in the PINNACLE trial were randomized into two study arms and received either 15mg/kg of tarextumab every three weeks in combination with six cycles of etoposide and platinum therapy followed by tarextumab maintenance to progression or six cycles of standard chemotherapy and a placebo. The primary endpoint of the trial is progression-free survival. Secondary endpoints include overall survival and overall response rate, pharmacokinetics, safety and biomarker analyses. Overall survival, progression-free survival and overall response rates will be assessed against elevated tumor expression of certain Notch pathway genes. The protocol for the Phase 2 trial was amended in May 2016 to enable the assessment of efficacy outcomes using Notch pathway genes Hes1, Hes6, Hey1 and Hey2 as a secondary endpoint.

The PINNACLE trial was conducted at 36 sites in the United States. Enrollment in the randomized, double-blinded, multi-center clinical study began in December 2014 and was completed three months ahead of schedule.

In the Phase 1b trial, all 26 patients evaluable for tumor response saw a reduction in target lesion size as measured by RECIST criteria, with an overall response rate of 77% and a 100% clinical benefit rate. Subjects receiving doses of tarextumab at or above 12 mg/kg plus chemotherapy achieved a median progression-free survival of 5.2 months and a median overall survival of 16 months. Results from OncoMed’s Phase 1b trial of tarextumab were most recently presented at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting.

About Small Cell Lung Cancer
According to the American Cancer Society, lung cancer (both small cell and non-small cell) is the second most common cancer in men and women and is by far the leading cause of cancer death. Small cell lung cancer is expected to make up about 10%-15% of the 224,390 newly diagnosed lung cancer cases and the 158,080 deaths estimated to occur in the U.S. in 20161. SCLC tends to grow and spread quickly, and is typically not discovered until it has metastasized to other parts of the body (extensive stage). The current standard of care in treating small cell lung cancer is the chemotherapeutic etoposide in combination with either cisplatin or caboplatin. In spite of a high sensitivity to chemotherapy and remission rates of up to 80% following initial treatment, the median overall survival is less than one year for patients with extensive stage disease2.

About Tarextumab (anti-Notch2/3, OMP-59R5)
Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies have suggested that tarextumab exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, tarextumab appears to have anti-cancer stem cell effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment. Tarextumab is being studied in the "PINNACLE" study (A Phase 1b/2 Study of OMP-59R5 in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer). Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK). GSK has an option to obtain an exclusive license to tarextumab during certain time periods through completion of the proof-of-concept Phase 2 trials.

On August 30, 2016 Oragenics (NYSE MKT: OGEN.BC), a leader in the development of novel antibiotics against infectious disease and developing effective treatments for oral mucositis (OM) reported that it has received feedback from the U.S. Food and Drug Administration (FDA) in response to the Company’s request for a Type C meeting, concerning Phase 2 study protocols for the Company’s OM therapeutic candidate, AG013. As part of the clinical protocol for the study, Oragenics expects to file the Investigational New Drug (IND) update in late 2016 and initiate the study with AG013 in the United States and Europe during early 2017.

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"We are pleased to have the FDA’s thorough feedback on protocol design for our Phase 2 trial and drug product manufacturing requirements for evaluating AG013 for the treatment of oral mucositis," said Alan Joslyn, Oragenics’ Chief Executive Officer and President. "This is an important milestone in our effort to potentially provide cancer patients with a new therapy for treatment of oral mucositis."

OM results in a painful inflammation and mucosal ulceration in the lining of the oral cavity, throat and esophagus and is one of the most commonly reported adverse events associated with cancer chemotherapy affecting up to 500,000 patients annually. OM has a negative effect on patient well-being and if severe, negatively affects a patient’s cancer treatment regimen. At present, no drug is approved to prevent the condition broadly and current therapies are primarily palliative in nature, only addressing symptom relief but not treating the underlying causes of the condition.

"Oral mucositis remains a major unmet need for cancer patients receiving cytotoxic radiation and chemotherapy," said Stephen T. Sonis, DMD, DMSc, Senior Surgeon, Divisions of Oral Medicine, Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. Dr. Sonis continued, "As suggested by the results of pre-clinical and clinical studies, AG013 may provide a unique delivery platform for an effective intervention. I’m excited that its development program has completed this important first step in moving forward."

Through the genetic engineering of a food grade microbe, Lactococcus lactis (L. lactis), by the Actobiotics Division of Intrexon Corporation (NYSE: XON), in situ production and secretion of peptide therapeutics has been developed, including AG013, an oral rinsing solution designed to deliver human Trefoil Factor 1 (hTFF1) to protect and regenerate damaged mucosal lining of the oral cavity. Under an Exclusive Channel Collaboration Agreement with Intrexon, Oragenics has an exclusive worldwide license to develop and commercialize AG013 to treat oral mucositis in cancer patients.

A Phase 1B clinical trial with AG013 in 25 head and neck cancer patients at high risk for OM demonstrated that AG013 was safe and well tolerated. Data published in the journal Cancer showed a 35% reduction in the duration of ulcerative OM in AG013-treated patients vs placebo treated patients. Additionally over 30% of patients treated with AG013 were complete responders, defined as patients who did not develop OM, while all patients receiving placebo developed OM. A Phase 1 pharmacokinetic study in 10 healthy volunteers showed that live AG013 L. lactis adhered to the entire oral mucosal surface up to 24 hours after administration of the rinse.

AG013 has already been granted Orphan Drug status in the European Union and applications for Biologic License Application exclusivity and Fast Track designation with the FDA will be filed in the coming months.

About the Study Design

The Phase 2 double blind placebo controlled trial has been designed to evaluate the efficacy, safety, and tolerability of AG013 in patients being treated with standard regimens of concomitant chemoradiation therapy for common cancers of the head and neck. Not only is severe mucositis among the most common complications of treatment in this population, but its impact on patients’ ability to tolerate cancer therapy and risk of adverse health and resource use outcomes are frequent and devastating. Oragenics expects to announce additional information about the study design and timelines for the study once they are finalized.

On August 30, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported it has completed the rolling submission of the New Drug Application (NDA) for its investigational anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, to the U.S. Food and Drug Administration (FDA) (Press release, Ariad, AUG 30, 2016, View Source [SID:1234514794]). ARIAD is seeking U.S. marketing approval of brigatinib for patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who are resistant or intolerant to crizotinib. The Company is seeking accelerated approval for brigatinib from the FDA and has requested a priority review of the application, which, if granted, would allow for approval of brigatinib eight months after the NDA submission, as opposed to 12 months for a standard review.

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"Many patients with ALK-positive non-small cell lung cancer eventually develop disease progression," said Corey Langer, M.D., director of thoracic oncology in the Abramson Cancer Center of the University of Pennsylvania and a professor of Hematology-Oncology in Penn’s Perelman School of Medicine. "We are excited that the brigatinib NDA submission is now complete and are hopeful that brigatinib’s data, including the observation of complete responses and activity in the central nervous system, will provide patients and their oncologists with a new treatment option."

ARIAD’s NDA submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. Data from the ALTA trial, in which patients who had experienced disease progression on crizotinib therapy were randomized to one of two brigatinib regimens, were presented at the 2016 Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). With a median follow-up of 8.3 months, the data show that, for patients treated with the 180 mg regimen with a seven day lead-in at 90 mg (Arm B), 54 percent achieved an investigator-assessed confirmed objective response, the trial’s primary endpoint. In this arm, the median progression free survival (PFS) exceeded one year (12.9 months). Additionally, a 67% confirmed intracranial objective response rate was achieved in patients with measurable brain metastases. The most common treatment-emergent adverse events (TEAEs; ≥ 25% of all patients in Arm B), regardless of relationship to treatment, were nausea (40%), diarrhea (38%), cough (34%), increased blood creatine phosphokinase (30%), headache (27%) and fatigue (27%). TEAEs, ≥ grade 3, occurring in ≥ 5 percent of all patients in Arm B, were increased blood creatine phosphokinase (9%), hypertension (6%) and pneumonia (5%). A subset of pulmonary adverse events with early onset (median: Day 2; range: Day 1-9) occurred in 6 percent of all patients (≥ grade 3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B.

"With the completion of the brigatinib submission this week, we are excited by its potential, if approved, to offer additional hope to patients and their families," stated Paris Panayiotopoulos, president and chief executive officer of ARIAD. "We are thankful to the patients and physicians who participated in the clinical trials of brigatinib. We remain grateful to the FDA for granting brigatinib a breakthrough designation and the benefit of a rolling submission process, unique to the U.S. regulatory system."

Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC. ARIAD plans to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC). The global Phase 2 ALTA trial is the basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.