publication date: Mar. 3, 2017

Drugs and Targets

FDA approves Xermelo as first and only treatment for carcinoid syndrome diarrhea

Lexicon Pharmaceuticals Inc. said FDA approved Xermelo (telotristat ethyl) 250 mg as a first and only orally administered therapy for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog therapy in adults inadequately controlled by SSA therapyi.

Carcinoid syndrome is a rare and debilitating condition that affects people with metastatic neuroendocrine tumors (mNETs)ii.

Xermelo targets the overproduction of serotonin inside mNET cellsiii, providing a new treatment option for patients suffering from carcinoid syndrome diarrhea.

Carcinoid syndrome is a rare condition that occurs in patients living with mNETsiv and is characterized by frequent and debilitating diarrhea that often prevents patients from leading active, predictable lives, as well as by facial flushing, abdominal pain, fatigue and, over time, heart valve damage.

“The approval of XERMELO establishes a new treatment option for patients with carcinoid syndrome diarrhea that is inadequately controlled by SSA therapy,” said Matthew Kulke, primary investigator of the company trial and director of the Program in Neuroendocrine and Carcinoid Tumors at Dana Farber Cancer Institute. “Inhibition of tumoral serotonin production represents a novel approach for patients with this condition.”

Discovered using Lexicon’s approach to gene science, Xermelo is the first and only approved oral therapy for carcinoid syndrome diarrhea. Xermelo targets tryptophan hydroxylase, an enzyme that mediates the excess serotonin production within mNET cells.

According to the label, a 12-week double-blind, placebo-controlled, randomized, multicenter trial of Xermelo was conducted in adult patients with a well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea who were having between four to 12 daily bowel movements despite the use of SSA therapy at a stable dose for at least three months.

Patients were randomized to placebo or treatment with Xermelo 250 mg three times daily. A total of 90 patients were evaluated for efficacy. The primary efficacy endpoint was the change from baseline in the number of daily bowel movements averaged over the 12-week treatment period.

In the 12-week study, a difference in average weekly reductions in bowel movement frequency between Xermelo and placebo was observed as early as one to three weeks, and persisted for the remaining nine weeks of the study.


FDA Accepts avelumab BLA for Priority Review for urothelial carcinoma

Merck and Pfizer Inc. said FDA accepted for priority review the BLAfor avelumab for patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-based therapy.

The BLA was submitted by EMD Serono, the biopharmaceutical business of Merck in the US and Canada. The FDA has set a Prescription Drug User Fee Act target action date of Aug. 27.

“Taken together with last year’s filing for metastatic Merkel cell carcinoma, this BLA acceptance confirms our rapid and continued progress in the clinical development of avelumab,” said Luciano Rossetti, executive vice president, global head of research & development at the biopharma business of Merck. “We continue to evaluate avelumab in cancers that have limited or suboptimal treatment choices, such as metastatic or locally advanced urothelial carcinoma, to hopefully be able to provide patients with new treatment options for fighting their disease.”

Despite advances in the treatment of UC, the prognosis for patients remains poor, particularly when the disease has metastasized. Bladder cancer makes up approximately 90% of urothelial cancers and is the sixth most common cancer in the US. 

Avelumab is an investigational, fully human anti-PD-L1 antibody. FDA’s priority review status reduces the review time from 10 months to a goal of six months from the day of filing acceptance and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. In November 2016, the FDA accepted, and granted Priority Review status to, the BLA for avelumab for the treatment of patients with metastatic Merkel cell carcinoma.

The international clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs, including nine phase III trials, and more than 4,000 patients evaluated across more than 15 tumor types. In December 2015, Merck and Pfizer announced the initiation of a phase III study (JAVELIN Bladder 100) of avelumab in the first-line setting as a maintenance treatment in patients with locally advanced or metastatic UC. This trial is enrolling patients.


BMS expands International Immuno-Oncology Network with addition of Columbia and MacCallum Cancer Centre

Bristol-Myers Squibb announced that Columbia University Medical Center and Peter MacCallum Cancer Centre joined the International Immuno-Oncology Network (II-ON), a global peer-to-peer collaboration between BMS and academia that aims to advance immuno-oncology science and translational medicine to improve patient outcomes.

Launched in 2012 by BMS, the II-ON was one of the first networks to bring academia and industry together to further the scientific understanding of I-O, and has expanded from ten to 15 sites including more than 250 investigators working on over 150 projects across 20 tumor types.

The II-ON has generated cutting-edge I-O data that have informed the development of new I-O agents, yielded publications and produced some of the earliest findings on a variety of biomarkers and target identification and validation.

Through the II-ON, Bristol-Myers Squibb is collaborating with leading cancer research institutions around the world to generate innovative I-O science, launch biology-driven trials and seek out cutting-edge technologies with the goal of translating research findings into clinical trials and, ultimately, clinical practice. Building on the II-ON, BMS has invested in several other models of scientific collaboration with academic partners across the globe, including the Global Expert Centers Initiative and the Immuno-Oncology Integrated Community Oncology Network.

The research in the collaboration is focused on three fundamental scientific pillars: understanding the mechanisms of resistance to immunotherapy; identifying patient populations likely to benefit from immunotherapy; and exploring novel combination therapies that may enhance anti-tumor response through complementary mechanisms of action.

The II-ON facilitates the translation of scientific research findings into drug discovery and development, with the goal of introducing new treatment options into clinical practice.

In addition to Bristol-Myers Squibb, the II-ON comprises 15 cancer research institutions, including: Clinica Universidad Navarra, Dana-Farber Cancer Institute, The Earle A. Chiles Research Institute, Institut Gustave Roussy, Istituto Nazionale per lo Studio e la Cura dei Tumori, Bloomberg-Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, Memorial Sloan Kettering Cancer Center, National Cancer Center Japan, The Netherlands Cancer Institute, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, University College London, the University of Chicago, West German Cancer Center/University Hospital Essen, and now Columbia University Medical Center and Peter MacCallum Cancer Centre.


Exelixis, BMS collaborate on late-stage combination trial in first-line RCC

Exelixis Inc. and Bristol-Myers Squibb Co. entered into a clinical development collaboration to evaluate Cabometyx (cabozantinib), Exelixis’ small molecule inhibitor of receptor tyrosine kinases, with BMS’s Opdivo (nivolumab), either alone or in combination with Yervoy (ipilimumab).

The clinical development program, which will be co-funded by the companies, is expected to include a phase III pivotal trial in first-line renal cell carcinoma, with additional trials planned in bladder cancer, hepatocellular carcinoma, and potentially other tumor types.

Cabometyx and Opdivo have both received approval in the U.S, and E.U. for specific uses in previously treated renal cell carcinoma, and both compounds are the subject of ongoing, global phase III pivotal trials in hepatocellular carcinoma. Opdivo is approved in the United States for previously treated bladder cancer.


Exelixis, Roche to evaluate cabozantinib and atezolizumab in solid tumors

Exelixis Inc. announced a new collaboration with Roche on a phase Ib dose escalation study that will evaluate the safety and tolerability of cabozantinib, Exelixis’ tyrosine kinase inhibitor, in combination with atezolizumab, Roche’s anti-PD-L1 immunotherapy, in patients with locally advanced or metastatic solid tumors.

Enrollment is scheduled to begin mid-year 2017; Exelixis will be the sponsor of the trial, and Rochewill provide atezolizumab.

Based on the dose-escalation results, the trial has the potential to enroll up to four expansion cohorts, including a cohort of patients with previously untreated advanced clear cell renal cell carcinoma and three cohorts of urothelial carcinoma, namely platinum eligible first-line patients, first- or second-line platinum ineligible patients, and patients previously treated with platinum-containing chemotherapy.

Ipsen, Exelixis’ global partner for cabozantinib, except in the United States and Japan, will participate in this study and have access to the results for potential future development in its territories.

Takeda may also participate in these and future studies and have access to the results to support potential future regulatory submissions in their territories, if they opt into their funding obligations under the respective collaboration agreement.


Advaxis, SELLAS announce licensing agreement to develop antigen-targeting immunotherapy

Advaxis Inc. granted SELLAS Life Sciences Group a license to develop a novel cancer immunotherapy agent using Advaxis’ proprietary Lm-based antigen delivery technology with SELLAS’ patented WT1 targeted heteroclitic peptide antigen mixture (galinpepimut-S).

Advaxis’ proprietary technology generates innate immune stimulation, alongside potent and sustained T-cell responses.

When combined with SELLAS’ WT1 antigens, this has the potential to precisely direct an immune response, yielding improved clinical activity against many cancer types that express WT1. SELLAS’ future clinical studies will investigate this capability in the presence of measurable residual or recurrent disease.

Galinpepimut-S has demonstrated positive phase II clinical results in acute myeloid leukemia and malignant pleural mesothelioma and positive early clinical data in multiple myeloma. It has been shown to induce strong immune responses (CD4+/CD8+) against the WT1 antigen and to access a broad range of HLA types.

Advaxis’s Lm-based antigen delivery technology has demonstrated the potential to induce an enhanced innate immune stimulation and generate specific T cells while reducing immune tolerance in the tumor microenvironment.

Advaxis will conduct all pre-clinical activities required for an IND filing.

Thereafter, SELLAS will be responsible for all clinical development and commercial activities. Advaxis will receive future payments of up to $358 million from SELLAS if development, regulatory, and commercial milestones are met.

Following any regulatory approval of the product candidate emanating from this particular program, SELLAS has agreed to pay Advaxis single-digit to low double-digit royalties based on worldwide net sales upon commercialization.

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