EXEL: Exelixis Analysis and Research Report

2018-02-15 - by Asif , Contributing Analyst - 251 views

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Exelixis is a biotechnology company committed to the discovery, development and commercialization of new medicines to improve care and outcomes for people with cancer. Since its founding in 1994, three products discovered at Exelixis have progressed through clinical development, received regulatory approval, and entered the marketplace. Two are derived from cabozantinib, an inhibitor of multiple tyrosine kinases including VEGF, MET, AXL and RET receptors: CABOMETYX® (cabozantinib) tablets approved for previously treated advanced renal cell carcinoma, or RCC, and COMETRIQ® (cabozantinib) capsules approved for progressive, metastatic medullary thyroid cancer, or MTC. The third product, COTELLIC® (cobimetinib) tablets, is a reversible inhibitor of MEK, marketed under a collaboration with Genentech (a member of the Roche Group), and is approved as part of a combination regimen to treat advanced melanoma. Both cabozantinib and cobimetinib have shown potential in a variety of forms of cancer and are the subject of broad clinical development programs for multiple oncology indications.

While its commercialization efforts for CABOMETYX and COMETRIQ are focused in the United States, or U.S., Exelixis has licensed development and commercialization rights to cabozantinib outside of the U.S. to Ipsen Pharma SAS, or Ipsen, and Takeda Pharmaceutical Company Ltd., or Takeda. Ipsen has been granted rights to cabozantinib outside of the U.S. and Japan, and Takeda has been granted rights to cabozantinib in Japan. Ipsen and Takeda also contribute financially and operationally to the further global development and commercialization of cabozantinib in other potential indications, and Exelixis is working closely with them on these activities.

Beyond its currently approved indications for RCC and MTC, Exelixis is pursuing other indications that have the potential to expand the number of cancer patients that could benefit from cabozantinib. Most advanced in the cabozantinib development program is its evaluation of CABOMETYX as a treatment for patients with previously untreated advanced RCC . On August 15, 2017, the company submitted a supplemental New Drug Application, or sNDA, for cabozantinib in this indication to the U.S. Food and Drug Administration, or FDA, and on October 16, 2017, the company announced that the FDA had accepted this filing and granted it Priority Review, assigning a Prescription Drug User Fee Act, or PDUFA, action date of February 15, 2018. The data in support of this filing are derived from CABOSUN, a randomized phase 2 trial comparing cabozantinib to sunitinib in the first-line treatment of patients with intermediate- or poor-risk RCC that was conducted by The Alliance for Clinical Trials in Oncology, or The Alliance, through its Cooperative Research and Development Agreement, or CRADA, with the National Cancer Institute’s Cancer Therapy Evaluation Program, or NCI-CTEP. In May 2016, The Alliance informed it that CABOSUN met its primary endpoint demonstrating a statistically significant and clinically meaningful improvement of progression-free survival, or PFS, compared with sunitinib. The CABOSUN primary efficacy endpoint results were later confirmed by a blinded independent radiology review committee, or IRRC, in June 2017.

Closely behind its FDA filing for first-line RCC is its investigation of CABOMETYX as a treatment for patients with advanced hepatocellular carcinoma, or HCC, who have previously been treated with sorafenib. On October 16, 2017, the company announced that, at the time of the second planned interim analysis, the study’s independent data monitoring committee had recommended that CELESTIAL, its company-sponsored, global phase 3 trial of cabozantinib versus placebo in patients with advanced HCC who have been previously treated with sorafenib, be stopped because it had met its primary endpoint, with cabozantinib providing a statistically significant and clinically meaningful improvement in overall survival, or OS, compared to placebo. Safety data from the study were consistent with the established profile of cabozantinib. Based on the results of CELESTIAL, the company plan to submit an sNDA to the FDA in the first quarter of 2018, for cabozantinib as a second-line treatment for patients with advanced HCC. The company will discuss the trial results with regulatory authorities and determine next steps for the trial, including offering patients currently receiving placebo the opportunity to cross over to cabozantinib.

The company believe that the available clinical data demonstrate that cabozantinib has the potential to be a broadly active anti-cancer agent that can make a meaningful difference in the lives of patients. Accordingly, Exelixis is engaged in a broad development program composed of over 50 ongoing or planned clinical trials to explore the clinical potential of cabozantinib in additional tumor types. This program includes Exelixis sponsored trials and trials conducted through its CRADA with NCI-CTEP or its investigator sponsored trial program. Exelixis is particularly interested in examining cabozantinib’s potential in combination with immunotherapies to determine if such combinations further improve outcomes for patients. Building on preclinical and clinical observations that cabozantinib creates a more immune-permissive tumor environment potentially resulting in the cooperative activity of cabozantinib in combination with these products, Exelixis is evaluating cabozantinib in combination with a variety of immune checkpoint inhibitors in multiple clinical trials. The most advanced of these combination studies includes a phase 3 trial evaluating cabozantinib with nivolumab ( Opdivo® ) or with nivolumab and ipilimumab ( Yervoy® ) in first-line advanced RCC and a phase 2 evaluation of the same combinations in HCC, each in collaboration with Bristol-Myers Squibb Company, or BMS. As a further part of its clinical collaboration with BMS, the company also plan to evaluate cabozantinib and nivolumab with or without ipilimumab in various other tumor types, including in bladder cancer. Diversifying its exploration of immunotherapy combinations, Exelixis has also initiated a phase 1b dose escalation study evaluating the safety and tolerability of cabozantinib in combination with The Roche Group’s, or Roche’s, atezolizumab ( Tecentriq® ) in patients with locally advanced or metastatic solid tumors.

Significant progress also continues to be made under its December 2006 worldwide collaboration agreement with Genentech, or the Genentech Collaboration Agreement, with respect to the phase 3 clinical development program for its second approved cancer agent, cobimetinib. Genentech is now conducting three phase 3 pivotal trials exploring the combination of cobimetinib with atezolizumab in colorectal carcinoma (IMblaze370) and BRAF wild type melanoma population (IMspire170) , and the combination of cobimetinib with atezolizumab and vemurafenib in BRAF V600 mutant melanoma (IMspire150 TRILOGY). Enrollment for IMblaze370 was completed in the first quarter of 2017, and Genentech has announced that top line results for the trial are expected during the first half of 2018. Should these trials prove positive, the company believe that cobimetinib will have the potential to provide it with a second meaningful source of revenue. With respect to COTELLIC commercialization in the U.S. under the Genentech Collaboration Agreement, Exelixis has been fielding 25% of the sales force promoting COTELLIC in combination with Zelboraf® as a treatment for patients with BRAF mutation-positive advanced melanoma. However, following a recent commercial review, commencing in January 2018, the company and Genentech will scale back the personal promotion of COTELLIC in combination with Zelboraf as a treatment for patients with BRAF mutation-positive advanced melanoma in the U.S. This decision is not indicative of any change in its intention to promote COTELLIC for other therapeutic indications for which it may be approved in the future.

As the company continue to maximize the clinical, therapeutic and commercial potential of cabozantinib and cobimetinib, the company remain steadfast in its commitment to discover and develop new cancer therapies for patients. In this regard, Exelixis has resumed internal drug discovery efforts with the goal of identifying new product candidates to advance into clinical trials. Notably, these efforts are led by some of the same experienced scientists responsible for the discovery of cabozantinib and cobimetinib, which have been approved for commercialization by regulatory authorities, as well as other promising Exelixis compounds that are in earlier stages of clinical and regulatory development pursuant to its collaborations with Daiichi Sankyo Company, Limited, or Daiichi Sankyo, Merck and BMS.

Recent development

February 13, 2018 Exelixis, Inc. announced results from a phase 2 investigator-sponsored trial (IST) of cabozantinib for the first-line treatment of metastatic radioiodine (RAI)-refractory differentiated thyroid carcinoma (DTC).

Patients with metastatic, RAI-refractory DTC were enrolled in this single-arm, open-label trial, and were administered oral cabozantinib 60 mg once daily. The primary endpoint of the trial is objective response rate. Among the 35 patients who were evaluable for response, partial response was achieved by 54 percent of patients (n=19), and stable disease was reported in 43 percent of patients (n=15) per RECIST 1.1. All but one evaluated patient experienced a decrease in tumor target lesions. Secondary endpoints of the trial include progression-free survival (PFS), time to progression (TTP), duration of response (DOR) and clinical benefit rate (CBR) defined as the number of patients achieving an objective response or stable disease for at least 6 months. The CBR at six months was 80 percent (n=28). With a median follow up for the study of 35 weeks the median PFS has not been reached. The median TTP among those patients who progressed was 35 weeks.

“While many patients with differentiated thyroid cancer can be treated successfully with radioiodine, there are very few options for those patients whose tumors have become resistant to treatment,” said Marcia Brose, M.D., Ph.D., Associate Professor of Otorhinolaryngology: Head and Neck Surgery and Director of the Center for Rare Cancers at the Abramson Cancer Center of the University of Pennsylvania, and principal investigator of the trial. “These findings suggest that cabozantinib, which showed encouraging efficacy and a manageable safety profile in this phase 2 trial, may be a promising treatment option for this patient population and warrants further evaluation.”

“Exelixis is dedicated to supporting investigator-sponsored trials focused on evaluating cabozantinib in a range of tumor types to help inform its ongoing development program whose main goal is to provide improved treatment options to patients in need,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “Based on these promising results and data from other studies of cabozantinib in previously treated DTC, Exelixis plans to initiate a pivotal phase 3 study with cabozantinib in patients with advanced DTC later this year.”

The most common treatment-related adverse events included hyperglycemia (80 percent), diarrhea (77 percent), malaise/fatigue (74 percent), and weight loss (71 percent). The majority of these adverse events were grade 1 or 2. The most comment grade 3-5 adverse events occurring in more than one patient included hypertension (14 percent), increased lipase (9 percent), pulmonary embolism (6 percent), and hyponatremia (6 percent).


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