On April 25, 2019 Exelixis, Inc. (Nasdaq: EXEL) reported that Takeda Pharmaceutical Company Limited (Takeda), its partner responsible for the clinical development and commercialization of cabozantinib in Japan, has applied to the Japanese Ministry of Health, Labor and Welfare (MHLW) for approval to manufacture and sell CABOMETYX (cabozantinib) as a treatment for unresectable and metastatic renal cell carcinoma (RCC) in the country (Press release, Exelixis, APR 25, 2019, View Source [SID1234535395]). As a result of the submission, Exelixis will receive a $10 million milestone payment from Takeda, anticipated to be received in the second quarter of 2019.
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Takeda’s application is based on the results of three clinical trials: METEOR, the Exelixis-sponsored phase 3 pivotal trial of cabozantinib versus everolimus in patients with advanced RCC that experienced disease progression following treatment with at least one prior VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI); CABOSUN, the Alliance for Clinical Trials in Oncology-sponsored phase 2 trial comparing cabozantinib with sunitinib in patients with previously untreated advanced RCC with intermediate- or poor-risk disease; and Cabozantinib-2001, a Takeda-sponsored phase 2 trial in 35 Japanese patients with advanced RCC who had progressed after prior VEGFR-TKI therapy. Takeda’s phase 2 trial was the subject of a late-breaking abstract at the 107th Annual Meeting of the Japanese Urological Society on April 18, 2019.
"Takeda has proven to be a very effective partner in cabozantinib’s development program in Japan since the signing of our collaboration and licensing agreement in early 2017," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "This Japanese regulatory filing is an important milestone on the path toward offering CABOMETYX as a new therapeutic option for patients with unresectable, metastatic renal cell carcinoma in Japan. We congratulate our Takeda colleagues on the filing and look forward to further progress."
Per the terms of Exelixis and Takeda’s collaboration and license agreement, Exelixis received a $50 million upfront payment at the time of signing. Following the milestone associated with this regulatory filing, Exelixis will be eligible to receive from Takeda further development, regulatory and first-sale milestone payments of up to $80 million related both to previously treated and previously untreated RCC and previously treated hepatocellular carcinoma (HCC), as well as additional development, regulatory and first-sale milestones for potential future cabozantinib indications. Exelixis is also eligible for sales revenue milestones and royalties on net sales of cabozantinib in Japan.
Takeda fully funds cabozantinib development activities that are exclusively for the benefit of Japan and is responsible for 20% of the costs associated with global cabozantinib clinical trials, providing the company opts into those trials. As of today, Takeda has opted into and is co-funding CheckMate 9ER, the ongoing phase 3 pivotal trial of cabozantinib plus nivolumab versus sunitinib in previously untreated advanced RCC.
About RCC
The American Cancer Society’s 2019 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.1 Approximately 32,000 patients in the U.S. and 70,000 globally require treatment, and an estimated 15,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.3
The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6
About CABOMETYX (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC and for the treatment of patients with HCC who have been previously treated with sorafenib. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan.
U.S. Important Safety Information
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.