Products

Date: 2018-09-18

Type of information: Granting of a Market Authorisation in Canada

Product name: Cabometyx™

Compound: cabozantinib

Therapeutic area: Cancer - Oncology

Action mechanism:

• tyrosine kinase inhibitor.  Cabozantinib is a kinase inhibitor that blocks abnormal kinase proteins involved in the development and growth of medullary cancer cells. Cabozantinib inhibits the activity of tyrosine kinases including MET, AXL and VEGFR-1, -2 and -3. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
• In February 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

Company: Exelixis (USA - CA) Ipsen (France)

Disease:

• advanced renal cell carcinoma

Latest news:

• • On September 19, 2018, Ipsen Biopharmaceuticals Canada received approval from Health Canada of Cabometyx® (cabozantinib) tablets for the treatment of adults with advanced renal cell carcinoma (RCC) who have received prior vascular endothelial growth factor (VEGF) targeted therapy. Health Canada granted Cabometyx® priority review status, which provided an accelerated review of Ipsen’s new drug submission.
• The Health Canada approval was based on results of the phase 3 pivotal METEOR trial in which Cabometyx® provided a statistically significant and clinically meaningful improvement in overall survival, progression-free survival and objective response rate as compared with everolimus in patients with advanced RCC who have received prior anti-angiogenic therapy.
• Under the terms of the collaboration agreement with Ipsen, Exelixis will receive a milestone payment of $5 million for the Health Canada approval. The payment will be made by Ipsen within the next 70 days.
• • On March 22, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Cabometyx®. The CHMP adopted an extension to the existing indication as follows: “Cabometyx® is indicated for the treatment of advanced renal cell carcinoma :
• • in treatment-naïve adults with intermediate or poor risk
• • in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.”
• • On September 8, 2017, Ipsen announced that the European Medicines Agency (EMA) has validated the application for variation to the Cabometyx® (cabozantinib) marketing authorization for the addition of a new indication in first-line treatment of advanced renal cell carcinoma. The filing is based on the results of CABOSUN, a phase II trial demonstrating that Cabometyx® prolongs progression free survival  in treatment-naive patients with intermediate- or poor-risk advanced renal cell carcinoma compared to sunitinib, the standard of care for more than 10 years.
• • On August 16, 2017, Exelixis announced it has completed the submission of a supplemental New Drug Application (sNDA) to the FDA for Cabometyx® (cabozantinib) tablets as a treatment for patients with previously untreated advanced renal cell carcinoma. The sNDA submission is based on results from the CABOSUN randomized phase 2 trial of Cabometyx® in patients with previously untreated advanced renal cell carcinom with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
• • On July 18, 2016, the Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Cabometyx™ (cabozantinib) 20, 40, 60mg for the treatment of advanced renal cell carcinoma in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy and recommended it for marketing authorization. The CHMP opinion was adopted following an accelerated review procedure reserved for medicinal products expected to be of major public health interest.
• • On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for Cabometyx™ (cabozantinib) as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.
• • On April 25, 2016, Exelixis announced that the FDA has approved Cabometyx™ (cabozantinib) tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. Cabometyx™, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a phase 3 trial for patients with advanced renal cell carcinoma, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression-free survival and objective response rate. The recommended dose and schedule for cabozantinib is 60 mg orally daily. The approval of Cabometyx™ is based on results of the METEOR phase 3  trial, which met its primary endpoint of improving progression-free survival. Compared with everolimus, a standard of care therapy for second-line renal cell carcinoma, Cabometyx™ was associated with a 42 percent reduction in the rate of disease progression or death. Median progression-free survival for cabozantinib was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx™ also significantly improved the objective response rate compared with everolimus. These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine. As announced in February 2016, Cabometyx™ also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with everolimus, Cabometyx™ was associated with a 34 percent reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabometyx™ versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003). The most common (frequency ?25 percent) adverse reactions in Cabometyx™-treated patients include diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, high blood pressure, vomiting, weight loss, and constipation. Dose reduction rates were 60 percent for Cabometyx™ and 24 percent for everolimus. The rate of treatment discontinuation due to adverse reactions was low (10 percent in each arm) and consistent with that previously reported for everolimus.
• • On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. • On January 11, 2016, Exelixis announced that it has submitted a Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma  who have received one prior therapy to the European Medicines Agency (EMA). The EMA will now conduct its standard validation process to determine whether the submission is sufficient to permit a substantive review for marketing authorization in the European Union.  The MAA is based on results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor.
• • On December 23, 2015, Exelixis announced that it has completed the submission of its rolling New Drug Application (NDA) with the FDA for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. Exelixis has requested Priority Review as part of the NDA filing. In August 2015, the FDA granted Breakthrough Therapy designation to cabozantinib for this indication.  In the European Union, Exelixis aims to complete its Marketing Authorization Application (MAA) in early 2016. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recently granted accelerated assessment to cabozantinib for advanced RCC. As a result, when filed, the company’s MAA may be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested from CHMP).
• • On October 22, 2015, Exelixis  announced the company has initiated submission of its rolling New Drug Application (NDA) to the FDA for cabozantinib for the treatment of advanced renal cell carcinoma (RCC) patients who have received one prior therapy. Cabozantinib was granted Breakthrough Therapy Designation by the FDA in August 2015. Exelixis agreed with FDA that the submission would be a rolling NDA and the company has filed the first component of the application for potential approval of cabozantinib in the United States. The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis. Exelixis plans to complete the NDA submission before the end of 2015. The rolling NDA submission is based on results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival (PFS); compared with everolimus, cabozantinib was associated with a 42% reduction in the risk of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.
• • On August 24, 2015, Exelixis announced the FDA has granted Breakthrough Therapy Designation to cabozantinib, as a potential treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy. Cabozantinib received Breakthrough Therapy Designation based on the results of METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in patients with RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI). In top-line results announced in July 2015, METEOR met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for cabozantinib as compared to everolimus in the first 375 patients randomized as determined by an independent radiology review committee. Cabozantinib reduced the rate of disease progression or death by 42 percent compared to everolimus (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.45-0.75, p<0.0001).
• Cabozantinib is currently marketed in capsule form under the brand name Cometriq ® in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. A distinct tablet formulation of cabozantinib is under investigation for advanced renal cell carcinoma and other types of cancer.
• • On April 9, 2015, Exelixis announced that the FDA has granted Fast Track designation to cabozantinib for treatment of patients with advanced renal cell carcinoma (RCC) who have received one prior therapy. Cabozantinib is the company’s lead compound and inhibits the activity of multiple tyrosine kinases including MET, VEGFRs and RET. Cabozantinib is the subject of METEOR, an ongoing phase 3 pivotal trial in patients with metastatic RCC who have experienced disease progression following treatment with at least one VEGFR tyrosine kinase inhibitor. Patients are randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily. The primary endpoint of METEOR is progression-free survival, and secondary endpoints include overall survival and objective response rate. Exelixis expects to release top-line results from the trial in the second quarter of 2015. In addition to the metastatic RCC development program, Exelixis is also evaluating cabozantinib in CELESTIAL, a phase 3 pivotal trial in second-line hepatocellular carcinoma (HCC).

Patents:

Submission of marketing authorization application USA : 2015-10-22

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2016-04-25/2017-12-19

UE authorization: 2016-09-13/2018-05-08

Favourable opinion UE: 2016-07-18/2018-03-22

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

• • On September 7, 2018, Exelixis announced that the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines to include new recommendations for Cabometyx® (cabozantinib) tablets. With the updates, Cabometyx® is recommended by the NCCN for the treatment of advanced renal cell carcinoma (RCC) regardless of patient risk status (favorable-, intermediate-, and poor-risk). Key Cabometyx®-related highlights from the updated NCCN Clinical Practice Guidelines for Kidney Cancer include:
• -Cabometyx® is the only preferred tyrosine kinase inhibitor (TKI) treatment option for first-line patients in the poor- and intermediate-risk groups (Category 2A)
• - Cabometyx® is a recommended first-line treatment option for favorable-risk patients (Category 2B)
• - Cabometyx® is the only preferred TKI treatment option for previously treated patients (Category 1)
• The NCCN kidney cancer panel’s decision to include Cabometyx® as a Category 2A preferred option for the treatment of patients with previously untreated advanced RCC with poor- or intermediate-risk disease was based on the results of the phase 2 CABOSUN trial.
• Additionally, in its recent update to the Clinical Practice Guidelines for Hepatobiliary Cancers, the NCCN added cabozantinib as a Category 1 option for the treatment of patients with hepatocellular carcinoma (HCC) (Child-Pugh Class A only) who have been previously treated with sorafenib.

Is general: Yes