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FDA approves melanoma drug Zelboraf from Roche
 
 
  pharmatimes.com
 
August 18, 2011
 
The US Food and Drug Administration approved Roche's Zelboraf yesterday for the treatment of patients with advanced melanoma that is beyond the reach of surgery.
 
Zelboraf (vemurafenib) was approved two months ahead of schedule by the FDA and is the second melanoma drug to be approved in 2011 after Bristol-Myers Squibb's Yervoy (ipilimumab), which debuted in March.
 
Both Zelboraf and Yervoy have been hailed as a major advance in melanoma care, as they are the first new agents in over a decade to show any improvement in survival for patients with the disease. Roche and BMS are also working together to see if their two drugs can provide additional benefits when used in combination.
 
Zelboraf's approval was supported by a single international trial of 675 previously-untreated patients with late-stage melanoma. Patients were assigned to receive either Zelboraf or dacarbazine and the median survival of those on Zelboraf has still not been reached, with 77% of patients still alive. For comparison, the median survival for patients on dacarbazine was 8 months (64% still living).
 
The drug is a personalised medicine, and is designed for use only in melanoma patients whose tumours express a gene mutation called BRAF V600E. The approval package for Zelboraf also includes a diagnostic to screen melanoma patients for the gene mutation, which occurs in around half of all cases of the cancer. Last year, there were around 68,000 cases of melanoma diagnosed in the USA, with 8,700 people dying from the disease.
 
"The FDA approval of Zelboraf marks a major step forward in personalising the treatment of metastatic melanoma, a devastating disease that until this year had limited approved treatment options," said Hal Barron, Roche's chief medical officer.
 
"We will continue to study this medicine with a goal of further improving outcomes for people with melanoma and other cancers that are driven by BRAF mutations."
 
Roche has high hopes for Zelboraf, particularly as Yervoy has already made rapid progress since its launch. BMS said last month that the drug had garnered $95 million in its first quarter on the US market, and analysts have suggested that it could bring in $1.5 billion in 2015.
 
Estimates are that the cost of treatment with Zelboraf will be in the region of $50,000-$60,000 over a six-month period, and on that basis the drug could achieve around $900 million in 2015 sales, according to analysts. Roche said Zelboraf would be launched within two weeks in the USA, and is also pending approval in the EU, Switzerland, Australia, New Zealand, Brazil, India, Mexico and Canada.
 
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Roche announces vemurafenib improved survival in people with metastatic melanoma who have BRAF V600 mutations
 
Roche's Personalised Healthcare approach demonstrated through vemurafenib and its investigational companion diagnostic, Roche's cobas 4800 BRAF V600 Mutation Test

 
Basel, 5 June 2011
 
Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that a Phase III study (BRIM3) showed vemurafenib (RG7204, PLX4032) significantly improved overall survival (OS) in people with previously untreated BRAF V600 mutation-positive metastatic melanoma, compared to chemotherapy. In the study, the risk of death was reduced by 63 percent for people who received vemurafenib compared to those who received chemotherapy (hazard ratio [HR]=0.37, p<0.0001). In addition, vemurafenib significantly reduced the risk of the disease getting worse (progression-free survival, or PFS, a co-primary endpoint), by 74 percent compared to chemotherapy (HR=0.26, p<0.0001). The safety profile of vemurafenib was consistent with previous clinical studies.
 
"We are greatly encouraged by the results of BRIM3, which showed that vemurafenib not only extended life and reduced the risk of disease worsening, but also led to significant tumour shrinkage, an important result for this devastating cancer," said Hal Barron M.D., Chief Medical Officer and head, Global Product Development. "We will continue to work closely with regulatory authorities to seek approval for vemurafenib and its companion diagnostic test to provide patients with BRAF-mutated metastatic melanoma a personalised option as soon as possible."
 
Vemurafenib, a "BRAF-inhibitor," is a personalised investigational medicine designed to specifically inhibit the activity of the mutant BRAF protein that is found in approximately half of all cases of melanoma, the deadliest and most aggressive form of skin cancer. People were enrolled into the study based on BRAF mutation status as determined by the cobas 4800 BRAF V600 Mutation Test, an investigational diagnostic from Roche.
 
"The joint development of the investigational cobas BRAF test and vemurafenib exemplify how our personalised healthcare approach is one step closer to becoming a reality for patients," said Paul Brown, Head of Roche Molecular Systems. "In BRIM3 our investigational test enabled rapid and accurate identification of eligible patients with metastatic melanoma."
 
The results are being featured in a press briefing titled, "Trials That Set New Standards of Care," at 10:00 a.m. on June 5th, 2011 at the Annual Meeting of the American Society of Clinical Oncology (ASCO), and will be presented by Paul Chapman, M.D., Memorial Sloan Kettering Cancer Center in New York, principal investigator of the pivotal BRIM3 study, in the ASCO plenary session (Abstract #LBA4,
 
June 5, 2011 3:15 - 3:30 p.m. CDT, Hall B1). Data will also be published today in the online edition of the New England Journal of Medicine.
 
Additional data from the BRIM3 analysis showed:
 
· The response rate (those who experienced tumour shrinkage) in the group of patients who received vemurafenib (48.4 percent) was nearly nine times higher than in the group who received chemotherapy (5.5 percent, p<0.0001).
 
· After six months, 84 percent of patients who received vemurafenib were alive compared to 64 percent who received chemotherapy.
 
· The improvement in OS, PFS and tumour shrinkage with vemurafenib was seen in patients regardless of age, gender, or disease risk factor.
 
· In January 2011, an independent data monitoring board reviewed data from a planned interim analysis of BRIM3 and recommended the release of study results due to compelling efficacy. The board also recommended that patients in the chemotherapy arm be permitted to crossover or receive vemurafenib instead of chemotherapy.
 
· The median length of time patients lived (median OS) cannot be reliably estimated at this time because of the small number of patients in long-term follow-up. Median OS estimates when BRIM3 met this co-primary endpoint in January 2011 were 9.2 months in patients receiving vemurafenib and 7.8 months in those receiving chemotherapy; an additional two months of follow-up showed an estimated median OS of 10.5 months for patients receiving vemurafenib, while the median OS estimate for patients receiving chemotherapy remained at 7.8 months.
 
· The most common Grade 3 or higher adverse events were keratoacanthomas, rash, joint pain, sensitivity to the sun and fatigue. Squamous cell carcinoma (cSCC, a common type of skin cancer) was reported in 12 percent of patients. In cases of cSCC, the lesions were removed and the patients continued with treatment.
 
Vemurafenib has been granted priority review by the United States (U.S.) Food and Drug Administration (FDA). Roche recently announced the submission of new drug applications for vemurafenib in the United States (U.S.) and European Union (E.U.). While Roche seeks regulatory approval of vemurafenib, a global Expanded Access Programme (EAP) is available for people with previously treated or untreated BRAF V600 mutation-positive metastatic melanoma.
 
About BRIM3
 
BRIM3 (Study NO25026) is a global, randomised, open-label, controlled, multicentre, Phase III study that compared vemurafenib to dacarbazine chemotherapy, a current standard of care, in 675 patients with previously untreated BRAF V600 mutation-positive, unresected locally advanced or metastatic melanoma. Co-primary endpoints were OS and PFS. Secondary endpoints included response rate, response duration and safety profile.
 
Other vemurafenib data at ASCO
 
Updated results from a single-arm Phase II study (BRIM2) of vemurafenib in previously treated BRAF V600 mutation-positive metastatic melanoma will also be presented in an oral session by Antoni Ribas, M.D., UCLA Jonsson Comprehensive Cancer Center (Abstract 8509). Additionally, results are being presented from an analysis of patients enrolled in a single-arm study that is exploring the use of vemurafenib in tumours that have spread to the brain (brain metastases) in people with BRAF V600 mutation-positive metastatic melanoma (Abstract 8548).
 
About BRIM2
 
BRIM2 (Study NP22657) is a global, single-arm, multicentre, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600 mutation-positive metastatic melanoma. Unlike BRIM3, BRIM2 enrolled people who have previously received a treatment for metastatic melanoma. The primary endpoint of the study was best overall response rate and the updated data showed that 53 percent of patients had tumour shrinkage (median duration of response = 6.7 months). People who participated in BRIM2 also lived a median of 6.7 months without their disease getting worse (median PFS). Median OS has not yet been reached after a median follow-up of 10 months.
 
The safety profile of vemurafenib in BRIM2 was generally consistent with that previously reported in clinical studies of vemurafenib. Grade 3 cSCC was reported in 26 percent of patients. In cases of cSCC, the lesions were removed and the patients continued with treatment. The most common adverse events of any severity were joint pain, rash, sensitivity to the sun, and fatigue.
 
About the vemurafenib brain metastases safety study
 
The vemurafenib brain metastases safety study is a single-arm study enrolling 20 patients with BRAF V600 mutation-positive metastatic melanoma with brain metastases. Preliminary data from patients enrolled in the study to date suggested that vemurafenib may have activity in brain metastases. The safety profile of vemurafenib was generally consistent with that observed in other clinical trials.
 
Roche is planning to initiate a global, multicentre Phase II study exploring the efficacy and safety profile of vemurafenib in people with BRAF V600 mutation-positive metastatic melanoma that has spread to the brain.
 
About metastatic melanoma and BRAF
 
When melanoma is caught early, it is generally a curable disease. However, when it spreads to other parts of the body, it is the deadliest and most aggressive form of skin cancer. A person with metastatic melanoma typically has on average a short life expectancy that is measured in months. Less than one in four people are expected to be alive one year after a diagnosis and every year there are an estimated 40,000 deaths worldwide from the disease.
 
The BRAF protein is a key component of the RAS-RAF pathway involved in normal cell growth and survival. Mutations that lock the BRAF protein in an active state may cause excessive signalling in the pathway, leading to uncontrolled cell growth and survival. These mutations are thought to occur in an estimated half of all cases of melanoma and eight percent of solid tumours.
 
About vemurafenib
 
Vemurafenib is an investigational, oral, small molecule that is designed to selectively inhibit a cancer-driving mutated form of the BRAF protein. Vemurafenib is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group. Roche is pursuing a broad development programme with vemurafenib that includes combinations with other medicines (both approved and investigational, from Roche and other companies), as well as studies in other tumour types. While Roche seeks approval of vemurafenib, vemurafenib is available to eligible patients with BRAF V600 mutation-positive metastatic melanoma through a global patient access programme.
 
About the cobas 4800 BRAF V600 Mutation Test
 
The cobas 4800 BRAF V600 Mutation Test is an investigational, polymerase chain reaction-based companion diagnostic being developed by Roche to identify people whose tumours carry the BRAF V600 mutation. Roche submitted a Premarket Approval Application (PMA) for the cobas 4800 BRAF V600 Mutation Test in the U.S. The test will also be registered in Europe.
 
About Roche
 
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2010, Roche had over 80'000 employees worldwide and invested over 9 billion Swiss francs in R&D. The Group posted sales of 47.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
 
All trademarks used or mentioned in this release are protected by law.
 
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Vemurafenib (Zelboraf®, PLX 4032) Melanoma: FDA Review & Approval BRAF V600E inhibitor (Roche,Daiichi Sankyo) targeted therapy for advanced melanoma
 
The FDA approved Zelboraf on 17 August 20111 for the treatment of late stage metastatic melanoma. EMA approval is expected soon in 2011. The price of the drug is not known but is expected to be high in the 100,000 dollar range per year of treatment. Sales in 2011 are projected at $150 million and peak sales 3 billion within 5 years of approvals in major markets. Only a single new investigation drug has produced a 81% response rate and extended overall survival by 7 months (range 2-18 months) in a Phase I trials in advanced melanoma. These results were confirmed in Phase III BRIM trials which were presnted at ASCO 2011 meeting. Treatment with Vemurafenib (Zelboraf®,PLX 4032, RG7204) at 960 mg BID produced 2 complete responses and 24 partial responses out of 32 patients. Responses were observed within a week 1-2 of initiating therapy. tumor shrinkage was observed at all metastatic sites like bone, liver and small bowel. Preliminary results from Phase II trials showed a RR of 52%, with PFS of 6.2 months. Vemurafenib (PLX 4032) is a BRAF gene mutaton inhibitor which may herald the era of personalized therapy for melanoma patients. It seems to work in patients who test positive for the gene mutation. In BRAF V600E gene mutation +ve patients it resulted in tumor regression and increased survival varying by few months and had complete and partial responses. However all the patients had relapse and progressive disease after a period of PFS. PLX 4032 is one of the rare drug to go directly in Phase III trials without completion of Phase II BRIM 2 trial. The clinical dose in Phase II and III trials is 960 mg oral twice a day. Active BRIM 3 trial is ongoing in 100 sites in US, Canada, Europe and Australia with each site expected to enroll between 10-20 patients. Roche has announced that BRIM 3 met its primary end point of efficacy and increased both the OS and PFS in treated patients. The product does not work in patients without BRAF gene mutation and failed to show activity in colon cancer patients with +ve gene mutation. A combination trial with Ipilimumab is planned in braf gene positive melanoma patients. Denial of PLX 4032 treatment to melanoma patients in Phase III (placebo or decarbazine) has generated intense debate over ethical and moral issues and design of current DB trials.
 
Contents
 
· FDA Review & Approval
 
· EMA Review & Approval
 
· Introduction
 
· Melanoma
 
· Images & Video...
 
· Diagnosis · BRAF Gene Mutation
 
· Vemurafenib ( Zelboraf®, PLX 4032, Roche, Daiichi Sankyo)
 
· Brand Name Zelboraf®
 
Vemurafenib (Zelboraf®, PLX 4032) Clinical Trials
 
 
 
 
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