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Plexxikon, a member of Daiichi Sankyo Group, has received European Commission approval for Zelboraf (vemurafenib) for the monotherapy treatment of adult patients with BRAF mutation-positive unresectable or metastatic melanoma.

Zelboraf is designed to selectively inhibit the BRAF mutation that occurs in about half of all cases of melanoma.

Zelboraf and its companion diagnostic, the cobas 4800 BRAF V600 mutation test, have been approved in the US, Switzerland, Israel, Brazil, New Zealand and Canada.

Plexxikon CEO Peter Hirth said the approval of Zelboraf by the European Commission marks a significant advancement for European patients with metastatic melanoma who historically have had very limited treatment options.

"We are very pleased that our strategy to co-develop Zelboraf along with a companion diagnostic helped accelerate the availability of this personalized medicine for these patients," Hirth added.

~ Health Canada approves Zelboraf, a targeted medicine designed to inhibit cancer growth in patients known to have a common type of metastatic melanoma ~

MISSISSAUGA, ON, Feb. 16, 2012 /CNW/ - Roche announced today that Zelboraf (vemurafenib) was approved in Canada as monotherapy for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma. A validated test is required to identify BRAF V600 mutation status.1

Melanoma is the deadliest and most aggressive form of skin cancer, killing 80 to 85 per cent of stage IV patients within five years.2 Approximately half of all patients with melanoma carry a genetic mutation in the BRAF gene.3 Zelboraf is the first and only medicine shown to improve survival in people with BRAF V600 mutation-positive metastatic melanoma. It works by targeting and inhibiting the mutated BRAF protein found in about half of all cases of melanoma.3

"The medical community has been waiting for a treatment that will extend patients' lives while vastly improving quality of life," says Dr. Joel Claveau , Dermatologist, Dermatologist and Pigmented Lesions Clinic, Hospital Hotel-Dieu de Quebec . "Zelboraf is part of an innovative concept called personalized medicine. With a quick genetic test, I can now have the confidence that I'm prescribing the right treatment to patients who will benefit from it."

In the pivotal BRIM3 study in treatment-naïve patients, Zelboraf was shown to reduce the risk of death by 56 per cent for people who received Zelboraf compared to those who received dacarbazine.3  The study also found that participants on Zelboraf had a 74 per cent reduced risk of dying or having their disease progress compared to those who received dacarbazine.3 In another study in patients who failed at least one prior systemic therapy (BRIM2), Zelboraf shrank tumours in 52 per cent of trial participants.3

Mark Wallis , a 49-year-old father of three, is one of the 50 per cent of melanoma patients who has the BRAF mutation. Wallis received Zelboraf as part of the BRIM3 trial.

"The cancer had spread to my liver, my bones, both lungs and numerous lymph nodes so I was in an incredible amount of pain. "I was increasingly worried about my life and how it was going to affect my family," says Wallis, a commercial airline pilot from Milton, Ontario. "Within days of taking Zelboraf, the extreme pain I experienced literally vanished. Within weeks, my tumours had shrunk in size. I felt like I had been given my life back."

Annette Cyr , chair of the Melanoma Network of Canada , lives with melanoma and is all too familiar with the unique challenges patients have faced until now.

"For Canadians living with metastatic melanoma, the approval of Zelboraf brings new hope," says Cyr. "Zelboraf offers BRAF-positive patients a chance to live; to raise their children, to spend time with loved ones and to continue to contribute to society."

Health Canada also recently approved the cobas® 4800 BRAF V600 Mutation Test,4 a diagnostic test developed by Roche to identify patients eligible for treatment with Zelboraf, enabling oncologists to prospectively identify patients who may benefit from the treatment.

"As someone who has been tested positive for the BRAF mutation, I understand the valuable role that Zelboraf can play in the treatment of metastatic melanoma," says Kathy Barnard , Founder, Save Your Skin Foundation. "Patients with melanoma simply don't have the luxury of time and there is tremendous value in knowing right away whether or not a treatment will be effective. Personalized medicines like Zelboraf ensure that patients can receive the best possible care for their type of melanoma."

Personalized medicine is an innovative approach to healthcare that identifies the specific characteristics of a patient's illness, enabling physicians to implement the most effective and efficient treatment plan for each individual patient.5

"We believe that investment in personalized medicines is critical for driving optimal patient care while maximizing the use of limited health care resources," says Ronnie Miller , President and CEO, Roche Canada . "Zelboraf is an innovative, targeted therapy that will deliver effective care and improve outcomes for patients who have been without adequate treatment options for many years."

About BRIM3 and BRIM2

BRIM3 is a global, randomized, open-label, controlled, multicentre, Phase III study that compared Zelboraf to dacarbazine chemotherapy, a standard of care, in 675 patients with previously untreated BRAF V600E mutation-positive, unresectable (inoperable) or metastatic melanoma. The endpoints of BRIM3 were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other endpoints included confirmed investigator-assessed best overall response rate. BRIM2 is a global, single-arm, multicentre, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600E mutation-positive, unresectable or metastatic melanoma. The primary endpoint of BRIM2 was confirmed best overall response rate as assessed by independent review. In BRIM3, a higher percentage of patients treated with Zelboraf (42%) than dacarbazine (18%) experienced serious adverse events (SAEs) and the most common treatment-related SAEs in the patients treated with Zelboraf were cutaneous squamous cell carcinoma (cuSCC).

About BRAF V600 Mutation Testing

The cobas® 4800 BRAF V600 Mutation Test is a real-time polymerase chain reaction assay diagnostic test developed by Roche enabling physicians to identify whether a person with metastatic melanoma is eligible for treatment with Zelboraf. This Health Canada-approved test was clinically validated in the BRIM2 and BRIM3 studies to identify tumors that carry the BRAF V600E mutation. The test is robust, rapid and accurate providing a higher sensitivity in detecting the V600E mutation than Sanger sequencing.9

About Zelboraf

Zelboraf is an oral, small molecule, kinase inhibitor indicated as a monotherapy for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma. Zelboraf should not be used in patients with wild-type BRAF melanoma or in patients where the BRAF mutational status is not known.

Zelboraf is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group.

By Kim Irwin - Patients with metastatic melanoma taking the recently approved drug vemurafenib (marketed as Zelboraf) responded well to the twice-daily pill, but some of them developed a different, secondary skin cancer.
Dr. Antoni RibasNow, researchers at UCLA's Jonsson Comprehensive Cancer Center, working with investigators from the Institute of Cancer Research in London, Roche and Plexxikon, have elucidated the mechanism by which the drug excels at fighting melanoma but also allows for the development of skin squamous-cell carcinomas.

Dr. Antoni Ribas
The very action by which the pill works — blocking the mutated BRAF protein in melanoma cells that spurs the growth and spread of tumors — sets off a cellular cascade in other skin cells (if they have another predisposing cancer mutation) and ultimately accelerates the secondary skin cancers, said Dr. Antoni Ribas, co-senior author of the paper and a UCLA professor of hematology–oncology.

The 18-month study appears in the Jan. 19 edition of the New England Journal of Medicine.

About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with vemurafenib, Ribas said. Of those, approximately one-fourth develop skin squamous-cell carcinomas. In study subjects, the squamous-cell carcinomas were removed surgically, and the use of vemurafenib was not discontinued because of this secondary skin cancer side effect.

"We wondered why it was that we were treating and getting the melanoma to shrink but another skin cancer was developing," said Ribas, who studies melanoma at the Jonsson Cancer Center. "We looked at what was likely making them grow, and we discovered that the drug was making preexisting cells with an RAS mutation grow into skin squamous-cell cancers."

The combined research team performed a molecular analysis to identify the oncogenic mutations in the squamous-cell lesions of patients treated with vemurafenib. Among 21 tumor samples studied, 13 had RAS mutations. In another set of 14 samples, eight had RAS mutations, Ribas said.

"Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous-cell cancers while being treated with vemurafenib," Ribas said. "This RAS mutation is likely caused by prior skin damage from sun exposure, and what vemurafenib does is accelerate the appearance of these skin squamous-cell cancers, as opposed to being the cause of the mutation that starts these cancers."

Ribas' group found that blocking the non-mutated BRAF in cells with mutated RAS in an animal model caused them to send signals around BRAF that induced the growth of the squamous-cell cancers.

The discovery of the squamous-cell cancer mechanism has led to strategies to inhibit both the BRAF mutation with vemurafenib and block the cellular cascade with a different drug — a MEK inhibitor — before it initiates the secondary skin cancers, said co-senior author Richard Marais, a professor at the Institute of Cancer Research in London, who developed the animal model for the study.

"By understanding the mechanism by which these squamous-cell cancers develop, we have been able to devise a strategy to prevent the second tumors without blocking the beneficial effects of the BRAF drugs," Marais said. "This may allow many more patients to benefit from these important drugs."

Ribas said that this is one of the very few times that oncologists understand molecularly why a side effect to cancer treatment is occurring.

"The side effect in this case is caused by how the drug works in a different cellular setting," he said. "In one case, it inhibits cancer growth, and in another, it makes the malignant cells grow faster."

Studies currently are under way testing BRAF and MEK inhibitors in combination in patients with metastatic melanoma, Ribas said.

"Our data provide a molecular mechanism for the clinical toxicity of a targeted oncogene inhibitor that apparently contradicts the intended effects," the study states.

The study was supported by Roche; Plexxikon; the Seaver Institute; the Louise Belley and Richard Schnarr Fund; the Fred L. Hartley Family Foundation; the Wesley Coyle Memorial Fund; the Ruby Family Foundation; the Albert Stroberg and Betsy Patterson Fund; the Jonsson Cancer Center Foundation; and the Caltech–UCLA Joint Center for Translational Medicine.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years.

During 2011, FDA approved 35 new medicines. This was, according to the agency, among the highest number of approvals in the past decade, surpassed only by 37 approvals in 2009.

Of the 35 drugs given the go-ahead, two were approved with a molecular test, making them the first companion drug-diagnostic sanctions. Such tests will be key drivers of drug development in the future. Seven newly sanctioned medications provided advances in cancer treatment, and 10 were for orphan diseases. Notably, the first new therapy for lupus in 50 years was green-lighted this past year.

In terms of how efficiently the FDA was able to do its job, three cancer drugs were given the go-ahead in less than six months. Two-thirds of all the drugs sanctioned last year were completed in a single review cycle and 34 were approved on or before the agreed-upon review time targets.

Cancer

On August 26, FDA green-lighted Pfizer’s Xalkori to treat locally advanced and metastatic non-small-cell lung cancers that express an abnormal anaplastic lymphoma kinase (ALK) gene. The agency approved the drug along with a diagnostic test for the ALK gene abnormality, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. Up to 7% of those with NSCLC, typically patients without a history of smoking, have the gene abnormality.

Pfizer says the tyrosine kinase inhibitor will cost $9,600 a month or $115,000 for patients who take it for a year. In clinical trials, the average duration of treatment was between 22 and 32 weeks, but because the drug appears to extend patients lives, many may be on it for far longer than that.

The other drug-diagnostic approval was Roche’s Zelboraf to treat metastatic or unresectable melanoma and the Cobas 4800 BRAF V600 Mutation Test. Zelboraf, an oral kinase inhibitor, acts by blocking the function of the V600E-mutated BRAF protein. The mutation is present in about half the patients with late-stage melanomas.

The diagnostic will cost around $150 and the drug about $9,400 per month. It assumes, based on progression-free survival data from clinical studies, a treatment course of roughly 6–8 months.

In 2011, FDA sanctioned another drug for metastatic melanoma, Bristol-Myers Squibb’s Yervoy. This mAb therapeutic acts by binding to and blocking the actions of the cytotoxic T-lymphocyte antigen 4 (CTLA-4).

The antibody can cause significant side effects, however, including fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with Yervoy. When severe side effects occurred, Yervoy was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Yervoy achieved sales of $121 million in the third quarter of 2011, with ISI Group analyst Mark Schoenebaum commenting that the number was $17 million above Wall Street projections. Bristol-Myers Squibb got Yervoy as part of its 2009 acquisition of Medarex.

Some analysts see obstacles ahead for Yervoy, which costs $120,000 for a full course of treatment, in the form of resistance from regulators overseas. Last October, the National Institute for Clinical Excellence recommended that at a cost of about £80,000, Yervoy “could not be considered a cost-effective use” of health funds. A final decision is expected after a public consultation.

Hepatitis C

Two drugs for the treatment of hepatitis C won approval in May, 2011—the first new drugs approved for the viral disease in 20 years: Vertex’ Incivek (telaprevir) and Roche’s Victrelis. Both drugs interfere with the ability of HCV to replicate by inhibiting a key viral enzyme (NS3/4A serine protease).

The FDA said that it may be possible to shorten Incivek treatment from 48 weeks to 24 weeks in most patients. Given the toxicity of hepatitis C therapies, a shortened treatment period represents a significant advance.

Incivek was widely expected to generate the biggest sales: $4 billion worldwide by 2016, with Vertex taking in $1.75 billion in the U.S. following a peak of $2.21 billion in 2014. Telaprevir’s market advantage, analysts said, will come from its slightly better efficacy and side-effect profile. Victrelis’ anemia side effect will require management with erythropoietin-stimulating agents in many cases. Further telepravir performed well in the null responder population, which had proven controversial for Victrelis.

Lupus

Last year also saw approval of the first new drug developed for lupus in 50 years, Human Genome Sciences (HGS) and GlaxoSmithKline’s Benlysta. The mAb therapy was green-lighted on March 9, 2011, for adult patients with active, autoantibody systemic lupus erythematosis who are receiving standard therapy.

Benlysta targets the B-lymphoycte stimulator (BLyS) protein and may reduce the number of abnormal B cells thought to contribute to the disease. Analysts predict sustainable, long-term blockbuster potential for Benlysta, with projected sales of $2 billion to $4 billion annually.

Good Year for FDA

In looking over 2011 drug approvals, FDA did a pretty good job despite the carping from the pharma industry, financial community, and some patient advocacy groups.

FDA’s new cancer drug sanction process is consistently faster than the EMA, according to Samantha A. Roberts, Jeff D. Allen, and Ellen V. Sigal, affiliated with Friends of Cancer Research. They conducted a review and analyses of data available on FDA and EMA websites for the period between 2003 and 2010.

Among 35 new cancer drugs reviewed by FDA, 32 were approved, 20 of them within 184 days. EMA, on the contrary, approved only 26 of these new cancer drugs within an average time of 350 days. “Contrary to repeated public assertions, we found that new oncology medicines are consistently available in the United States before they are in Europe, and they are more likely to be approved by the FDA than by the EMA,” wrote the authors.

The report went on to say, rightly so, that its findings reinforced the need for strong financial and public support of the FDA so that “such medicines can continue to be made available speedily to patients in need.”

Dec. 16 (Bloomberg) -- Roche Holding AG’s Zelboraf treatment for a specific type of melanoma was recommended for approval by the European Union’s drug regulator.

Zelboraf may be used on metastatic or unresectable melanoma, a form of the skin cancer with lower rates of survival than localized melanoma, the European Medicines Agency said in a statement today.

The drug, a so-called BRAF inhibitor that was cleared for sale in the U.S. in August, works by blocking a protein that fuels tumor growth in about half of patients with advanced forms of the skin cancer. Zelboraf would help treat a disease that kills 8,300 men and 7,600 women a year in Europe, according to the EMA.

“There is a high unmet medical need for alternative treatments for metastatic melanoma that improve survival of patients,” the London-based agency said. About 25 percent of patients diagnosed with metastic or unresectable melanoma survive a year after diagnosis, compared with 90 percent of patients with localized melanoma, it said.

The recommendation to approve Zelboraf “represents an important milestone for people with metastatic melanoma who until recently had limited treatment options,” Hal Barron, chief medical officer at Basel, Switzerland-based Roche, said in a statement. “We are working closely with health authorities worldwide to bring Zelboraf to people with this deadly disease as soon as possible.”

BRAF-Inhibitor Work

Zelboraf was developed by Roche and Plexxikon Inc., which was acquired this year by Tokyo-based Daiichi Sankyo Co. Other companies working on BRAF inhibitors include Amgen Inc., GlaxoSmithKline Plc, Novartis AG and Pfizer Inc., according to the Bloomberg drug database.

The agency’s recommendations are the final stage before the European Commission, the EU’s executive arm, approves or rejects a drug for sale to patients in the 27-nation region.

Plexxikon Advances Novel Targeted Treatment PLX3397 in Blood Cancer

Berkeley, CA, December 12, 2011

Plexxikon Inc., a member of Daiichi Sankyo Group, today announced scientific findings from preclinical studies showing that treatment with a novel oral agent, PLX3397, selectively inhibited key cancer-driving Flt3 mutations that occur in 20-30 percent of acute myeloid leukemia (AML) patients. In a preclinical model of AML, PLX3397 showed significant tumor regression. This preclinical work also showed that PLX3397 retained activity against certain drug-resistant forms of mutated Flt3 that can occur with other treatments. These scientific findings were presented during the American Society of Hematology (ASH) Conference, taking place December 10-13, 2011 in San Diego (Abstracts #764 and #3632). Plexxikon recently initiated a Phase 1/2 study in AML patients, further described at www.clinicaltrials.gov.

“Given PLX3397’s selectivity for relevant mutations, we are exploring this potential personalized medicine for AML patients with Flt3 mutations,” said K. Peter Hirth, Ph.D., chief executive officer of Plexxikon. “Plexxikon’s hallmark capability to design selective kinase inhibitors enables clinical researchers to test the hypotheses of such targeted therapies directly and rapidly.”

Phase 1 dose escalation testing in patients with solid tumors has been completed, and showed that PLX3397 reached therapeutic drug levels that were well tolerated at the doses tested. Two Phase 2 studies are now under way to further evaluate PLX3397, including one study in Hodgkin lymphoma and another study recently initiated in patients with Flt3-mutated AML. Plasma from Phase 1 patients contained sufficient levels of PLX3397 to block signaling in Flt3-mutant AML cells ex vivo. Additionally, PLX3397 has been tested in primary AML patient blood samples, which showed a clear dose response to drug at clinically achievable drug levels.

About PLX3397
PLX3397 is an oral agent that is being evaluated in several clinical trials for the treatment of different cancers, including AML. PLX3397 selectively co-inhibits three key targets, allowing down-modulation of a number of cell types, including macrophages, microglia, osteoclasts and mast cells, as well as the inhibition of Flt3 mutations that are key oncogenic drivers in AML.

About Plexxikon
Plexxikon, a member of Daiichi Sankyo Group, is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company’s lead drug Zelboraf™ (vemurafenib/PLX4032) was approved by the FDA in August 2011, and is being co-promoted in the U.S. by Daiichi Sankyo Inc. and Genentech. The company is developing a portfolio of clinical and preclinical stage compounds to address significant unmet medical needs in oncology, as well as several other therapeutic indications. Plexxikon’s Scaffold-Based Drug Discovery™ platform integrates multiple state-of-the-art technologies, including structural screening as a key component that provides a significant competitive advantage over other drug discovery approaches.