PLX4032

On January 19, 2011, Plexxikon and Roche announced the results of an interim analysis of a large multicenter Phase 3 clinical study (the BRIM3 trial) of the targeted anticancer drug PLX4032 (which Roche has designated as RG7204). PLX4032 is a kinase inhibitor that is exquisitely specific for B-Raf carrying the V600E mutation [B-Raf(V600E)]. This is the most common somatic mutation found in human melanomas (accounting for approximately 50% of cases of this disease), and is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation.

According to the Plexxikon and Roche press releases, the Phase 3 trial met its prespecified criteria for co-primary endpoints of overall survival and progression-free survival, as compared to a control arm, in which patients were treated with the current standard of care, dacarbazine. The safety profile was consistent with previous clinical studies of the drug.

Based on the results of the interim analysis, patients in the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Moreover, the Expanded Access Program will be opened to previously untreated melanoma patients whose tumors carry the B-Raf(V600E) mutation. As the companies announced in November 2010, as the result of widespread demand from patients, oncologists, and patient advocates, they had been in discussion with global regulatory authorities regarding an Expanded Access Program for PLX4032. In late December 2010, the Expanded Access Program for PLX4032 was initiated. A cofounder of one of the patient advocate organizations pushing for expanded access to PLX4032 prior to its FDA approval, the Abigail Alliance, commented on this issue on our blog in November 2010.

The big news in Plexxikon and Roche’s report on the BRIM3 trial is that treatment with PLX4032 gave enhanced overall survival as companied with dacarbazine in previously untreated metastatic melanoma patients carrying the B-Raf(V600E) mutation. Although previous studies showed tumor shrinkage and enhanced progression-free survival (by approximately seven months) in the majority of PLX4032-treated patients as compared to dacarbazine, this is the first report that PLX4032 give enhanced overall survival. However, the companies did not report the extend of the enhanced overall survival. They plan to present comprehensive data from the BRIM3 trial at a major scientific meeting later this year. We expect that in due course the researchers that have been conducting the trial will publish the results in a peer-reviewed medical journal, as in the case of the published Phase 1 trial.

On November 8, 2010, Plexxikon and Roche reported preliminary results of a parallel open-label Phase 2 trial (designated BRIM2) of PLX4032 in previously treated metastatic melanoma patients whose tumors carried the B-Raf(V600E) mutation. Researchers who had been conducting that trial presented the data at the Seventh Annual International Melanoma Research Congress of the Society for Melanoma Research (SMR) in Sydney, Australia. Consistent with earlier Phase 1 trials, the BRIM2 trial showed that of the 132 patients enrolled, 3 patients had complete responses, and 66 had partial responses (i.e., tumor shrinkage of over 30 percent). The overall response rate was 52 percent, with a median duration of response of 6.8 months. At the time the results were reported, it was too early to gauge overall survival.

The Biopharmconsortium Blog has been following the PLX4032 story since March 2010. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues:

https://biopharmconsortium.com/blog/2010/03/02/bringing-targeted-therapy-of-metastatic-melanoma-into-the-clinic-the-crucial-role-of-translational-researchers/

https://biopharmconsortium.com/blog/2010/03/10/plexxikon’s-discovery-of-plx4032-a-selective-targeted-therapeutic-for-metastatic-melanoma/

https://biopharmconsortium.com/blog/2010/08/27/phase-i-trial-of-plx4032-a-selective-therapeutic-for-metastatic-melanoma-published-in-nejm/

https://biopharmconsortium.com/blog/2010/10/13/translational-research-in-cancer-makes-a-big-splash-in-nature-part-1/

https://biopharmconsortium.com/blog/2010/10/25/translational-research-in-cancer-makes-a-big-splash-in-nature-part-2/

The last two articles discuss the novel personalized medicine (or “stratified medicine”) hypothesis-testing clinical trial strategy, which is especially applicable to highly targeted oncology drugs (such as PLX4032) for which the relevant biomarkers are available.

The dramatic results of the Phase 1 trials of PLX4032 (now confirmed by Phase 2 and Phase 3 trials) led some oncologists, as well as patient advocates, to question the ethics of conducting standard controlled Phase 3 trials in which some patients were placed in a dacarbazine arm.  This question might apply to other drugs for cancer and other very serious diseases for which personalized medicine hypothesis-testing clinical trials indicate superior performance as compared to the standard of care. Such cases would at least call for establishment of  Expanded Access Programs for such drugs, on a case-by-case basis.

The clinical trial community, as well as regulatory agencies such as the FDA and the European Medicines Agency, also need to continue to monitor and study the progress of the personalized medicine hypothesis-testing clinical trial strategy. This may led to modifications in clinical trial standards for approval if they deem they are warranted. We can also expect that patient advocates (including M.D. and non-physician advocates), as well as other stakeholders (e.g., third party payers) would be participating in that process.

In parallel with the development of PLX4032, Plexxikon and Roche Molecular Diagnostics are developing a DNA-based companion diagnostic to identify patients whose tumors carry B-Raf(V600E). The companies plan to launch PLX4032 together with the companion diagnostic, so that oncologists can readily identify patients who would benefit from treatment with the drug.

Despite the dramatic results with PLX4032, so far all patients treated with the drug eventually suffer relapses, and die of their disease. This presumably occurs because a fraction of tuner cells develop resistance to PLX4032. Oncologists, especially those who have been involved in the clinical trials of the drug, therefore advocate using PLX4032 as the basis for potentially still more effective treatments, especially combination therapies.

With respect to combination therapies, on January 6, 2011, Plexxikon announced that it had signed an agreement with Genentech (a member of the Roche group) to co-promote PLX4032 (RG7204) in the United States. Plexxikon will also codevelop PLX4032 with Genentech in addition to Roche. Plexxikon and Genentech are planning, beginning in the first quarter of 2011, to begin a Phase 1b clinical trial of a combination therapy of PLX4032 and Exelixis/Genentech’s oral, small-molecule MEK inhibitor RG7420/GDC-0973. MEK is downstream from B-Raf in the signaling pathway by which B-Raf(V600E) acts to produce the malignant phenotype. Researchers studying mechanisms by which PLX4032 resistance occurs have found evidence that suggests that combination therapy with PLX4032 and a MEK inhibitor may overcome resistance that occurs via some mechanisms. More generally, studies of mechanisms of PLX4032 resistance may provide means of developing specific combination therapies for different mechanisms of resistance, and of stratifying patients to determine which particular personalized combination therapy will best treat their disease.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Source: Mnolf http://bit.ly/gEg5yo

In our November 11, 2010 blog post, we discussed the September 2010 acquisition of Seattle biotech firm ZymoGenetics by Bristol-Myers Squibb (BMS). Also in November 2010, Nature Biotechnology published an article about this acquisition, in which I was quoted.

As our blog post states, most commentators believe that BMS’ main motivation for acquiring ZymoGenetics was to gain full ownership of ZymoGenetics’ pegylated interferon-lambda (Peg-IFN-λ) program for treatment of hepatitis C (HepC). The two companies had been been collaborating to develop Peg-IFN-λ since January 2009. However, ZymoGenetics was much more than a one-product company. Its other pipeline drugs included interleukin-21 (denenicokin) for treatment of metastatic melanoma, which is now in Phase 2b development.  And over the years, ZymoGenetics has proven to be an important drug discovery engine, from the days in which it was a division of Novo Nordisk, and continuing on into 2010.

Now–as of the first week of January 2011–we learn that former ZymoGenetics CEO Douglas E. Williams Ph.D. has been named as Executive Vice President, R&D., at Biogen Idec (Weston, MA).

Dr. Williams has over 20 years of biotech R&D and senior leadership experience. He was the chief technology officer at Seattle biotech firm Immunex, and played a significant role in the discovery and development of the blockbuster tumor necrosis factor (TNF) inhibitor etanercept (Enbrel). After Amgen’s 2002 acquisition of Immunex, Dr. Williams resigned from Amgen later in 2002, and moved on to Seattle Genetics in 2003 as chief scientific officer (CSO). In 2004, he joined ZymoGenetics as chief scientific officer (CSO). On January 1, 2009, he became ZymoGenetics’ CEO.

During his tenure as CSO and then CEO of ZymoGenetics, the company achieved considerable success in the development of its pipeline products, especially Peg-IFN-λ and  interleukin-21. And the company entered into its $1.1 billion agreement with BMS to codevelop Peg-IFN-λ. However, during Dr. Williams’ tenure as CEO, ZymoGenetics had some financial rough spots, mainly caused by the lack of commercial success of the company’s first self-marketed product, recombinant thrombin (Recothrom). This was compounded by failed clinical trials of the company’s immunomodulatory drug atacicept, which is now being developed by Merck Serono. After a series of downsizing moves, ZymoGenetics agreed to be acquired by BMS in October 2010. In November 2010, Dr. Williams left ZymoGenetics and became a “free agent”, followed by his joining Biogen Idec in January 2011.

Biogen Idec, which was founded as Biogen in 1978 and merged to form Biogen Idec in 2003, is one of the world’s major biotech companies, and has long been a major fixture of the Boston-Cambridge biotech scene. The company had 2009 revenue of $4.38 billion. However, Biogen Idec had some ups and downs of its own in recent years. It has been targeted for reorganization, breakup, or sale by activist investor Carl Icahn, who currently owns 5.4% of the company’s shares, and who controls three seats on Biogen Idec’s board as the result of  series of proxy fights.

During 2010, long-time CEO (and Icahn target) James Mullen retired from the company, and was succeeded by former Exelixis (South San Francisco, CA) CEO George Scangos, Ph.D. In January 2011, at the same time as Dr. Williams joined Biogen Idec, the company announced that Steven H Holtzman (who was formerly the CEO of Cambridge MA biotech Infinity Pharmaceuticals) would be executive vice president of corporate development.

Biogen Idec derives most of its revenues from three drugs–multiple sclerosis (MS) treatments Avonex (interferon beta-1a) and Tysabri (natalizumab), and Rituxan (rituximab), a treatment for non-Hodgkin’s lymphoma. Tysabri is also approved for treatment of Crohn’s disease and is co-marketed with Élan, and Rituxan is also approved for rheumatoid arthritis and is co-marketed with Roche/Genentech.

Among these products, Avonex (which was introduced in 1996, and is Biogen Idec’s largest selling drug) and Rituxan are maturing. In particular, Avonex faces increased competition from newer products. Growth in sales and revenues from these two products is slowing.

Tysabri is intended to be Biogen Idec’s growth driver. However, Tysabri has had major issues. Soon after its launch in 2004, Biogen Idec withdrew Tysabri from the market, after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML), when co-administered with Avonex.  PML is caused by the JC virus, which is normally controlled by he immune system, but which can rarely cause disease in patients under immunosuppresive therapies such as the Tisabri/Avonex combination. After a safety review and no further deaths, the drug was returned to the US market in 2006 under a special prescription program, in part as the result of pleas by MS patients. However, since then additional cases of PML–including fatalities–have occurred.

In December 2010, Biogen Idec and Elan submitted a supplemental Biologics License Application (sBLA) to the FDA and a Type II Variation to the European Medicines Agency (EMA), proposing updated product labeling to include anti-JC virus antibody status. The companies propose using this test to help stratify the risk of developing PML in patients treated with Tysabri. Biogen Idec expects that a commercial anti-JC virus antibody test will be available later in 2011. It is expected that this test will help to lower the risk of Tysabri-associated PML, which is low to begin with.

In addition, Tysabri faces potential strong competition from the first approved oral treatment for MS, fingolimod (Novartis’ Gilenya), which the FDA approved in September 2010. The day that Gilenya was approved, Biogen Idec issued a press release acknowledging the desire of MS patients for an oral treatment, and noting that it also has an oral MS treatment in Phase 3 trials, BG-12.

Biogen Idec estimated that as of the end of 2010, approximately 56,600 MS patients were using Tysabri worldwide. That represented an increase of 1,700 patients in the fourth quarter and 8,200 patients over the course of 2010.

In November 2010, Dr. Scangos announced a reorganization of Biogen Idec. As of that date, the company would focus on neurology, and leverage its strengths in biologics research and development (R&D) and manufacturing to pursue select, high-impact biologic therapies and to be a leading collaborator in the biotechnology industry. (Biogen Idec’s efforts in biologics might, for example, include entering the biosimilars market.) Biogen Idec also terminated its efforts in cardiovascular medicine, and is seeking to spin out or outlicense its oncology programs.

The restructuring also involved consolidating its sites, and reducing its work force by 13%, or 650 full-time positions. As a result of the restructuring, the company expected to save approximately $300 million annually. Dr. Scangos said that the restructuring would enable Biogen Idec to gain focus and to become more nimble.

The company intends to become a global leader in neurological diseases. This will involve not only maximizing the potential of its two marketed MS drugs, but also bringing forward its MS pipeline products. Biogen Idec will also pursue programs in amyotrophic lateral sclerosis (ALS)/Lou Gehrig’s disease and Parkinson’s disease.

Biogen Idec’s late-stage products in neurology are shown in the table. (Please click on the table to read it clearly.) The company intends to launch five new products by 2015.

Source: Haberman Associates

Although Biogen Idec now has several late-stage products moving toward commercialization, the company’s R&D productivity has lagged in recent years. The company has not launched a new drug since Tysabri was approved in 2004. Dr. Williams says that he is planning a review of he company’s R&D organization and its pipeline. He intends especially to focus on Biogen Idec’s early- and mid-stage programs. Dr. Williams intends to boost these programs both via internal R&D and via licensing and acquisition to bring in externally developed compounds.

Overall, Dr. Williams hopes to return Biogen Idec to the culture of a biotech start-up. “We don’t have the luxury of sitting back. We have to push hard like we are a scrappy, hungry, cash-starved biotech,” he says. Dr. Williams’ statement is in accord with that of Dr. Scangos, who speaking at the J.P. Morgan 29th Annual Healthcare Conference in January 2011, said that Biogen Idec had the choice of being either a small pharma or a big biotech. The company has chosen to be a big biotech.

We wish Dr. Williams–working together with George Scangos and Steven Holtzman–well as they work to return Biogen Idec to productive and innovative R&D.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.