Red blood cell, platelet, and lymphocyte

Since the publication of our March 30, 2011 article on melanoma on this blog, interest in melanoma has remained high. This is to be expected, with the March 2011 approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy), and the expected approval of Daichi Sankyo/Plexxikon/Roche’s PLX4032/RG7204 in the near future.

The April 2011 issue of the Faculty of 1000’s The Scientist included two articles that focused on melanoma. The first article, entitled “Taking Aim at Melanoma”, was written by leading clinician and scientist Keith T. Flaherty, M.D., whose work (especially with respect to development of PLX4032) has been discussed in  several articles on this blog. The second article, which we shall discuss further below, is entitled “Imagining a Cure”.

Then there was the American Association for Cancer Research (AACR) meeting (April 2-6, 2011, Orlando FL). This included numerous presentations on melanoma, including strategies for overcoming resistance to PLX4032 via development of combination therapies. There were parallel discussions on similar strategies in other cancers.

Haberman Associates will have a major new publication out shortly. This will (among other things) include discussions of combination therapies designed to overcome resistance to targeted therapies in several cancers, including melanoma.

The article entitled “Imagining a Cure” in The Scientist was written by National Cancer Institute (NCI) principal investigator Nicholas P. Restifo, M.D., and writer Megan Bachinski.

This article begins with what is the real desire of every cancer patient–a durable complete response, which is tantamount to a cure. In the case of patients with early-stage, localized melanoma, the disease is completely curable via surgery. However, metastatic melanoma is almost always fatal. Pre-March 2011 treatments, dacarbazine and interleukin-2 (IL-2), have reported complete response rates of 2.7 percent and 6.3 percent respectively. Even the newer treatments, ipilimumab and PLX4032, although they give improved survival over earlier treatments, only have reported rates of durable complete responses of 0.6 percent and 2.0 percent, respectively.

The authors then go on to discuss the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma patients–adoptive cell transfer (ACT), also known as adoptive immunotherapy. Dr. Restifo works in this area, as well as in other aspects of tumor immunology. Adoptive immunotherapy was pioneered by Steven A. Rosenberg, M.D. Ph.D., the Chief of Surgery and Head of the Tumor Immunology Section at the NCI, since the 1980s. Dr. Rosenberg remains a leader in the field, and Dr. Restifo works with him.

In ACT, a physician/researcher extracts a patient’s antigen-specific immune cells, which are usually found in tumor tissue. [Such cells are known as “tumor infiltrating lymphocytes” (TILs).] He or she then expands the numbers of the antitumor T lymphocytes in cell culture, using the T-cell growth factor, IL-2. The physician/researcher then infuses the cells, plus IL-2, intravenously into the patient. The infused T cells traffic to tumors and can mediate their destruction. Prior to TIL infusion, the patient may have his or her immune system temporarily ablated via “preparative lymphodepletion” with chemotherapy and sometimes also total-body irradiation. The preparative lymphodepletion treatment is associated with enhanced persistence of the transferred TILs.

In a recent clinical study of ACT, the treatment resulted in the disappearance of all tumors in 20/93 patients (21.5%) with advanced metastatic melanoma. For 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, in some cases lasting for over 7 years. (See also the Faculty of 1000 evaluation.)  Research on the mechanistic basis of adoptive immunotherapy, as well as on means to improve ACT technologies, is ongoing, so there is the potential to improve the durable complete response rate further.

Adoptive immunotherapy is not the only cancer immunotherapy that is in clinical studies or on the market. The newly-approved ipilimumab is a nonspecific T-cell modulator. Then there are the therapeutic cancer vaccines, including sipuleucel-T (Dendreon’s Provenge), which was approved for treatment of prostate cancer in 2010, as well as other cancer vaccines in clinical trials. Sipuleucel-T, which costs about $93,000, provides only a modest survival benefit (in one Phase 3 trial, 25.8 months compared to 21.7 months for placebo-treated patients) and is not associated with tumor regression. Overall, cancer vaccine clinical trials have resulted in an overall response rate of less than 4 percent. There have been no complete responses.

The authors of the article ask the following questions: If adoptive immunotherapy for metastatic melanoma has such a high durable complete response rate, why is it only available in a small number of cancer canters worldwide? Why is there little commercial interest in developing ACT? What can be done to facilitate the more widespread adoption of adoptive immunotherapies?

The authors give the following explanations: Adoptive immunotherapies are still considered experimental, are not FDA-approved, and are not paid for by third party payers. Thus only a handful of locations can bear the financial burden of administering adoptive immunotherapy. However, if a cancer center has a cell production facility with the required staff, the cost of producing a single dose of T-cells for adoptive transfer is approximately $20,000, much lower than a full course of Provenge or ipilimumab (approximately $120,000) treatment. ACT treatment also entails factoring in the cost of hospitalization. Most patients only require a single dose, however.

Adoptive immunotherapy is also comparable or less expensive than the cost of other, non-immunotherapy antitumor biologics, such as bevacizumab (Avastin) or cetuximab (Erbitux)—where the cost of the drug alone can exceed $80,000, and no patients are cured.

Moreover, according to the article, it would be difficult for a private company to pursue clinical trials for FDA approval and commercialization of ACT. To conduct such trials, a company would need to build a specialized cell processing and treatment facility, with a highly trained and competent staff. Adoptive immunotherapies also appear to lack a clearly defined claim to intellectual property (IP), since the patient’s own cells are not a “drug” to be patented. Nevertheless, Provenge also uses the patient’s own cells (in this case, antigen-presenting dendritic cells), and must be prepared specifically for each patient. In the case of Provenge, the cells are combined with a proprietary antigen/growth factor fusion protein (PA2024), however.

In the case of adoptive immunotherapies, various technologies for TIL isolation, selection, and expansion might be patentable, as might the use of genetically-engineered antitumor T cells.

The public sector might, according to the article’ authors, provide an alternative sponsor for adoptive immunotherapy. A network of cancer centers, institutes, and hospitals might form a consortium to refine ACT technology, and sponsor clinical trials aimed at FDA approval. Such FDA approval might provide substantial financial benefits for institutions in the consortium.

Moreover, research is underway to expand the types of cancers to be treated via adoptive immunotherapy. This research involves adoptive immunotherapy for synovial-cell sarcomas, B-cell lymphomas, and renal cancer. The expansion of adoptive immunotherapy beyond melanoma might, according to the authors, bring in new groups of stakeholders with an interest in making this type of treatment more widely available. Moreover, it might also encourage corporate and/or nonprofit organizations to envision the possibility of treating more common cancers, with the potential for larger financial rewards.

Given the superior results in terms of durable complete responses and comparable costs to other types of metastatic melanoma treatments, and the potential to treat other cancers, adoptive immunotherapy should not be ignored. However, it faces considerable hurdles to its widespread adoption.

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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.

 

On March 1, 2011, Plexxikon, Inc. (Berkeley, CA) announced that it has agreed to be acquired by Daiichi Sankyo, Japan’s third-largest pharmaceutical company, via an all-cash purchase. Under the merger agreement, Daiichi will pay $805 million up-front to purchase Plexxikon. Near-term milestone payments associated with the approval of Plexxikon’s lead drug candidate PLX4032 could total an additional $130 million.

The main driver for the merger is Plexxikon’s lead drug, PLX4032, for the treatment of metastatic melanoma. Plexxikon and its development and commercialization partner Roche/Genentech expect to file for U.S. and European approval of PLX4032 this year; the drug is expected to reach the market in 2012. By acquiring Plexxikon, Daiichi will gain the right to co-promote the drug in the U.S. with Genentech. PLX4032 is a novel oral drug that specifically targets B-Raf kinase carrying the V600E mutation, which is present in the majority of human melanomas.

We have been covering the development of PLX4032 on the Biopharmconsortium Blog. Our most recent article, “Phase 3 trial of targeted anticancer drug PLX4032/RG7204 shows overall survival benefit in melanoma patients”, was posted on January 23, 2011. That article, which discusses the successful Phase 3 trial of PLX4032 (which Roche has designated as RG7204), includes a list of links to our earlier articles. The Phase 3 trial showed that treatment with PLX4032 gave enhanced overall survival as compared with dacarbazine (the standard of care) 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.

PLX4032 is a personalized medicine, which Plexxikon has planned to pair with a companion diagnostic, developed in partnership with Roche Molecular Diagnostics. The DNA-based companion diagnostic will 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.

In acquiring Plexxikon, Daiichi also gains a pipeline that includes the kinase inhibitor PLX3397, which is in Phase 1 safety studies, with Phase 2 studies planned in metastatic breast cancer, and PLX-204, an oral PPAR alpha, gamma, and delta partial agonist that is In Phase 2 clinical trials in type 2 diabetes.

Daiichi will also gain Plexxikon’s drug discovery and development technology and strategy. We discussed how Plexxikon used its proprietary scaffold-based drug design technology platform to discover PLX4032, in our March 10, 2010 article on this blog. Daiichi says that it plans to “provide a high degree of independence to the Plexxikon group to support their continuing success,” and to leverage Plexxikon’s technology platform to discover and develop newer drug candidates.

Daiichi’s purchase of Plexxikon is part of a recent trend, in which the leading Japanese pharmaceutical companies have been investing in  oncology R&D in the United States. Two of these investments were large acquisitions. In 2008, Takeda acquired Millennium Pharmaceuticals (Cambridge, MA) for $8.8 billion; Takeda operates its acquisition, renamed Millennium: The Takeda Oncology Company, as a wholly-owned subsidiary. Astellas acquired OSI (Melville, NY) for $4 billion in 2010; OSI also operates as a wholly-owned subsidiary.  Both of the acquired companies boast large-selling drugs–Millennium’s Velcade (bortezomib) and OSI’s Tarceva (erlotinib) (which is partnered with Genentech/Roche).

The Japanese pharmaceutical companies aim to utilize U.S. innovation to compete in the lucrative global oncology market, which analysts project will expand 12 to 15 percent per year, reaching as much as $80 billion by 2012. In contrast, annual sales growth for Japanese pharmaceutical companies is projected to average 1.4 percent from 2009 to 2015. Overseas investments by Japanese companies are also being driven by a strong yen; the yen gained 8 percent gain over the dollar during the past year.

Some analysts believe that Daiichi paid too much for Plexxikon, and that even with the Plexxikon acquisition, Daiichi will not be very competitive in oncology with Takeda and Astellas, each of which acquired much larger U.S. oncology companies. Moreover, Daiichi has other issues to deal with, such as slow sales for its oral antiplatelet agent Effient (Prasugrel) (codeveloped with Lilly, and approved in 2009), which Daiichi hoped would be a blockbuster drug. Moreover, Daiichi’s majority-owned Indian generic drug company Ranbaxy has experienced a fourth-quarter loss due to rising operating expenses.

In addition to its acquisition of Plexxikon, Daiichi is also codeveloping (with ArQule, of Woburn MA) ARQ 197, a c-Met kinase inhbitor; this compound is in Phase 3 clinical trials in non-small cell lung cancer (NSCLC). Daiichi also acquired German oncology firm U3 Pharma (Martinsried, Germany) for $235 million in 2008. U3 Pharma (which operates as a wholly-owned subsidiary of Daiichi) is developing MAb-based anticancer therapies. Daiichi also, in 2007, licensed Japanese development and commercialization rights to Amgen’s MAb drug denosumab. Denosumab, marketed as Xgeva, was approved in the U.S. in 2010 for prevention of skeletal-related events in patients with bone metastases of solid tumors.

Will the acquisition of Plexxikon help Daiichi to compete in the worldwide oncology market, with its Japanese rivals and with other pharmaceutical companies? Only time will tell. PLX4032 is an exciting, breakthrough medicine that is likely to be approved in 2012. Moreover, if Daiichi allows Plexxikon the freedom to innovate and invests in its R&D activity, and if it can also harness Plexxikon’s technology platform to discover and develop novel drugs across different therapeutic areas, the Plexxikon acquisition may prove to be a major competitive advantage despite its small size.

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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.

"That's all, folks!" http://bit.ly/gSgL6b

“That’s all, folks!” http://bit.ly/gSgL6b

As we said in our December 8, 2010 blog post, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the FDA approve Orexigen’s Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.

This followed the earlier rejections in 2010 by the Advisory Committee and the FDA of two other preregistration antiobesity drugs–Vivus’  Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. Concern about long-term safety was the major consideration in the rejection of Qnexa and lorcaserin, and safety issues (increased risk of cardiovascular events) were the reason for the withdrawal of sibutramine. Thus the Advisory Committee’s recommendation for approval of Contrave was surprising, to us as well as to many others.

Despite the Advisory Committee’s vote to recommend approval of Contrave, it did have safety concerns. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as sibutramine.

As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.

Yesterday–January 31, 2011–was the Prescription Drug User Fee Act (PDUFA) deadline for the FDA to act on the approval of Contrave. This morning, Orexigen and its partner for Contrave commercialization, Takeda, announced that the FDA had issued a Complete Response Letter regarding the New Drug Application for Contrave.

The FDA’s Complete Response Letter stated, “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.”  Essentially, the FDA required Orexigen and Takeda to conduct the cardiovascular safety trial of Contrave prior to marketing approval, not post-marketing as recommended by the Advisory Committee. The safety trial required by the FDA will be neither fast nor inexpensive.

As a result of the FDA ruling, what we called “the pall of gloom” descended once again on the antiobesity drug field. Forbes’ Matthew Herper, for example, declared the antiobesity drug field “effectively dead”. Herper further said, “The clear lesson is that weight-loss medicines simply do not have enough of a benefit to justify any risk – and that this makes getting them approved just about impossible.”

If you click on the “metabolic diseases” category on the right-hand panel of this blog, you will see that we have quite a number of blog articles on obesity, usually in the more holistic context of metabolic diseases–obesity, type 2 diabetes, and metabolic syndrome (which is a major risk factor for cardiovascular disease). In these articles, you will see that we are not negative about antiobesity drug development. However, we are–and have been for some time–quite negative about developing appetite suppressant drugs that address common neurotransmitter receptors in the CNS.  Such agents might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy.

If you read our articles, you will see that there are several companies that have strategies to develop antiobesity agents that are not appetite suppressants, and that are being–or can be–developed for diabetes and/or metabolic syndrome in addition to obesity.  A common strategy is to develop diabetes/obesity drugs first for diabetes, resulting in easier FDA approval. Such drugs may later also be developed for obesity, after they prove to be safe and to induce weight loss in diabetes trials. For example, Novo Nordisk is following this strategy with the development of liraglutide (Victoza), which is already approved for treatment of type 2 diabetes.

Other established companies are pursuing different strategies, such as Amylin/Takeda’s development of pramlintide/metreleptin for obesity. This is really a metabolic syndrome-based approach to obesity. Indeed, Amylin (whose assets have passed on to AstraZeneca as of early 2014) had been developing metreleptin as a single agent for treatment of diabetes and high triglycerides in patients with lipodystrophy.

Then there are several young companies covered in this blog that are developing antiobesity treatments via innovative biology-driven strategies. Two of these companies, Energesis and Acceleron, are developing antiobesity therapies that target brown fat. Such an approach is really a metabolic syndrome-based one, and might also be applied to various diabetes and/or cardiovascular indications for easier regulatory approval.

Meanwhile, a News and Analysis article in the January 2011 issue of Nature Reviews Drug Discovery lists several agents not covered in our blog. One agent, tesamorelin (Theratechnologies/Merck KGaA’s Egrifta) was approved by the FDA in November 2010 as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy. Tesamorelin is a synthetic analogue of growth hormone–releasing factor — a hypothalamic peptide that acts on the pituitary to stimulate production and release of human growth hormone. This drug is now in a Phase 2 clinical study for treatment of human growth hormone deficiency associated with abdominal obesity. This represents a potential personalized medicine approach for treatment of a specific population of obese patients. Such an approach may be looked at more favorably by regulatory agencies than a “diet pill” for the general obese population.

As we also discussed in another article, John C. Lechleiter, Ph.D., the chairman, president and CEO of Lilly, outlined the need for “public policies that enable and reward medical innovation”, especially in the metabolic syndrome/diabetes/obesity therapeutic area. This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the PDUFA, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for negotiation between industry and the FDA to achieve these ends.

We hope that industry and the FDA can work toward a more favorable environment for the approval of safe and efficacious antiobesity drugs. And Dr. John Jenkins, director of the FDA office of new drugs, said that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.” Nevertheless, we do not see the FDA approving a minimally-efficacious CNS-acting appetite suppressor for the general obese population any time in the foreseeable future.

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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.

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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