Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: March 2011

FDA approves ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy) for treatment of metastatic melanoma

Melanoma

On March 25, 2011, the FDA approved ipilimumab (Medarex/Bristol-Myers Squibb’s [BMS’s] Yervoy) for treatment of unresectable or metastatic melanoma. The drug has been approved for patients with either newly-diagnosed or previously-treated disease.

According to Richard Pazdur, the director of the FDA’s office of oncology drug products, none of the previously-approved treatments for metastatic melanoma, a disease with a poor prognosis, prolonged a patient’s life. “Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment.”

We discussed ipilimumab briefly in a previous article on this blog. As we stated in that article, the results of a Phase 3 trial of ipilimumab were published in the August 19, 2010 issue of the New England Journal of Medicine.  Ipilimumab is an immunomodulator that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) to potentate an antitumor T-cell response. The drug is a monoclonal antibody (MAb). In this NEJM article, the researchers reported that ipilimumab treatment–given with or without a gp100 peptide vaccine–showed a median overall survival of 10 months, as compared to 6.4 months in patients receiving gp100 alone. Ipilimumab treatment also gave improved one-year survival compared with gp100 alone–46% versus 25%. Two-year survival was 24% in the ipilimumab group and 14 percent in the gp100 group.

Decision Resources published our report on development of immunomodulators in treatment of cancer in 2007. This report includes a discussion of ipilimumab, and provides further information on its mechanism of action, adverse effects, etc., as well as on other immunomodualtors for treatment of cancer, some of which are now on the market.

BMS plans to report on the results of a later Phase 3 study, which also demonstrated significantly improved survival as compared to a control treatment, at the American Society of Clinical Oncology (ASCO) meeting in Chicago in June.

In its March 25, 2011 press release, BMS said that it had agreed with the FDA to conduct a post-marketing study comparing the safety and efficacy of the 3 mg/kg dose vs. an investigational 10 mg/kg dose in patients with unresectable or metastatic melanoma.

The Full Prescribing Information for ipilimumab will include a boxed warning for immune-mediated adverse effects. Ipilimumab treatment can result in severe or fatal immune-mediated adverse effects, especially enterocolitis, hepatitis, dermatitis, neuropathy, or endocrinopathy. These are usually reversible by discontinuing  ipilimumab therapy and treatment with high-dose steroids. According to the FDA, severe to fatal autoimmune reactions were seen in 12.9% of patients treated with the drug.

As part of the approval of ipilimumab, BMS is collaborating with the FDA to develop a Risk Evaluation and Mitigation Strategy,  to help inform patients and providers about these safety risks. The company  has put in place a system that will enable it to deliver these educational materials to healthcare professionals at the time they order the drug.

Strategic implications for BMS

BMS has hailed the approval of ipilimumab as a victory for its strategic changes over the past several years. The company has been focusing on its pharmaceutical business, selling off such nonpharmaceutical assets as the Mead Johnson Nutrition Company (MJN), and instituting other cost-cutting measures. BMS has at the same time been developing its “String of Pearls” strategy. In this strategy, BMS has been forming a series of acquisitions, alliances and partnerships with biopharmaceutical companies, involving both small molecules and biologics. According to BMS, the String of Pearls strategy has enabled BMS to expand its pipeline by nearly 40 percent. About one-third of BMS’ pipeline drugs are now biologics.

We have discussed the String of Pearls strategy, and two acquisitions that have been part of it, on this blog. These were the acquisition of Medarex (the largest of the “pearls”), and the newest acquisition, ZymoGenetics. It was MAb-therapeutic leader Medarex, now a wholly-owned subsidary of BMS, that initially developed ipilimumab.

BMS faces the expiration of patent protection for its best-selling product,  the anticlotting drug Plavix, in 2012. The introduction of ipilimumab, which several analysts expect to become a blockbuster, should help mitigate the results of the Plavix patient expiration. However, ipilimumab is not likely to fully replace the lost sales due to generic competition with Plavix. Moreover, the approval of one drug–ipilimumab–does not necessarily mean that BMS’ new R&D strategy, based on the String of Pearls acquisitions and partnerships, will yield a rich series of important approved drugs in the next 5-10 years. However, ipilimumab itself is such an important drug, in terms of its path-breaking mechanism of action, its addressing unmet medical need in a fatal disease, and its likely blockbuster status.

Another melanoma drug is on the way

The Biopharmconsortium Blog has been following the development of Daichi Sankyo/Plexxikon/Roche’s PLX4032/RG7204 (now designated as vemurafenib) for about a year. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues. This targeted kinase inhibitor, which is exquisitely specific for the melanoma driver mutation B-Raf(V600E), has been in Phase 3 clinical trials, and its developers filed for U.S. and European approval in May 2011. The drug is expected to reach the market in 2012. As with ipilimumab, Plexxikon and Roche reported that a Phase 3 trial of PLX4032 gave enhanced overall survival as compared with treatment with the standard of care, dacarbazine. The companies also plan to present the results of this trial at the ASCO meeting in June.

Metastatic melanoma patients, who have had few options for treatment, will now have two new, breakthrough drugs that can give them additional months of life, and in some cases longer. However, no treatment now on the horizon will result in long-term survival. In the case of PLX4032, this is due to the development of resistance to the drug. As we discussed previously, researchers are studying mechanisms of PLX4032 resistance, and developing potential combination therapies to overcome it. A clinical trial of at least one combination therapy, in collaboration with Genentech, is planned to begin soon.

A new approach to PLX4032-based combination therapy for melanoma

Meanwhile, another approach to development of an effective combination therapy with PLX4032 comes from an unexpected source.

We had discussed a zebrafish model of melanoma, developed by Leonard Zon’s laboratory at Children’s Hospital/Howard Hughes Medical Institute/Harvard Medical School (Boston, MA), in our 2010 Insight Pharma Report Animal Models for Therapeutic Strategies. In this model, the researchers created transgenic zebrafish strains in which B-Raf(V600E) is expressed under control of the melanocyte-specific mitfa promoter. Wild-type zebrafish expressing B-Raf(V600E) in their melanocytes developed benign nevi, while those with germline mutations in p53 may develop either nevi or melanomas. This suggests these two mutations are necessary, but not sufficient, to cause melanoma. (In humans, nevi may express B-Raf(V600E), which also indicates that it is not sufficient to cause melanoma. And in human melanomas, p53 is either mutated or otherwise rendered inactive.)

Now, in the 24 March issue of Nature, Dr. Zon and his colleagues used this model to study the mechanism of tumorigenesis in melanoma. They found that early-stage embryos of the transgenic zebrafish showed abnormal expansion of neural crest progenitors, and that these progenitors failed to terminally differentiate. (Melanocytes are one of the cell types that develop from the neural crest lineage.) In adult transgenic zebrafish, melanomas develop and are positive for neural crest progenitor markers, and thus appear to retain a neural crest progenitor-like phenotype.

The researchers therefore screened 2,000 compounds to identify those that act as suppressors of neural crest progenitors, without displaying toxicity. The one compound that satisfied these criteria, NSC210627, was similar to brequinar, an inhibitor of dihydroorotate dehydrogenase (DHODH), and NSC210627 also inhibited DHODH in vitro. The researchers therefore tested another more readily-available DHODH inhibitor, leflunomide (Sanofi-Aventis’ Arava). It had the same effects on the zebrafish as NSC210627 and was used for further studies.

Leflunomide treatment resulted in a nearly complete inhibition of neural crest development in zebrafish embryos, and specifically resulted in abrogation of melanocyte development both in zebrafish embryos and in Xenopus (African clawed frog) embryos. The drug’s target, DHODH, catalyzes a step in the synthesis of pyrimidine nucleotides, and thus inhibits transcriptional elongation. The researchers found that leflunomide caused specific defects in the transcriptional elongation of genes necessity for neural crest development in zebrafish. In human melanoma cell lines, leflunomide also inhibited transcriptional elongation in genes necessary for neural crest development and for melanoma growth (e.g, the Myc oncogene, which is required for both processes). Leflunomide (or its active metabolite, A771726) caused inhibition of growth both of human melanoma cell lines in vitro and in vivo in mouse xenograft models, but had little effect on non-melanoma cell lines in vitro. Combined treatment with leflunomide and PLX4032 showed even greater inhibition of growth of human melanoma cells in vitro and in vivo than treatment with either single agent.

Leflunomide is a marketed drug that is approved for treatment of moderate to severe rheumatoid arthritis and psoriatic arthritis. In these diseases, it appears to work via inhibiting the expansion of autoimmune lymphocytes by inhibiting transcriptional elongation in specific genes in these cells. Although leflunomide can have serious adverse effects in a minority of patients (e.g., liver damage), it has a generally favorable safety profile. Dr. Zon and his colleagues suggested that combination therapy of patients whose tumors are positive for B-Raf(V600E) with PLX4032 and leflunomide would be more effective than treatment with either drug alone, and that this combination therapy might help to overcome PLX4032 resistance.

Since leflunomide is already approved by the FDA, and both leflunomide and PLX4032 have been proven to be safe in clinical trials, researchers should be able to readily initiate clinical trials of the combination therapy. Dr. Zon says that  he is now working toward initiation of a clinical trial of the drug combination.

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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.

For the people of Japan

On March 3, 2011, we posted an article on this blog on the acquisition of Plexxikon by Daiichi Sankyo.

Then on March 11, 2001, came the 9.0-magnitude Tōhoku earthquake, followed by the devastating tsunami, with the loss of thousands of lives, and extensive damage to the infrastructure of Japan. Particularly troubling is the damage to the Fukushima I nuclear power plant, as well as several other nuclear power plants in Japan, and the uncertainty as to current and future effects of these events on Japan and its people. Also devastating is the economic loss due to the earthquake.

I cannot look at our blog post without thinking about the continuing events in Japan. Our thoughts and prayers are with the Japanese people in their hour of need.

According to a March 14 2011 news release, several employees suffered minor injuries, but all are safe. Two Daiichi Sankyo production facilities in Japan have been partly damaged by the earthquake. The company will assess the situation at these plants–especially with respect to employee safety–as power is restored. Several Daiichi Sankyo sales facilities were also affected by the earthquake, and with employee safety as its first priority, the company will work to restore operations.

The acquisition of Plexxikon by Daiichi Sankyo is on schedule to close at the end of 2011.

Meanwhile, Daiichi Sankyo announced that it would donate 100 million Japanese Yen (JPY) (approximately $1.2 million) to the Japanese Red Cross Society, as well as medical supplies, for relief efforts; it has also implemented a matching gift program for employee donations. Takeda will donate 300 million JPY, as well as medical supplies, and Eisai will donate 200 million JPY and will establish a crisis center in the Tōhoku region. Astellas and Chugai are both donating 100 million JPY.

Non-Japanese Big Pharma and Big Biotech companies–Merck, Abbott, Lilly, GlaxoSmithKline, Johnson & Johnson, and Amgen–are each contributing over $1 million to Japanese aid. Many other corporations outside the pharmaceutical industry have pledged donations for Japanese relief.

The Japanese and American Red Cross, as well as many other secular and religious relief agencies, are assessing the situation in Japan and requesting donations.

Meanwhile, the Japanese people are behaving admirably in this crisis. There has been little or no looting or profiteering, and there is a sense of national cooperation. The resilience of the Japanese people, and their engineering skill and experience in rebuilding from previous disasters, will contribute mightily to Japan’s ability to rebound from this devastating earthquake and tsunami.

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Addendum, March 27, 2011: See the news article in the 22 March 2011 issue of Nature, entitled “The meltdown that wasn’t”.  According to this article, the operators in unit 1 of the Fukushima Daiichi nuclear power station acted competently and courageously in dealing with the effects of the earthquake and tsunami on the reactor on 11 March, 2011. They averted a catastrophic full meltdown of the reactor, and their actions also provided a model for stabilizing the other two reactors at the station.

Radiation exposure due to the Fukushima nuclear accident continues, however, as do the other effects of the earthquake and tsunami on Japan and her people.

For Nature’s full coverage of the continuing story of the Japanese earthquake and nuclear crisis, see http://www.nature.com/news/specials/japanquake/index.html.

Plexxikon acquired by Daiichi Sankyo

 

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.