Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Among big news was Roche’s companion diagnostic alliance with Clovis, a melanoma deal with BMS, and FDA’s Avastin decision.

Major biotech headlines last June for the most part had a common theme: heightened focus on personalized medicine. Companies were not only looking to advance targeted mAb therapeutics through development deals but were also vying to bolster their positions in the diagnostic segment. The other piece of big news last June was from the obesity sector.

In terms of molecular tests, Qiagen bought French diagnostics firm Ipsogen and Roche agreed to develop a companion test for Clovis Oncology’s preclinical drug candidate. The antibody sector saw Roche in the news again, with its melanoma alliance with Bristol-Myers and Avastin losing FDA confidence with regard to its breast cancer indication. And Orexigen received a complete response letter for its anti-obesity compound.

Eye on Diagnostics

Last June Qiagen said that it would buy Ipsogen for €12.90 a share in a deal valued at around €70 million (about $101 million at the time), representing a 71.3% premium to Ipsogen’s share price the day before the announcement. The acquisition gave Qiagen access to a broad range of assays covering 15 biomarkers used for the diagnosis, prognosis, and monitoring of patients with various blood cancers. Most of Ipsogen’s assays were developed for use on Qiagen’s Rotor-Gene Q real-time PCR instrument and have CE-IVD marking in Europe.

This January Ipsogen acquired exclusive, worldwide rights to testing for mutations of the IDH1 and IDH2 genes from Personal Genome Diagnostics. These genes are thought to play a role in brain cancers, acute myelogenous leukemia, and other malignancies.

Another interesting diagnostic deal was signed in June 2011. Roche entered an agreement to develop a companion diagnostic for Clovis’ CO-1686, a drug in preclinical development for advanced non-small-cell lung cancer (NSCLC). The in vitro PCR test aims to identify activating epidermal growth factor receptor (EGFR) mutations in NSCLC patients, including the EGFR T790M mutation. It will run on the Roche Cobas 4800 System, which was recently approved in the U.S. and all countries accepting a CE mark for use with the HPV test.

CO-1686 was designed to target and covalently bind to the activating and T790M mutant forms of EGFR, while sparing wildtype EGFR. In March Clovis announced that it had begun the first clinical study. Following the establishment of an appropriate dose, Clovis will use the companion diagnostic to study CO-1686 in an expansion cohort of NSCLC patients in whom EGFR-directed therapies such as Tarceva or Iressa have failed and whose tumors have developed the T790M mutation. This mutation is, according to the company, the dominant resistance mechanism to both drugs.

Antibodies in the Headlines

June 2011 saw the formation of a partnership that employs a strategy now being used by some pharma companies to facilitiate development of their individual targeted drugs. BMS and Roche said they would conduct a Phase I/II study to evaluate the combination of BMS’ approved melanoma drug, Yervoy, and Roche’s marketed melanoma therapy, Zelboraf, in patients with a specific type of late-stage melanoma.

Yervoy is a recombinant mAb that blocks CTLA-4, and Zelboraf is an orally administered BRAF inhibitor. FDA approved Yervoy in March 2011 for unresectable or metastatic melanoma and Zelboraf last August for late-stage or unresectable BRAF V600E melanoma. The combo will be tested in patients with tumors expressing a mutant form of the BRAF oncogene (V600E). The hope is that the combination will increase the duration of response and improve the immune response attack.

In forming their collaboration, BMS and Roche are responding to a trend among oncologists who favor the use of combinations of new therapeutics to treat cancer. This May BioTrends Research Group released findings from the second wave of its LaunchTrends® Yervoy and Zelboraf report, in which 103 U.S.-based medical oncologists were surveyed about their treatment patterns in advanced melanoma.

The surveyed medical oncologists noted positive patient treatment experiences with these agents and plans to utilize them more often when treating advanced melanoma. In terms of interest in late-stage candidates for advanced melanoma, doctors were most interested in Yervoy in combination with another agent such as Zelboraf, Merck & Co.’s Temodar, or generic dacarbazine.

Another targeted anti-cancer mAb therapeutic that has been on the market for a while received a blow in June 2011. The Onoclogy Drug Advisory Committee (ODAC) sided with FDA staff officials, who had concluded that Avastin does not prolong overall survival in metastatic breast cancer patients or offer a benefit in slowing the progression of the disease that outweighs the drug’s risks. In three 6–0 votes, the panel recommended reversal of the FDA’s approval of the $7.7 billion drug in combination with paclitaxel for Her2-negative breast cancer patients who have not been treated with chemotherapy. Avastin remains on the U.S. market as an approved treatment for certain types of colon, lung, kidney, and brain cancers.

Coincident with the ODAC decision, the EC broadened the existing breast cancer label for Avastin to include its use in combination with Xeloda as first-line therapy against metastatic disease.

Avastin may stage a comeback, though, as findings reported in the January issue of The New England Journal of Medicine suggest the antibody might be useful in patients in which the cancer has not spread. The study was supported by grants from Roche, Genentech, Eli Lilly, NCI, HHS, and the Public Health Service.

In one of two studies, a little over 33% of women given Avastin plus chemotherapy for a few months prior to surgery had no sign of cancer in their breasts at surgery compared to 28% of women given chemotherapy alone. In the other study, over 18% of patients treated with Avastin with chemotherapy had no cancer in their breasts or lymph nodes at surgery, compared to 15% of those on chemo alone. Both studies noted, however, that use of the antibody added to the toxicity of an already difficult treatment regimen.

Update on Obesity Treatments

Also last June, Orexigen stopped developing its anti-obesity drug, Contrave, after FDA asked the company to conduct additional testing. The firm received the complete response letter (CRL) in January 2011. The letter noted a single approval deficiency related to cardiovascular safety and asked Orexigen to conduct a randomized, double-blind, placebo-controlled cardiovascular outcomes trial prior to approval. Orexigen had proposed a post-marketing study of 12,000 to 15,000 patients, with a planned interim analysis in early 2013.

This February the company reached an agreement with the FDA on a Special Protocol Assessment for the Contrave outcomes trial. About 10,000 patients will be enrolled in this trial, set to begin this year and focused on capturing infrequent major adverse cardiac events (MACE). An interim analysis and NDA resubmission is planned once approximately 87 MACE events have occurred, which is anticipated to be less than two years from the start of the trial.

This February brought some good news for another obesity drug. Vivus reported that FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended its Qnexa be granted approval in a 20–2 vote.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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