Bristol-Myers Squibb’s PGx strategy is attempting to slice through the conventional wisdom that pharmacogenomics is counter to the blockbuster model.
In a recent interview with Pharmacogenomics Reporter, BMS clinical discovery director Edwin Clark likened the company’s pharmacogenomics strategy to a pie, in which each slice is filled with a specific population from different blockbuster drugs.
“Envision a set of columns where you have breast, lung, colon and prostate cancers. But you also have rows across which if you pick out a subpopulation within each of those cancers, that market could be greater than the whole colorectal market is,” Clark said. “Some people may look at it as a small piece of the pie. We look at it as if you take five pieces from [different] pies, you build another pie.”
Based on previous company presentations, BMS’ biomarker programs, particularly in oncology, appear to be conducted in parallel with its drug discovery and development. It is a technique that may or may not lead to pharmacogenomic programs, but the thrust toward personalized medicine is a prominent feature at the company.
“A lot of people look at [the use of biomarkers] and they say, ‘Well, you’re going to reduce your market share,’” Clark said. Pharmacogenomics “may focus in on a smaller percentage of third-line colorectal cancer patients, but it opens up front-line colorectal cancer patients.”
BMS has several blockbuster therapeutics to its name, including the anticoagulant drug Plavix and the oncologic Taxol. The company also markets the targeted colorectal cancer drug Erbitux, for which nine-month US net sales ending Sept. 30, 2006, was $481 million, a 66 percent increase from the year-ago period.
Discussing the company’s PGx strategies for Erbitux and the investigational breast cancer agent ixabepilone, Clark said that pharmacogenomics may help to expand the drugs’ indications into earlier stages of cancer, as well as other cancer types.
“For both Erbitux and ixabepilone we’ve run 100-patient-plus clinical trials in which the primary endpoint has been to identify markers that would help us identify patients who are going to benefit most from our therapies,” Clark said.
Industry observers have noted that big pharma will not abandon the blockbuster model, but instead use pharmacogenomics opportunistically to arrive more efficiently at cash cow drugs. Pharmaceutical companies will eventually warm up to pharmacogenomics in their own way, they say, using molecular tools to reduce the drug-discovery timelines, quicken regulatory reviews, and remove unpromising or unsafe drugs from the pipeline earlier [see PGx Reporter 09-15-05].
In line with this view, BMS appears to be using pharmacogenomics to grow the blockbuster potential of its cancer drugs.
The Plan for Erbitux
Erbitux, currently approved as a third-line colorectal cancer therapy, is in clinical studies to identify candidate markers that could move the agent into earlier cancer settings and new indications, as well as increase response and garner a survival advantage in select populations.
“We will begin discussing those results with the outside world as early as the American College of Radiology meeting in April,” Clark said.
Also known as cetuximab, Erbitux is the first monoclonal antibody approved by the US Food and Drug Administration to treat metastatic colorectal cancer. Cetuximab is indicated as a combination treatment with irinotecan (Camptosar) or as a standalone drug if patients cannot tolerate irinotecan.
According to the label, although patients enrolled in the clinical studies were required to have immunohistochemical evidence of positive EGFR expression using the DakoCytomation EGFR pharmDx test kit, “response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.”
Effectiveness of Erbitux is based on objective response rates, and currently no data are available that show that the drug can improve disease-related symptoms or increase survival, according to its label.
To locate the Erbitux response markers, BMS researchers used Affymetrix chips to identify promising genes from 164 colon tumor and 31 colon cell samples in a Phase I study known as CA225-045. According to BMS, the study, which began in September 2005, aimed to “predict response to Erbitux as a single agent in patients with metastatic colon cancer” [see PGx Reporter 07-15-06]. The trial has finished recruiting patients.
With regard to Erbitux, BMS is looking at RNA profiles, EGFR and KRAS mutations, immunohistochemical protein staining, and gene-copy numbers for EGFR. “We’re hoping that some of these markers will work not only in colorectal cancer but now can be applied into lung cancer and into breast cancer, into other areas where the drug is not currently approved,” Clark said.
In 2005, BMS and Genomic Health announced a collaboration to develop a genetic test to predict the likelihood of response to Erbitux in metastatic colorectal carcinoma. Under the terms of the agreement, Genomic Health will receive research funding support and milestone payments and retains the commercial rights to any resulting diagnostic tests.
Ixabepilone’s PGx Plan
BMS is also looking for diagnostics partners for ixabepilone, Clark said.
“We have discussions with other diagnostics companies with regard to ixabepilone … but nothing has been finalized there so I can’t give you any names,” he said. “Part of the [PGx] strategy involves bringing in diagnostics companies to work with on these projects.”
For ixabepilone, which is currently in Phase III studies for highly refractory breast cancer, BMS is developing response-predicting biomarkers. The company plans to validate these results in early 2007, and use the biomarkers in subsequent trials to enrich for patients who will most benefit from treatment, Clark said.
“Within the highest levels of [Bristol-Myers Squibb] there is an understanding that [PGx] is going to play an important part in the future of oncology drugs and drugs in general.”
“We’re really looking to move ixabepilone into earlier lines, both into front-line metastatic as well as eventually into the adjuvant breast-cancer lines,” Clark said. “That’s where these markers will be most beneficial, is to utilize those in the adjuvant settings.” The company hopes to run the adjuvant breast cancer studies with ixabepilone in 2009.
PGx a Prominent Fixture at BMS
In addition to Erbitux and ixabepilone, BMS is developing pharmacodynamic biomarkers for its chronic myelogenous leukemia drug Sprycel. The company is also recruiting patients for a Phase II study to determine predictive markers of response for the investigational agent ipilimumab, or BMS-734016 (MDX-010), in melanoma.
According to Clark, pharmacogenomics figures “quite prominently” within BMS’ overall drug-development and research strategy. “That’s one of the reasons I came to Bristol,” Clark said. “Within the highest levels of the organization there is an understanding that [PGx] is going to play an important part in the future of oncology drugs and drugs in general.”
Part of BMS’ plans involve bringing Dx firms in during the clinical development stage. Early Rx/Dx partnerships to co-develop and then market targeted therapies have been touted by the FDA and industry observers as the best way to introduce patients and physicians to this still new concept of personalized treatment [see PGx Reporter 01-03-07].
However, “the diagnostics companies don’t want to get on board too early, because there is nothing there for them to make money on,” Clark cautioned.
If Dx firms get involved in the very nascent stages of drug development, “they are spending money without getting anything in return. The idea is we do a lot of the early discovery work first, but when it comes time to validate them, not just the finding of the marker but the assay itself, that we bring these diagnostics companies on board,” he explained.
Clark used the impending ixabepilone Rx/Dx partnership as an example. “For ixabepilone, when we want to move it into the adjuvant setting, we will get the diagnostic company already on board. They will already have the diagnostic validated and then we’ll be using that diagnostic, not discovering and developing it at all,” he said.
According to Clark, BMS is also internally conducting pharmacoeconomic studies for its PGx projects. “Internally we’re doing these sorts of analyses. And we do them sort of generally if you had ‘Drug X’ and then you had a companion ‘Diagnostic Y,’ what’s the value of that,” Clark said. “That generally tells us that under favorable conditions it makes sense to do” these tests.
With Erbitux there is “a whole team looking at how best to bring the diagnostic forward, whether it goes in the label, whether it’s part of the publication strategy. Exactly how that’s done is still to be determined.”