LOS ANGELES — Although biomarker-based PGx studies cost more and are more complex than traditional clinical trials at Eli Lilly, the drug maker has made pharmacogenomics an integral part of its overall R&D strategy, according to one Lilly official.
Lilly’s experience goes against conventional wisdom that predictive technologies would reduce the cost of drug development by enabling smaller clinical trials and by lowering drug attrition in late-stage studies.
“What we said initially was that this is going to be much cheaper” by allowing for smaller patient populations, Richard Gaynor, vice president of Lilly Oncology, told Pharmacogenomics Reporter this week. “Maybe one day we’ll get to a point” where the biomarkers will be validated and robust enough to accommodate smaller trials, Gaynor said. “But right now, with the current [state of] biomarkers … you have to look at both selected and non-selected populations.”
Despite the costs and uncertainties of an emerging field, Lilly said it is committed to spending its intellectual and economic capital on PGx studies if they yield better therapies. According to Gaynor, PGx technologies have become an integral part of Lilly’s overall R&D strategy over the past two years.
“One of Lilly’s major focuses is getting the right patient with the right drug for the right disease,” said Gaynor, who spoke at the 2007 Annual Meeting of the American Association for Cancer Research, held here this week. “So it’s kind of a corporate-wide priority to go into trials to really define what patients are right for what drug.”
And even though personalized medicines have been slow to reach the market, Gaynor projected that the pharma industry will widely adopt PGx technologies between 2010 and 2012.
“I think a lot of groups are trying to do similar things, but for us it’s really important in both early- and late-stage drug development,” he said. “There is always a lag phase between when you change your strategy and when you see the technology is available and you say, ‘We’ll use it.’”
At AACR, Lilly presented ongoing studies for the marketed lung cancer chemotherapies Alimta and Gemzar, as well as for the targeted brain-cancer drug enzastaurin currently in Phase III trials. According to the company, many of these studies have a PGx component that relies on biomarkers to improve patient outcomes.
Depending on the types of biomarkers identified in its ongoing studies, Gaynor said Lilly plans to engage in drug-diagnostic co-development deals for several of its oncology products.
Costly But Worth It
While Gaynor didn’t say how much more a PGx-based trial costs, he estimated that the figure would depend on the biomarker’s ability to target patients and narrow study populations.
“If you have a marker that will remove 5 percent to 10 percent of patients for lack of response, you will still have to perform a large clinical trial, develop a diagnostic, and use it to test a lot of subjects,” he explained. “Thus, your trials will be more expensive.”
Ultimately, Lilly believes it is economically sound to use PGx strategies to develop targeted therapies. “Let us be able to define patients who optimally respond to our drugs,” Gaynor said. “If they do that they will want to take the drugs, they will comply with them, they will get good results. Will the economics work in that case? We think they will.
“The economics have to work if the patient is happy: they are seeing a response, they are living longer, they are tolerating the drug,” he continued. “If you have medicines like that then everyone wins and interests are aligned.”
The characteristics of most oncologics – low efficacy and high toxicity – contribute to low patient compliance rates. If patients cannot tolerate their treatment, “that’s not a good economic model, or a [good] societal model. It’s not good for the patients or the payors,” Gaynor noted.
One of the PGx studies Lilly reported at AACR was from a translational study involving the investigational protein kinase C-b inhibitor enzastaurin and Alimta, which is a thymidylate synthase inhibitor. In the study, investigators concluded that the enzastaurin/pemetrexed combination is “a very synergistic, cytotoxic combination” that also enhanced thymidylate synthase inhibition, increased apoptosis, and increased VEGF accumulation.
“What we said initially was that this is going to be much cheaper” by allowing for “smaller patient populations. Maybe one day we’ll get to that point … but right now, with the current [state of] biomarkers… you have to look at both selected and non-selected populations.”
“What we’re trying to do is see how these enzymes correlate with response,” Gaynor, said referring to Lilly’s PGx plans for Alimta. According to Gaynor, Lilly is collecting tumor samples, performing transcription profiling and immunohistochemistry, and studying expression signatures that might correlate with response to Alimta.
Lilly is also “looking at a number of prognostic markers – ERCC1 in lung cancer is a really important one – to try to see how that correlates with response,” he added.
Although Lilly has not identified a biomarker with Alimta yet, the company is continuing to focus on promising targets, genes that may be prognostically meaningful, and conducting exploratory research.
“Although Alimta and Gemzar are chemotherapy and they are not targeted agents, we’re still using the same kind of approach we would use for the so-called targeted agents,” Gaynor said.
Alimta and Gemzar have been available on the market for three and 10 years, respectively.
Alimta is approved as a single agent for the treatment of second-line non-small cell lung cancer and for patients with malignant pleural mesothelioma. Currently, Lilly is studying Alimta in several Phase III trials: in first-line metastatic NSCLC; as a maintenance therapy in metastatic NSCLC; for the treatment of small cell-lung cancer; for the treatment of head and neck cancer; as well as in locally advanced and adjuvant NSCLC, ovarian, and gastric cancers.
Gemzar is indicated in the US for the treatment of pancreatic, NSCLC, breast, and ovarian cancers. Lilly is investigating genes involved in metabolizing Gemzar, as well as other markers pertinent in the lung cancer setting, Gaynor said.
Enzastaurin, currently pending at FDA, selectively targets the PKC-beta and PI3/AKT signaling pathways. Lilly is studying the product in seven studies, including a Phase III trial for the treatment of diffuse large B-cell lymphoma — the most common form of non-Hodgkin’s lymphoma — and a Phase II trial in breast, colon, NSCL, pancreatic, ovarian, and prostate cancer.
In the large B-cell lymphoma trial, Lilly is looking for signaling pathways in an effort to correlate response with the activation of the signaling pathways. The company is also applying this approach to studying enzastaurin in other tumor types. In these studies, Gaynor said IHC, sequencing expression profiling, and diagnostics could apply.
For Alimta, Gemzar and enzastaurin, Lilly anticipates drug-diagnostic co-development deals.
“Once we find good biomarkers the plan is we will collaborate with diagnostic companies to develop a test,” Gaynor said. “[It] depends on what the assay is – is it going to be an immunohistochemistry staining assay, could it be DNA-based? But we really plan on partnering with diagnostic companies to get these drugs to the market.”