This article has been updated from a previous version to include additional information from Debiopharm on the biomarker-guided development program for tremelimumab.
Originally published April 23.
By Turna Ray
Pfizer's attempt to use pharmacogenetics to revive a melanoma drug that it had stopped developing in 2008 due to unimpressive efficacy has experienced some hiccups when it comes to identifying clinically valid gene-response markers, but the company is moving forward with a protein biomarker linked to response to the drug.
In the Feb. 1 issue of Clinical Cancer Research, researchers from Pfizer and other research institutions published results from a Phase II study on patients treated with the melanoma drug tremelimumab, which included pharmacogenetic assessment of polymorphisms in the CTLA4, FcγRIIa, and IgG2 genes. However, no clinically meaningful associations emerged from this investigation.
Although past studies have suggested a possible link between certain CTLA4 polymorphisms and tremelimumab response, "this pharmacogenetic analysis indicated no major influence of genetic variation in CTLA4," the study authors wrote in the paper. "In addition, no genetically defined subpopulation of patients that could be targeted for efficacy or safety was identifiable based on these analyses."
In the overall study cohort of 246 relapsed or refractory metastatic melanoma patients on tremelimumab, 6.6 percent saw a response rate. These results did not exceed the 10 percent response threshold with 97.5 percent confidence targeted by the study authors.
Despite the lackluster pharmacogenetic data and the modest response to the drug in the overall study population, it seems Pfizer still wouldn't mind resuscitating tremelimumab, as long its own development risks are minimal and the responsibility of clinically validating a biomarker linked to drug response belongs to a co-development partner.
A spokesperson from Debiopharm, a company Pfizer is working with to codevelop the personalized drug, told Pharmacogenomics Reporter this week that the company is investigating tremelimumab in a Phase III study with a protein marker, not a gene marker.
"The new phase III study will not focus on a particular genotype but on a biomarker to identify patients that are likely to respond to tremelimumab," the Debiopharm spokesperson said.
The spokesperson said that the company is moving forward with a protein marker discovered at Pfizer and that it is not pursuing any of the gene markers from the Phase II study.
The Clinical Cancer Research paper was initially submitted to the journal in July 2009, revised in November, and accepted for publication in December. A month before the Phase II data was published in February, by which point the results were surely known to the company, Pfizer announced a codevelopment deal for tremelimumab with Debiopharm Group. Under the terms of the partnership, Debiopharm is responsible for taking the melanoma drug through Phase III studies. And a statement describing the partnership notes that in Phase III studies, "a biomarker will be used to select patients considered likely to respond to tremelimumab."
The Pfizer spokesperson said that information on the biomarker of interest will be presented in June at the American Society of Clinical Oncology's annual meeting in Chicago.
According to the Debiopharm spokesperson, the assay for the biomarker will need to be validated before the Phase III study can start. The company is currently in discussions with the US Food and Drug Administration regarding the design of the validation study and is aiming to start the trials in the fourth quarter of this year.
Two years ago, Pfizer discontinued development of the igG2 monoclonal antibody after review by a data safety monitoring board of a Phase III study revealed that the investigational drug for advanced melanoma would not be more efficacious than standard chemotherapy. However, analysis of that initial, unsuccessful Phase III trial suggested that a biomarker may be used to identify a subpopulation of patients who could see increased benefit with tremelimumab compared to standard care.
Financial terms of the co-development agreement between Debiopharm and Pfizer were not disclosed at the time the deal was announced. However, by giving Debiopharm responsibility for advancing the targeted drug through the Phase III trial, Pfizer is taking on little risk during late-stage development of tremelimumab.
However, if Debiopharm's biomarker-guided Phase III trials are able to successfully identify a response marker for tremelimumab, Pfizer will retain responsibility for worldwide commercialization of the drug.
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There are few details about what role Debiopharm would play if Pfizer decides to market the drug with a companion diagnostic at the end of Phase III trials. Pfizer has not made any announcements about a companion diagnostic for tremelimumab.
In the past, big pharmas have worked with small firms to identify and validate biomarkers in clinical trials, but have then opted to partner with a larger company with multinational scale-up capabilities for the development of a commercial test (PGx Reporter 07-15-09).
Debiopharm, which describes itself as a Swiss-based global biopharmaceutical group of companies, recently entered the field of companion diagnostics and aims to expand into the personalized medicine space. The company earlier this month penned a companion diagnostics agreement with Biocartis. In that partnership, Debiopharm will contribute validated biomarkers linked to drug response and Biocartis will use its molecular diagnostics platform acquired from Philips to develop diagnostics that personalize treatments.
In addition to melanoma, Pfizer is also studying tremelimumab in pancreatic cancer, genitourinary and gastrointestinal cancers, and renal cell carcinoma.
Although Pfizer may not be applying a pharmacogenomic strategy to develop tremelimumab, it's no surprise that Pfizer wants to assume minimal risk while attempting to relaunch a previously failed drug. Resuscitating drugs using a genomic, proteomic, or metabolomic markers has often been cited as one avenue for drug companies to enter personalized medicine, but so far it's not a path that many have taken.
Currently no failed drugs have been successfully brought to market via such strategies, though a few companies are trying to resuscitate drugs that have been abandoned due to efficacy or safety issues.
For example, ARCA Discovery is in the process of submitting the beta blocker bucindolol for the treatment of heart failure. Incara Pharmaceuticals and Indevus Pharmaceutical outlicensed bucindolol to ARCA in 2003, after clinical trials showed that the beta blocker lacked efficacy in certain patients. The Laboratory Corporation of America is developing a companion test for bucindolol, but the timeline for when the Rx/Dx product will be submitted for regulatory approval is currently uncertain, as ARCA is awaiting approval from the FDA regarding a revised clinical study protocol assessment and needs additional funding to begin the study (PGx Reporter 03-31-10).
In addition, AstraZeneca recently received approval of its marketing application in the UK for its non-small cell lung cancer drug Iressa. The drug company is paying for EGFR mutation testing for lung cancer patients in the UK before prescribing them the drug under a patient access scheme with the National Health Service (PGx Reporter 04-07-10).
Due to a study showing Iressa to have low efficacy in the general NSCLC population, AstraZeneca in 2005 withdrew its application in the EU. The company reapplied for marketing approval in 2008 with efficacy data in EGFR-positive patients, and last year the drug was approved for marketing in Europe as a treatment for locally advanced or metastatic NSCLC patients whose tumors have EGFR mutations.
Finally, Novartis is the only drug company using pharmacogenomics to revive a drug that was abandoned from development due to safety concerns. Novartis announced earlier this year that it was planning to relaunch Prexige — a painkiller that was withdrawn from several international markets due to the risk of serious liver damage — with a companion diagnostic that would help doctors exclude patients who will experience adverse events (PGx Reporter 02-10-10).
Prexige, or lumiracoxib, was approved in the EU in 2006, but was withdrawn a year later from most of the 50 countries it was marketed in, including several European countries, Canada, and Australia, following reports of serious liver adverse events and deaths. In the US, the FDA deemed Novartis' initial application for lumiracoxib in 2007 "not approvable." The drug is currently marketed in a few Latin American and Caribbean countries with risk mitigation strategies.
Novartis submitted lumiracoxib and a PGx marker associated with hepatic safety, DQA1*0102, for the management of osteoarthritis pain to the European regulatory authorities in December 2009. The company said that it is discussing its submission strategy for the Rx/Dx product with US regulatory authorities, and has sought advice through FDA's Voluntary Exploratory Data Submissions program.
'Get it Right the First Time'
Although it seems pharma is starting to become comfortable with the idea of using PGx to resuscitate drugs that previously failed in clinical trials due to efficacy or safety issues, the strategy is still very much in beta mode. And how readily this pathway will be utilized by drug companies in the future still remains to be seen.
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For the time being, at least one FDA official isn't too crazy about the idea of using biomarkers to resuscitate drugs.
As reported in the spring issue of the Personalized Medicine Coalition's newsletter, Lawrence Lesko, Director of the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, is happy that industry is using biomarkers to hone on subpopulations that may incur greater benefits from treatments, but he feels that companies should be using biomarkers earlier in clinical trials to avoid late-stage failures.
"Why can’t we do a better job, so we don’t have to wait to see the drug fail and then rescue it?" Lesko posited to the PMC. "Let’s shift the paradigm and say, 'Why do we have to rescue failed drugs at all? Let’s do a better job of looking at their benefit/risk profiles in a prospective way and get it right the first time.'"
Indeed, the agency is currently developing systems and processes that may obviate the need for drug and diagnostic companies to test out PGx-guided drug resuscitation strategies with much frequency.
The FDA said earlier this year that it is building a predictive safety system that integrates pharmacogenomics, chemical structural data, and systems biology approaches to determine drug-induced adverse reactions before they happen. Additionally, the FDA is mulling the circumstances under which it should "strongly urge" DNA sample collection by sponsors (PGx Reporter 03-24-10).