By Turna Ray
GlaxoSmithKline has decided that Abbott will develop a commercial pharmacogenomic test to accompany its investigational non-small cell lung cancer immunotherapeutic, after regulatory discussions with the US Food and Drug Administration revealed that a companion diagnostic would be required for marketing approval of the drug.
GSK and Abbott announced this week a deal to develop a PCR-based molecular diagnostic test, based on Abbott's m2000 instrument platform, which will screen NSCLC tumors for expression of the MAGE-A3 antigen, in order to determine which patients should receive GSK's MAGE-A3 Antigen Specific Cancer Immunotherapy.
"It was clear from regulatory discussions that in order to launch a therapy for MAGE-A3, a regulatory approved companion diagnostic would need to be available," a GSK spokesperson told Pharmacogenomics Reporter this week.
The terms of the agreement stipulate that both Abbott and GSK will be responsible for developing and commercializing the PCR test.
"The agreement is indicative of our focus on personalized medicine and developing analytical molecular tools to identify patients most likely to benefit from important pharmacogenomic therapies," Stafford O'Kelly, head of Abbott's molecular diagnostics business, said in a statement.
According to the GSK spokesperson, the FDA has indicated that the MAGE-A3 ASCI and the PCR-based companion diagnostic will be reviewed simultaneously. However, pending completion of a long-term Phase III study, the company could not approximate when it would submit applications to the agency for review.
Currently, GSK's MAGE-A3 ASCI is being studied in a large international Phase III clinical trial. Only patients with stage 1B, 2, or 3A NSCLC, whose tumors express MAGE-A3, can enroll in this trial. Response Genetics is providing the genetic screening services for the trial.
When GSK will submit its application for the MAGE-A3 ASCI "depends on the results from the Phase III study MAGRIT, which is ongoing," the company spokesperson said via e-mail. "As the Phase III analysis is driven by the number of events (relapses) rather than time we are not in position to provide an accurate expectation for filing externally at this point in time."
However, the spokesperson noted that since the diagnostic and therapeutic will be simultaneously reviewed by the FDA, and based on the criteria of pivotal clinical trials, the labeling for MAGE-A3 ASCI will require genetic testing prior to treatment.
"Yes, it is anticipated that the label will include screening for patients whose cancer is MAGE-A3 positive," the GSK spokesperson said. "All trials to date … enroll only patients whose tumor expresses MAGE-A3."
There are currently no FDA-approved nucleic acid-based tests that help guide treatment for NSCLC. According to the American Society of Clinical Oncology, last year approximately 172,000 people in the US were diagnosed with NSCLC. Between 35 percent and 50 percent of NSCLC patients express the MAGE-A3 tumor-specific antigen.
Based on these figures, a recommendation from the FDA that all NSCLC patients be tested for their MAGE-A3 status prior to treatment with GSK's immunotherapy could carve out a sizeable market for Abbott's diagnostic.
The investigational MAGE-A3 ASCI is currently being evaluated as an adjuvant treatment for NSCLC in a 2,300-patient, international Phase III trial, called MAGE-A3 as Adjuvant, Non-Small Cell Lung Cancer Immunotherapy, or MAGRIT. In order to receive the drug in the study, patients' NSCLC tumors must express MAGE-A3, a tumor-specific antigen that is expressed in cancer cells. The primary endpoint for the randomized, double-blind, placebo-controlled trial is disease-free survival.
Data from a Phase II, proof-of-concept trial showed that MAGE-A3 ASCI treatment following surgery reduced the relative risk of NSCLC recurrence by 25 percent after 44 months median follow-up, compared to placebo.
In another Phase II study, for patients who were selected based on MAGE-A3 antigen status, the relative risk of cancer recurrence was reduced by 43 percent over those receiving placebo.
In previous clinical trials, commonly reported adverse events were mild local or systemic reactions observed within the 24 hours of injection. Out of 182 patients enrolled in the study, two were withdrawn due to adverse events possibly related to the MAGE-A3 treatment.
When GSK began recruiting patients for the Phase III MAGRIT trial last year, it said it was using Response Genetics' genetic screening services [see PGx Reporter 01-30-2008].
Although the agreement between GSK and Response Genetics does not extend to commercial development of a diagnostic, Response Genetics is still providing genetic screening services for GSK's clinical trials for MAGE-A3 ASCI.
"The GSK-Response Genetics collaboration is ongoing, and RGI is continuing to support GSK’s MAGRIT trial by assessing MAGE-A3 gene expression in enrolled patients," Kathy Danenberg, Response Genetics CEO, told Pharmacogenomics Reporter this week.
According to a spokesperson for Abbott, GSK evaluated potential partners for diagnostic development based on a number of criteria, including experience navigating FDA regulations, capabilities to handle large-scale kit manufacturing, distribution, and implementation in a laboratory network.
So, while Response Genetics was "short listed" by GSK as a potential diagnostics partner, when it came to developing a commercial assay, GSK ultimately picked Abbott, a 72,000-employee multi-national healthcare company, over Response Genetics, a 50-person, Los Angeles-based diagnostics firm.
"Abbott was chosen as a partner to develop the assay as its proposal fulfilled the key selection criteria," the Abbott spokesperson said. "In particular, the m2000 system, the instrument on which the test will be run, has already obtained [FDA] regulatory approval and [the company has] the ability to fulfill the regulatory requirements for a commercial test."
Although the details of GSK's deal with Abbott are not known, working with a larger company means the regulatory, marketing, and development costs for the diagnostic will be more evenly split among the partners.
In contrast, large pharma companies that work with smaller diagnostics firms to develop companion diagnostics for their products generally have to shoulder the brunt of the development and marketing costs.
For instance, in using Monogram to develop the companion diagnostic tests for the HIV drug Selzentry, Pfizer took over global distribution for the test and invested $25 million in the diagnostics company [see PGx Reporter 05-10-2006].
With Response Genetics conducting genetic screening in clinical trials for MAGE-A3 ASCI, it is not immediately clear whether Abbott will have to run separate clinical trials to validate the commercial assay it is developing for the drug.
An Abbott spokesperson did not disclose the research and clinical development milestones for the diagnostic.