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FDA's ODAC Recommends Companion Dx for ChemGenex's Investigational CML Drug Omapro

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By Turna Ray

An advisory committee of the US Food and Drug Administration has recommended that Australian drug developer ChemGenex submit a validated companion diagnostic to determine patients most likely to respond to its investigational chronic myeloid leukemia drug Omapro.

The FDA's Oncologic Drugs Advisory Committee this week voted 7 to 1 in favor of requiring ChemGenex to submit "a well characterized" in vitro diagnostic to identify patients with T315I mutations prior to the approval of Omapro (omacetaxine mepesuccinate).

ChemGenex has scheduled a meeting with the FDA on April 9 to discuss its diagnostic strategy with the agency. Following the advisory committee meeting the company held a call with investors who were clearly concerned by ODAC's recommendation.

After the ODAC meeting on March 22, ChemGenex shares hit the lowest point in 16 years in Sydney trading, falling 37 percent to 44 cents. This was the biggest decline for the firm since December 1993 and the lowest stock valuation since May

However, ChemGenex CEO Greg Collier said that the company has been working with the FDA on developing a T315I test. ChemGenex is seeking FDA approval for Omapro for the treatment of adults with CML who have previously not benefited from treatment with imatinib (Novartis' Gleevec) and have the BCR-ABL T315I mutation, which renders CML patients resistant to all tyrosine kinase inhibitors.

"FDA has emphasized now in this new era of personalized medicine [that] it is important to make sure that the diagnostic tests that are out there in the market are validated and reproducible," Collier said. "And that was a clear message ... the FDA has made generally to the public."

Even though Collier told investors that the company wasn't surprised by ODAC's recommendation for a companion genetic test for Omapro, until the advisory committee's discussion materials were posted a day ahead of the meeting the company expected the committee to review the safety and efficacy profile of the drug.

In briefing materials for the meeting, FDA said it planned to seek ODAC's advice on whether the sample size of studies, as well as the duration and clinical significance of observed responses in the intent-to-treat population, were adequate. Additionally, the agency asked ODAC's input on whether the risk/benefit ratio for Omapro is favorable for omacetaxine-treated patients with T315I mutations and imatinib resistance.

The new drug application that ChemGenex submitted to the FDA for Omapro is based on a single efficacy study, CML-202, which is a multicenter, open-label, single-arm trial in 66 patients who were unresponsive to imatinib and had the T315I mutation. Patients were divided into cohorts of chronic phase, accelerated phase, or blast phase disease. Patients received 1.25 mg/m2 of Omapro subcutaneously twice daily for two weeks in a 28-day cycle for up to six induction cycles. If a patient experienced complete hematologic response, hematologic improvement, or any cytogenetic response, the patient was put on a maintenance dose of Omapro, 1.25 mg/m2 twice daily for a week in a 28-day cycle. The primary endpoint of the study was major cytogenetic response (MCyR).

For the chronic-phase cohort of 40 patients, the MCyR rate was 15 percent with a median duration of response of 7.7 months. For the 16 patients in the accelerated-phase cohort, the MCyR rate was 6.3 percent and the complete hematologic response rate was 31.3 percent with a median duration of response of 22 weeks. There were no responders in the blast-phase cohort.

In briefing documents to ODAC, the FDA indicated that "the response rate observed in the clinical trial was low." The agency also pointed out that ChemGenex had planned to study 100 patients in CML-202 but the NDA only includes efficacy data on 66 patients.

Additionally, although the indication ChemGenex has applied for is for the treatment of CML patients with BCR-ABL T3i5I mutations, "there is no commercially available assay for the detection of this mutation and the applicant has not submitted any data related to the assay methods to FDA's" diagnostics division. The agency also pointed out that 35 percent of patients had no confirmation of their T315I mutation at the time of enrollment, which was a study-entry criterion.

In US clinical studies, ChemGenex analyzed study participants for BCR-ABL T315I mutations through gene amplification and sequencing. Once a mutation was detected, the mutated BCR-ABL T315I transcript was quantified via rapid pyrosequencing. For studies conducted in Europe, study participants' T315I mutations were detected by liquid chromatography, and then if the sample was found to be mutation-positive, the mutation was quantified by qRT-PCR.

According to Collier, ChemGenex will work with a diagnostic developer to validate a T315I test to accompany Omapro. He told investors that the FDA review of a forthcoming companion diagnostic will take months, rather than years.

The Laboratory Corporation of America performs quantitative BCR-ABL1 transcript detection for CML by RT-PCR. Quest Diagnostics also performs PCR-based detection of BCR-ABL T315l mutations. Genzyme and Qiagen also perform this kind of analysis.

ChemGenex evaluated the safety of Omapro in 131 patients, including 66 patients from the CML-202 efficacy study. Most common adverse events seen with Omapro treatment were thrombocytopenia (60 percent), anemia (49 percent), diarrhea (43 percent), neutropenia (38 percent), fatigue (31 percent), pyrexia (30 percent), and several others.

Collier reassured investors that ODAC seemed to approve to the efficacy/safety profile of Omapro. "If approved, Omapro will be the only drug approved for this critical patient population ... where there are no treatment options and patients have a very poor prognosis of survival."

During a recent meeting of the Centers of Medicare & Medicaid Services' Medicare Coverage and Evidence Development Advisory Committee to consider the available clinical utility data for several pharmacogneomics-based cancer diagnostics, including BCR-ABL testing in CML patients, an independent review of the technologies identified "consistent evidence" from studies that testing for T315I mutations predicted which patients would not respond to treatment with certain tyrosine kinase inhibitors [see PGx Reporter 02-03-2010].

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