Biopharmaceutical Report I
• Historical responses meaningful, but approvability based on transfusion changes unclear
• Gene expression based screening could better direct use of drug considering its expense
Celgene’s (NASDAQ:CELG) Phase III trial of Revlimid (lenalidomide) in non-5q deletion lower-risk myelodysplastic syndrome (non-del (5q) MDS) has experts generally optimistic about the chances of achieving the primary endpoint. The study is being done in patients with MDS-related anemia who are transfusion dependent and aims to reduce the number of red blood cell transfusions.
Still, experts said, while the drug could demonstrate clinical meaningfulness by making at least 25% of patients transfusion-independent, they were not unified on whether such a rate would be sufficient for regulatory approval.
Identifying a gene signature would allow for more directed use of the drug in non-del(5q) MDS, which could be helpful because of the drug’s high cost and increasing scrutiny of off-label prescribing in some countries, several experts noted. Revlimid is approved for patients with transfusion-dependent anemia due to low- or intermediate-1 risk MDS associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.
The randomized, placebo-controlled, double-blind Phase III trial (NCT01029262) is expected to have data in 2H14, according to Celgene. The trial has an estimated primary completion date of April 2016, according to ClinicalTrials. gov.
Approximately 228 patients with low or intermediate-1 risk MDS will be enrolled and randomized to receive either 10 mg of Revlimid if their creatinine clearance is at least 60 milliliters per minute or 5 mg if their creatinine clearance is between 40-60 milliliters per minute. Dose adjustments for creatinine clearance rates are recommended in the prescribing information for Revlimid.
The primary endpoint is proportion of subjects that become transfusion independent and proportion with an erythroid differentiation gene expression signature that become transfusion independent.
A Celgene spokesperson said the company would not speculate on the study’s outcome but would have more to say when the results are known.
Interim data from the Phase II MDS002 trail showed that 25% of patients became transfusion-independent
Enthusiasm about primary endpoint success
The trial has a very good chance of meeting the primary endpoint, said Dr. Steve Allen, professor, medicine, Hofstra North Shore-LIJ School of Medicine, Lake Success, New York, pointing to previously published studies.
Interim data from the Phase II MDS-002 trial showed that 25% of patients became transfusionindependent (Ther Clin Risk Manag. Aug 2007; 3(4): 553- 562.), though later analysis showed the rate to be 26% (Seminars in Oncology, Vol. 38, No 5, October 2011, pp 648-657).
The drug has a medium probability of reaching its primary endpoint, said Dr. Emmanuel Gyan, hematologist, School of Medicine, François Rabelais University, Tours, France. Previous data indicates Revlimid is an active drug in nondel (5q) MDS, he noted.
If the trial indicates there is a significant reduction in blood transfusions and is associated with lower transformation rates to acute myeloid leukemia or lower rates of death, then Revlimid could be very interesting, noted Dr. Amit Verma, associate professor, Albert Einstein College of Medicine, New York.
Investigator Dr. Maria Diez Campelo, hematologist, University Hospital of Salamanca, Spain, said she was uncertain the primary measure would show success, though it was a reachable endpoint. She also pointed to previous study data and estimated that among her five trial patients, there appeared to be a 25% response rate.
It is hard to say whether the trial will reach the primary endpoint, said Dr Johnson Liu, associate professor, Hofstra North Shore-LIJ School of Medicine, Lake Success, New York, but the drug will add to the armamentarium even if it is not a game changer. Liu said he did not expect response rates in non-del(5q) to be as high as in del(5q). Studies have indicated Revlimid makes about 70% of del(5q) patients transfusion independent.
Historical response rates meaningful but unclear if sufficient for approval
At least 30% of patients achieving transfusion independence would not be bad, Verma said, though in the absence of good therapies in this setting, 25% is also worthwhile. It is unclear whether 25% would be enough for FDA approval, and the bar for approval is higher than in the past, he noted.
“They want survival; sometimes they are not happy with transfusion independence,” he added. Still, it might be good enough if there is a large enough difference between the study arm and the placebo arm, he said.
EU approval would be more difficult than in the US, Gyan noted. He was not aware if the FDA or EMA had any defined threshold.
But 25% could be enough for FDA approval, Allen said. Low and intermediate-1 risk patients can have severe, life-threatening anemia, risks associated with transfusions including viral infections, fluid overload, iron overload and congestive heart failure. After 20 transfusions, patients are at risk for significant iron overload that can cause organ damage, Allen noted, adding that iron chelation therapy is controversial, because it is expensive and not well tolerated.
Secondary end points in the trial include safety as well as impact on health-related quality of life and use of healthcare resources.
Besides the 25% benchmark, the FDA would have to look at other issues like quality of life and survival, a Florida expert noted. Still, he said, the FDA has approved drugs before based on factors like reductions in transfusions, and definitely if there is a survival benefit.
Secondary endpoints in the trial include safety as well as impact on health-related quality of life and use of healthcare resources.
The toxicity profile is unlikely to be different in non-del(5q) MDS from del(5q), Liu said. Nonmyeloid toxicity should not be different, but the drug may be more myelosuppressive in nondel (5q) than in del(5q), because the drug drives down blood counts, and MDS patients already have low counts, Allen added. If the patients respond to treatment, he explained, the counts rise, but if not, then they can drop to levels lower than without Revlimid.
Screening could better direct use of drug
While the ability of patients with non-del (5q) MDS to respond to Revlimid has been known for some time, it is unknown whether the response is because patients have the same kind of target as those with del(5q) disease, so there is a lot of interest in trying to understand why that is, Liu said. Revlimid can be clinically significant in non-del (5q) despite being not as effective as in del(5q), he added.
Part of the problem with Revlimid is its pricing, two experts noted. Gyan pointed out that it costs EUR 6,000-8,000 per month, while Allen said in the US it is USD 7,500-10,000. Hence, said Gyan, a biomarker is needed to avoid “throwing away” too much of the drug. Even though 25% would indicate the drug’s activity, he noted, “I don’t want to treat 10 patients and only see three responses.”
Gyan and Allen pointed to a February 2008 study (PLoS Med 5(2): e35. doi:10.1371/journal. pmed.0050035) that identified a molecular signature in a set of 16 pretreatment bone marrow aspirates from non-del(5q) MDS patients. It is on the basis of this study that patients are being screened for the gene expression signature before starting treatment, the Celgene spokesperson said.
Proving that the gene signature is predictive, Allen said, would help direct Revlimid usage in the non-del (5q) population. Even if a test for such a signature is expensive, Gyan added, it could mitigate giving a costly drug to nonresponsive patients. Gyan and Liu said they would like to see anything that could indicate whether a response is seen in 70% or more patients.
The trial is analyzing how many subjects with the gene expression profile achieve transfusion independence, the Celgene spokesperson noted but could not say yet whether the information would translate into a biomarker.
Celgene’s market cap is USD 64.8bn.
Alaric DeArment covers cancer drugs and vaccines for BioPharm Insight. Previously, he was associate editor at Drug Store News, covering retail and specialty pharmacy, pharmaceuticals, biologics and regulatory affairs. A native of Seattle, he graduated with honors with a bachelor degree in journalism from Ball State University and also lived in China from 2001-2004