Cancer cachexia is a wasting condition that is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. There is currently no drug treatment that can effectively improve cancer cachexia. When promising results for Helsinn Birex’s Adlumiz (anamorelin) were presented at the 2014 European Society for Medical Oncology (ESMO) Congress, hopes were high that it could address this unmet need. Adlumiz is a once-daily drug with a novel mechanism of action that functions by mimicking ghrelin, an appetite-stimulating hormone. The drug attaches to and activates a target on ghrelin receptors, which causes the release of substances in the body that are expected to act in the brain to increase appetite and prevent weight loss. However, in May 2017, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended that the drug be refused marketing authorization in Europe due to “marginal” effects.
To arrive at its decision, the CHMP reviewed results from two 12-week, placebo-controlled, Phase III clinical trials, ROMANA 1 (n=484) and ROMANA 2 (n=495), which were conducted in unresectable advanced non-small cell lung cancer (NSCLC) patients with cachexia. According to the investigators, these identical studies were carried out as per regulatory advice in order to secure evidence from two well-controlled trials. ROMANA 1 was conducted in 15 countries, and ROMANA 2 was carried out across seven countries. Co-primary endpoints for the studies were change from baseline over 12 weeks in lean body mass and handgrip strength. Results from the ROMANA 1 study showed that the median increase in lean body mass was 1.10kg with Adlumiz, compared to a loss of 0.44kg in the placebo group. ROMANA 2 showed the median increase to be 0.75kg compared to a loss of 0.96kg in the placebo group (P < .0001 for both studies). Change in handgrip strength was not statistically different between study arms.
Secondary endpoints included change in body weight. In ROMANA 1, body weight increased by an average of 2.2kg with Adlumiz versus 0.14kg with placebo. In ROMANA 2, body weight increased by 0.75kg with Adlumiz, compared to a loss of 0.96kg with placebo (P < .0001 for both studies).
The CHMP’s rejection was based on its conclusion that Adlumiz’s effect on lean body mass was “marginal” and that it had no proven effect on hand grip strength or patients’ quality of life. In addition, following an inspection at clinical study sites, the CHMP believed that the safety data on the drug had “not been recorded adequately,” meaning that a thorough evaluation of potential risks with Adlumiz was not possible. Based on the above, the CHMP concluded that the benefits of Adlumiz did not outweigh its risks, leading to its rejection of the drug. In June 2017, the CHMP announced that Helsinn Birex Pharmaceuticals Ltd had requested a re-examination of the opinion, and that it would reassess and issue a final recommendation upon receipt of the grounds of the request.
If the final recommendation remains negative, it will come as a big blow to Helsinn, which has already signed multiple distribution and license agreements for Adlumiz in Europe and around the world, including Spain, Italy, Norway, Sweden, China, Brazil, and Switzerland. One potential course of action is to address the CHMP’s concerns about the recording of safety data with a new trial. This may lead to the CHMP re-considering its decision, and it may even tolerate “marginal” effects of the drug, given the severe unmet need and lack of effective drug treatments within in this indication.