DUBLIN – In one of the most baffling decisions the EMA has made in recent years, the agency's Committee for Human Medicinal Products (CHMP) last week issued a negative opinion in response to Takeda Pharmaceutical Co.'s application for approval of Ninlaro (ixazomib) in relapsed or refractory multiple myeloma. It's the same drug – an oral proteasome inhibitor – that the FDA took just four months to approve last year. (See BioWorld Today, Nov. 23, 2015.)

Osaka-based Takeda plans to appeal the decision and request a re-examination.

The ruling is a big setback for the company, as it has blockbuster ambitions attached to the drug, which it has long positioned as a successor to the injectable proteasome inhibitor Velcade (bortezomib). The latter drug comes off patent in May 2017, but there is no guarantee that Ninlaro will inherit that franchise, as competition in myeloma is heating up.

Amgen Inc. is making a big play for the same space and, to add insult to injury, the CHMP also voted last week in favor of a line extension for Kyprolis (carfilzomib). It will enable Amgen, of Thousand Oaks, Calif., to drop Revlimid (lenalidomide) from combination-based regimens in the treatment of myeloma patients who have relapsed after one prior therapy – having received approval in Europe for the three-way combo comprising Kyprolis, Revlimid and dexamethasone last November. It received a similar approval from the FDA back in January.

The evidence in support of the decision was solid. In the 929-patient Endeavor phase III trial, patients (n=464) on a combination of Kyprolis plus dexamethasone had a median progression-free survival (PFS) of 18.7 months vs. 9.4 months for those (n=463; p<0.0001) on Velcade plus dexamethasone, a current standard-of-care regimen. Amgen touted the data as the first ever head-to-head study of two proteasome inhibitors. Given Velcade's venerability – it was first approved back in May 2003 – it would be surprising if the industry had not managed to better it in the interim.

Whether Ninlaro will be competitive against Kyprolis is an open question for now – and one that can only be answered definitively by another head-to-head trial. It's unlikely that Takeda will contemplate such a study at this point, however. It has harbored hopes that Ninlaro would have a more benign safety profile than either Kyprolis or Velcade, which would convert into an improved therapeutic index.

In support of its European application, Takeda submitted data from a 722-patient phase III study, dubbed Tourmaline-MM1, which pitted a three-way combo of Ninlaro plus Revlimid plus dexamethasone against Revlimid plus dexamethasone only. Those in the Ninlaro group (n=360) had a median PFS of 20.6 months vs. 14.7 months for those in the control arm (n=362; p=0.01). Overall survival data are not yet mature. At 23 months of follow-up, 171 deaths had occurred, which represents 35 percent of the total specified in the study's statistical analysis plan. Of those, 81 had occurred in the drug treatment arm while 90 occurred in the control arm.

The data were reported in the April 28, 2016, issue of the New England Journal of Medicine, in a paper, titled "Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma."

The CHMP, however, ruled the data "insufficient to demonstrate a benefit of Ninlaro in the treatment of multiple myeloma." It added that subgroup data on difficult-to-treat patients whose disease had recurred after one or two prior treatments "were not compelling enough and the rationale for assuming greater effectiveness in these patients was not clear."

Takeda offered three prespecified subgroup analyses, in each of which the Ninlaro-based regimen outperformed the control treatment. In patients with high-risk cytogenetic abnormalities, those in the drug treatment arm (n=75) had a median PFS of 21.4 months vs. 9.7 months for those in the control arm (n=62; p=0.02). In patients positive for the 17p deletion (a partial deletion of chromosome 17, the locus of the gene encoding the p53 tumor suppressor), which is associated with a poor outcome, those in the drug treatment group (n=36) had a median PFS of 21.4 months vs. 9.7 months for those in the control arm (n=33). Of the patients with the chromosomal abnormality t(4;14), which also is associated with poor survival, those in the drug treatment arm (n=36) had a median PFS of 18.5 months vs. 12 months for those in the control arm (n=25).

PROTEASOME COMPETITION

Takeda is standing by its data but has yet to indicate how it will approach the appeal. "It is common for FDA and EMA reviews to differ in timing of approval or indication statements. At this time, Takeda cannot comment on the appeal process, the data submitted or the label. We are not working alone, and we expect the support of physicians, nurses, study investigators, patients, caregivers and advocacy organizations by our side," a company spokesman told BioWorld Today.

It has already elicited comment from one supportive clinical researcher, Philippe Moreau, of the University of Nantes, France: "After years of treating patients, I have yet to see two people whose diseases are exactly alike.

The diversity of patients with multiple myeloma demands a wide range of innovative treatment options that offer efficacy, tolerable safety profiles and convenience, which are especially important benefits for elderly populations," he stated in a press release issued by Takeda.

Meanwhile, the Darzalex (daratumumab) juggernaut, steered by Johnson & Johnson, rumbles on. J&J paid a $30 million milestone to its original developer, Copenhagen, Denmark-based Genmab A/S last week to mark the first commercial sale of the anti-CD38 antibody in Europe.

It is indicated for later-stage patients – who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. But phase III trials in frontline settings are under way as well – and additional approvals could eat into the longstanding dominance of proteasome inhibitors.