Anyone would think that the US FDA was window-dressing before ASH. Yesterday’s green light for Empliciti makes it three approvals for multiple myeloma treatments in the space of two weeks, the last coming just days before the US haematology meeting kicks off on December 4.
Of the trio, Empliciti and Darzalex carry nearly identical consensus sales forecasts, suggesting that their makers, Bristol-Myers Squibb/AbbVie and Johnson & Johnson respectively, will fight it out head to head. Look more closely at the data, however, and important differences emerge.
Most importantly, the settings in which they were tested in phase III are different, and study design hints that Empliciti’s monotherapy potential could be limited. Then there are their competitive profiles, and delicate pricing considerations.
And the third drug to be approved, Takeda’s Ninlaro, fits into yet another category. As the first oral proteasome inhibitor it forms a neat lifecycle strategy for the injectable Velcade, which loses patent protection in 2017; Ninlaro’s pivotal Tourmaline-MM1 trial is being profiled at ASH.
The similarities between Empliciti and Darzalex are superficial. Both carried US breakthrough therapy designations, and Darzalex, with EvaluatePharma sellside consensus forecasts for 2020 sales of $1.17bn, was approved four months before its PDUFA date; Empliciti ($1.18bn) got the thumbs up almost three months early.
But they are approved in different settings – Darzalex has the green light in relatively sick fourth-line patients, while Empliciti can be used as early as second line.
Both made a splash at this year’s Asco conference, though Empliciti was tested in combination with Revlimid, raising important questions about the cost of two expensive drugs being given together. In a recent interview with EP Vantage Jan van de Winkel, chief executive of Genmab, which originated Darzalex, said: “Empliciti has zero monotherapy efficacy.”
The J&J/Genmab drug’s pivotal Eloquent-2 study yielded a 4.5-month improvement in progression-free survival versus control, and 78.5% overall response rate. Darzalex’s open-label Sirius trial had ORR as primary endpoint, and this came in at 29%.
Genmab stands to receive royalties from J&J on Darzelax sales. Empliciti is the result of a collaboration between Bristol and Facet Biotech, a company acquired by Abbott, whose pharma business was then split off as AbbVie, so Bristol and AbbVie effectively have a co-promote deal over Empliciti.
Ultimately the exact place of these novel agents in the multiple myeloma landscape will depend on trials in first-line use, such as Eloquent-1, which tests Empliciti plus Revlimid, and three studies of Darzalex combos with Revlimid or Velcade (Genmab nabs multiple myeloma lead, November 17, 2015).
First in class
Mechanistically Darzalex and Empliciti are both first in class, though the former, an anti-CD38 MAb, could at some point face competition from the similarly acting SAR650984, from Sanofi, or MOR202, from Morphosys.
Empliciti is the only MAb targeting CS1 (SlamF7). Interestingly, Cellectis has the preclinical CAR-T projects UCART38 and UCARTCS1, against CD38 and CS1 respectively; these also carry gene deletions for CD38 and CS1, to avoid CAR-T fratricide.
Meanwhile, Takeda’s Ninlaro, which carries 2020 sellside consensus revenue forecasts of $1.53bn, looks like it will challenge Amgen’s proteasome inhibitor Kyprolis. Ninlaro's Tourmaline-MM1 trial, in second-line use and beyond, met its primary endpoint at its first interim analysis in February.
However, Takeda held back the numerical data from the study for ASH, meaning that presentation of the PFS and ORR numbers on December 7 will be keenly watched.
|Ninlaro||Tourmaline-MM1||Second line, plus Revlimid||NCT01564537|
|Empliciti||Eloquent-2||Second line, plus Revlimid||NCT01239797|