Empliciti’s front-line flop underlines Darzalex’s dominance

The CS1 approach to treating multiple myeloma was once thought capable of matching CD38, but that train left the station some time ago.

Trial Results

It’s official: Bristol-Myers Squibb/Abbvie’s Empliciti will not be used in earlier multiple myeloma than relapsed/refractory disease. This is the immediate significance of the 750-subject front-line Eloquent-1 study, which, almost nine years after it started, was today revealed to be a dud.

In reality, of course, most analysts had already written off Empliciti as a multiple myeloma also-ran. Certainly, the drug has failed miserably to keep pace with Johnson & Johnson/Genmab’s rival, Darzalex, and today’s study failure lays bare the divergence in these two products’ fortunes.

It also shows how one mechanism of action beat the other. Blocking CD38 (Darzalex’s pharmacology) and CS1 (Empliciti’s) were once neck and neck in a rivalry to become the next big mechanism in multiple myeloma. Today, while there are numerous industry projects targeting CD38, the anti-CS1 pipeline is virtually bare.

Empliciti’s failure to move earlier in the treatment cascade will do nothing to redress the balance. The drug remains approved for second-line or later multiple myeloma in combination with Revlimid, or for third-line disease as part of a Pomalyst combo.

Darzalex, meanwhile, has established a broad US label; having initially been launched in the fourth-line salvage setting as monotherapy, the drug now boasts second and third-line use in different combinations, and no fewer than three different first-line settings.

According to EvaluatePharma’s archived consensus, Empliciti’s near-term revenue forecasts peaked in mid-2016, when the drug was expected to sell some $2bn in 2022. In fact Empliciti only sold $357m last year, and 2022 and 2024 sellside consensus now stand at a feeble $483m and $497m respectively.

This is in stark contrast to Darzalex, whose sales rocketed to nearly $3bn within four years of its 2015 launch. Its 2022 forecast stands at an awesome $5.2bn, EvaluatePharma computes, versus a little over $2bn that it had in 2016 been thought capable of selling within six years.

The divergence in fortunes of the two drugs, both launched at roughly the same time, is largely down to J&J’s ability to expand Darzalex’s multiple myeloma use to ever earlier lines of therapy. And, while Darzalex has gone from strength to strength, Empliciti’s last major win was the Eloquent-2 study, highlighted at Asco way back in May 2015, which secured its second-line label.

Eloquent-1 was intended to secure the front-line setting, but today Bristol said it had failed to extend progression-free survival, its primary endpoint, when Empliciti was added on top of Revlimid and dexamethasone.

Just last week the US FDA approved the second anti-CD38 MAb, Sanofi’s Sarclisa (isatuximab), for third-line disease. A final irony is that, with a consensus forecast of $499m, Sarclisa is in 2024 expected to be selling more than Empliciti.

Selected multiple myeloma studies
Setting Combined with  Study Timeline
Darzalex (J&J/Genmab), anti-CD38 MAb
4L –  Sirius ORR backed accelerated approval 
3L Pomalyst + dex Equuleus ORR backed approval 
2L Velcade + dex Castor PFS backed full approval 
2L Revlimid + dex Pollux PFS backed full approval 
1L, transplant-ineligible Velcade + mel + pred Alcyone PFS backed full approval 
1L, transplant-ineligible Revlimid + dex Maia PFS backed full approval 
1L, transplant-eligible Thalidomide + Velcade   Cassiopeia PFS backed full approval 
Empliciti (Bristol-Myers Squibb/Abbvie), anti-CS1 MAb
2L-4L Revlimid + dex Eloquent-2 PFS & OS backed full approval
3L Pomalyst +dex Eloquent-3 PFS backed full approval
1L Revlimid + dex Eloquent-1 Failed Mar 2020
Sarclisa (Sanofi), anti-CD38 MAb
3L Pomalyst + dex Icaria PFS backed full approval 
2-4L Kyprolis + dex Ikema Data & filing 2020
1L, transplant-ineligible Velcade + Revlimid + dex Imroz Data & filing 2021
Source: clinicaltrials.gov.

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