How Darzalex could surge clear of its multiple myeloma rival

Darzalex’s failure in a non-Hodgkin’s lymphoma study last month was a blip for what still promises to be a major growth driver for Johnson & Johnson – at least if you believe the drug’s sellside forecasts, which have ballooned sixfold over the past two years.

Darzalex was approved for multiple myeloma in 2015 at roughly the same time as Bristol-Myers Squibb’s Empliciti; while these were then neck and neck, expectations now see Darzalex surging well clear of its rival. Novel indications – and for Darzalex there are plenty – provide only part of the reason why this might be the case (see tables below).

An analysis of numerous ongoing studies involving each drug shows Empliciti largely confined to multiple myeloma, while Darzalex is being tested in myelodysplastic syndromes, amyloidosis and even solid tumours. Still, EvaluatePharma’s consensus attributes 100% of Darzalex’s expected 2022 sales of $5.8bn to multiple myeloma.

Front line

As such the answer might lie in Darzalex’s ability to break into front-line multiple myeloma – both drugs are being studied in this setting – and physicians’ perception of its superior efficacy. Certainly, the sellside is in no doubt which drug will win out: consensus for 2022 Empliciti sales sits at a mere $827m.

Leerink analysts recently cited a key opinion leader who said Darzalex was likely to migrate to first-line multiple myeloma. Empliciti, however, ultimately had “no role” in the relapsed/refractory setting, and would only enjoy front-line use briefly by virtue of timing.

“Over time the specialist believed Darzalex would phase out Empliciti from first and second-line use, and the [Bristol] drug seems likely to be marginalised in his practice and other centres,” Leerink wrote.

This is ironic, since Empliciti initially had the upper hand: it was approved for second-line multiple myeloma, on the strength of the Eloquent-2 study. Genmab/J&J's Darzalex, meanwhile, was initially only green-lit in the fourth-line setting – and that was an accelerated approval.

Selected studies of Darzalex
Indication(s) Study name Combined with Trial ID Completion Note
4L multiple myeloma Sirius NCT01985126 ORR backed accelerated approval
2L multiple myeloma Pollux* Revlimid NCT02076009 PFS backed full approval
2L multiple myeloma Castor* Velcade NCT02136134 PFS backed full approval
1L multiple myeloma Alcyone* Velcade NCT02195479 Nov 2017 Transplant-ineligible patients
1L multiple myeloma Maia* Revlimid NCT02252172 Dec 2019 Transplant-ineligible patients
1L multiple myeloma Cassiopeia* Thalidomide & Velcade NCT02541383 Aug 2022 Transplant-eligible patients
1L multiple myeloma MMY2004 Revlimid & Velcade NCT02874742 Jan 2020
Smouldering multiple myeloma Centaurus NCT02316106 Nov 2017
Multiple myeloma maintenance 2015-12 Total therapy NCT03004287 Jan 2021 Not yet recruiting
R/r MDS MDS2002 Talacotuzumab** NCT03011034 Dec 2018
R/r AML / MDS NCT03067571 May 2021 Not yet recruiting
AL Amyloidosis Amydara NCT02816476 Jun 2019 Investigator-initiated
AL Amyloidosis AMY2002 NCT02841033 Aug 2018 Investigator-initiated
NKT-cell lymphoma NKT2001 NCT02927925 Aug 2019 Not yet recruiting
2L NSCLC LUC2001 Tecentriq NCT03023423 Jul 2018
NSCLC, H&N, panc, CRC & TNBC Opdivo NCT03098550 Sep 2020 Not yet recruiting
Note: all phase II unless marked *; **anti-CD123 MAb.

Back in 2015, of course, Empliciti was expected to bring in $836m in 2020 sales, versus Darzalex’s $551m, EvaluatePharma’s archived forecasts reveal. Darzalex’s full approval came on the back of survival in the second-line Castor and Pollux studies, and since then sellside expectations have taken off.

A first-line label is within reach of both drugs, but beyond that it will be down to novel indications, in which Darzalex is clearly ahead of Empliciti.

Selected studies of Empliciti
Indication Study name Combined with Trial ID Completion Note
R/r multiple myeloma Eloquent-2* Revlimid NCT01239797 Interim PFS backed approval 
R/r multiple myeloma Checkmate-602* Opdivo & Pomalyst NCT02726581 Nov 2018
R/r multiple myeloma Eloquent-3 Pomalyst NCT02654132 Sep 2017
1L multiple myeloma Eloquent-1* Revlimid NCT01335399 Apr 2018
1L multiple myeloma Revlimid & Velcade NCT02375555 Oct 2018
1L multiple myeloma Revlimid & Kyprolis NCT02969837 Dec 2019 Not yet recruiting
Post-ASCT multiple myeloma maintenance Revlimid NCT02420860 Apr 2018
Smouldering multiple myeloma Revlimid NCT02279394 Jan 2020
Note: all phase II unless marked *.

Darzalex and Empliciti target different antigens seen on plasma cells – CD38 and CS1 respectively. The rationale behind Darzalex’s potential in other tumours is that CD38 is also present on immune-suppressive cells, J&J tells EP Vantage, the inhibition of which could release a brake on the immune system and allow combination with Tecentriq or Opdivo, for instance, to be effective.

However, CD38 is also present on some CD4+ and CD8+ effector T cells, so striking a balance between immune system activation and suppression could be tricky.

Either way the solid tumour indications are mere icing on the cake. Before that the battle for first-line use must be fought.

This story was amended to correct a mistake in the description of the Cassiopeia study.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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