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.
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.