The multiple myeloma therapy Darzalex became a blockbuster in 2017. Its originator, Genmab, hopes for more growth by moving it into earlier therapy lines and, further into the future, brand new indications including solid tumours.
The product’s first approval in front-line multiple myeloma looks certain after last year’s win in the phase III Alcyone trial, which tested Darzalex in combination with Velcade, melphalan and prednisone, a backbone used in Europe. But it is data from another phase III trial, Maia, that will determine whether Genmab and its partner Johnson & Johnson have a chance of cracking the US – a more lucrative first-line setting.
Maia, due to yield interim results in mid-2018, is evaluating Darzalex plus Celgene’s Revlimid; as Revlimid dominates in the US, this is the combo that more is likely to gain traction there.
The country is the key to Darzalex’s success: of the anti-CD38 MAb’s total 2022 sellside consensus forecast of $4.9bn – all of which is attributed to multiple myeloma – $3.1bn is expected to come in the US, according to EvaluatePharma.
And Bernstein analysts say around 30% of US Darzalex sales could be in first-line indications as early as 2020.
However, the bear case – that Revlimid’s entrenched position in the US, where it is commonly used in combination with Velcade and dexamethasone, could make the first-line market hard to penetrate – has been picking up steam of late, and analyst expectations for Darzalex have come off in the past few months.
Genmab needs a knockout result in Maia to keep its cash cow looking healthy, and Genmab’s chief executive, Jan van de Winkel, has high hopes.
He believes that progression-free survival, the primary endpoint, will surpass that seen in the phase III Pollux trial of Darzalex plus Revlimid in second-line multiple myeloma: “At 33 months, median PFS was not reached in the Pollux study. In front line we believe it could be much, much longer.” Bernstein analysts estimate that PFS in Maia could exceed 50 months.
This kind of result might be necessary if Darzalex is to defend itself against an expected onslaught from CAR-T therapy in multiple myeloma; current contenders include BCMA-targeting agents such as Bluebird Bio’s bb2121 and Nanjing Legend Biotech’s LCAR-B38M.
J&J signed a deal with Nanjing Legend late last year, but Mr van de Winkel does not agree that this reflects a lack of confidence in Darzalex, saying: “J&J had to do that to cover all their bases.”
He contends that CAR-T will not be a threat for several years, if ever. “It will probably be approved in a number of years for the fourth or fifth line of therapy, in very sick patients who cannot be helped with any other regimen. Then in six or seven years it might start competing in [stem cell] transplant-eligible patients – that’s 10-15% of front-line patients.”
One issue with CAR-T is its cost, and Mr van de Winkel points out that, while CAR-T patients require access to intensive care units, “the majority of US patients receiving Darzalex are treated in community healthcare centres”.
Still, the price of Darzalex is not to be sniffed at either, with the combination with Revlimid costing around $240,000 per patient per year. Here, the uptake of Darzalex-containing combos could benefit from the advent of generic versions of Revlimid, slated to enter the market by 2022.
As well as an FDA approval decision on the first-line Darzalex, Velcade, melphalan and prednisone regimen, due by May 21, and the Maia data, Mr van de Winkel highlights the Cassiopeia study, which is also set to read out this year. This tests Darzalex alongside thalidomide and Velcade in the smaller front-line transplant-eligible population; Alcyone and Maia enrolled transplant-ineligible patients.
While Genmab and J&J already have a lot on their plate, this has not stopped them pursuing new indications for Darzalex – the most interesting being solid tumours, where the drug is being tested in combination with PD-(L)1 inhibitors.
“Preclinical data suggest that when tumours become resistant to PD-(L)1 blockade, you could add a CD38 [inhibitor] and the combination could push these tumours into responses,” says Mr van de Winkel – the rationale being that CD38-positive immune-suppressing cells are seen in various solid cancers.
The first solid tumour data look likely to come from a trial of Darzalex plus Roche’s Tecentriq in second-line non-small cell lung cancer in the second half of 2018, while Bristol-Myers Squibb has several trials under way evaluating Darzalex plus Opdivo. The completion of the first of these, Checkmate-142 in colon cancer, was recently delayed from March 2018 to January 2019.
If Darzalex’s potential in solid tumours is confirmed “sales estimates will go up by billions”, Mr van de Winkel says. But there is a long way to go; all of the ongoing studies are phase II, and J&J will presumably have to commit to larger pivotal trials.
Studies of Darzalex are also under way or planned in other indications, including amyloidosis and rheumatoid arthritis, but it is clear that, for now, multiple myeloma is the main event. A result in solid tumours would be a bonus, but a win in the upcoming Maia trial is vital for the product’s prospects.
|Upcoming Darzalex trial readouts|
|Study||Setting||Combination||Trial ID||Data due|
|Maia||1L multiple myeloma||+ Revlimid||NCT02252172||Mid-2018|
|Cassiopeia||1L multiple myeloma||+ Velcade + thalidomide||NCT02541383||Mid/H2 2018|
|LUC2001||2L NSCLC||+ Tecentriq||NCT03023423||H2 2018|
|Checkmate-142||Colon cancer||+ Opdivo||NCT02060188||Jan 2019|
|Checkmate-358||Virus-associated tumours||+ Opdivo||NCT02488759||May 2019|
|-||Metastatic pancreatic, NSCLC, TNBC||+ Opdivo||NCT03098550||Jun 2019|