Darzalex's ambitions extend beyond Maia

Data from quad therapy and a subcutaneous formulation could resuscitate enthusiasm even if the US government shutdown delays Darzalex's upcoming first-line approval.

Darzalex has to be rated as one of the biggest successes of recent years, even if the $2bn in sales achieved in 2018 disappointed Genmab investors. And the coming months could provide a couple of opportunities for new sales surges: the product is being tested as a subcutaneous formulation and in combination with a first-line multiple myeloma triple therapy.

The Columba trial will test the hypothesis that the subcutaneous formulation is equal to the currently marketed intravenous Darzalex; subcutaneous delivery could knock hours off every dose and make the Genmab/Johnson & Johnson antibody more attractive to patients. Meanwhile, the partners want to build on the success of the Maia trial, which showed that Darzalex on top of Revlimid and dexamethasone could improve on the doublet, commonly used on newly diagnosed US patients. Soon Griffin could do the same for Darzalex on top of a Velcade-Revlimid-dexamethasone triplet.

Long infusion times

Genmab and J&J hope that the 480-patient Columba trial can show the same blood concentrations as intravenous delivery at the beginning of the third cycle, as well as similar response and survival rates in patients who have undergone at least three lines of therapy. The subcutaneous formulation is administered over three to five minutes, compared with three hours for the intravenous.

The first dose of intravenous Darzalex takes even longer, at seven hours, so the companies have been pursuing a split dosing regimen to improve convenience. This was recently approved by the European Commission, meaning patients can now receive their first infusion of the drug over two consecutive days. J&J has also applied for split dosing in the US.

Still, the subcutaneous version could make Darzalex more patient friendly. The phase I Pavo trial, released at Asco 2018, showed similar blood concentrations and objective response rates between the two formulations.

Bernstein reckons that approval of subcutaneous Darzalex will occur in early 2020, a decision that could help sustain long-term forecasts that put sales at $5.1bn in 2024.

Quad goals

Meanwhile, the Griffin trial, in 222 newly diagnosed patients eligible for stem cell transplantation, will provide the first data from a multiple myeloma quad, measuring improvement in strict complete responses. The goal is to improve on the survival seen in various triple combinations that are emerging as a standard of care.

This phase II trial might not be enough to win immediate approval, and Genmab and J&J already have the quad in two phase III studies that got off the ground in late 2018, although only one of these is in patients set for stem cell transplant.

Still, Genmab's chief executive, Jan van den Winkel, recently told Vantage that he hoped that Griffin data would be sufficient for payers to include the quad in compendia and begin paying for it.

At last year's Ash meeting the partners published data from the safety run-in to the Griffin trial, showing the combo achieving a 100% very good partial response rate. There was also a strict complete response or complete response rate of 63% as assessed by investigators.

Darzalex has already won first-line US approval as part of a Velcade, melphalan and prednisone combination, for patients ineligible for stem-cell transplant. This combo is used less commonly in the US than the Revlimid and dexamethasone backbone that was the subject of the Maia trial, also in transplant-ineligible patients, showing that adding Darzalex can reduce the odds of progression or death by 44% versus Revlimid-dexamethasone alone (Ash 2018 – Survival benefit or no, Darzalex has a new use, December 4, 2018).

Earlier this week, J&J submitted Maia data to the FDA under the real-time oncology review pilot, a disclosure that the Bernstein analyst Wimal Kapadia said could result in approval by the end of the first quarter. However, with long-term funding for the agency still uncertain owing to a budget impasse between the White House and Congress, that is not at all certain.

In spite of its quick sales growth, Darzalex is one of the most controversial products in biopharma. There is scepticism as to whether consensus can be reached, and indeed the 2024 number has fallen by nearly $1bn in the past few months (The most disputed sales outlooks in biopharma, October 30, 2018).

Expanding the drug's role in front-line disease and making it more convenient for patients and physicians could help restore enthusiasm.

Study Trial ID
Griffin NCT02874742
Columba NCT03277105

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