Janssen Biotech, Inc. is putting its foot on the gas in the development of Genmab A/S’s anti-CD38 multiple myeloma antibody daratumumab. Although it does not yet have any final phase II data in hand, it feels sufficiently emboldened by what it’s seen so far to move the drug into an extensive-phase pivotal program.

The first phase III study will compare a regimen comprising daratumumab in combinatino with Revlimid (lenalidomide) and dexamethasone (Len/Dex) vs. Len/Dex alone. The trial will recruit about 500 patients with relapsed or refractory multiple myeloma.

“It’s a confirmation of the belief we and Janssen Biotech have in the potential of daratumumab,” Jan van de Winkel, CEO of Copenhagen-based Genmab, told BioWorld Today. “Multiple pivotal studies have been planned already.”

Several of them could get under way later this year. Positive data from four small-scale phase Ib studies testing the safety of different daratumumab-based combinations could swiftly trigger further efficacy trials. Those include daratumumab in combination with: Velcade (bortezomib, Millennium: The Takeda Oncology Co.), a proteasome inhibitor, plus the steroid dexamethasone; Velcade plus the alkylating agent melphalan, plus the steroid prednisone; Velcade plus the immunomodulatory agent thalidomide plus dexamethasone; and Pomalyst (pomalidomide, Celgene Corp.), a second-generation immunomodulator, plus dexamethasone.

In all, some 3,500 patients could be recruited into the phase III program. “This is one of the molecules which has unqualified support at Janssen Biotech right now,” van de Winkel said. Peter Lebowitz, Janssen Biotech’s head of oncology, will lead the program, fresh from completing the development of Imbruvica (ibrutinib), the first-in-class Bruton’s tyrosine kinase inhibitor recently approved in mantle cell lymphoma and chronic lymphocytic leukemia.

Janssen, a subsidiary of New Brunswick, N.J.-based Johnson & Johnson Co., and Genmab want to position daratumumab, which has shown strong activity as a monotherapy, as part of a backbone regimen for all stages of multiple myeloma. The condition, which occurs in antibody-producing plasma cells, remains incurable, although survival times are gradually improving following the introduction of new drug classes during the past decade.

Those include proteasome inhibitors, which push myeloma cells (which have high levels of proteasome activity) into apoptosis, and immunomodulatory thalidomide analogues which, through an unknown mechanism, have antineoplastic and pro-apoptotic effects on tumor cells. Steroids are also widely used for their induction of apoptosis on immune cells, such as plasma cells.

As yet, no biologic drug has gained approval in multiple myeloma. The most advanced antibody, elotuzumab (HuLuc63), which targets the CS1 cell surface receptor, is already in phase III trials. The drug, which originated at PDL Biopharma Inc., at Redwood City, Calif., is now under the joint control of New York-based Bristol-Myers Squibb. Co., which entered a deal with PDL in 2008, and of Abbvie Inc., of Chicago, whose predecessor, Abbott, acquired PDL’s remaining interest in the drug through its 2010 acquisition of PDL spinout Facet Biotech. (See BioWorld International, Aug. 21, 2008, and March 11, 2010.)

It may gain approval ahead of daratumumab, but van de Winkel said he sees plenty of room for differentiation. “Elotuzumab has zero monotherapy efficacy,” he said. Moreover, it appears to work in synergy with some drugs – but not all. “It doesn’t work with Velcade – it works only with Revlimid,” he said. “It’s a very strange antibody actually.”

Two other anti-CD38 antibodies are in the clinic, although they are at earlier stages of development. Morphosys AG, of Martinsried, Germany, licensed MOR202 to myeloma heavyweight Celgene Corp. last year, in a deal worth up to $818 million. The drug is currently in phase I/IIa trials. SAR650984, which Paris-based Sanofi Group gained through a 2003 drug discovery collaboration with Waltham, Mass.-based Immunogen Inc., is undergoing Phase I studies. (See BioWorld Today, June 28, 2013.)

Genmab has conducted preclinical studies, which indicate daratumumab has a broader mechanism of action, van de Winkel said, better phagocytosis and complement-dependent cytotoxicity. In addition, he said, MOR202 faces an additional hurdle as it is produced in the Per.C6 cell line, now owned by Johnson & Johnson, which has yet to give rise to an approved product. “Right now nobody is using that cell line anymore,” he said. “Johnson & Johnson doesn’t really believe in Per.C6 anymore.”