Bristol-Myers Squibb (BMS) has quietly changed the protocol of clinical trial NCT01592370. This Phase 1 clinical trial has evolved from a nivolumab (anti-PD-1) study in hematological malignancies (5/4/14) to include ipilimumab (anti-CTLA4) with nivolumab (4/8/14) to now include nivolumab, ipilimumab and lirilumab (anti-KIR) as of 10/30/14. The changes were noted on Twitter (where else?) by several biotech experts who posted this screen shot:

The striking thing to notice is the addition of lirilumab across the board.

The clinical trial includes the following indications/inclusion criteria:

• Subjects must have histological confirmation of relapsed or refractory hematologic malignancy
• Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma must have at least one measureable lesion >1.5 cm as defined by lymphoma response criteria. Tumor sites that are considered measureable must not have received prior radiation therapy
• Subjects with Multiple Myeloma (MM) must have detectable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM,(M-protein ≥0.5 g/dl or serum IgD M-protein ≥0.05 g/dl) or serum free-light chain or 24 hour urine with free light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or non-secretory myeloma
• Subjects with Chronic myelogenous leukemia (CML) must have evidence of the Philadelphia chromosome by polymerase chain reaction (PCR) or chromosome analysis
• Life expectancy of at least 3 months
• For subjects with lymphoma, either an archived Formalin fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative studies
• Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 3 weeks (2 weeks for oral agents) prior to Day 1

The trial covers Non-Hodgkin Lymphomas (NHL), Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Acute Myelogenous Leukemia (AML), a subset of Chronic Myelogenous Leukemia (CML) and other hematologic malignancies. The requirement for biopsy tissue is to support biomarker analyses.

Lirilumab is an antibody developed by Innate Pharma (IPH.PA) that binds to the KIR2DL1, -2, and -3 receptors and prevents them from binding to HLA-C. HLA-C is a B2-microglobulin bound MHC family member with antigen presenting function. As an ancient system of antigen presentation, HLA-C is expressed on virtually all cell types. Binding of HLA-C to KIR2DL isoforms induces an inhibitory signal that prevents NK cells from engaging in cytotoxic control of tumors. By preventing KIR-mediated suppression of NK cells, lirilumab increases NK cell–mediated killing of HLA- C+ tumor cells.

Lirilumab showed signs of clinical activity in a Phase 1 trial and acceptable toxicity was observed (Vey et al. 2012. Blood 120: 4317, Vey et al. 2013. Blood. 122: 21, abstracts). A Phase II study of lirilumab in AML is in progress and combination Phase 1 trials of lirilumab in combination with ipilimumab and nivolumab for a variety of tumor types have begun. Lirilumab is also being tested in combination with the depleting antibody elotuzumab (anti-CS1) in refractory MM. The lirilumab-titled trials are listed below:

So what to make of all this activity? One reasonable conclusion is that enough data from interim analyses of the AML trials has come in to convince BMS to double-down on the partnership with IPH and move lirilumab forward aggressively. The breadth of indications is impressive. A second, related, conclusion is that preliminary data on lirilumab’s clinical activity in AML is ready for presentation at the American Society of Hematologists (ASH) Conference in December. The abstracts from that conference will come out on November 6th, so we’ll see.

There is considerable interest in combining T cell directed immune checkpoint therapeutics with those that act on NK cells. Innate Pharma (IPH.PA) has additional programs of interest in the NK cell space, including an antibody that targets MICA, a negative regulator of NKG2D-mediated activation of NK cells and an antibody that targets NKG2A, an inhibitory receptor.

The focus of this company on NK cell biology is impressive and may finally drive strong valuation. Innate has some very vocal supporters, but many investors seem reluctant to back this company. One reason perhaps is that it trades in Europe and liquidity of the corresponding US shares (OTC:IPHYF) is low. Another reason is perhaps the relationship with Novo Nordisk, which owns about 15% of company equity. From the scientific perspective the company is innovative and exciting, and I would love to have someone explain the stock valuation issues. Innate raised significant capital earlier this year with a round led by Orbimed, Redmile, FMR and about a dozen other top tier investors. An early look at AML results for ASH, or perhaps at ASCO, and strong clinical data thereafter could make many retail and institutional investors happy.

stay tuned