Celldex: Crossing the Border Towards a Higher Status

As you would observe when reading the most recent Prohost Letters, our recent enthusiasm for Celldex Therapeutics (CLDX) emanated from its products’ combinationsc with novel immunotherapy drugs. In the past months, yesterday and today CLDX has outperformed for the same reason we mentioned in our most recent Prohost Letters. The reason for the current out-performance was the announcement that Celldex entered into a clinical trial collaboration with Roche to evaluate the safety, tolerability and preliminary efficacy of varlilumab investigational antibody, and MPDL3280A (anti-PDL1), Roche’s investigational cancer immunotherapy in a Phase 1/2 study in renal cell carcinoma.

Varlilumab and MPDL3280A are part of a new class of investigational medicines known as cancer immunotherapies that are designed to harness the body’s own immune system to fight cancer through separate yet complementary mechanisms of action that may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells.

Preclinical data were encouraging, suggesting that the combination of these two mechanisms are synergistic and may enhance anti-tumor immune response compared to either agent alone.

Celldex’s Phase 1 study of varlilumab in multiple solid tumors demonstrated promising signs of clinical activity in patients with refractory renal cell carcinoma, including a durable partial response (11.0+ months) that has continued to decrease in tumor volume over time and prolonged stable disease (4 patients with a range of 5.3 to 30.7+ months).

According to Thomas Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics, the collaboration with Roche furthers Celldex’s ongoing initiative to investigate varlilumab’s potential in combination with a broad range of mechanisms and across multiple tumor types. He reminded that Varlilumab is being already in two Phase 1/2 combination studies and expects it enter at least another four combination studies this year. This latest trial is supported by promising signs of single-agent activity observed in the drug’s Phase 1 study in patients with renal cell carcinoma.

Bottom line: Celldex believes that combining an immune activator with a checkpoint protein inhibitor in this disease setting may augment this activity and the synergy demonstrated in preclinical varlilumab/anti-PDL1 combination models provide further support for this approach.

This is typical to what many observers, including Prohost have expected. Prohost has stated the same in its most recent Prohost Letters #375 and #376.

The Agreement with Roche: Under the terms of this agreement, Roche will provide study drug and Celldex will be responsible for conducting and funding the study, which is expected to begin in 2015.

Celldex’s drug Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation.

Varlilumab induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels. It may also have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease.

No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs.

Varlilumab is currently being studied in two Phase 1/2 combination studies and several additional combination studies will be initiated in 2015.

Roche’s MPDL3280A (anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. MPDL3280A is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable restoring their ability to effectively detect and attack tumor cells.

Prohost Observation:

Since immune checkpoint protein inhibitors have been validated and some approved, oncologists recognized the fact that these products represent a new advanced era in cancer treatment, They also recognized the fact that combination drugs in immunotherapy might lead to better outcomes than using each drug alone. We appreciate the exciting news coming from Celldex, which we have the feeling that it is taking this firm into a much higher level with a much higher value.

We hope for the best.

See Prohost Letter #376 to read about more immunotherapy combinations and the firms behind them.

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