Merck & Co. today raised the stakes for its investigational cancer immunotherapy MK-3475 by signing agreements through subsidiaries for clinical collaborations to assess the PD-1 inhibitor in combination with drugs from three biopharma giants.
Financial terms were not disclosed for the collaborations with Amgen, Incyte, and Pfizer—all of which come less than a month after Merck started a rolling submission to the FDA seeking to market MK-3475 for advanced melanoma in patients who were previously treated with ipilimumab.
The newly signed collaborations will all entail Phase I/II clinical studies focused on combinations of MK-3475 with:
- Incyte’s investigational immunotherapy agent INCB24360, an oral indoleamine dioxygenase-1 (IDO1) inhibitor, in patients with previously-treated metastatic and recurrent non-small cell lung cancer (NSCLC), among other advanced or metastatic cancers.
- Pfizer’s small molecule kinase inhibitor axitinib (Inlyta®) in patients with renal cell carcinoma (RCC), as well as the combination of MK-3475 plus Pfizer’s investigational immuno-oncology agent PF-05082566 (PF-2566) in multiple cancer types.
- Amgen’s investigational oncolytic immunotherapy talimogene laherparepvec in patients with previously untreated advanced melanoma.
The collaborations are similar to one announced by Merck in December, in which it agreed to assess the combination of MK-3475 with the GlaxoSmithKline (GSK) oral kinase inhibitor Votrient® (pazopanib) in advanced renal cell carcinoma, and study other combinations of MK-3475 and other GSK drugs. Financial terms were not disclosed.
Amgen said the MK-3475/ talimogene laherparepvec trial is planned to begin in the fall of 2014, and will consist of two parts: a Phase Ib study assessing the safety and tolerability of talimogene laherparepvec in combination with MK-3475 in patients with previously untreated, unresected, stage IIIB to IVM1a melanoma; and a Phase II study evaluating efficacy, based on the confirmed objective response rate (ORR), of talimogene laherparepvec in combination with MK-3475 versus MK-3475 alone in patients with previously untreated, unresected, stage IIIB to IVM1c melanoma.
The study will also evaluate the efficacy of treatment with talimogene laherparepvec in combination with MK-3475 following disease progression on MK-3475 alone.
Talimogene laherparepvec works through injection directly into tumor tissue, where it is intended to replicate preferentially in tumor cells causing lytic cell death and releasing an array of tumor-derived antigens. Talimogene laherparepvec is also engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), a white blood cell growth factor believed to help activate the immune system. The two mechanisms are designed to initiate a systemic antitumor immune response that targets tumor cells throughout the body.
Pfizer said that under its program with Merck, it will conduct the Phase II RCC study of MK-3475 plus Inlyta. It will also carry out a Phase I study evaluating the safety and tolerability of MK-3475 and PF-2566. PF-2566 is a fully humanized monoclonal antibody (mAb) that stimulates signaling through 4-1BB (CD-137), a protein involved in regulation of immune cell proliferation and survival.
Mace Rothenberg, M.D., svp of clinical development and medical affairs and CMO for Pfizer Oncology, noted in a company statement that over the last year, clinical data has shown promising efficacy and tolerability for emerging therapies that target the PD-1 pathway.
“These investigational therapies, which harness the body’s immune system to treat disease, may hold the greatest potential for patients with cancer when used in combination with other immuno-oncology agents, like PF-2566, to amplify antitumor immune responses, or with targeted agents, like axitinib, to optimize their effectiveness,” Dr. Rothenberg said.
Incyte’s study with Merck will consist of a Phase I portion expected to establish a recommended dose regimen of INCB24360 and MK-3475, followed by a Phase II portion in which all patients receive MK-3475 and are then randomized to receive either INCB24360 or matching placebo. The study is expected to begin in the first half of 2014 and will be conducted by Incyte, which will co-fund the study with Merck. According to Incyte, results from the study with Merck will be used to determine whether further clinical development of this combination is warranted.
Incyte said its collaboration with Merck follows preclinical studies that suggested a combination of INCB24360 and MK-3475 may enhance the antitumor immune response more than either agent alone.
“Given the synergistic activity we have seen with our IDO1 inhibitor when combined with checkpoint inhibitors in preclinical models, we look forward to working with Merck on this initial clinical collaboration,” Hervé Hoppenot, Incyte’s president and CEO, said in a company statement. “To further our understanding of the therapeutic value of our IDO1 inhibitor, we intend to establish additional clinical collaborations with other companies, cancer networks, and academia.”
In addition, Merck said it will launch a new Phase I “signal finding” study to evaluate the safety and efficacy of MK-3475 monotherapy in 20 different PD-L1-positive solid tumor types that have “not responded to current therapy, for which current therapy is not appropriate, or for which no current therapy exists,” according to Merck’s description of the trial on ClinicalTrials.gov (clinical trials identifier: NCT02054806). As of February 3, the trial was not yet open for participant recruitment.
MK-3475 is already being studied in 13 clinical trials that, according to Merck, have enrolled more than 4,000 patients and are designed to assess the compound across more than 30 types of cancer including: bladder, colorectal, gastric, head and neck, melanoma, non-small and small cell lung, renal, pancreatic, prostate, triple negative and estrogen-receptor positive HER 2-negative breast, gynecologic, and hematological malignancies.
MK-3475 is designed to restore the immune system’s natural ability to recognize and target cancer cells by selectively achieving a dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein, enabling the drug to activate the immune system’s T cells that target cancer. Last year, MK-3475 received a breakthrough therapy designation for advanced melanoma from the FDA.
Merck is counting on MK-3475 to deliver blockbuster trial results—followed, it hopes, by equally blockbuster sales—at a time when it is scrambling like other big biopharmas to recoup patent-cliff sales losses. Merck saw its GAAP earnings slide nearly 14% during the fourth quarter, to $781 million, and its earnings per share skidded 13% from 30 to 26 cents, as sales slipped 3.6% to $11.319 billion. Those numbers all reflected employee separation costs and accelerated depreciation associated with facilities to be closed or divested related to actions under the company's formal restructuring programs. Most recently, in October, the company announced plans to eliminate an additional 8,500 jobs by the end of 2015.
Aside from those expenses, net income actually rose 2.3% to $2.599 billion, with earnings per share rising from 83 to 88 cents.
The company also trumpeted strong full-year sales for several of its best-selling drugs, with the strongest performance by Gardasil, which jumped 12% (14% at constant currencies) to $1.831 billion. The company’s best seller, Januvia, racked up $4.004 billion in 2013 sales, down 2% (but up 3% in constant currencies).