Dose escalation completed with 200 mg twice daily selected as Phase 2 dose for monotherapy and checkpoint combination trials
SAN DIEGO, May 11, 2018 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, today announced that it has dosed the first patient in the randomized portion of its Phase 2 clinical trial of eFT508, the company’s lead product candidate, in combination with avelumab*, an anti-PD-L1 checkpoint inhibitor, for the treatment of microsatellite stable colorectal cancer (MSS CRC). eFT508 is an oral, small molecule inhibitor of MNK1/2. The company also announced that it has selected 200 mg twice daily delivered orally as its dose for its Phase 2 clinical program of eFT508, both as a monotherapy and in combination with immune checkpoint inhibitors.
“We are rapidly expanding our Phase 2 program for eFT508 in a range of cancers and in combination with checkpoint inhibitors such as anti-PD-1 and anti-PD-L1,” said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. “Establishing the tolerability of eFT508 in combination with a checkpoint inhibitor at a dose that thoroughly inhibits its target is an important milestone in the development of our eFT508 combination program. Our hope is that by targeting dysregulated protein translation, which is a hallmark of a number of cancers, we will help provide new avenues for overcoming tumor resistance to existing checkpoint inhibitor therapies, such as in the treatment of MSS CRC.”
The trial, which is being conducted under a clinical collaboration and supply agreement announced in 2017 between eFFECTOR and a global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer, is designed to evaluate the antitumor activity of eFT508 in combination with avelumab versus eFT508 as a monotherapy. Patients are being randomized 2:1 between eFT508 in combination with avelumab versus eFT508 as a monotherapy, and overall response rate is the primary endpoint.
Avelumab has received accelerated approval** by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic Merkel cell carcinoma (MCC) and previously treated patients with locally advanced or metastatic urothelial carcinoma (mUC), and is under further clinical evaluation across a range of tumor types under a global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer.
*Avelumab is under clinical investigation for treatment of microsatellite stable colorectal cancer and has not been demonstrated to be safe and effective for this indication. There is no guarantee that avelumab will be approved for microsatellite stable colorectal cancer by any health authority worldwide.
eFT508 is a selective translation regulator and is part of a new class of cancer treatments known as immunotherapies that are designed to harness the body’s own immune system in fighting cancer. eFT508 is a highly potent and selective, oral inhibitor of MNK1 and MNK2. MNK1/2 are terminal kinases in key oncogenic signaling pathways, including KRAS-BRAF-MEK-ERK, and are activated by the mitogen dependent protein kinases (MAPK) in multiple immune cell types. MNK1 and MNK2 integrate MAPK pathway signaling at the level of mRNA translation, resulting in decreased anti-tumor immune activity due to selective upregulation of several immune checkpoint receptors and specific immunosuppressive cytokines. eFT508 selectively blocks MNK1/2 driven mRNA translation, thereby promoting anti-tumor immune response. In addition to the trial in MSS CRC (NCT03258398) eFT508 is also being evaluated in a Phase 1 clinical trial in patients with solid tumors (NCT02605083) and in a Phase 1/2 clinical trial in patients with lymphoma (NCT02937675).
Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models. Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.
Avelumab is currently being evaluated in the JAVELIN clinical development program, which involves at least 30 clinical programs, including nine Phase III trials, and more than 7,000 patients across more than 15 different tumor types, including gastric/gastroesophageal junction, non-small cell lung cancer, renal cell carcinoma and ovarian cancer. For a comprehensive list of all avelumab trials, please visit clinicaltrials.gov.
Approved Indications in the US**
The US Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO®) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response.
Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Important Safety Information from the US FDA Approved Label
The warnings and precautions for avelumab (BAVENCIO®) include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO for mMCC and patients with locally advanced or metastatic UC include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash.
For full prescribing information and medication guide for BAVENCIO, please see www.BAVENCIO.com.
Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US
Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer’s PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab as a monotherapy, as well as in combination regimens, and is striving to find new ways to treat cancer.
About eFFECTOR Therapeutics
eFFECTOR Therapeutics is a clinical-stage biopharmaceutical company focused on pioneering the discovery and development of selective translation regulators as a new class of oncology drugs. The company’s investigational compounds are designed to restore the translational control of processes which tumors have hijacked for their benefit, while preserving normal cell function. eFFECTOR’s most advanced program focuses on the development of eFT508, a MNK1/2 inhibitor in development for the treatment of patients with solid tumors and lymphoma. The company has additional selective translation regulator programs currently in discovery and development and maintains global rights to all of its development programs. For more information visit www.effector.com.
Robert H. Uhl
Heidi Chokeir, Ph.D.