TAK-079 is an experimental, lab-generated, high-affinity antibody against a specific molecule called CD38, which is found in abundance on the surface of malignant myeloma cells and at low levels on the surface of normal immune cells, including activated natural killer (NK) cells, T- and B-cells, among others.
The second-generation anti-CD38 antibody is being investigated as a treatment for newly diagnosed and relapsed or refractory myeloma patients by Millenium Pharmaceuticals, a Takeda Oncology company. It is generally administered either as an injection into the bloodstream (intravenous) or under the skin (subcutaneous).
How TAK-079 works
Myeloma is a type of blood cancer where B-cells start to divide uncontrollably. Because myeloma cells have high levels of CD38 protein on their surface, CD38 has emerged as an important target for immunotherapy.
TAK-079 binds with great affinity to myeloma cells in the bone marrow and other organs. It is hoped that this binding will induce the cells to activate mechanisms that will initiate programmed cell death.
Moreover, TAK079-bound myeloma cells will be bound by the complement proteins or other antibodies, which will then mediate their killing through various mechanisms including phagocytosis by macrophages, a type of immune cell that “eats up” cells and then destroys them internally.
TAK-079 in clinical trials
A preliminary, randomized, double-blind, placebo-controlled study assessed the dosage and safety of single intravenous and subcutaneous injections of TAK-079 in multiple groups of healthy volunteers. The maximum dose was 0.06 mg/kg for intravenous injections and 0.6 mg/kg for subcutaneous injections. Each group included four people receiving TAK-079 and two on a placebo. Participants were monitored for 92 days after dosing.
Results presented at the American Society of Hematology (ASH) annual meeting in 2018 showed that all doses of TAK-079 were safe and well-tolerated. All adverse events reported were mild or moderate. The main clinical symptoms reported included mild fever, headache, and low blood pressure. The counts of neutrophils, lymphocytes, monocytes, red blood cells, and platelets in the blood remained within normal ranges at all doses of TAK-079.
An open-label Phase 1/2a clinical trial (NCT03439280) is now investigating the safety, tolerability, and efficacy of TAK-079 administered subcutaneously as a single agent in patients with relapsed and refractory multiple myeloma.
The goal of the Phase 1 portion of the trial is to assess the safety, tolerability, and maximum tolerated dose of TAK-079 as a monotherapy and when combined with Pomalyst (pomalidomide) and dexamethasone (PomDex). This part aims to enroll 55 participants who will receive escalating doses of TAK-079 ranging from 45 mg to 1,800 mg. TAK-079 will be injected subcutaneously once a week for eight doses followed by every other week for another eight doses, and then once a month until disease progression or unacceptable toxicity.
Phase 1 is expected to last for up to a year in each patient; they will be followed for 30 days after the last dose or until the start of subsequent alternative anti-cancer therapy, whichever comes first.
Interim results from this part of the study were presented at the ASH meeting in December 2019. A total of 31 patients received four dose regimens (45, 135, 300, and 600 mg) of TAK-079, administered subcutaneously. As of June 14, 2019, data were available for 28 patients. They showed that TAK-079’s clinical activity occurred early and was observed across all dose levels.
The most common treatment-related adverse events were fatigue and anemia. Low lymphocyte and platelet counts, infusion-related reactions, or dose-related toxicity were not reported. Among the 28 patients, 14 stopped treatment due to disease progression and one patient withdrew consent. In the remaining 14 patients who received at least four cycles of therapy by the time of the data cutoff, the clinical benefit rate (minimal response or better) was 57%. A dose of 300-mg TAK-079 achieved maximal depletion of the malignant myeloma cells in the bone marrow.
The Phase 2a portion of the study aims to enroll at least 48 participants and will study the safety and efficacy of TAK-079 as monotherapy. The study is still enrolling participants at several sites in the U.S. It is expected to be completed by December 2022.
The primary outcome measure will be the overall response rate, which is defined as the percentage of patients who show a partial or better response to treatment. Secondary outcome measures such as the number of treatment-emergent adverse events that lead to treatment discontinuation or dosage alteration, progression-free survival, and overall survival rates will also be documented.
Another open-label, multicenter Phase 1b study (NCT03984097) is aiming to enroll 36 participants across the U.S. to evaluate the recommended dose of TAK-079 in combination with standard regimens such as Revlimid (lenalidomide) plus dexamethasone (LenDex) or Velcade (bortezomib) plus Revlimid plus low-dose dexamethasone (VRd) in newly diagnosed multiple myeloma patients for whom a stem cell transplant is not planned.
Patients will be randomly assigned into two groups: TAK-079 plus LenDex or TAK-079 plus VRd. Patients will be treated for three years. The primary outcome measure is to determine the number of patients in either group with dose-limiting toxicity of TAK-079. The study will also analyze the overall response rate and the number of patients with treatment-emergent adverse events that may lead to treatment discontinuation or death.
The patients will have a follow-up 30 days after the last dose of the treatment or before the start of subsequent alternative anticancer therapy to detect any delayed side effects. This study is expected to be completed by February 2022.
Last updated: Nov. 25, 2019
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