Kyprolis-Plus-Darzalex Boosts Amgen's Myeloma Pipeline, After MCL-1 Drugs' Clinical Holds
Executive Summary
The company's proteasome inhibitor reduced the risk of death in combination with J&J's CD38 inhibitor in a Phase III trial. A day earlier, Amgen reported clinical holds on its Phase I MCL-1 inhibitors due to cardiac safety.
Amgen Inc.'s multiple myeloma pipeline received a needed boost on 13 September when the company reported that its proteasome inhibitor Kyprolis (carfilzomib) in combination with dexamethasone and Johnson & Johnson/Genmab AS's Darzalex (daratumumab) reduced the risk of death in relapsed or refractory patients following one to three prior lines of treatment.
The company's stock closed 0.8% higher at $195.47 per share after it reported results from the Phase III CANDOR clinical trial. However, Amgen's stock fell 0.9% to $194 a day earlier when it announced plans to present data for Kyprolis and two early-stage drug candidates at the International Myeloma Workshop (IMW) between 12 and 15 September in Boston, noting that trials for the MCL-1 inhibitors AMG 397 and AMG 176 have been placed on clinical hold.
Kyprolis – purchased in the $10.4bn acquisition of Onyx Pharmaceuticals Inc. in 2013 – is Amgen's only approved drug for multiple myeloma. (Also see "Amgen buying Onyx for $10.4 billion to be bigger player in cancer therapies" - Scrip, 26 Aug, 2013.) However, the company has several high-profile development programs for the blood cancer, including the BCMA-targeting bispecific T-cell engagers (BiTEs) AMG 420 and AMG 701 and the two MCL-1 inhibitors. (Also see "ASH Preview: BCMA-Targeting CAR-Ts And Bispecifics Hog The Spotlight" - Scrip, 28 Nov, 2018.)
Amgen said in its 12 September IMW preview – which highlighted presentations for Kyprolis, AMG 420 and AMG 176 – that a Phase I dose escalation trial for the oral small molecule AMG 397 was placed on a clinical hold to evaluate a safety signal for cardiac toxicity. The company said it also instituted a voluntary hold on new patient enrollment in the Phase I trial for intravenously administered AMG 176 while the safety review for AMG 397 is ongoing.
Kyprolis Data May Hold Up Well Versus Competing PI
Things are looking much more promising for Amgen's sole commercial myeloma drug Kyprolis based on early results from CANDOR. The Phase III trial was conducted under a collaboration with J&J, which co-funded the study.
CANDOR enrolled 466 relapsed or refractory multiple myeloma patients who received one to three prior treatment regimens. The trial tested Kyprolis plus dexamethasone and Darzalex (KdD) versus Kyprolis and dexamethasone (Kd) with progression-free survival (PFS) as the primary endpoint; overall response rate, minimal residual disease and overall survival were secondary endpoints.
The company said KdD-treated patients had a 37% reduction in the risk of progression or death compared with patients who were treated with Kd (HR=0.630; p=0.0014). Median PFS hasn't been reached yet in the KdD arm of CANDOR, but it was 15.8 months in the Kd-only arm of the trial.
By comparison, Darzalex is approved in combination with the now-generic Takeda Pharmaceutical Co. Ltd. proteasome inhibitor (PI) Velcade (bortezomib) plus dexamethasone for relapsed and refractory multiple myeloma patients who have been treated with at least one prior regimen, based on the Phase III CASTOR trial. In that study, median PFS for Velcade and dexamethasone alone was 7.2 months and hadn't been reached for the three-drug regimen after a median follow-up of 7.4 months. (Also see "Expanded US Approval Set To Take Janssen’s Darzalex Higher" - Scrip, 22 Nov, 2016.)
Amgen said there was a higher frequency of adverse events in the KdD arm of CANDOR, but noted that the adverse events were consistent with the known safety profiles of the drugs evaluated in the study. Treatment-emergent adverse events observed in 20% or more of the patients treated with KdD were thrombocytopenia, anemia, diarrhea, hypertension, upper respiratory tract infection, fatigue and dyspnea.
The company plans to submit the CANDOR results for presentation at a future medical meeting and will discuss the data with health authorities in preparation for regulatory submissions.
Amgen believes that Kyprolis is a best-in-class PI and has been working to increase physician awareness of the drug, which competes with lower-cost generics to Velcade and Takeda's follow-on PI Ninlaro (ixazomib). Kyprolis sales totaled $968m in 2018, up 16% year over year, and the drug may be able to break into blockbuster territory in 2019 after generating $512m in the first half of this year.
Uncertainty About Myeloma Pipeline Setback
Multiple myeloma is an increasingly competitive indication with companies rushing programs through clinical development so that they can be first-to-market in certain new mechanisms of action, like B-cell maturation antigen (BCMA) inhibition, but Amgen is the only company in the clinic with drugs that inhibit myeloid cell leukemia sequence 1 (MCL-1). (Also see "Myeloma Milestones: Selinexor May Be Next Novel Agent While Established Drugs Expand Indications" - Scrip, 8 May, 2019.)
SVB Leerink analyst Geoff Porges pointed out in a 12 September note that MCL-1 inhibition has been associated with sudden onset heart failure in animal studies – although these were not preclinical studies conducted by Amgen.
"Preclinical research does suggest that MCL-1 activity may be required for normal cardiac myocyte mitochondrial activity; while many adverse event liabilities are acceptable for cancer medicines, sudden onset of severe heart failure is probably not," Porges wrote.
While the number of cardiac events observed in the Phase I study for AMG 397 apparently was small, the analyst noted that only a small number of patients have been treated with the drug to date. He pointed out that AMG 176 adverse events reported at IMW were largely hematologic and gastrointestinal, but a lot of side effects were reported in the interim Phase I data.
Porges reported that "treatment emergent adverse events (TEAE) ≥ grade 3 occurred in 62% (n=16) subjects despite not reaching the maximum tolerated dose (MTD); and included two fatal adverse events (AE) described as hepatic failure (considered to be related to disease progression) and tumor lysis syndrome (considered to be related to study treatment). Although no overt cardiac toxicity was disclosed, hemodynamic changes consisting of hypertension (≥ grade 3) occurred in 8% (n=2) of subjects."