AMG-397

Nathan Stirk/Getty Images A trial assessing an experimental AstraZeneca cancer drug has been placed on clinical hold due to safety concerns. The trial pause comes two years after Amgen was also forced to pause a study of a drug within the same class. AstraZeneca quietly announced the study on clinicaltrials.gov, but did not issue any formal statement regarding the pause. The company said the trial, which assesses AZD5991 in subjects with relapsed or refractory hematologic malignancies, was paused to allow “further evaluation of safety related information.” The pause was put into place on Oct. 19, according to the site. AZD5991 is a direct inhibitor of Mcl-1, a difficult target for oncology drugs and a well-known drug-resistance driver. AstraZeneca’s experimental drug is designed to target apoptosis, which is the process of programmed cell death in hematological cancer. AstraZeneca was assessing AZD5991 in combination with Roche’s venetoclax in patients with relapsed or refractory acute myeloid leukemia (AML), as well as a monotherapy treatment. Venetoclax, co-developed by Roche and AbbVie, is a small molecule inhibitor of the BCL-2 protein. According to multiple outlets, the trial was placed on clinical hold following signs of heart issues in one patient who received the combination treatment. In a statement sent to Fierce Biotech, the first outlet to report on the hold, the company noted “asymptomatic elevation in cardiovascular laboratory parameters.” According to the report, this occurred in an AML patient who had additional comorbidities. AstraZeneca noted there were no safety signs in individuals who received AZD5991 as a monotherapy. “It is important to note that the asymptomatic elevation has since resolved. We are now in the process of conducting a full analysis of the study data and working closely with the FDA for the benefit of the patients,” an AstraZeneca spokesperson said according to the report. The study was designed to be a three-part, open-label, non-randomized trial designed to test the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of AZD5991 alone or in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. The safety concern noted in the AstraZeneca study is similar to what Amgen faced two years ago when its study was placed on clinical hold. Earlier this year, California-based Amgen opted to scrap its study of AMG 397, an oral MCL-1 inhibitor. As BioSpace previously reported, the Amgen study was terminated to shift focus to studies of AMG 176, an intravenously dosed inhibitor of MCL-1. That asset is currently being assessed in a Phase I study for hematological malignancies.

Amgen Chief Executive Officer Bob Bradway. (Polk/Getty Images for International Medical Corps) Amgen released its fourth-quarter and full-year 2020 results today, and although there was good news financially, there was also news of five cancer programs that have either been halted or abandoned. One of the programs was the company’s BCMA BiTE (bispecific T cell engager) program for pavurutamab (AMG 701), which Amgen was developing to replace AMG 420. The company stated, “Enrollment in the Phase I study has been paused while we discuss protocol modifications to optimize safety monitoring and mitigation with the FDA. Currently enrolled patients who are demonstrating benefit may continue to receive investigational product and the Company expects to resume patient enrollment in H1 2021.” BiTE is a class of artificial bispecific monoclonal antibodies. They direct the body’s immune system, specifically the cytotoxic activity of T cells, against cancer cells. They are fusion proteins made up of two single-chain variable fragments of different antibodies. Also paused was AMG 673, a CD33-targeting BiTE for acute myelogenous leukemia (AML). They are delaying that program while they determine if AMG 330 would be a better choice. Three other programs were halted altogether. One is AMG 596, abandoned because of reprioritization of their R&D programs. The Phase I trial of AMG 397, an oral MCL-1 inhibitor, was halted to shift to intravenous MCL-1 inhibitor AMG 176, which is being evaluated in a Phase I study for hematologic malignancies. And then Imlygic (talimogene laherparepvec)’s Phase III in combination with Merck’s checkpoint inhibitor Keytruda (pembrolizumab) for melanoma—it was halted over futility. In the Q4 conference call, Chief Executive Officer Bob Bradway and R&D Chief David Reese focused on the progress of the company’s BiTE platform, despite the apparent slashing of several of its programs. “Rather than calling it targeted protein degradation, we’re describing it as our induced proximity platform,” Bradway said. “The intention there as I said, it’s just to be clear that we think the technology that we’re building can be used not just to degrade proteins, but other molecules as well. So we’re excited about it. This is as I said again in my remarks, this is a long-term research strategy and Dave and his team and I spent a lot of time with each other, trying to think about how to position for the long-term.” He then seems to hint there may be some M&A activity in their future in this area, saying, “it will be both internal and external and remind you that we acquired New Evolution now years ago for the purpose of helping to build out the set of capabilities and I would imagine, we’ll continue to look as I said, both internally and externally.” Otherwise, for the fourth quarter, Amgen reported total revenues increased 7% to $6.6 billion compared to the fourth quarter of 2019. Product sales grew 8% globally, driven by 13% volume growth across the portfolio, including Otezla (apremilast), MVASI (bevacizumab-awwb), Canjinti (trastuzumab-anns), and Repatha (evolcumab). Amgen acquired Otezla for $13.4 billion from Celgene, after Celgene was acquired by Bristol Myers Squibb and they were forced to divest the drug by the U.S. Securities and Exchange Commission (SEC). For the full year, total revenues grew 9% to $25.4 billion. GAAP earnings per share (EPS) dropped 3% to $2.76 for the fourth quarter and 4% to $12.31 for the full year, driven mostly by the Otezla acquisition, and partially offset by increased revenues. GAAP operating income for the fourth quarter decreased 2% to $2 billion and GAAP operating margin decreased 3.1% to 31.7%, also driven by amortization of intangible assets from the Otezla buy. For the full year, GAAP operating income decreased 6% to $9.1 billion. The company generated $9.9 billion of free cash flow for the full year compared to $8.5 billion in 2019. Total revenue guidance for 2021 is $25.8 billion to $26.6 billion, with EPS guidance of $12.12 to $13.17 on a GAAP basis. “In a year marked by the disruption of COVID-19, we served patients around the world without interruption, advanced our pipeline and delivered strong financial performance, all while keeping our employees safe,” Bradway said. “As we move into 2021, we look forward to commercializing our pipeline successes.” Featured Jobs on BioSpace