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NOAC Reversal Agent Granted Priority Review, New Drug for Rare Type of Leukemia, and more

December 30, 2021

Dabigatran Reversal Agent Idarucizumab Granted Priority Review by the FDA

The U.S. Food and Drug Administration has granted priority review to the biologics license application (BLA) for idarucizumab, which is being investigated to specifically reverse the anticoagulant effect of dabigatran in patients needing emergency intervention or experiencing an uncontrolled or life-threatening bleeding event. The idarucizumab BLA will be reviewed under Accelerated Approval and is the first review for a reversal agent for a novel oral anticoagulant (NOAC). Currently, no NOAC has an approved reversal agent. The FDA granted Breakthrough Therapy Designation for idarucizumab in June 2014. The BLA includes phase I data demonstrating idarucizumab's potential to provide immediate reversal of the anticoagulant effect of dabigatran. In these studies, there were no clinically relevant adverse events or procoagulant effect observed after the administration of idarucizumab. Interim data from the ongoing RE-VERSE AD trial, a phase III global study investigating idarucizumab in actual clinical settings, were also included in the application.

Source: Boehringer Ingelheim press release

FDA Grants Priority Review to Brentuximab Vedotin Consolidation in Hodgkin Lymphoma

The FDA has accepted a supplemental BLA for brentuximab vedotin for post-transplant consolidation treatment of Hodgkin lymphoma patients at high risk for relapse or progression. The FDA granted Priority Review for the application, and the Prescription Drug User Fee Act (PDUFA) target action date is August 18, 2015. The BLA submission is based on positive results from the phase III AETHERA clinical trial, which determined whether 16 cycles of brentuximab vedotin as consolidation therapy immediately following an autologous stem cell transplantation (ASCT) could extend progression-free survival (PFS) in these high-risk Hodgkin lymphoma patients. The positive results from the phase III AETHERA trial were published in The Lancet in March 2015 and were presented at the 56th American Society of Hematology Annual Meeting in December 2014. In 329 patients with Hodgkin lymphoma at high risk for relapse following ASCT, brentuximab vedotin led to a significant increase in PFS – 43 months versus 24 months for patients who received placebo (hazard ratio = 0.57; p=0.001).

Source: Seattle Genetics press release

Scientists Trace Genomic Evolution  of ALL

By using genomic sequencing of leukemia cells from relapsed patients with acute lymphocytic leukemia (ALL), researchers discovered key details about how ALL cells mutate to survive chemotherapy. These findings, published in Nature Communications, will potentially lead to new tests to monitor children in remission and to detect signs of relapse. ALL is a leading cause of cancer deaths in children, with 15 percent of ALL patients relapsing with poor survival. In the study, researchers analyzed the genomes of cells from 20 children who had ALL that returned following treatment. Cell samples were taken at three stages – diagnosis, remission, and relapse – to better determine the mutations that drove the relapse of leukemia. New highly sensitive genomic analytic technologies allowed the researchers to pinpoint seven specific genes that were highly likely to be mutated in relapsed disease, as well as how diverse those mutations were at both diagnosis and relapse. Hopefully, the authors wrote, the methodology used in this pediatric study may aid in developing ways to identify drugs to target their function.

Source: Ma X, Edmonson M, Yergeau D, et al. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukemia. Nat Comm. 2015 March 19. [Epub ahead of print]

Researchers Develop New Potential Drug for Rare Leukemia

A new mixed lineage leukemia– (MLL-)menin inhibitor shows potential in laboratory studies against acute MLL. Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, from the University of Michigan Health System, Department of Pathology, developed the compound after identifying a small-molecule inhibitor that would block the interaction between the protein menin and MLL fusion proteins that cause acute MLL.

MLL represents up to 10 percent of acute leukemias in adults and about 70 percent of acute leukemias in infants. Current treatments are not very effective, with just over a third of patients surviving five years. Protein-protein interactions such as the menin-MLL fusion protein interactions in leukemia are generally considered "undruggable," meaning it can be particularly challenging to develop drugs that target those interactions, the researchers explained in their paper published in Cancer Cell. Despite the difficulty, Dr. Grembecka said that the MLL-menin interaction remained tempting: "The MLL-menin interaction is a good drug target because it's the primary driver in this type of leukemia. By blocking this interaction, it's very likely to stop the cancer." In the study, researchers tested two compounds (MI-463 and MI-503) in cell lines and in mice with MLL leukemia. The compounds blocked the MLL-menin interaction without harming normal blood cells. Both compounds were delivered into the blood and metabolized at a good rate.

Source: University of Michigan Health System press release; Borkin D, He S, Miao H, et al. Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015;27:589-602.

FDA Panel Votes in Favor of Cangrelor for Blood Clot Prevention

Cangrelor, a P2Y12 inhibitor under investigation as an antiplatelet drug for use during percutaneous coronary interventions, was recently recommended for approval by the FDA's Cardiovascular and Renal Drugs Advisory Committee. The panel voted 9-2 (with one abstention) in favor of a narrow antithrombotic indication as an adjunct to PCI for reducing risk of periprocedural ischemic complications. This was a reversal from the 2-7 vote the drug received recommending against drug approval during an initial panel meeting in February 2014. Panelists who voted in favor of approval cited a relatively small benefit with cangrelor but also a smaller risk than clopidogrel, another P2Y12 inhibitor approved for use during PCI. Several panelists expressed concerns that cangrelor's approval could change practice by giving clinicians a convenient, although no better and possibly less effective, alternative to preloading. They called for the FDA to reflect such concerns in the label if it does follow their recommendation for approval.

Source: FDA Briefing Document

FDA Strengthens Warning, Changes Prescribing Instructions for Ferumoxytol

The FDA approved the addition of a boxed warning and updated the prescribing instructions for ferumoxytol, an anemia drug approved by the agency in 2009. The action was prompted by 79 cases of anayphylactic reactions that occurred with ferumoxytol in patients with chronic kidney disease who have iron-deficiency anemia; 18 of those cases were fatal, according to data from the FDA. Forty-three percent of these patients had a medical history of drug allergy, and 24 percent had a history of multiple drug allergies. The boxed warning strengthens the existing warning that serious, potentially fatal allergic reactions that can occur with the drug and also added a new contraindication for patients who have had an allergic reaction to any IV iron replacement products. The new warning and prescribing instructions to health-care professionals include:

  • Administer IV iron products solely to patients who require IV iron therapy
  • Closely monitor patients for signs and symptoms of serious allergic reactions
  • Carefully consider the potential risks and benefits of administering ferumoxytol to elderly patients with multiple or serious medical conditions and patients who have a history of multiple drug allergies

Source: FDA press release

Response-Adapted Approach Helps Identify Hodgkin Lymphoma Patients Who Can Avoid Radiation Therapy

Results from a new randomized trial published in the New England Journal of Medicine showed that the use of a response-adapted approach to therapy led to a progression-free survival (PFS) rate of more than 90 percent in patients with early Hodgkin lymphoma. The trial investigators examined whether patients with newly diagnosed stage 1A or stage 2A Hodgkin lymphoma and negative positron emission tomography (PET) scans after receiving three cycles of ABVD chemotherapy could successfully be treated without radiation therapy – maximizing durable response while minimizing toxic effects. After a median of 60 months' follow-up, the three-year PFS rates were 94.6 percent (95% CI 91.5-97.7) for the study participants who received radiation therapy and 90.8 percent (95% CI 86.9-94.8) for those who did not. The absolute risk difference was -3.8 percentage points (95% CI −8.8-1.3). Although the results of the study did not show the noninferiority of the chemotherapy-alone group, the authors pointed out that study patients with early-stage Hodgkin lymphoma and negative PET findings experienced a good outcome either with or without consolidation radiation therapy, suggesting that radiation therapy can be avoided for patients with negative PET findings. Longer follow-up is required to determine whether PET-directed therapy can reduce the number of second cancers, cardiovascular disease, and deaths as compared with a strategy of administering consolidation radiotherapy to all patients, they added.

Source: Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med. 2015;372:1598-1607.


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