Pegylation
Pegylated compounds include polyethylene glycol, an inert polymer, covalently bound to the therapeutic protein to extend its half-life, and theoretically, reduce immunogenicity.
Many patients may already have exposure to pegylated products in the form of peginterferon to treat hepatitis C, consumer products such as toothpaste, cough medicine, and cosmetics, and, more recently, in vaccines against COVID-19.
Safety considerations with pegylated agents in hemophilia include concerns about accumulation of polyethylene glycol (PEG), although “some of the preclinical models looking at excretion of PEG are difficult to interpret in my view, and people debate about whether studies are long enough, but it’s undoubtedly the case that toxicology dosing is order of magnitude higher than the routine dosing in hemophilia,” he said.
After more than 5 years of experience with pegylated products there is no clinical evidence of concern, although “it’s not clear, actually, what we’re looking for, whether it’s a clinical parameter, or imaging or histological parameter.”
Patients may also not have lifelong exposure to pegylated products, as it is unlikely that they will stay on the same product for decades, Dr. Hart said.
Thrombosis
As of June 30, 2020, more than 7,200 persons with hemophilia have received emicizumab, and there have been 23 reported thrombotic events, 19 of which occurred in the postmarketing period. Of the reported cases, six patients had a myocardial infarction, and all of these patients had at least one cardiovascular risk factor.
The antithrombin agent fitusiran was associated with one fatal thrombotic event in a phase 2, open-label extension trial, leading to a pause and resumption with mitigation protocols, but that trial has since been paused again because of additional, nonfatal thrombotic events.
Nonfatal thrombotic events have also occurred in clinical trials for the investigational anti-TFPI monoclonal antibodies BAY 1093884 and concizumab, but none have thus far been reported in phase 3 trial of marstacimab.
“We need renewed efforts for prospective reporting and independent review of all adverse events of all agents, old and new: This will need some guidance nationally and internationally, and I think the relevant trial [serious adverse events] need to be reported in peer review literature, and clinicaltrials.gov updated in a timely manner, regardless of whether that strategy was successful or unsuccessful,” Dr. Hart said.
Risk with longer-acting agents?
In the question and answer following his presentation, Christoph Königs, MD, PhD, from University Hospital Frankfurt, asked whether there was potential for increased thrombosis risk with second-generation extended half-life (EHL) molecules in clinical trials.
“As we edge towards normalization of hemostasis, clearly the other non–hemophilia dependent issues of thrombosis risk come into play,” Dr. Hart acknowledged. “I think it will be an inevitability that there will be events, and we need to understand what the denominators are – hence my pitch for there being a renewed effort to try and collate sufficient data that we can really define events happening with people treated with standard half-life [products] through into the novel agents,” he said.
Dr. Hart disclosed grant/research support and speaker bureau activities for Bayer, Octapharma, Takeda, and others. Dr. Königs has reported no relevant disclosures.