Despite their similar functions, each current and emerging therapy for treating hemophilia has a unique safety profile, and each needs to be weighed apart from agents both within and outside its pharmacologic class, a hemophilia specialist said.
“My view is that each new molecule coming to the hemophilia space, including variant factor molecules, needs to be scrutinized separately, without class assumptions or extrapolations, and it’s clear that thrombosis risk has become a priority safety consideration,” said Dan Hart, MBChB, MRCP, FRCPath, PhD, from Barts and the London School of Medicine and Dentistry.
He reviewed the comparative safety of standard and novel therapies for hemophilia at the annual congress of the European Association for Haemophilia and Allied Disorders.
Factor inhibitors
Inhibitors occur in both hemophilia A and hemophilia B, and are primarily seen in patients with childhood exposure to factor concentrates. Inhibitors, which include anti–factor VIII and factor IX alloantibodies, are more common among patients with severe hemophilia and those with more disruptive factor VIII and factor IX mutations.
“There can be transient vs. persistent inhibitors, and arguably the more you look, the more you find, but clinically we never miss high-titer inhibitors that have a big impact on individuals and the subsequent decisions about management,” he said.
Hamster vs. human
It’s currently unclear whether there is an immunologic advantage for previously untreated patients to be started on factor VIII concentrates derived from recombinant human cells lines, or from products derived from Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines, Dr. Hart said.
“We need to ensure that we’re not selective about comparator choice for new products in the absence of head-to-head studies,” he said.
Route of administration matters
Inhibitors appear to be a more common occurrence among patients who received factor concentrates subcutaneously, compared with intravenously, Dr. Hart noted, pointing to a 2011 study indicating a background annual risk of 5 cases of inhibitor development per 1,000 treatment years in previously treated patients who received intravenous therapy (Blood. 2011 Jun 9;117[23]:6367-70).
In contrast, in a phase 1 trial of subcutaneous turoctocog alfa pegol, 5 out of 26 patients had detectable N8-GP–binding antibodies after 42-91 exposure days. Of these patients, one developed an inhibitor to factor VIII, and anti–N8-GP antibody appearance was associated with a decline in factor VIII plasma activity in four of the five patients. In addition, five patients reported a total of nine bleeding episodes requiring treatment during prophylaxis. As a result of this trial, further clinical development of the subcutaneous version was suspended. (J Thromb Haemost. 2020 Feb;18[2]:341-51).
Other subcutaneously administered factors are currently in development, Dr. Hart noted.
Nonfactor inhibitors?
“The nonfactor agents do have the risk of generating antibodies: Monoclonal antibodies outside the hemophilia setting provoke antidrug antibodies,” he said.
Although there is no consensus regarding which assay can best monitor antidrug antibodies (ADA), enzyme-linked immunosorbent assay (ELISA) can detect neutralizing antibodies and other antibodies.
In the hemophilia setting, surrogate markers for loss of drug efficacy include longer activated partial thromboplastin time (ATTP) or a drop in serum drug levels. Worsening bleeding phenotype can also be a marker for loss of efficacy, albeit an imperfect one.
Emicizumab (Hemlibara), the first nonfactor monoclonal agent to make it to market, has the largest dataset available, and evidence suggests a rate of neutralizing antibodies with this agent of less than 1% in the HAVEN clinical trial series, but 5.2% in the single-arm STASEY trial.
“We shouldn’t assume that other biophenotypics will have a similar ADA rate, and this needs to be evaluated for each molecule, as it will need to be for other monoclonals” such as anti–tissue factor pathway (TFPI) antibodies, Dr. Hart emphasized.