By Fiona Soltes
The last time Tyler Buckner, MD, gave a presentation akin to his Friday afternoon talk at this year’s NHF Bleeding Disorders Conference, emicizumab was still in clinical trials. That was back in 2017, and the now commercially available bispecific antibody has proven to be not only more effective than other treatments for those with hemophilia A and inhibitors, but also less expensive.
“That’s an unusual situation for us in medicine,†he said, “to find ourselves to have a treatment that’s better, more effective and less expensive.â€
In research—as in the rest of life—time marches on.
Buckner, a hematologist from the University of Colorado Hemophilia and Thrombosis Center, presented the session Inhibitor Treatments: Now and the Future, exploring current treatment options for those with hemophilia A and hemophilia B inhibitors; other non-bypass, non-replacement therapies in development; and approaches being taken in gene therapy.
He began with a delineation of the three main goals of treatment: treating acute bleeding events; preventing bleeds; and, if possible, getting rid of the inhibitor. Two bypass agents products currently treat bleeds: activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa); aPCC, he noted, is not always for factor IX inhibitors.
Prophylaxis, or preventing bleeds, happens with emicizumab, rFVIIa and aPCC, and sometimes giving factor VIII or factor IX is seen as prophylaxis for low-level inhibitors, as well. Getting rid of the inhibitor may involve immune tolerance induction (ITI) for severe hemophilia and immune suppression/modulation for mild to moderate hemophilia. Some mild/moderate patients also try ITI.
Naturally, there are limitations with current treatments. ITI, for example, isn’t always effective. And aPCC and rFVIIa don’t work as well as factor. Among other challenges, there’s no real way to monitor these medications. You can’t just check levels, he said, “and get a meaningful result.†There’s also a thrombosis risk when using medicines to stop bleeding.
Goals for improving treatments, then, include higher success rates with—and fewer bleeds during—ITI, as well as safer and more effective treatment overall. That means better prevention of bleeds, better treatment when a bleed happens, better control of bleeding with surgery, improved logistics, and availability of lab monitoring.
Buckner then introduced non-replacement therapies as alternatives. Factor VIII mimetics, for example, do the job of factor VIII, but don’t “look†like factor VIII to the body, so they’re not inhibited by factor VIII inhibitors. Emicizumab is one such factor VIII mimetic. Multiple clinical trials have been completed, and others are ongoing; it was approved for use for those with hemophilia A with inhibitors in 2017, and for all people with hemophilia A the following year. He was careful to note that it cannot be used to treat acute bleeding.
Clinical trial results have shown low/decreased rates of bleeding, regardless of inhibitor status, and that it was “comparable†to effective factor prophylaxis. Overall, there are very few side effects. The main thing to know, he said, is that during the first clinical trial, some blood clots occurred. As such, it’s important to avoid using aPCC with emicizumab.
Buckner also dove into rebalancing therapies, including two in clinical trials: fitusiran and concizumab. As for gene therapy, the point is to replace the missing/defective gene so the body will make factor VIII or factor IX, he said. The approach may be in vivo (in the body), in which a vector takes the gene to cells inside the body via injection, or ex vivo (outside the body) in which target cells are pulled out, modified and returned back to the body.
Two trials are now investigating in vivo gene transfer for those with hemophilia A with inhibitors; there are no gene therapy studies yet for those with hemophilia B. A third trial is exploring ex vivo gene transfer. There are, he said, many advances still to come. Those interested in being involved can search for opportunities at www.clinicaltrials.gov.
