Rilzabrutinib Offers a New, Well-Tolerated Option for Patients With ITP: David Kuter, MD, DPhil

In late August, the FDA approved rilzabrutinib (Wayril; Sanofi) as a first-in-class treatment for patients with immune thrombocytopenia (ITP), a rare autoimmune disorder. The approval was supported by results from the phase 3 LUNA 3 study (NCT04562766), which evaluated the efficacy and safety of rilzabrutinib vs placebo in adults and adolescents with persistent or chronic ITP.

In this clip from an interview with The American Journal of Managed Care®, David Kuter, MD, DPhil, the lead investigator of the LUNA 3 study, shares what distinguishes rilzabrutinib, the first Bruton tyrosine kinase (BTK) inhibitor approved for ITP, from existing treatments. He also compares its safety profile with that of other ITP therapies.

Watch part 1 to learn what rilzabrutinib's approval means for patients with ITP and the challenges clinicians may face when incorporating this treatment into routine clinical practice.

This transcript has been lightly edited; captions were auto-generated.

Transcript

Rilzabrutinib is the first Bruton BTK inhibitor approved for ITP. How does its mechanism of action differ from other treatments currently available for ITP?

Other treatments for ITP include things like, 100 years ago, taking your spleen out. We still do that in some places; it is an effective therapy, but it has side effects to it, which most patients and doctors reject. The other current therapy is a thrombopoietin receptor agonist, which is a medication that makes you make more platelets and gives you good response rates in many patients.

The third is to use an older immunosuppressive drug called rituximab, which decreases your immune system, and it has a response rate of about 57% in patients who receive it. Finally, there is a newer medication called fostamatinib, which inhibits a different pathway, called the SYK [spleen tyrosine kinase] pathway, which has a response rate of some 18% but brings with it side effects of usually diarrhea and hypertension, which many patients find disconcerting. Those are the standard therapies. Some are quite effective. They all come with their own negatives.

When we come to a BTK, this is a unique pathway. Bruton kinase is part of our immune system and part of our cellular biology. It's necessary for many functions in cells. In the immune system, it's responsible for lymphocyte maturation and the production of antibodies. In the macrophage, which is the cell that chews up platelets and is a huge part of the destructive component of ITP, it makes the macrophages chew up less robustly, and hence the platelet counts are decreased to a much lesser degree. You have effects on antibody production, potentially, and effects upon destruction, so you affect both the underlying cause of the disease and also turn off how it works.

Thirdly, it has a huge effect upon your inflammatory milieu, and it decreases inflammatory responses in many different ways. That may be a mechanism by which it's improving the fatigue level. So, it has a unique pathway in affecting multiple aspects of your immune system, and hence, it is a drug that is highly adept at addressing many of the immunologic disorders, in this case, ITP, which affect humans. I think right now, it provides an interesting target, and I think it's a target that's different than other targets for similar BTK inhibitors.

As you may know, BTK inhibitors have been around for about 10 years to treat a clonal lymphocyte disorder or leukemia called chronic lymphocytic leukemia (CLL). Those BTK inhibitors, which many physicians are familiar with, are highly effective in treating chronic lymphocytic leukemia, but they carry with them baggage that we don't want to see in autoimmune diseases. The classic CLL therapies, which are BTK inhibitors, help destroy lymphocytes, but they also make the platelets not work very well and convey an increased risk of bleeding, [and] they also convey an increased risk of heart rhythm (HR) problems and an increased risk of infection.

To a general extent, and a major extent, those have been engineered out of rilzabrutinib, which does not have troubles with making platelets not work, is not associated with HR arrhythmias, and, to the extent the study [LUNA 3] was able to study this in a modest number of patients, did [not] really increase the rate of infection in this patient population. It's a nice therapy for a whole cadre of immune disorders, of which ITP is the one we studied in the study.

How does rilzabrutinib's safety profile compare with other therapies for ITP?

Major teachers in medical school taught me that all medications were poisons, and I say that tongue-in-cheek, but all medications carry with them some baggage.

The drug rituximab may decrease your antibody levels and make you more likely to have an infection, and its effect in ITP doesn't last very long. As I said, fostamatinib brings with it the lowest response rate and an increased risk of hypertension and an increased risk of diarrhea, which many patients don't like, but it's manageable in some patients.

The thrombopoietin receptor agonists bring with them a possible increased risk of thrombosis. They need to be taken every day, but that's also true of rilzabrutinib. I think rilzabrutinib's safety profile, which was something to me that was quite astounding, was a pretty well-tolerated medication for which patients did not need to stop the study because of side effects from the medication.

So, it was well tolerated, as I mentioned. But again, all medications for ITP and almost any disease, whether it be hypertension or diabetes, have side effects that one has to discuss with patients beforehand. Rilzabrutinib so far has had a very low rate of adverse complications with it.