Unmet Need Remains in iTTP Treatment, but Caplacizumab Could Be Major Step Forward

Treatment of the ultra-rare blood clotting disorder immune-mediated thrombotic thrombocytopenic purpura (iTTP) with plasma exchange (PEX) and immunosuppression is often beneficial, but there remains a significant unmet need and a significant mortality rate.

In a new report, investigators from the United Kingdom and Scotland discussed their recommendations for diagnosing and treating patients with iTTP, and outlined the evidence for a potential new therapy for the condition, caplacizumab (Cablivi). The report was published in the journal eJHaem.

Corresponding author Marie Scully, MD, of University College London, and colleagues, wrote that only about 600 suspected cases of iTTP have been reported in the United Kingdom over the past decade.

“The rarity of the condition and its typically sudden onset make iTTP particularly challenging to manage, which can lead to fatal outcomes,” they wrote.

The new report is a modified Delphi study, based on questionnaires and interviews with a panel of 9 hematologists and one pharmacist from England and Scotland.

The blood-clotting disorder is believed to be due to a deficiency in ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) caused by an autoantibody to the enzyme, they explained. ADAMTS13 is a cleaving enzyme for von Willebrand factor, and the autoantibodies present in these patients inhibit that cleaving function, leaving von Willebrand factor to circulate and eventually cause ultra-large von Willebrand factor (ULVWF) multimers in the plasma.

“This leads to partial vessel occlusion, which can ultimately result in microangiopathic hemolytic anemia, organ ischemia, and widespread organ damage,” the authors explained.

Without intervention, only about 10% of patients will survive, the authors said. However, even with intervention, 10-20% of patients still die of the disease.

Historically, patients have been treated with PEX and immunosuppression, with the goal of removing ULVWF, replacing ADAMTS13, and preventing further autoantibody formation. Some patients who undergo the treatment will experience relapses and/or exacerbations, and others will not respond at all, the authors said.

In assessing the current unmet need, the experts said one problem is that the time it takes to achieve platelet normalization (time to platelet normalization; TTPN) with the standard therapy still leaves patients at risk of adverse outcomes, even if the treatment will eventually work. Some patients also experience long-term adverse health consequences, they said.

One potential step forward, Scully and colleagues said, is the novel therapy caplacizumab, a humanized Nanobody that binds to von Willebrand factor and inhibits platelet aggregation. Following a phase 3 study, the drug was approved by the FDA to treat acquired (immune-mediated) TTP in combination with PEX and immunosuppression, thanks to its apparent ability to prevent the formation of microthrombi and thus ischemic organ damage.

The panel of experts said the novel therapy appears to significantly reduce TTPN when added to the historic treatment regimen.

“Through a reduction of the thrombotic burden associated with an acute episode of TTP, this has the potential to prevent some of the long-term consequences of such episodes, although this requires further study and follow-up,” the authors said.

Scully and colleagues noted that a 3-year follow-up study is currently underway to better understand the long-term impact of caplacizumab therapy in patients with iTTP. They added, though, that since their original panel meetings, other studies have come out with positive results, and in December 2020, the United Kingdom’s National Institute for Health and Care Excellence recommended caplacizumab as a treatment option for acute TTP, along with PEX and immunosuppression.

Reference

Scully M, Dutt T, Lester W, et al. Unmet needs in the management of immune‐mediated thrombotic thrombocytopenic purpura and the potential role of caplacizumab in the UK—a modified‐delphi study. eJHaem. 2022. doi:10.1002/jha2.435