Cablivi, the first nanobody-based medicine, for adults with acquired thrombotic thrombocytopenic purpura, approved by FDA

The FDA ( U.S. Food and Drug Administration ) has approved Cablivi ( Caplacizumab-yhdp ) in combination with plasma exchange and immunosuppression for the treatment of acquired thrombotic thrombocytopenic purpura ( aTTP ) in adults.
Cablivi is the first FDA approved therapy specifically indicated for the treatment of aTTP.

Caplacizumab targets von Willebrand factor ( vWF ), a protein in the blood involved in hemostasis. It is designed to inhibit the interaction between vWF and platelets.

Cablivi is an anti-vWF nanobody and is the first nanobody-based medicine to receive approval in the U.S.
Nanobodies are a novel class of proprietary therapeutic proteins based on single-domain antibody fragments that contain the unique structural and functional properties of naturally-occurring heavy chain only antibodies.

Cablivi received FDA Fast Track designation and was evaluated under Priority Review, which is reserved for medicines that represent significant improvements in safety or efficacy in treating serious conditions.

The approval of Cablivi in the U.S. is based on the results of the pivotal multicentre, randomized, double-blind, placebo-controlled phase 3 clinical study known as HERCULES.
This trial evaluated the efficacy of Caplacizumab in combination with plasma exchange and immunosuppressive therapy ( n=72 ) versus placebo, plasma exchange and immunosuppressive therapy ( n=73 ) in 145 adults experiencing an episode of aTTP.

In the HERCULES study, treatment with Caplacizumab in combination with plasma exchange and immunosuppression resulted in a significantly shorter time to platelet count response versus plasma exchange and immunosuppression alone ( hazard ratio, HR=1.55 [ 1.10; 2.20 ] p=0.01 ), the study's primary efficacy endpoint.
In secondary endpoints, Caplacizumab showed a significant reduction on a composite endpoint of aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment versus plasma exchange and immunosuppression alone ( 12.7% vs. 49.3%; p less than 0.0001 ); and a significantly lower percentage of aTTP recurrences in the overall study period versus plasma exchange and immunosuppression alone ( 13% vs. 38%; p less than 0.001 ).

In the HERCULES and TITAN ( phase 2 ) clinical trials, the most frequently reported adverse reactions were epistaxis 29%, headache 21% and gingival bleeding 16%.
In the placebo group, two deaths were reported in the TITAN study and three deaths in the HERCULES study.
No deaths were reported during the study drug treatment period in the Cablivi group in the TITAN and HERCULES studies. However, one death was reported in the HERCULES study during the treatment free follow up period, which was determined not to be Cablivi treatment related.

Cablivi should be administered upon initiation of plasma exchange therapy, based on a diagnosis of aTTP. Cablivi is first administered as an 11 mg intravenous injection prior to plasma exchange, followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1. During the daily plasma exchange period and 30 days following daily plasma exchange, patients will take daily 11 mg subcutaneous injections. If after the initial treatment symptoms of the underlying disease are unresolved the treatment can be further extended for a maximum of 28 days. Subcutaneous injection can by administered by a patient/caregiver following proper training.

aTTP is a rare, life-threatening, autoimmune blood disorder. aTTP is considered an urgent, medical emergency.
For some patients, resuscitative measures might be required and the immediate outcome might not be predictable.
In most cases, patients are routinely treated in intensive care units ( ICU ) during the first few days following their aTTP diagnosis.
It is estimated that up to 20% of patients die from TTP episodes, despite currently available treatments ( plasma exchange and immunosuppression ), with most deaths occurring within 30 days of diagnosis.
In the U.S., aTTP affects fewer than 2,000 adults each year.
In aTTP, accumulation of ultra-large vWF causes extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia, microangiopathic hemolytic anemia, and ischemia. ( Xagena )

Source: Sanofi, 2019



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