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February 07, 2019 – The American Food and Drug Administration (FDA) just approved Caplacizumab-yhdp (Cablivi), the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.
aTTP is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cell count due to their breakdown, and often kidneys, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur.
In about half of cases a trigger is identified, while in the remainder the cause remains unknown. Known triggers include bacterial infections, certain medications, autoimmune diseases such as lupus, and pregnancy. Moreover, patients can develop aTTP because of conditions such as cancer, HIV, or after having surgery, bone marrow transplantation or chemotherapy. The underlying mechanism typically involves antibodies inhibiting the enzyme ADAMTS13, the von Willebrand factor-cleaving protease (VWFCP ). This results in decreased break down of large multimers of von Willebrand factor (vWF) into smaller units. Less commonly TTP is inherited from a person’s parents, known as Upshaw–Schulman syndrome, such that ADAMTS13 dysfunction is present from birth. Diagnosis is typically based on symptoms and blood tests. It may be supported by measuring activity of or antibodies against ADAMTS13. About 1 per 100,000 people are affected. Onset is typically in adulthood and women are more often affected.
With plasma exchange the risk of death has decreased from more than 90% to less than 20%. However, plasma exchange is an ordeal in its own right. Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, such as glucocorticoids and rituximab, many patients will have a recurrence of aTTP.
Caplacizumab-yhdp (Cablivi) is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences. Caplacizumab-yhdp (Cablivi) is a bivalent VHH designed an an anti-von Willebrand factor humanized immunoglobulin. It acts by blocking platelet aggregation to reduce organ injury due to ischemia.
The efficacy of Caplacizumab-yhdp (Cablivi) was studied in a clinical trial of 145 patients who were randomized to receive either Caplacizumab-yhdp (Cablivi) or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Caplacizumab-yhdp (Cablivi), compared to placebo. Treatment with Caplacizumab-yhdp (Cablivi) also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Caplacizumab-yhdp (Cablivi) group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.
Common side effects of Caplacizumab-yhdp (Cablivi) reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Caplacizumab-yhdp (Cablivi) includes a warning to advise health care providers and patients about the risk of severe bleeding. Health care providers are advised to monitor patients closely for bleeding when administering Caplacizumab-yhdp (Cablivi) to patients who currently take anticoagulants.
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