Sanofi SA's $4.8 billion bet on Nanobody developer Ablynx NV gained further validation Wednesday, with the pharma winning an FDA nod for Cablivi (caplacizumab-yhdp) in rare and sometimes fatal blood disorder acquired thrombotic thrombocytopenic purpura (aTTP). U.S. approval comes about six months after the first commercial nanobody – a single-domain antibody that offers the specificity with the advantages of a smaller-sized molecule – gained approval in Europe for the same indication. (See BioWorld, Jan. 30, 2018.)

The first product indicated specifically for aTTP, Cablivi is expected to be available in the U.S. late this quarter, according to Paris-based Sanofi, which has disclosed a U.S. list price for treating a typical aTTP episode at $270,000.

A disorder in which extensive blood clots can develop in blood vessels through the body, aTTP is estimated to effect fewer than 2,000 adults per year in the U.S., according to Sanofi. Currently available therapy usually involves plasma exchange – an often hours-long treatment – and immunosuppression, and up to 20 percent of patients die from TTP episodes. Most of those deaths occur within a month of diagnosis.

Cablivi is designed to work by neutralizing the large blood glycoprotein von Willebrand factor (vWF), which is involved in homeostasis and is critical for thrombus formation. In patients with aTTP, there is an accumulation of vWF that results in a formation of clots in the small blood vessels, causing severe thrombocytopenia, tissue ischemia and organ damage.

Upon aTTP diagnosis, administration of Cablivi should occur with the start of plasma exchange therapy, first given as an 11-mg intravenous injection prior to plasma exchange and followed by an 11-mg subcutaneous injection after completion of plasma exchange on day one. Subsequent daily 11-mg subcutaneous injections following daily plasma exchange will follow, and treatment can be further extended for up to 28 days if symptoms have not yet resolved.

In late 2017, Ablynx reported strong phase III results, showing that patients treated with caplacizumab showed a statistically significant reduction in time taken to restore platelet count (p<0.01), along with a 74 percent reduction in the percentage of patients who suffered either aTTP-related death, recurrence of an episode of aTTP, or at least one major thromboembolic event vs. placebo. Data were so promising TTP expert Marie Scully, of the University College London Hospital and study investigator, called the findings a "complete game-changer," and predicted "they will revolutionize how we manage the acute phase of the disease, which is when patients are at the highest risk for organ damage, recurrence and death." (See BioWorld, Oct. 3, 2017.)

Full results from the 145-patient trial, dubbed HERCULES, were published last month in The New England Journal of Medicine.

Cablivi received orphan and fast track designations and was evaluated under FDA priority review.

Sanofi noted that Cablivi is the first U.S. nod since it began building a rare blood disorders franchise, which also boasts approved extended half-life recombinant protein therapies, Eloctate (antihemophilic factor) and Alprolix (coagulation factor IX), for treating hemophilia A and B, respectively. Both were acquired in last year's buyout of Biogen Inc. spin-off Bioverativ Inc. for $11.6 billion. (See BioWorld, Jan. 23, 2018.)

Also in the pipeline is fitusiran, an antithrombin-targeting RNAi candidate developed by Alnylam Pharmaceuticals Inc., for which Sanofi holds global development and commercialization rights.

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