Impact of Recombinant Replacement Therapy Detailed in Genetic Clotting Disorder

A recombinant replacement for the ADAMTS13 protein (Adzynma) missing in congenital thrombotic thrombocytopenic purpura (TTP) restored levels and reduced acute TTP events, according to interim trial data that led to FDA approval.

For the primary endpoint, no acute TTP events occurred among patients getting prophylactic ADAMTS13 compared with one case on standard therapy with plasma-derived products (mean annualized event rate 0.05) over 6 months, reported Marie Scully, MD, of University College London Hospitals, and colleagues in the New England Journal of Medicine.

Thrombocytopenia, the most common disease manifestation, was also less common with recombinant ADAMTS13 (annualized event rate 0.74 vs 1.73).

With just 30 of the randomized 48 patients having finished the trial by the time of the interim analysis and given the rarity of congenital TTP, the trial did not have sufficient power to enable statistical hypothesis testing, the researchers cautioned. They could only calculate 95% confidence intervals unadjusted for multiplicity, the width of which "should not be used to infer definitive treatment effects," they wrote.

Nevertheless, these data led to FDA approval in November 2023 for recombinant ADAMTS13 as prophylactic or on-demand enzyme replacement therapy for the extremely rare, chronic disorder that causes clotting in the small blood vessels throughout the body and can lead to severe bleeding episodes, strokes, and organ damage.

Scully's group suggested that "prophylaxis with recombinant ADAMTS13 may allow the treatment landscape for congenital TTP to evolve toward preventing long-term organ damage by minimizing the formation of platelet-rich microthrombi."

Its apparently more acceptable side-effect profile and higher average ADAMTS13 activity levels (mean 101% vs 19% with standard therapy) seen in the trial "may, in clinical practice, help expand patient access to long-term prophylaxis," they added.

ADAMTS13 replacement through prophylactic or on-demand infusions of fresh-frozen plasma, plasma treated with a solvent-detergent process, or ADAMTS13-containing plasma-derived factor VIII/von Willebrand factor concentrates relies on donor plasma given as lengthy in-hospital infusions and carries the potential for severe and treatment-limiting allergic reactions to plasma.

"Patients appreciate it -- it's much much easier for them," Spero R. Cataland, MD, of the Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute in Columbus, told MedPage Today. It's minutes versus hours for infusion, "and side effects are much better on this recombinant."

Severe adverse events occurred in 7% of patients receiving recombinant ADAMTS13 compared with 14% on standard therapy. The most common adverse events of any severity were headache, migraine, nasopharyngitis, and diarrhea.

Their phase III trial enrolled patients in two cohorts. A total of 48 patients were randomized in a crossover design to thromboprophylaxis with weekly or every-other-week IV recombinant ADAMTS13 (40 IU/kg) or investigator's choice of standard therapy with plasma-derived products. After 6 months, they switched to the other treatment for another 6 months, followed by 6 months when everyone received recombinant ADAMTS13.

An on-demand cohort of five patients who enrolled during an acute congenital TTP event were eligible to join the prophylactic cohort after resolution of the initial event, which three did.

At the interim analysis, 32 patients had completed the trial in the prophylactic cohort (all adults and adolescents) and another 14 patients (including eight younger than 12 years of age) were still underway in the trial. One adult discontinued due to a severe allergic reaction to prophylaxis with standard therapy; a second stopped after their diagnosis was confirmed as immune-mediated TTP. The trial protocol called for enrollment of only congenital TTP as confirmed by molecular genetic testing and ADAMTS13 activity of less than 10%.

Given that the disease affects only one or two persons per million, "those numbers are actually pretty good, all things considered," Cataland noted.

For the primary outcome endpoint, acute TTP events were defined as a drop in platelets by at least 50% from baseline or to a level less than 100,000 platelets/mL and either a doubling in lactate dehydrogenase or rise to more than two times the upper limit of normal. While an objective and laboratory-based definition, it was "probably conservative as compared with clinical practice and existing literature," Scully's group noted.

Among the secondary endpoints, two subacute TTP events occurred in patients while on recombinant ADAMTS13 compared with five occurring in four patients on standard therapy (raw mean annualized event rate 0.07 vs 0.25).

"When these patients have episodes, their platelet counts are dropping because they are consuming their platelets to form clots throughout the body," Cataland said. "So when you see a high platelet count, that's a good thing."

The researchers acknowledged the risk of immunogenicity with the enzyme replacement but noted no neutralizing antibodies in any patient during 12 months of prophylactic use.

"Historically, an important consideration with recombinant hematologic products has been the development of inhibitors against the product, such as factor VIII," they wrote. "Given these findings and the results reported here, the overall immunogenic potential for ADAMTS13 replacement in patients with congenital TTP appears to be low."

No other safety concerns emerged with recombinant ADAMTS13.

The trial's open-label design was a limitation, albeit "necessary because the substantial differences in volume between recombinant ADAMTS13 and standard therapy could not be masked," the researchers wrote. Another limitation was the lack of data on pediatric patients, for whom limited data were available because of age-staggered enrollment.

Importantly, "owing to the rarity of congenital TTP, limited available data on the natural history of the disorder, and lack of data from controlled clinical trials, our trial did not have sufficient power to detect differences between comparator groups," Scully and team wrote.

In announcing approval, drugmaker Takeda had noted that a continuation study of both the prophylactic and on-demand cohorts supported approval, although these data have not yet been published. Follow-up is planned for a total duration of approximately 6 years for a maximum of approximately 77 participants.

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