DRUG INFORMATION
ADAMTS13, recombinant-krhn (Adzynma), is a human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) indicated for prophylactic or on-demand enzyme replacement therapy (ERT) in adult and pediatric individuals with congenital thrombotic thrombocytopenic purpura (cTTP).
CONGENITAL ADAMTS13 DEFICIENCY
cTTP is an autosomal recessive disorder caused by biallelic mutations on the ADAMTS13 gene. It is characterized by less than 10% ADAMTS13 enzyme activity and the accumulation of ultra-large von Willebrand factor (VWF). The buildup of ultra-large VWF multimers leads to uncontrolled platelet aggregation, platelet adhesion, and abnormal clotting in the small blood vessels. cTTP often causes seemingly mild and nonspecific symptoms such as lethargy, headache, loss of concentration, and abdominal discomfort.
ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene.
cTTP is a rare blood disorder characterized by blood clotting due to a deficiency in the enzyme ADAMTS13, affecting fewer than 1000 people in the United States. Most common presentation of cTTP are thrombocytopenia, microangiopathic hemolytic anemia, headaches, and abdominal pain. Mortality of acute TTP events can reach 90% or higher if the disease is left untreated. Treatment has normally included prophylactic plasma-based therapy.
The 2020 International Society on Thrombosis and Haemostasis (ISTH) good practice statements for the clinical care of individuals with thrombotic thrombocytopenic purpura (TPP) state TTP should be considered in individuals presenting with thrombocytopenia and microangiopathic hemolytic anemia. cTTP should be suspected in individuals with any of the following presentations: severe neonatal hyperbilirubinemia, recurrent thrombocytopenia in a child or young adult, transient neurologic symptoms of stroke in a child or young adult, embolic stroke of undetermined source, or new onset TTP and absence of an ADAMTS13 inhibitor. Once suspected, individuals should be tested for decreased ADAMTS13 enzyme activity, and if the enzymatic activity is less than 10% of normal without ADAMTS13 antibodies, genetic testing showing biallelic mutations in the ADAMTS13 gene will be confirmatory of cTPP.
PEER-REVIEWED LITERATURE
SUMMARY
The safety and effectiveness of ADAMTS13, recombinant-krhn (Adzynma), were demonstrated in a global study evaluating prophylactic and on-demand ERT with ADAMTS13, recombinant-krhn (Adzynma) compared to plasma-based therapies in individuals with cTTP. The efficacy of ADAMTS13, recombinant-krhn (Adzynma) in the prophylactic treatment of individuals with cTTP was evaluated in 46 individuals who were randomly assigned to receive 6 months of treatment with either ADAMTS13, recombinant-krhn (Adzynma) or plasma-based therapies (Period 1), then crossed over to the other treatment for 6 months (Period 2). The efficacy was demonstrated based on the incidence of TTP events, and TTP manifestations, as well as the incidence of the need for supplemental doses.
The efficacy of on-demand ERT was evaluated based on the proportion of acute TTP events responding to ADAMTS13, recombinant-krhn (Adzynma) in both the prophylactic and the on-demand cohorts throughout the duration of the study. All acute and subacute TTP events resolved after treatment with either ADAMTS13, recombinant-krhn (Adzynma) or plasma-based therapies.
The most common side effects associated with ADAMTS13, recombinant-krhn (Adzynma), include headache, diarrhea, migraine, abdominal pain, nausea, upper respiratory tract infection, dizziness and vomiting. During the clinical studies, no adverse events, including allergic reactions, were observed during the administration of ADAMTS13, recombinant-krhn (Adzynma). Thirteen (one individual in Study 1 and 12 individuals in a long-term extension study) of 67 individuals treated prophylactically with ADAMTS13, recombinant-krhn (Adzynma) with confirmed cTTP tested positive for low-titer binding antibodies against ADAMTS13 with no observable clinical impact on the safety or efficacy of ADAMTS13, recombinant-krhn (Adzynma), and no increase in antibody titers over time. No individuals with cTTP tested positive for neutralizing antibodies against ADAMTS13.
The application was awarded a Rare Pediatric Disease Priority Review Voucher, and granted Priority Review, Fast Track, and Orphan designations.
OFF-LABEL INDICATIONS
There may be additional indications contained in the policy section of this document due to evaluation of criteria highlighted in the company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
