Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

Abstract

BackgroundThis study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy.MethodsImmunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE).FindingsAll patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted.InterpretationDespite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile.FundBioMarin Pharmaceutical Inc.

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“…The administered enzyme is a pegylated recombinant Anabaema variabilis phenylalanine ammonia lyase (PAL) to be administered daily. About 60% of treated patients in a phase III clinical trial achieved blood Phe ≤ 360 µM, but adverse reactions and anaphylaxis were associated with this therapy [41]. To overcome these limitations, a RBC-mediated delivery of PAL was investigated in a validated murine model of PKU [42,43].…”

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“…8 These abnormalities can include lower IQ, executive functioning deficits, and psychiatric disorders (anxiety and depression), with the incidence of deficits increasing with increased blood Phe concentration. [10][11][12] A recent US Food and Drug Administration (FDA)-approved enzyme substitution therapy (pegvaliase) for adults with uncontrolled hyperphenylalaninemia on a diet has revealed dramatic improvements in blood Phe management [13][14][15][16] but is associated with a significant incidence of immune-mediated hypersensitivity reactions against the foreign protein. Additionally, pegvaliase is not approved for use in individuals less than 18 years of age.…”

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“…Indeed, PEGylation is a commonly used strategy to extend in vivo duration of action of therapeutics protein by reducing its immunogenicity and protecting it from the inactivation by anti-drug antibodies. However, many clinical studies have demonstrated that in some cases patients can also develop anti-PEG antibodies which caused adverse reactions and anaphylaxis (Hershfield et al, 2014;Gupta et al, 2018). Differently, by delivering the therapeutic enzymes through RBCs, PEGylation step can be avoided since the foreign enzyme is confined inside the erythrocytes, allowing it to be hidden from the immunological system and thus from any neutralizing antibodies that may be present in circulation.…”