Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

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Abstract

<div class="section"> <a class="named-anchor" id="d1318511e355">  </a> <h5 class="section-title" id="d1318511e356">Introduction</h5> <p id="Par1">This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. </p> </div><div class="section"> <a class="named-anchor" id="d1318511e360">  </a> <h5 class="section-title" id="d1318511e361">Objective</h5> <p id="Par2">We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. </p> </div><div class="section"> <a class="named-anchor" id="d1318511e365">  </a> <h5 class="section-title" id="d1318511e366">Methods</h5> <p id="Par3">Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, <i>n</i> = 102 patients; postmarketing surveillance, <i>n</i> = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. </p> </div><div class="section"> <a class="named-anchor" id="d1318511e376">  </a> <h5 class="section-title" id="d1318511e377">Results</h5> <p id="Par4">The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. </p> </div><div class="section"> <a class="named-anchor" id="d1318511e381">  </a> <h5 class="section-title" id="d1318511e382">Conclusions</h5> <p id="Par5">Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity. </p> </div><div class="section"> <a class="named-anchor" id="d1318511e386">  </a> <h5 class="section-title" id="d1318511e387">Supplementary Information</h5> <p id="d1318511e389">The online version contains supplementary material available at 10.1007/s40264-021-01107-6.</p> </div>

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Most cited references 33

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Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

W. Arnold, Louise Rodino‐Klapac, Thomas Prior … (2017)

Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

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Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

Catherine Manno, Glenn F. Pierce, Valder Arruda … (2006)

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

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Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN

Christian Hinderer, Nathan Katz, Elizabeth L. Buza … (2018)

Neurotropic adeno-associated virus (AAV) serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously (i.v.) at high doses. This observation led to the recent successful application of i.v. AAV9 delivery to treat infants with spinal muscular atrophy, an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons. To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, three juvenile nonhuman primates (NHPs; aged 14 months) and three piglets (aged 7-30 days) were treated with an i.v. injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the spinal muscular atrophy clinical trial. Administration of 2 × 1014 genome copies per kilogram of body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevations. In two NHPs, the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was euthanized 4 days after vector injection. Degeneration of dorsal root ganglia sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits. There was no correlation between clinical findings and T-cell responses to the vector capsid or transgene product in NHPs. Piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection, all three animals exhibited proprioceptive deficits and ataxia, which profoundly impaired ambulation and necessitated euthanasia. These clinical findings correlated with more severe dorsal root ganglia sensory neuron lesions than those observed in NHPs. The liver and sensory neuron findings appear to be a direct consequence of AAV transduction independent of an immune response to the capsid or transgene product. The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of i.v. delivery of AAV vectors at high doses, irrespective of the capsid serotype or transgene. Preclinical and clinical studies involving high systemic doses of AAV vectors should include careful monitoring for similar toxicities.