European Medicine Agency (EMA) released a direct healthcare professional communication (DHPC) pertaining to the risk of thrombotic microangiopathy (TMA) associated with Zolgensma gene therapy to bring increased awareness of TMA for patients receiving onasemnogene abeparvovec.

Zolgensma (onasemnogene abeparvovec) is a gene therapy medication used in the treatment of spinal muscular atrophy indicated for children of less than 2 years of age.

Spinal muscular atrophy is a rare genetic disease caused due to defect in the survival motor neuron (SMN) gene, which encodes the SMN protein essential for the survival of motor neurons. This disease involves deterioration of the neuromuscular functioning of the body by causing motor neurons loss and associated muscle weakness and paralysis.

Zolgensma is an adeno-associated virus (AAV) 9 based gene therapy designed to deliver a copy of the SMN1 gene to encode for human SMN protein.

In May 2019, the marketing authorisation holder for Zolgensma, Novartis availed approval from United States Food and Drug Administration (USFDA) and this medication holds PRIME and SAKIGAKE designations from EMA (Europe) and MHLW (Japan) regulatory bodies. Till date, total 800 patients were exposed to this therapy. It is one of the most expensive drug in the world, costing at 2.1 million dollars for five year therapy.

TMA is an acute and life-threatening condition characterized by thrombocytopenia, haemolytic anaemia and acute kidney injury representing a diverse group of conditions, which includes haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The incidence of TMA in children overall is estimated to be only a few cases/million/year. TMA occurs due to dysregulation and/or excessive activation of the alternative complement pathway.

Safety information from DHPC:

  • Total 5 cases were reported with TMA in patients of age 4 to 23 months age with a temporal relationship of 6-11 days after onasemnogene abeparvovec infusion with the below presented symptoms –
  • Vomiting, hypertension, oliguria/anuria, and/or oedema. Laboratory data revealed thrombocytopenia, elevated serum creatinine, proteinuria and/or hematuria, and haemolytic anaemia (decreased hemoglobin with schistocytosis on peripheral blood smear).
  • Two of the patients also had infections, and both of them had recently (within 2-3 weeks after onasemnogne abeparvovec administration) been vaccinated. Information on how to schedule administration of vaccinations with Zolgensma is described in the product information.
  • In the acute phase, all patients responded well to medical interventions including plasmapheresis, systemic corticosteroids, transfusions and supportive care.
  • Two patients underwent renal replacement therapy (haemodialysis or haemofiltration). Unfortunately, one patient who required renal replacement therapy (haemofiltration) died 6 weeks after the event. The product information for onasemnogene abeparvovec will be updated to reflect the risk of TMA, and to provide monitoring advice for timely recognition of TMA as well as advice to inform the caregivers about the need to seek urgent medical care if signs and symptoms of TMA occur.

Important information for Healthcare professionals and patient care providers

  • Performing creatinine and complete blood count (including hemoglobin and platelet count) tests before administration of onasemnogene abeparvovec in addition to the currently recommended baseline laboratory testing.
  • Close monitoring of platelet count in the week following infusion and on a regular basis afterwards.
  • In case of thrombocytopenia, further evaluation including diagnostic testing for haemolytic anaemia and renal dysfunction should be undertaken.
  • Aware of the signs & symptoms (bruises, seizures, oliguria etc.,), and If patients exhibit any symptoms or abnormal laboratory findings suggestive of TMA, direct specialist and multidisciplinary advice should be sought and TMA should be immediately managed as clinically indicated.

Voluntary ADR reporting

Every medicinal product has both benefits and risks. Medicines are authorized to market based on the favorable benefit-risk profile anticipated at the time of regulatory approval/entry into market. However, the safety profile of medicine would continuously updates owing to safety data from the postmarketing experience from public. If the rate of reporting of suspected adverse drug reactions (ADR) from public is line with the actual occurrence of ADRs, the time lapse for taking regulatory action can be reduced and thereby improving patient safety.

All health care professionals and consumers of pharmaceutical medicinal products are encouraged to be aware of this fact and observe/monitor for any possible adverse events, reactions, medication errors, or quality complaints of medicinal products and report the same to your respective national health authority.

This would accumulate safety evidence for medicinal products which in turn help health authorities to take regulatory actions at the earliest possibility for a better patient safety and overall public health.

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