Case Report: Elevated Transminases After Spinal Muscular Atrophy Treatment

Case 1

Clinical Presentation

CP, age 23 months with weight 11.9 kg, and gastrojejunal tube dependence, had elevated serum transaminases 4 weeks after treatment with 60.5 mL of onasemnogene for spinal muscular atrophy (SMA). He had received 7 doses of nusinersen between age 5 and 21 months. Elevated transaminase levels were observed during weekly monitoring, which also included metabolic panels, complete blood counts, prothrombin/partial thromboplastin times, and troponins, which were all otherwise normal. CP had a normal physical examination with no hepatomegaly or jaundice and had gained motor milestones since treatment.

Treatment

CP was treated with an increase in prednisolone to 20 mg/ day, but his transaminase levels remained elevated at week 5 (Figure Part A). He was admitted to the hospital and treated with intravenous (IV) methylprednisolone 10 mg/ kg/day for 3 days via pulsed doses. Subsequently, his transaminase levels trended downward. At discharge, he continued being treated with 20 mg/day prednisolone.

Follow-up Care

CP had an elevation of his serum transaminase levels, which spiked 2 weeks after discharge (7 weeks after onasemnogene treatment). He was treated with 1 additional pulse of IV methylprednisolone but was not admitted to the hospital, instead returning home for continued treatment with prednisolone 20 mg/day for 1 week with a plan to taper over 4 weeks as long as transaminase levels decreased. CP had gamma-glutamyl transferase (GGT) levels measured at weeks 5 and 9, which were within normal range at both timepoints.

Case 2

Clinical Presentation

HK, a female child age 9 months, weight 5.4 kg, with gastrostomy tube dependence had elevated transaminase levels approximately 3 weeks after treatment with 30.3 mL of onasemnogene. She had been diagnosed with SMA the previous week. HK’s increased transaminase levels began just as the US began experiencing the SARS-CoV-2 pandemic. She had otherwise normal laboratory testing and a normal physical examination without hepatomegaly or jaundice.

Treatment and Follow-up Care

Because HK moved out of state, making it difficult to obtain testing and modify treatment, she continued treatment with prednisolone 1 mg/kg/day. Without further intervention, her transaminase levels began to normalize (Figure Part B). HK’s prednisolone treatment was tapered after nearly 11 weeks.

Discussion

In these 2 infants with known SMA type 1 who had been treated with onasemnogene, SMA type 1 diagnosis was confirmed by the identification of biallelic pathogenic variants in survival motor neuron 1 (SMN1) with biallelic wildtype SMN2 via molecular genetic testing. Both had normal serum transaminase levels at baseline, before treatment was initiated, no history of liver disease, and adeno-associated virus 9 (AAV9) antibody titers less than 1:25. In anticipation of transaminase elevation as a possible adverse effect of treatment, both infants received oral prednisolone 1 mg/kg/day starting 1 day before infusion. Transaminase elevations, observed on weekly follow-up testing, were attributed to onasemnogene treatment. Further hepatic evaluation was considered for both children but deemed unnecessary given the normal liver synthetic function and eventual decreases in transaminases.

SMA is an autosomal recessive motor neuron disease caused by loss-of-function mutations in SMN1. SMA is characterized by progressive weakness and muscle atrophy and classified into 5 subtypes, based on age of onset and severity of weakness. The most common and severe form, SMA type 1 (Werdnig-Hoffmann disease), has typically been fatal before age 2 years.¹ Disease severity correlates with expression of SMN2 that is alternatively spliced to produce mostly protein without biologic function.² Treatment of SMA has become available in the last 4 years and is aimed at increasing expression of functional protein from either SMN1 or SMN2.

On May 24th, 2019, the Food and Drug Administration (FDA) approved the SMN1 gene replacement therapy, onasemnogene, for the treatment of children under age 2 years with SMA and documented biallelic mutations in SMN1.³ Onasemnogene is given as a single IV infusion on an AAV9 vector. In clinical trials, onasemnogene treatment resulted in survival without need of ventilatory support for 34 of 36 infants with no waning of effect over 4 years and achievement of motor milestones typically not achieved during the natural history of SMA.⁴ Serum transaminase elevation was identified as an adverse effect of treatment in the clinical studies and listed as a black-box warning, mandating liver function monitoring in infants treated with onasemnogene.⁵ Despite this designation, very little data are available regarding the extent of transaminase elevation or recommended treatment strategies. Because participants in the clinical trials were treated at the age of 8 months or less, adverse effects in children age 9 to 24 months may be particularly underreported.

A recent study of infants with SMA who met FDA treatment guidelines and subsequently received onasemnogene found a higher rate of serum transaminase elevation in children who were age 8 to 23 months at the time of treatment compared with children who were age 6 months or less.⁶ In this study, the highest peak elevation of aspartate transaminase (AST) was 1,953 IU/L, compared with an upper limit of normal (ULN) of 59 IU/L. The highest levels of alanine transaminase (ALT) were, similarly, 1,935 IU/L vs ULN 34 IU/L; the highest GGT was 376 IU/L vs ULN 77 IU/L. These maximal levels were observed in an infant age 22 months with weight 8 kg. There was no significant relationship between previous nusinersen treatment and transaminase elevation.

The cases of CP and HK demonstrate similar elevations in infants ages 9 months and 23 months. For CP, with weight 11.9 kg, maximal AST and ALT elevations were 1,389 IU/L and 2,014 IU/L, respectively. Notably, this is higher than any other ALT published after onasemnogene treatment. CP’s serum GGT level remained below the ULN but was not measured as often as AST and ALT. CP had previously received nusinersen, an antisense oligonucleotide that treats SMA by increasing translation of functional SMN protein from SMN2.⁷ Further evaluation is needed to determine if nusinersen or the newly approved SMA therapy risdiplam modulate transaminase elevation in patients receiving onasemnogene.

The optimal treatment paradigm for elevated transaminases after onasemnogene infusion is unknown, although suboptimal prednisolone treatment appears to be associated with higher elevations.^5,6 The first infant treated with onasemnogene in a clinical trial was not given prophylactic prednisolone, and at 30 days had elevated AST (861 IU/L) and ALT (1,397 IU/L). After that event, the trial protocol was amended, and all other participants received prednisolone 1 mg/kg/ day before onasemnogene infusion. Another 14 participants were enrolled and only 3 had transaminase elevations (1 with AST and ALT elevations 37 times and 35 times ULN, respectively) and were treated with additional prednisolone. Another 2 participants who had transaminase less than 10 times the upper normal limit did not receive additional prednisolone.⁵

The prescribing information for onasemnogene includes initiation of oral prednisolone 1 mg/kg/day the day before infusion and continuing for at least 1 month.³ Appropriate prednisolone administration is the key protective factor for transaminase elevation,⁶ although it remains unclear, why some infants develop such high elevations despite appropriate therapy. Clinical evidence suggests older and heavier children, who require larger absolute doses, are more likely to have significant transaminase elevations.⁶ We theorize elevations are caused by larger absolute doses with more viral vectors, which could elicit a response similar to a viral infection.⁸

In both CP and HK, described here, transaminase elevation began 3 weeks after infusion and peak AST and ALT elevations occurred 6 to 8 weeks later. Although it is not clear if additional steroid treatment is needed for those who experience severe elevations, based on limited published data and clinical experience, we propose increasing prednisolone to 2 mg/kg/day for elevations greater than 10 times ULN is a rational approach.⁶ If elevations greater than 30 times the ULN occur, pulsed methylprednisolone 10 mg/kg/day can be considered.

Summary

Development and approval of onasemnogene are major steps forward for treating SMA. Understanding potential side effects and how individuals may respond to side effects is critical as this treatment continues to be used for more infants. We report 2 cases of extreme serum transaminase elevation after onasemnogene treatment in infants more than age 8 months, despite prophylactic treatment with prednisolone. These cases add to the limited literature of transaminase elevation and its subsequent management in this age group. Larger and more systematic reports on the frequency of transaminase elevations and treatment approaches will help advance the field.