Astellas’s gene therapy aspirations crumble

AT132 has prompted more safety concerns, this time at a lower dose than before.

A year ago Astellas disclosed that a third patient in the Aspiro trial of its rare paediatric disease gene therapy AT132 had died. Today the group said it had paused Aspiro after another serious adverse event. 

The recurrent safety signals with this project suggest that Astellas’s $3bn acquisition of its originator, Audentes Therapeutics, might not have been the wisest strategic decision. This is arguably borne out by the fact that of the 10 assets under development by Audentes at the time of the takeout in 2019 only two remain in Astellas’s pipeline today – one of which is the now possibly doomed AT132.

Aspiro is evaluating AT132 in X-linked myotubular myopathy (XLMTM), a condition that causes extreme muscle weakness and respiratory failure; half of all patients die before they reach 18 months of age. AT132 is an AAV8 vector containing a functional copy of the MTM1 gene, mutations in which cause the disease.

Stop, start, stop

Today Astellas said it had paused the study after abnormal liver function was seen in one of the subjects in the weeks following administration of AT132. The FDA had put AT132 on hold in response to the earlier fatalities but has not done so again, though it might yet do so.

Perhaps worryingly, the patient was on the lower dose in the trial, 1.3x1014vg/kg. The three trial deaths, which were caused by liver failure, occurred in patients given the higher dose, 3.5x1014vg/kg. One of the conditions the FDA required to lift its earlier clinical hold was that future dosing would be at the lower, 1.3x1014vg/kg level. 

So far 24 Aspiro participants have been treated, seven at the low dose and 17 at the high level. The patient who suffered the more recent adverse event was treated after the clinical hold was lifted last December. 

Still, even the relatively low 1.3x1014vg/kg dose is still on the high side for a gene therapy, and that might be a problem. Only a few other trials have dosed gene therapies at higher levels than Aspiro, and one of them, the Ignite DMD study of Solid Bio’s SGT-001, has been halted more than once. Another was the phase Ib trial of Pfizer's Duchenne gene therapy, PF-06939926. Dosing occurred at 1x1014 and 3x1014 vg/kg, and there were three serious adverse events.

Solid’s gene therapy, like AT-132, uses an adeno-associated virus vector, though they are slightly different, Solid’s being AAV9-based where Astellas’s project uses AAV8. Perhaps the choice of vector also contributes to any potential toxicity – though it should be noted that Novartis’s Zolgensma, also based on AAV9, tripped no alarms on safety when dosed nearly as high as AT132 in the Str1ve trial.


Of the long-term prospects for AT132 Astellas has said nothing, merely noting that it would be monitoring all the patients dosed so far for any sign of liver abnormalities. But the gene therapy appears to stand little chance of approval in the near future. 

When Astellas bought Audentes in late 2019 AT132 was expected to reach market in 2020, and the figure for 2024 sales, compiled by Evaluate Pharma from sellside forecasts, stood at $381m. Now equity analysts do not see it launched until 2023, and 2026 sales forecasts are just $91m – a number that does not take account of today’s news. 

And there is little remaining from the Audentes acquisition that might make up the shortfall. Only two Audentes-originated therapies appear in Astellas’s current pipeline, quite the step down from the 10 it obtained via the takeout (Astellas spends $3bn on a bold move into gene therapy, December 3, 2019). 

True, seven of those 10 were preclinical, and Astellas’s pipeline lists only those projects in human trials. But one or two of Audentes’ preclinical assets might be expected to have entered the clinic by now. 

Should AT132 be a write-off, the sole clinical-stage project still standing from the Audentes deal is AT845, designed to deliver a healthy copy of the gene that encodes the enzyme acid alpha-glucosidase directly to muscle cells in patients with Pompe disease. 

The phase 1 Fortis trial kicked off in April, seeking to treat eight patients at a dose of 3x1013vg/kg. This will be closely watched for any signs of toxicity. So far the sellside has declined to forecast revenues.

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