According to fiercebiotech.com

Applied Genetic Technologies Corporation has run into safety problems after escalating the dose in its pediatric gene therapy trial. Sixty percent of subjects in the small high-dose cohort suffered suspected unexpected serious adverse reactions (SUSARs) after being treated for a rare eye disease.

The study followed a dose escalation and age de-escalation model, giving progressively higher doses first to adults and then to children. AGTC gave the second highest dose to children without incident. After safely dosing adults with the highest dose, which was around threefold higher than the next rung down, AGTC enrolled five kids with total color blindness to receive the gene therapy.

Three of the five pediatric patients who received the highest dose developed severe inflammation around one month after dosing. Investigators saw inflammation in both segments of the eye and needed to perform a second procedure to diagnose or treat the condition with medications delivered to the jellylike fluid inside the eye. A fourth patient developed significant inflammation but didn’t meet the SUSAR definition.

“Part of the reason to do a dose escalating study is to identify if there is a maximum tolerated dose. That’s exactly what we think we’ve identified here for pediatric patients. And it shouldn’t be all that surprising in the realm of drug development that a maximum tolerated dose for pediatrics might be different than a maximum tolerated dose for adult patients,” CEO Sue Washer said on a conference call with investors.

One analyst questioned Washer about whether it is normal for adults and children to have different maximum tolerated doses for such therapies. Systemic gene therapies are dosed in vector genomes per kilogram, meaning body weight dictates dose, but AGTC’s ocular prospect is given per milliliter. Washer said there aren't enough ophthalmology gene therapy data to answer the dosing question.

AGTC is confident the adverse events aren’t related to a manufacturing problem, because it used the same lot to treat all patients in the study, and the material had just undergone a stability test. With the adverse events limited to children who received the highest dose, AGTC is pushing ahead.

“These new data do not change our plans to continue development of the achromatopsia product candidates as the body of data gives us confidence in our plan to move forward at appropriate doses,” Washer said.

AGTC is still figuring out exactly what the path forward looks like. The divergence in responses in adults and children at the highest dose points to the potential to choose different doses for further study in each population. But Washer said “it’s premature to decide on the exact dosing plan” while AGTC is still finalizing the protocol ahead of submission to the FDA.