Applied Genetic Technologies Corporation encountered safety issues after increasing the dose in its pediatric gene therapy trial. After receiving treatment for rare eye diseases, 60% of subjects in the small-scale high-dose cohort were suspected to have unexpectedly severe adverse reactions (SUSAR).

The study followed a model of increasing dose and decreasing age, first gradually increasing the dose for adults and children. AGTC was given the second highest dose to children without any accidents. After safely administering the highest dose to adults, AGTC recruited five children with complete colorblindness to receive gene therapy. 

Three of the five pediatric patients who received the highest dose developed severe inflammation about a month after the administration. The researchers found that there is inflammation in both parts of the eye, and a second procedure is needed to diagnose or treat the condition, to deliver the drug into the jelly-like liquid in the eye. The fourth patient developed severe inflammation, but did not meet the SUSAR definition.

"Part of the reason for the dose escalation study is to determine whether there is a maximum tolerated dose. This is what we think we are determining here for pediatric patients. In the field of drug development, the maximum tolerated dose for pediatrics may be the same as the maximum tolerated dose for adult patients. The dosage is different, which is not surprising," CEO Sue Washer said in a conference call with investors.

Related: Biogen waives AGTC after failing trial of eye gene therapy

An analyst questioned Washer, whether it is normal for adults and children to have different maximum tolerated doses of this type of therapy. The dose of systemic gene therapy is based on the unit of the carrier genome per kilogram, which means that the weight determines the dose, but the eye outlook of AGTC is given per milliliter. Washer said there are not enough ophthalmic gene therapy data to answer the dosage question. 

AGTC is convinced that adverse events are not related to manufacturing issues because it uses the same batch to treat all patients in the study and the material has just been tested for stability. As adverse events are limited to children receiving the highest dose, AGTC is advancing.

"These new data will not change our plan to continue developing candidate products for full color blindness, because the large amount of data gives us confidence in the plan to advance with the appropriate dose," Washer said. 

AGTC is still figuring out what the road forward is like. The difference in response between adults and children at the highest dose suggests that it is possible to choose different doses for further studies in each population. But Washer said that “it’s too early to decide on the exact dosage plan,” and the AGTC is still finalizing the agreement before submitting it to the FDA.

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