Intravitreal injections of anti-HtrA1 well tolerated in patients with geographic atrophy
Patients treated with intravitreal injections of anti-high temperature requirement A1, a novel serine protease inhibitor, for the treatment of geographic atrophy experienced no serious study drug-related ocular or systemic adverse events.
“Single ascending dosages, as well as multiple dosages of 20 mg intravitreal anti-HtrA1, were well tolerated in patients. There were no dose-limiting toxicities observed at any level. There were no study drug-related ocular or systemic adverse events or serious adverse events observed,” Dante Pieramici, MD, said at the virtual Association for Research in Vision and Ophthalmology meeting.
Pieramici and colleagues investigated the safety and tolerability of anti-high temperature requirement A1 (anti-HtrA1) as a single intravitreal dose and multiple intravitreal doses.
All participants in the study had geographic atrophy secondary to age-related macular degeneration. The study was split into two groups, with 15 participants in a single-ascending dose (SAD) group and 13 participants in a multiple dose (MD) group. The SAD group consisted of three participants each in five dose-escalation cohorts ranging from 1 mg to 20 mg, with patients followed for 12 weeks. Participants in the MD cohort received three doses of 20 mg monthly and were followed for 20 weeks.
The doses in both the SAD and MD groups were well-tolerated, and no adverse events or serious adverse events were observed.
In the SAD group, the ocular and systemic anti-HtrA1 pharmacokinetics (PK) were consistent with other intravitreally administered antigen-bindings fragments (Fab), Pieramici said.
“We can see the levels of the drug actually remain in the aqueous and eye for a fairly long period of time, and it’s dose dependent. The half-life for vitreal elimination of anti-HtrA1 was 4.8 days. Again, the PK data seems to be consistent in the multiple dose and single dose groups to what we see in other intravitreal administered Fab,” he said.
An enzyme assay was conducted based on a pharmacodynamic assay looking at the reduction of cleaved DKK3. Pieramici said DKK3 was identified as a substrate for HtrA1, so HtrA1 cleaves DKK3 into cleaved-DKK3. The researchers assumed if HtrA1 is blocked by the anti-HtrA1 Fab, cleaved-DKK3 would also be reduced, he said.
“Enzyme activity based on pharmacodynamic assay suggests the potential for 8-week target inhibition at higher doses,” Pieramici said.
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Pieramici D. Phase 1 safety study of intravitreal anti-high temperature requirement A1 (aHtrA1), a novel serine protease inhibitor, in patients with geographic atrophy. Presented at: Association for Research in Vision and Ophthalmology annual meeting; June 12, 2020 (virtual meeting).