High-temperature requirement A1 (HtrA1) is an enzyme that may be implicated in the progression of age-related macular degeneration.1 In 2017 Genentech applied for a patent on anti-HtrA1 antibodies,2 and has pursued a clinical trial of RO7171009, an investigative intravitreal treatment that targets this novel pathway in geographic atrophy secondary to AMD.3 At the Angiogenesis, Exudation and Degeneration 2020 meeting last month in Miami, principal investigator Vrinda Hershberger, MD, PhD, of Florida Eye Associates in Melbourne, reported on a Phase I trial in which anti-HtrA1 was well tolerated and showed pharmacodynamic assay results relating to drug activity in patients with GA.
HtrA1 is a trimeric serine protease that’s widely expressed in the retina, and the ARMS2/HtrA1locus has a compelling genetic association with AMD. When targeted with the anti-HtrA1 antibody, a Fab of humanized monoclonal antibody, HtrA1 forms a cage-like inhibition complex, as the Genentech developers described.1
The Phase I open-label trial in GA reported no ocular or systemic adverse events in the 28 patients dosed, and showed a potential for eight-week target inhibition at the maximum 20-mg dose, Dr. Hershberger reported at the conference. Now the Phase II GALLEGO trial of 285 patients with GA is enrolling.4 It has a primary completion date of March 2022. Here, Dr. Hershberger answers questions about the clinical trials and describes how the drug candidate works.
Q. Describe the mechanism of action of anti-HtrA1 in your own words.
Let’s start with the therapeutic hypothesis for targeting HtrA1. HtrA1 induces breakdown and elimination of the extracellular matrix protein, resulting in atrophy of the photoreceptors, retinal pigment epithelium and Bruch membrane choroid. HtrA1 may also affect the visual cycle, as well as the stability of proteins required for photoreceptor and RPE cell survival.
We also know that in the human retina, HtrA1 expression is increased in the area perilesional to the GA. Mice overexpressing human HtrA1 have thinner retinas and decreased electroretinography activity compared to wild-type mice. So, Genentech has developed the anti-HtrA1 antigen-binding fragment that’s a potent inhibitor of HtrA1 activity, with the hypothesis that inhibiting HtRA1 may slow the progression of lesion growth in GA.
Q. What’s the significance of targeting ARMS2/HtrA1 loci?
Human genetics highlights pathways important for AMD pathogenesis. Several genetic studies over the past 20 years have shown the ARMS2/HtrA1
locus is one of the strongest genetic factors for risk of advanced AMD. Furthermore, the ARMS2/HtrA1 risk variants are associated with progression from intermediate to advanced AMD and with increased lesion growth rates in geographic atrophy.
Q. What are the key findings from the Phase I open-label trial?
The primary objectives of the study were to investigate the ocular and systemic safety and tolerability of anti-HtrA1 following single and multiple intravitreal doses. Another objective was to determine the maximum-tolerated dose of anti-HtrA1 administered as a single dose and as multiple intravitreal doses.
The study found that the intravitreal-administered anti-HtrA1 as single doses (ranging from 1 to 20 mg) as well as multiple doses of 20 mg administered every four weeks over 12 weeks were well-tolerated. The study found no dose-limiting toxicities, ocular serious adverse events or systemic or ocular AEs.
Q. How did the trial evaluate the drug activity?
This study design incorporated mandatory aqueous humor sampling. Not only did this allow for evaluation of drug concentration and elimination, but because of a novel enzyme-activity-based pharmacodynamic (PD) assay, the study was able to evaluate actual drug activity. The aqueous humor samples were analyzed for cleaved-DKK3, which is produced by cleavage of DKK3 by HTra1. In the presence of the anti-HTRA1 antibody, cleaved-DKK3 levels drop. Dose-dependent duration of reduction of cleaved-DKK3 was seen in the single-ascending-dose cohort, with the higher doses showing eight-week inhibition. Similar results were seen in the multiple dose cohort, demonstrating the direct ability to show downstream activity and duration of action of the drug.
Q. How have those findings informed the Phase II trial design?
Because we don’t know how much HtrA1 inhibition is necessary to slow progression of GA, we wanted to test the maximum-tolerated dose in the Phase I study, which was 20 mg administered every four weeks for three months. However, because decreasing frequency of intravitreal injections is very important to patients, we also decided to test the 20-mg dose every eight weeks, which was informed by the PD biomarker data.
Q. Are there any potential challenges with the Phase II trial?
This trial is unique because it uses a three-month pre-screening period. We will collect baseline images three months before the actual screening date so we can assess the actual growth rate of GA. That information will be used to stratify patients to four- or eight-week treatment arms. The prescreening increases the length of the trial. The primary endpoint is change in GA area from baseline at 72 weeks. RS
1. Ciferri C, Lipari MT, Liang WC, et al. The trimeric serine protease HtrA1 forms a cage-like inhibition complex with an anti-HtrA1 antibody. Biochem J. 2015;472:169-181.
2. Yan WU, Campagne ML, Kirchhoffer D, et al, inventors; Genentech Inc., assignee. Anti-HtrA1 antibodies and methods of use. US patent application 2017/0342163 AI. November 30, 2017.
3. Safety and tolerability study of RO7171009 in participants with geographic atrophy (GA) secondary to age-related macular degeneration. ClinicalTrials.gov identifier: NCT03295877. https://clinicaltrials.gov/ct2/show/NCT03295877 Accessed February 28, 2020.
4. A study assessing the safety, tolerability and efficacy of RO7171009 in participants with geographic atrophy secondary to age-related macular degeneration (AMD) (GALLEGO). ClinicalTrials.gov identifier: NCT03972709. https://clinicaltrials.gov/ct2/show/NCT03972709 Accessed February 28, 2020.