Phase IIa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation

Abstract

BackgroundGingivitis and periodontitis are prevalent inflammatory diseases of the periodontal tissues. Current treatments are often ineffective or do not prevent disease recurrence. Uncontrolled complement activation and the resulting chronic gingival inflammation are hallmarks of periodontal diseases. We determined the efficacy and safety of a complement 3-targeted therapeutic, AMY-101, which was locally administered to adult patients with periodontal inflammation.MethodsThirty-two patients with gingival inflammation were enrolled in a randomized, placebo-controlled, double-blind, split-mouth phase IIa trial that followed a dose escalation study to select a safe and effective dose in an additional 8 patients. Half of the patient's mouth was randomly assigned to AMY-101 (0.1 mg/site) or placebo injections at sites of inflammation, administered on days 0, 7, and 14, and then evaluated for safety and efficacy outcomes on days 28, 60, and 90. The primary efficacy outcome was a change in gingival inflammation, measured by a modified gingival index (MGI), and secondary outcomes included changes in bleeding on probing (BOP), the amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days.ResultsA once-weekly intragingival injection of AMY-101 for 3 weeks was safe and well tolerated in all participants and resulted in significant (P < 0.001) reductions in clinical indices measuring gingival inflammation (MGI and BOP). AMY-101 significantly (P < 0.05) reduced MMP-8 and MMP-9 levels, indicators of inflammatory tissue destruction. These therapeutic effects persisted for at least 3 months after treatment.ConclusionAMY-101 treatment resulted in a significant and sustainable reduction in gingival inflammation without adverse events and, we believe, merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions.Trial registrationClinicalTrials.gov identifier NCT03694444.FundingAmyndas Pharmaceuticals.

Keywords: Clinical Trials; Complement; Drug therapy; Immunology.

Conflict of interest statement

Conflict of interest: JDL is the founder of Amyndas Pharmaceuticals, which develops complement inhibitors (including third-generation compstatin analogs such as AMY-101). JDL is an inventor on patents and patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which were clinically developed by Amyndas Pharmaceuticals (“Compstatin Analogs with Increased Solubility and Improved Pharmacokinetic Properties,” patent no. 10,800,812; “Compstatin Analogs with Improved Pharmacokinetic Properties,” patent no. 10745442; “Modified Compstatin with Peptide Backbone and C-Terminal Modifications,” patent no. 8946145). JDL and GH are inventors on a joint patent that describes the use of complement inhibitors for therapeutic purposes in periodontitis (“Methods of Treating or Preventing Periodontitis and Diseases Associated with Periodontitis,” patent no. 10,668,135). JDL is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals [i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan (Empaveli). “Compstatin Analogs with Improved Activity,” US patent no. 7989589; “Peptides which Inhibit Complement Activation,” patent no. 6319897; “Potent Compstatin Analogs,” patent no. 7888323]. DY is the managing director of Amyndas Pharmaceuticals, the sponsor of this study.

Figures

Figure 1. CONSORT diagram.

CONSORT subject flow diagram shows the number of subjects screened, enrolled/randomized, and included in the interim, primary safety, and secondary efficacy analyses. Of the 98 patients screened, 40 were found eligible, agreed to participate, and enrolled in the study. The first 12 subjects were randomized into 3 escalating dose groups (dose group 1, dose group 2, and dose group 3; 4 individuals/group). After selection of the dose of 0.1 mg/interdental papilla, 28 more individuals (total of 32) were randomized to the main study group (orange shaded boxes) and treated split-mouth with AMY-101 at 0.1 mg/interdental papilla and placebo (saline) injections at baseline, on day 7 and on day 14, as 3 once-weekly injections. The safety population included all participants (n = 40) treated with at least 1 dose of AMY-101 or placebo, including the participants from the dose selection phase. The efficacy population included those who completed at least 1 post-baseline visit (starting on day 21) for efficacy analysis in the selected dose group. One participant dropped out before completing the necessary day-21 visit and was thus replaced per protocol. Red asterisk indicate that of the 31 patients treated with AMY-101 at a dose of 0.1 mg/interdental papilla and placebo, 1 failed to complete the day-90 visit; dose group 1: 0.025 mg/interdental papilla; dose group 2: 0.05 mg/interdental papilla; dose group 3: 0.1 mg/interdental papilla.

Figure 2. Change in the gingival index over time (primary efficacy endpoint) following treatment with AMY-101.

The key clinical endpoint associated with gingival inflammation was measured using the MGI, scored as 0–4 (0 = healthy; 1 = localized mild; 2 = generalized mild; 3 = moderate; 4 = severe). The change from baseline on days 21, 28, 60, and 90 was compared between treatment groups. The LSM difference, along with its SE, 95% CI, and P value, was obtained through a GEE method with a normal distribution and identity link including treatment group, study visit (days 21, 28, 60, and 90), and interaction between the treatment group and study visit as fixed effects with the baseline as a covariate. Data are presented as the LSM ± SE (n = 31). ***P < 0.001 compared with saline (placebo).

Figure 3. Change in the BOP percentage over time (secondary efficacy endpoint) following treatment with AMY-101.

Another key clinical endpoint associated with gingival inflammation, BOP, was assessed using a dichotomous measurement ( 1 = bleeding and 0 = no bleeding within 15 minutes of probing the site). Changes from baseline on days 21, 28, 60, and 90 were compared between the treatment groups. The LSM difference, along with its SE, 95% CI, and P value, was obtained using a GEE method with the normal distribution and identity link including treatment group, study visit (days 21, 28, 60, and 90), and interaction between the treatment group and study visit as fixed effects with the baseline as the covariate. Data are presented as the LSM ± SE (n = 31). ***P < 0.001 compared with saline (placebo).

Figure 4. Change in gingival inflammation following treatment with AMY-101.

Scatter plots showing the individual’s response to each treatment on day 28 (A and B) and day 90 (C and D), as measured by the MGI and BOP percentage, respectively. Each dot represents each subject treated either with AMY-101 or saline, and the bar graphs show the mean with a 95% CI (n = 31). ****P < 0.0001, by 1-way ANOVA with 95% CIs.

Figure 5. Changes in the GCF levels of MMP-8 and MMP-9 following treatment with AMY-101.

The levels of MMP-8 (A) and MMP-9 (B) were measured in the GCF from 2 separate sites on each treatment side (AMY-101 or saline) and were compared within groups (e.g., different time points after AMY-101 treatment) as well as between groups (i.e., AMY-101 vs. saline). The LSM, its 95 % CI, SE, and LSM difference, along with its SE, 95% CI, and the P value, were obtained through a GEE method with normal distribution and identity link including treatment group, study visit (day 21, day 28, day 60, and day 90), and interaction between the treatment group and study visit as fixed effects with the baseline as the covariate. Dot plots with whiskers represent individual values and the mean ± SE. Within-group comparisons were performed using repeated-measures 1-way ANOVA followed by Sidak’s multiple-comparison test. *P < 0.05, **P < 0.01, and ***P < 0.001. For baseline (day 0), day 21, and day 28, n = 62; for day 60, n = 56; and for day 90, n = 60.