AKANTIOR 0.8 MG/ML Eye drops, solution in single-dose container

Pharmacotherapeutic group: Ophthalmologicals, other anti-infectives, ATC code: S01AX24 Acanthamoeba keratitis is a serious, progressive corneal infection characterized by intense pain, photophobia, and threat to vision.‍‍‍‍‍‍​​​‍​​​​​​ Acanthamoeba keratitis is a very rare disease primarily affecting contact lens wearers, with an incidence of 1–4 per million. Results from a cohort of 227 patients in a retrospective study showed considerable differences in patient treatment approaches; the combination of polihexanide at a concentration of 0.2 mg/ml and propamidine at a concentration of 1.0 mg/ml was used in 45 patients, and 57.8% of patients were cured within one year. Mechanism of action Pharmacodynamics were not tested in clinical trials. Polihexanide acts on both the active trophozoites and the dormant cyst forms of the protozoan Acanthamoeba. Polihexanide is a polycationic polymer composed of hexamethylene biguanide units and has a dual targeted mechanism of action involving: Disruption of cell membranes of the protozoan Acanthamoeba. Positively charged polihexanide binds to the negatively charged phospholipid bilayer of trophozoite membranes, causing membrane damage, cell lysis, and cell death through leakage of essential cellular components. Polihexanide is also capable of penetrating the ostiole of Acanthamoeba in the encysted stage and achieving the same effect. This effect has only marginal impact on neutral phospholipids in mammalian cell membranes. Binding to DNA. Once polihexanide has passed through the cell membrane, it condenses and damages the chromosomes of the protozoan Acanthamoeba. Polihexanide interacts extensively with the phosphate backbone of DNA and blocks the DNA replication process of the protozoan Acanthamoeba. This mechanism is limited to Acanthamoeba cells because polihexanide is unable to penetrate the nucleus of mammalian cells. Clinical efficacy The absolute efficacy of Akantior was determined by comparing the results obtained in a randomised, double-blind, actively controlled phase III clinical trial with historical control data from subjects who received no treatment. These subjects were identified based on a systematic review of the scientific literature (n = 56); the clinical cure rate without surgical intervention in this historical control group was 19.6% (95% CI: 10.2%; 32.4%). The remaining 80.4% of patients required surgical intervention (keratoplasty 38/56: 67.9% [48.0%; 83.0%], enucleation 4/56: 7.1% [3.0%; 18.0%], or minor surgical procedure 4/56: 7.1% [1.0%; 29.0%]). The treatment effect (percentage of patients cured without surgical intervention) of Akantior compared with no treatment (historical control) is shown in Table 2. The estimated treatment effect in the absence of treatment of 30.7% (95% CI: 14.2%; 47.2%) was also determined based on the results obtained with the chosen comparator in study 043 and the extended retrospective study published by Papa et al. 2020. By simply adding the estimated value of 30.7%, the estimated placebo effect would reach a hypothetical clinical cure rate of 50.3% (95% CI: 36.6%; 64.1%). Table 2. Absolute efficacy of Akantior Treatment Akantior + placebo No treatment Source Phase III clinical trial Historical control n 66 56 Cured 56 11 Clinical cure rate (exact binomial 95% CI) 84.8% (73.9%; 92.5%) 19.6% (10.2%; 32.4%) Clinical cure rate adjusted for the 30.7% value derived from additional studies (exact binomial 95% CI) 84.8% (73.9%; 92.5%) 50.3% (36.6%; 64.1%) Treatment effect – mean difference (exact binomial 95% CI), unadjusted 65.2% (49.3%; 77.5%) Treatment effect – mean difference (exact binomial 95% CI) adjusted based on results from additional studies 34.5% (16.8%; 49.8%) CI = confidence interval In the phase III clinical trial, polihexanide at a concentration of 0.2 mg/ml with propamidine 1 mg/ml was used as the active control. A total of 135 patients with Acanthamoeba keratitis without a history of prior anti-amoebic treatment were enrolled in this study. Subjects requiring urgent surgical intervention in either eye due to advanced Acanthamoeba keratitis (e.g., due to advanced corneal thinning/lysis) were excluded. The overall mean age was 36.5 years; 58.2% of patients were female. Four patients were aged 15–17 years and two patients were aged > 65 years. Patients were randomised 1:1 to receive Akantior with placebo (n = 69) or the combination of polihexanide at a concentration of 0.2 mg/ml with propamidine at a concentration of 1 mg/ml (n = 66). Both treatment arms followed the same dosing regimen with an intensive 19-day treatment phase (16 times daily for 5 days, 8 times daily for 7 days, 6 times daily for a further 7 days) during daytime only, followed by treatment 4 times daily until resolution of keratitis. Investigators also received instructions on when to discontinue or restart treatment (see section 4.2). Treatment was permitted for a maximum of one year. Of the 135 enrolled patients, 127 (66 patients with Akantior and 61 patients with the comparator) had a confirmed diagnosis of Acanthamoeba keratitis by in vivo confocal microscopy, PCR, or culture. The intent-to-treat (ITT) population included 127 patients and the per-protocol (PP) population included 119 subjects (62 with Akantior and 57 with the comparator). The primary efficacy endpoint was the clinical cure rate within 12 months of randomisation. Patients who required dose escalation due to disease worsening (n = 4), all in the monotherapy group, were classified as treatment failures in the primary analysis. Analyses were performed in the ITT population. Clinical cure was defined as absence of keratitis requiring treatment, no or mild conjunctivitis, absence of limbitis, scleritis, or anterior chamber inflammation, and no relapse within 30 days of discontinuation of all topical treatment administered for Acanthamoeba keratitis. The clinical cure rate observed in the study is presented in Table 3. Table 3. Primary efficacy analysis: cure rate within 12 months Treatment n Cured % cured (95% CI) Difference in proportions (95% CI) Akantior + placebo 66 56 84.8% (73.9%; 92.5%) -0.04 (-0.15; 0.08) Polihexanide 0.2 mg/ml + propamidine 1 mg/ml 61 54 88.5% (77.8%; 95.3%) CI = confidence interval The median time to cure was 140 days (95% CI: 117; 150) for polihexanide at a concentration of 0.8 mg/ml and 114 days (91; 127) in the control arm (p = 0.0442, log-rank test). A total of 2 subjects underwent corneal transplantation, both in the polihexanide 0.8 mg/ml with placebo treatment group (1 subject was classified as "corneal infiltrates" and was therefore not included in the relevant table as "corneal transplantation"). There were small differences between the treatment types in the proportion of treatment failures (subjects who withdrew early): 10/66 (15.2%) in the polihexanide 0.8 mg/ml group and 7/61 (11.5%) in the polihexanide 0.2 mg/ml with propamidine 1 mg/ml group. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Akantior in all subsets of the paediatric population with Acanthamoeba keratitis (see section 4.2 for information on paediatric use).