AKANTIOR Eye drops Ref.[113673] Active ingredients: Polihexanide

Pharmacotherapeutic group: Ophthalmologicals, other antiinfectives
ATC code: S01AX24

Acanthamoeba keratitis is a severe, progressive corneal infection characterized by intense pain, photophobia, and is sight threatening. Acanthamoeba keratitis is an ultra-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 indicated substantial variations in the way patients are treated; a combination of polihexanide 0.2 mg/ml and propamidine 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 the scope of clinical trials. Polihexanide acts on both the active trophozoite and dormant cystal forms of Acanthamoeba. Polihexanide is a polycationic polymer composed of hexamethylene biguanide units and has a dual-targeted mechanism of action that involves:

• Disruption of Acanthamoeba cell membranes. Polihexanide, positively charged, binds to the phospholipid bilayer of the trophozoites membrane, negatively charged, causing membrane damage, cell lysis and death due to leakage of essential cell components. Polihexanide is also able to penetrate the ostiole of the encysted Acanthamoeba to exert the same effect. This action only marginally affects the neutral phospholipids in mammalian cell membrane.
• DNA binding. Once polihexanide has passed through the cell membrane, it condenses and damages Acanthamoeba chromosomes. Polihexanide interacts extensively with the DNA phosphate backbone to block the Acanthamoeba DNA replication process. This mechanism is restricted to Acanthamoeba cells as polihexanide is unable to penetrate the nucleus of mammalian cells.

Clinical efficacy

The absolute efficacy of AKANTIOR was determined by comparing results observed in a randomised, double-blind, active-controlled phase III clinical trial with historical control data on subjects who received no treatment. These subjects were identified through a systematic literature review (n=56); the clinical resolution rate with no surgery in this historical control was 19.6% (95%CI: 10.2%, 32.4%). The remaining 80.4% of patients required surgery (keratoplasty 38/56: 67.9% [48.0%, 83.0%]), enucleation 4/56: 7.1% [3.0%, 18.0%]) or minor surgery 4/56: 7.1% [1.0%, 29.0%])).

The treatment effect (percentage of patients cured without surgery) of AKANTIOR versus absence of treatment (historical control) is shown in Table 2. A study effect of 30.7% (95%CI: 14.2%; 47.2%) was also estimated based on results observed for the chosen comparator in study 043 and the expanded retrospective study published by Papa et al. 2020. By performing a crude adjustment method of adding this estimated value of 30.7%, the estimated placebo effect would reach a hypothetical clinical resolution of 50.3% (95%CI: 36.6%; 64.1%).

Table 2. Absolute efficacy of AKANTIOR:

CI=confidence interval

The phase III clinical trial was conducted using, as active control, 0.2 mg/ml polihexanide plus 1 mg/ml propamidine. In total, 135 patients with Acanthamoeba keratitis and no history of previous anti-amoebic treatment were enrolled in this trial. Subjects requiring urgent surgical intervention for advanced Acanthamoeba keratitis in either eye (e.g., for advanced corneal thinning/melting etc.) were excluded. The overall mean age was 36.5 years; 58.2% 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 plus placebo (n=69) or a combination of polihexanide 0.2 mg/mL plus propamidine 1 mg/mL (n=66). Both treatment arms followed the same dosing regimen with an intensive 19-day treatment (16 times daily for 5 days, 8 times daily for 7 days, 6 times daily for a further 7 days) during the daytime only, followed by 4 times daily treatment until resolution of corneal inflammation. The investigators also received instructions when to stop or reinitiate treatment (see section 4.2). Treatment was allowed for a maximum of one year.

Of the 135 patients enrolled, 127 (66 AKANTIOR and 61 comparator-arm) had a confirmed diagnosis of Acanthamoeba keratitis by in vivo confocal microscopy, PCR, or culture. The intention-to-treat (ITT) population included 127 patients, and the per protocol (PP) population included 119 subjects (62 AKANTIOR and 57 comparator-arm).

The primary efficacy endpoint was the clinical resolution rate within 12 months from randomisation. Patients requiring an increase of the dose due to worsening of the condition (n=4), all of them in the monotherapy treatment group, were counted as treatment failure in the primary analysis. Analyses were performed on the ITT population.

Clinical resolution was defined as no corneal inflammation requiring treatment, no or mild conjunctival inflammation, no limbitis, scleritis or anterior chamber inflammation, and no relapse within 30 days of discontinuing all topical therapy given for Acanthamoeba keratitis. The clinical resolution rate obtained in the study is shown in Table 3.

Table 3. Primary efficacy analysis: cure rate within 12 months:

CI=confidence interval

The median time-to-cure was 140 days (95%CI=117,150) for 0.8 mg/ml polihexanide and 114 days (91,127) for the control arm (p=0.0442, log rank test).

Overall, 2 subjects had corneal transplantation, both in the 0.8 mg/ml polihexanide + placebo treatment group (1 was coded as “Corneal infiltrates” and therefore, it was not included in the respective table as “Corneal transplant”). There were small differences in the proportion of treatment failures (prematurely withdrawn subjects) between treatments: 10/66 (15.2%) in the group treated with 0.8 mg/ml polihexanide and 7/61 (11.5%) in the group treated with 0.2 mg/ml polihexanide plus 1 mg/ml propamidine.

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).