SIFI Reports Detailed Positive Results and New Data from the Completed Phase 3 Trial of AKANTIOR® in Patients with Acanthamoeba Keratitis presented at the American Academy of Ophthalmology Annual Meeting in Chicago

• 87% of patients receiving AKANTIOR^®  in the Phase 3 Trial were medically cured within a median duration of 4 months compared to 55% with the treatment protocols used in real-world clinical practice today.
• With the AKANTIOR^® protocol used in the Phase 3 Trial, 62% of patients achieved full vision restoration compared to 28% with the treatment protocols used in real-world clinical practice today.
• 3% of patients receiving AKANTIOR^® in the Phase 3 Trial required cornea transplant which increased to 7.6% after leaving the trial, compared to 25% or more reported in recent published literature.
• SIFI reaffirms guidance of potential regulatory approval of AKANTIOR^® by the European Commission and New Drug Application to the US Food and Drug Administration (FDA) in 2023.
• AKANTIOR^® is available via Early Access Program in the meantime.

CATANIA, Italy, Oct. 13, 2022 /PRNewswire/ -- SIFI S.p.A (SIFI or "the Company"), a leading international ophthalmic company headquartered in Italy, today reported the presentation of positive results from the positive Phase 3 Study [NCT03274895] of AKANTIOR^® (polihexanide 0.8mg/ml), an investigational anti-amoebic polymer, an orphan drug, for the treatment of acanthamoeba keratitis ("AK"). The Company also reported new data of an indirect comparison of the Phase 3 Trial with the comparable Retrospective Study. The results were presented by Professor John Dart, the Principal Investigator of the Phase 3 trial for AKANTIOR^®, at the American Academy of Ophthalmology (AAO) Annual Meeting 2022 (Jones-Smolin lecture), which occurred on October 2, 2022, in Chicago. The Company previously announced positive top-line results from the Phase 3 Trial in October 2021 after more than 15 years of research & development efforts.

The 135-patient randomised, assessor-masked, active-controlled, multiple-centre pivotal Phase 3 Trial showed 84.8% of patients on AKANTIOR^® reached a clinical resolution of acanthamoeba keratitis and associated inflammation (medical cure) within a median of 4 months of treatment vs 88.5% of the control arm of an unlicensed combination of PHMB 0.2mg/ml + propamidine 1.0mg/ml reaching the pre-defined non-inferiority primary endpoint.

The new analysis presented at the AAO showed that when corrected for risk and other potentially confounding factors – including the stage of the disease at baseline, delay in diagnosis, prior-corticosteroid use and others – the clinical resolution rate increased to 86.7% in the AKANTIOR^® arm. This compares to cure rates with unlicensed therapies of 55% as reported in a subgroup of the 227-patient real-world Retrospective Study (Papa V. British Journal of Ophthalmology 2020) of treatment protocols used in clinical practice today. Additionally, with the AKANTIOR^® protocol, 62% of patients achieved full visual acuity restoration compared to 28% with the treatment protocols used in the Retrospective Study. Similarly, the proportion of patients ending up with poor visual acuity of BCVA of less than 6/18 were decreased from 47% in the Retrospective Study to 19% with the AKANTIOR^® protocol.

Only 3% patients (2 out 66) receiving AKANTIOR^® required cornea transplant in the Phase III Trial, which increased to 7.6% (5 out 66) after leaving the trial. This compares to 25% or more as reported in the recent published literature.

The safety & tolerability profile was similar to what was seen in the previously reported Phase 1 results on healthy volunteers as well as in extensive pre-clinical and toxicology studies with only 1 patient on AKANTIOR^® failing treatment because of toxicity.

John Dart, Professor at the University College London Institute of Ophthalmology said "The medical cure rate of 86.7% for AKANTIOR^® in our Phase 3 Trial was similar for the widely used, dual agent, control treatment of PHMB 0.2mg/ml and propamidine 1.0 mg/ml. These results are better than we had anticipated and amongst the best reported. We have shown that much of this improvement is the result of the detailed delivery protocol, developed and evaluated by the 6 European study centres, and which is now available to clinicians. Unlike the control treatments, AKANTIOR^® is a monotherapy which has been through extensive safety, stability, and efficacy tests. As monotherapy it is both easier to use and, if licensed as we expect, will become widely available unlike current therapies which have to be manufactured by compounding pharmacies resulting in frequent treatment delays."

Based on these and full study results, the Company currently plans to file New Drug Application (NDA) with U.S. Food and Drug Administration (FDA) in 2023, which is consistent with previous guidance. Further, as previously announced, the European Medicines Agency (EMA) validated the Company's Marketing Authorization Application (MAA) for AKANTIOR^® in May 2022 Accordingly, the Company maintains its guidance of expecting full regulatory approval by the European Commission mid-2023. In the meantime, as previously announced, the Company make AKANTIOR^Ò available for patients within the Early Access Program (EAP) currently running in several European countries

Dr. Vincenzo Papa, Head of Scientific Affairs, stated, "This is a culmination of our research and development as well as complex manufacturing and chemistry efforts which required huge investment for more than 15 years." Dr. Papa continued, "Acanthamoeba keratitis is a life-changing eye infection and, despite being rare, it is responsible for 50% of blindness among contact lens users. Finally, we can do something about this by potentially bringing the first approved medicine to patients with acanthamoeba keratitis."

SIFI is evaluating different options for the commercialization of AKANTIOR^® globally, including potential out-license agreements outside its core markets.

ABOUT Phase 3 TRIAL: This was a randomized, assessor-masked, active-controlled, multiple-centre pivotal Phase 3 Trial designed to evaluate the efficacy, safety and tolerability of AKANTIOR^® compared to a control arm of an unlicensed combination of polihexanide 0.2mg/ml + propamidine 1.0mg/ml for the treatment of acanthamoeba keratitis [NCT03274895]. Both treatment arms used a standardized, day-only treatment protocol. The primary endpoint was defined as the 'clinical resolution rate over a 12-month timeframe', based on the percentage of patients cured following 30 days after the discontinuance of all study therapies and within 12 months of randomization. 135 patients were randomized in the trial, of which 69 were randomized into the treatment arm and the remaining 66 into the control arm. The average age of the patients was 36.5 years old (ranging from 15–73); 58.2% of the patients were female. 127 patients received a study drug and had its diagnosis confirmed via independent laboratory and constitute the Intention-To-Treat (ITT) population. The main study results are as follows:

• The primary endpoint demonstrated non-inferiority of AKANTIOR^® + placebo versus a combination regimen of polihexanide 0.2 mg/mL + propamidine 1 mg/mL (control arm). Respectively, the clinical resolution rate within 12 months of patients treated with AKANTIOR^® + placebo was 84.8% (56 out of 66) and 88.5% (54 out of 61) for the control arms (p=0,544).  When the data is corrected for risk-factors using multi-variate ANCOVA model: age, severity at baseline, delay in diagnosis, study centre, and drugs used prior to baseline (including steroids), the clinical resolution rate in the AKANTIOR^® arm was 86.7% versus 86.6% in the control arm.
• Patients treated with AKANTIOR^® + placebo experienced statically significant improvement in BCVA at the end of the study compared to baseline (0.188 vs 0.473 LogMAR; p < 0.0001), with more than 50% of patients achieving normal vision (LogMAR = 0). There were no statistically significant differences between the two treatment arms.
• The median time to cure on AKANTIOR^® was 4 months (125 days). 80% of patients achieved a cure with less than 6.6 months of treatment. 
• There were no statistically significant differences between the two treatment arms.
• The impact of acanthamoeba keratitis on patients' health status was analysed with Visual Function Questionnaire 25 (VFQ–25) and quality of life with EuroQoL five-dimension five-level (EQ–5D–5L) instrument. Both instruments showed a statistically significant improvement in quality of life on AKANTIOR^® at the end of the trial compared to baseline.  There were no statistically significant differences between the two treatment arms.
• 3% patients (2 out 66) receiving AKANTIOR^® required cornea transplant in the Phase 3 Trial, and 5 out 66 (7,6%) after leaving the Trial. No patients in the control arm required cornea transplant during the Phase 3 Trial and to 4 out 61 (6.6%) after leaving the Phase 3 Trial.
• The adverse events reported were similar between both arms of the trial. 1 patient in each arm (1,5% vs 1,6%) failed therapy because of toxicity. There were no abnormalities in blood chemistry.

ABOUT AKANTIOR^®: AKANTIOR^® (polihexanide) stands to become the first approved drug for the treatment of acanthamoeba keratitis in the world. It is an anti-amoebic polymer that acts on both the trophozoites and cysts of the protozoan Acanthamoeba. It is formulated at a unique 0.8mg/ml high dose strength which makes it possible to administer as monotherapy eye drops in single-dose containers. In contrast, the various unlicensed or off-label, non-standardised, multi-agent management approaches used currently are based on antimicrobials which often must be compounded or imported. Polihexanide is also being developed by SIFI for the treatment of fungal keratitis for which indication it also has FDA Orphan Drug Designation. AKANTIOR^® is now available for patients through an Early Access Program (EAP).

ABOUT Acanthamoeba Keratitis (AK): AK is a rare, severe, life-changing progressive parasitic corneal infection caused by Acanthamoeba, a free-living amoeba. Urgent medical intervention is required to save the patient's sight. The disease has shown resistance, leads to poor vision, blindness, or even eye loss and often requires single or multiple corneal transplant procedures. It affects people of all ages, most of whom are young or middle-aged soft contact lens wearers. Patients report unbearable pain and extreme light sensitivity and can rarely work or lead normal lives until symptoms resolve. The incidence of acanthamoeba keratitis has been rapidly growing in recent years.

ABOUT SIFI: SIFI is a leading international ophthalmic company, headquartered in Italy, focusing on eye care since 1935. SIFI develops, manufactures, and markets innovative therapeutic solutions for patients with ophthalmic conditions. SIFI is fully committed through its R&D to improving the quality of life of patients, exporting treatments to more than 20 countries worldwide with a direct presence in Italy, Spain, France, United Kingdom, Romania, Mexico, and Turkey.

Key Contact AKANTIOR^®:
Jelle Kleijn
Global Head of AKANTIOR^®
+31 615643708
jelle.kleijn@sifigroup.com

Key Scientific Contact:
Vincenzo Papa
Head of Scientific Affairs AKANTIOR^®
+39 3453698813
vincenzo.papa@sifigroup.com