Efficacy and Safety of NFL-101 as a Smoking Cessation Therapy: A Randomized Phase II Clinical Trial CESTO2.

Introduction: Tobacco addiction remains a major public health challenge. Existing smoking cessation treatments require prolonged daily use with potentially poor adherence and reduced efficacy.

Methods: The phase II study was a multicenter, randomized, double-blind, placebo-controlled trial with a one-year follow-up to assess the efficacy, safety, and immunogenicity of NFL-101 as a potential aid for smoking cessation. 318 adult daily smokers were randomized to receive subcutaneous injections of NFL-101-100 μg, NFL-101-200 μg or placebo on Day1 and Day8. The primary outcome was 6-week post-quit 28-day continuous abstinence (CA, Day15-Day43), validated by exhaled CO.

Results: CO verified 6-week post-quit CA was: NFL-101-100 μg: 31/108(28.7%), 200 μg: 23/109(21.1%), and placebo: 18/101(17.8%). NFL-101-100 μg vs placebo, RR = 1.61, p=.063, and 200 μg vs placebo RR = 1.18, p=.5492). CA, when urinary cotinine was used, was: 26/108(24.1%) for NFL-101-100 μg, 18/109(16.5%) for 200 μg and 13/101(12.9%) for placebo. NFL-101-100 μg vs placebo showed an RR = 1.87, 95%CI:1.02-3.44, p=.0378 and 200 μg vs placebo was RR = 1.28, 95%CI:0.66-2.48, p=.4572. If individuals who used NRTs/e-cigarettes were classified as non-abstinent, then 29/108(26.9%) were abstainers for NFL-101-100 μg and 14/101(13.9%) for placebo (p=.0203). NFL-101-100 μg RR remained stable between 28-day and 12-month. At Day43, NFL-101-100 μg reduced craving (p<.05), with no significant difference for withdrawal symptoms. Abstainers experienced greater increases in anti-NFL-101-IgG concentrations compared to nonabstainers (p<.009). NFL-101 was well-tolerated.

Conclusions: Although the pre-specified primary endpoint was not statistically significant, if the primary outcome had been defined as nicotine abstinence, the results would have reached statistical significance. Efficacy, craving reduction and minimal dosing regimen of NFL-101-100 μg support its potential as a promising smoking cessation therapy.

Implications: In this multicenter randomized clinical trial that included 318 smokers, effect sizes between groups were sufficiently large to suggest a meaningful clinical effect. NFL-101 at a dose of 100 μg increased 6-week post-quit 28-day continuous smoking abstinence that was confirmed by urinary cotinine concentrations and reduced craving, suggesting psychological benefits that could mitigate relapse risks. Abstainers experienced a significant increase in anti-NFL-101 IgG concentrations compared to those who continued to smoke.Findings from the present study offer support for an entirely new category of treatment that acts through immune modulation. Additional strengths include a subcutaneous route of administration in the form of two injections spaced a week apart (thus, enhances treatment adherence) and has demonstrated a safe profile with minimal adverse effects. These results support a follow up Phase III clinical trial.

Trial registration: ClinicalTrials.gov identifier: NCT04571216.