Abstract
Background:
Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF.
Methods:
A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks.
Results:
A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile.
Conclusion:
Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.
Keywords: LAU-7b, Cystic fibrosis, Inflammation, Lung function loss reduction, CFTR modulators
1. Introduction
Cystic Fibrosis (CF) is a life-shortening, hereditary disease affecting over 100,000 people worldwide [1]. It is caused by variants in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, a chloride ion channel. CFTR dysfunction leads to mucus dehydration in exocrine tissues, with the lungs contributing most to morbidity and mortality. Hyperviscous airway secretions and impaired mucociliary clearance lead to infection with opportunistic pathogens.
CFTR dysfunction also alters innate immunity [2], causing an aberrant immune-inflammatory neutrophilic response that appears early in life [3,4], hinders bacterial clearance and propagates inflammation [5, 6], leading to progressive irreversible lung damage [7]. Although advancements have been made in understanding CF pathogenesis, elucidation of the mechanism(s) by which CFTR gene mutations lead to chronic airway inflammation remains incomplete, leaving this component among the least developed aspects of CF treatment [8].
Even though highly effective CFTR modulator therapy (HEMT) improves lung function and quality-of-life in people with CF (PwCF) [9, 10], it remains unclear if rescuing CFTR with HEMT effectively addresses chronic airway inflammation and how inflamed airways affect CFTR activity [11–14].
PwCF carry an innate cell membrane lipid imbalance that contributes to lung inflammation [15–17]. LAU-7b is a novel oral form of fenretinide acting on cell membrane lipids to control inflammation and protein trafficking, as shown in-vitro and in-vivo in cell and mouse models of CF [18,19]. Treatment improved resolution of inflammation and preservation of CFTR function in lung epithelial cells during inflammatory stress, which was complementary to HEMT [20]. We conducted a Phase 2 trial to assess the efficacy and safety of LAU-7b in adult PwCF, including those treated with HEMT, and hypothesized that LAU-7b would reduce the loss of lung function, improve the systemic inflammatory profile and the respiratory domain quality of life scores compared to placebo.
2. Methods
2.1. Participants, trial design and oversight
This 40-site, randomized, double-blind, placebo-controlled, 24-week trial of LAU-7b enrolled adult PwCF, with ppFEV1 40–100 % at screening who had at least one pulmonary exacerbation (PEx) in the prior 12-month period, and were clinically stable for 5 weeks prior to randomization. Subjects were randomized 1:1 to either LAU-7b or placebo after stratification for screening ppFEV1 (<70 % vs. ≥70 %), the number of PEx in prior year (≤3 vs. >3), and co-administration or not of CFTR modulators. All subjects continued their standard CF care, recorded during the study. LAU-7b 300 mg/day, or matching placebo, was taken orally once daily, with food, for six 21-day treatment cycles each separated by 7-days, over 24 weeks. (For complete inclusion and exclusion criteria, details on endpoints and statistical analyses, see Supplement). The protocol and informed consent were approved by ethics committees at each participating site in the U.S., Canada, and Australia. Safety oversight was provided by an independent Data Monitoring Committee.
2.2. Endpoints
Subjects were evaluated before, serially during and after the 24-week intervention period. The primary endpoints were the absolute change from baseline in ppFEV1 at 24 weeks as well as all ppFEV1 data through 24 weeks, and safety. A sample size of 60 completers/arm with a 4 ppFEV1 points difference at 24 weeks was adequate to detect with >80 % power a between-group difference with an alpha of 0.05. Key secondary endpoints were time to and incidence of intravenous antibiotic-treated PEx after the first cycle of treatment up to the last follow-up visit, as defined by Fuch’s criteria [21]; number of PEx-related antibiotic treatments and days receiving these antibiotics; the change from baseline in systemic biomarkers of inflammation, oxidative stress, lipidomics and metabolipidomics, body weight, body mass index (BMI) and quality of life assessed by the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain [22,23]; and exploratory Matouk Disease Score [24].
2.3. Statistical analyses
Primary efficacy and safety analyses were carried out on the ITT population consisting of subjects who received at least one dose of treatment. Subjects who received ≥5 treatment cycles without major protocol deviations (such as missed Week 24 data) constituted the PP population, used for secondary analyses.
The absolute change from baseline in ppFEV1 points was analyzed with a mixed-effects model for repeated measures (MMRM). The model included the terms: treatment group, visit, treatment group-by-visit interaction, and the three stratification factors described above as fixed effects. Secondary, pre-planned analyses of the primary endpoint included the terms: usage of elexacaftor-tezacaftor-ivacaftor (ETI or pre/post pandemic confinement as additional fixed effects. Finally, sensitivity analyses of the impact of missing data were performed by 1) multiple imputation assuming missing at random (MAR) data in both treatment arms, and 2) a tipping point analysis, where progressively unfavorable ppFEV1 responses (up to 1.0 ppFEV1 by 0.1 steps) were imputed into missing data points in the LAU-7b arm.
A similar mixed-effects model was used for the analyses of continuous numerical secondary endpoints. The proportion of subjects with values for AA, DHA, and their ratio within the normal range of healthy volunteers were compared with a logistic regression with treatment group and stratification factors included in the model. Similarly, PEx incidence and antibiotic use were analyzed with a Poisson regression with treatment group and stratification factors included in the model as well as the time on study (days) as covariates. In addition, the treatment effect for most endpoints was analyzed by pre-planned subgroups corresponding to the three stratification factors as well as the usage or not of ETI.
3. Results
A total of 166 subjects were randomized from November 2018 to March 2021 (ITT/safety population), of which 122 constituted the PP population. Key demographics and baseline characteristics are presented in Table 1 and were comparable between study arms. The subject disposition is presented in FIg. 1. In both arms, but more frequently with LAU-7b, some subjects discontinued from the study, left the study early for initiating ETI, or missed the Week 24 visit due to COVID-19 pandemic restrictions. These contributed to a higher-than-expected drop-out rate in both arms.
Table 1.
Subject demographic and study populations.
| Characteristics ITT/Safety population | LAU-7b (n=83) |
Placebo (n=83) |
|---|---|---|
| Age, years (mean, SD) | 31.5 (10.7) | 33.9 (13.0) |
| Female, n (%) | 50 (60.2) | 49 (59.0) |
| Height, cm (mean, SD) | 165.1 (9.6) | 165.6 (8.4) |
| Body weight, kg (mean, SD) | 63.9 (12.2) | 64.5 (14.3) |
| BMI, kg/m2 (mean, SD) | 23.3 (3.4) | 23.4 (4.1) |
| PEx count in prior year (mean, median) | 2.3 (2.0) | 2.1 (2.0) |
| Percentage of subjects with prior year PEx hospitalizations | 62.7 | 56.6 |
| CFQ-R respiratory domain (mean, SD) | 67.2 (18.5) | 71.0 (16.0) |
| Study treatment exposure, days (mean, SD) | 138.3 (69.0) | 150.2 (39.1) |
| Compliance, % (mean, SD)* | 94.4 (12.8) | 98.3 (4.1) |
| Key relevant concomitant medication usage n(%) | ||
| Dornase alfa | 67 (80.7) | 68 (81.9) |
| Inhaled adrenergics with and without corticosteroids | 82 (98.8) | 79 (95.2) |
| Azithromycin | 46 (55.4) | 57 (67.5) |
| CFTR modulators | ||
| Ivacaftor | 2 (2.4) | 4 (4.8) |
| Lumacaftor/Ivacaftor | 9 (10.8) | 7 (8.4) |
| Tezacaftor/Ivacaftor | 12 (14.5) | 12 (14.5) |
| Elexacaftor/Tezacaftor/Ivacaftor | 18 (21.7) | 23 (27.7) |
| Baseline ppFEV1 by study population/key subgroups | n | n |
| ITT, n | 83 | 83 |
| Mean (SD) | 63.18 (16.77) | 62.29 (15.13) |
| PP, n | 55 | 67 |
| Mean (SD) | 62.67 (16.26) | 62.13 (14.67) |
| ITT Subgroup ppFEV1≥70 %, n | 29 | 27 |
| Mean (SD) | 83.06 (7.55) | 79.87 (8.61) |
| ITT Subgroup ppFEV1<70 %, n | 54 | 56 |
| Mean (SD) | 52.50 (8.52) | 53.81 (9.01) |
| ITT Subgroup using CFTR modulators, n | 41 | 46 |
| Mean (SD) | 59.70 (15.46) | 63.33 (15.73) |
| ITT Subgroup not on CFTR modulators, n | 42 | 37 |
| Mean (SD) | 66.57 (17.48) | 60.99 (14.45) |
| ITT Subgroup using ETI, n | 18 | 23 |
| Mean (SD) | 56.30 (16.25) | 64.42 (19.00) |
| ITT Subgroup pre-pandemic onset, n | 32 | 32 |
| Mean (SD) | 60.51 (15.97) | 62.58 (12.67) |
| ITT Subgroup post-pandemic onset, n | 51 | 51 |
| Mean (SD) | 64.85 (17.20) | 62.10 (16.60) |
Percentages based on the number of randomized subjects; ppFEV1 = Percent Predicted Forced Expiratory Volume in 1 second; PEx = Pulmonary Exacerbation; CFQ-R = Cystic Fibrosis Questionnaire-Revised; ITT population: all subjects randomized to a treatment group who received at least one dose of study treatment; PP population: all subjects randomized to a treatment group with at least 5 cycles of study treatment administered in accordance with the protocol (defined as at least 80 % compliance).
Compliance to concomitant CF care was not the subject of formal analyses but was carefully monitored and recorded.
Fig. 1.
Subject disposition breakdown and study populations – CONSORT Diagram. ITT – Intent to treat; PI – Principal investigator; AE – Adverse event; ETI - elexacaftor,tezacaftor,ivacaftor.
3.1. Efficacy
3.1.1. Primary endpoint (ITT and PP populations)
Both treatment arms showed a loss of lung function at 24 weeks, numerically smaller by 0.77 ppFEV1 points in the LAU-7b arm relative to placebo in ITT population (1.18 versus 1.95 ppFEV1, 40 % difference, p=0.345), and by 0.95 ppFEV1 in PP population (0.97 versus 1.91 ppFEV1, 49 % difference, p=0.263). (Table 2). The primary analysis of mean ppFEV1 through 24 weeks showed similar differences between arms in the ITT population (1.01 ppFEV1, 65 % difference, p=0.067), and reached statistical significance in the PP population (1.23 ppFEV1, 78 % difference, p=0.049).
Table 2.
Primary and Secondary analyses of the primary endpoint “Absolute change from baseline of ppFEV1”, by population and by planned subgroups.
| Absolute change from baseline of ppFEV1 | LAU-7b | Placebo | LSMeans Difference (95 % CI) | Difference in % relative to placebo | p-value |
|---|---|---|---|---|---|
| ITT population | |||||
| n=83 | n=83 | ||||
| At Week 24 | −1.18 | −1.95 | 0.77 (−0.84 to 2.38) | 40 % | 0.345 |
| Through Week 24 | −0.54 | −1.55 | 1.01 (−0.07 to 2.08) | 65 % | 0.067 |
| PP population | |||||
| n=55 | n=67 | ||||
| At Week 24 | −0.97 | −1.91 | 0.95 (−0.72 to 2.61) | 49 % | 0.263 |
| Through Week 24 | −0.34 | −1.56 | 1.23 (0.01 to 2.44) | 78 % | 0.049 * |
| Subgroups (ITT and PP populations) | |||||
| Subjects with ppFEV1 ≥70 % at screening | |||||
| n=29 | n=27 | ||||
| At Week 24 (ITT) | −1.41 | −4.07 | 2.66 (−0.21 to 5.53) | 65 % | 0.069 |
| At Week 24 (PP) | −1.22 | −3.81 | 2.58 (−0.42 to 5.59) | 68 % | 0.092 |
| Subjects taking CFTR modulators | |||||
| n=41 | n=46 | ||||
| At Week 24 (ITT) | −0.33 | −1.72 | 1.39 (−0.92 to 3.70) | 81 % | 0.236 |
| At Week 24 (PP) | −0.13 | −1.61 | 1.48 (−0.90 to 3.87) | 92 % | 0.220 |
| Subjects taking elexacaftor-tezacaftor-ivacaftor (ETI) | |||||
| n=18 | n=23 | ||||
| At Week 24 (ITT) | −0.74 | −1.87 | 1.13 (−2.44 to 4.71) | 60 % | 0.532 |
| At Week 24 (PP) | −0.88 | −2.02 | 1.14 (−2.50 to 4.79) | 56 % | 0.536 |
Statistically significant at p<0.05. LSMeans: Least Squares Means. CI: Confidence Interval. LSMeans and p-values from MMRM analysis on the change from baseline in ppFEV1. The model includes treatment, visit (End of Cycles 1, 2, 3, 4 and 6), stratification variables (Screening FEV1 (<70 %, ≥70 %), Prior PEx frequency (≤3, >3), Co-administration of CFTR modulator product (Yes, No) or Co-administration of ETI (Yes, No) and treatment-by-visit interaction as fixed effects.
The between-arm difference in lung function change, while present at all post-randomization visits, had a rapid onset followed by its maintenance (Figs. 2A-B). The multiple imputation sensitivity (MAR) and tipping point analyses both showed that the outcomes of the primary analysis were unchanged, confirming the lack of impact of missing data points (Supplement).
Fig. 2.
Time course of changes from Baseline in ppFEV1, by treatment arm and subgroups, along with maximum changes from baseline in key biomarkers. (A, B) Absolute change from baseline of ppFEV1, based on a mixed-effects model for repeated measures, for ITT (Intent-To-Treat) and PP (Per-Protocol) populations, respectively. Data are least-squares means with standard error of the mean (SEM) bars; (C) Time course of ppFEV1 changes from baseline for pre-planned ITT subgroups analyses; Right hand brackets represent numerical Week 24 differences in ppFEV1 between LAU-7b and placebo arms; ETI – elexacaftor-tezacaftor-ivacaftor.
3.1.2. ITT Subgroup analyses
Across all planned subgroups for both ITT and PP, LAU-7b showed reduced loss of lung function relative to placebo at 24 weeks but these numerical differences did not reach statistical significance (Table 2 and FIg. 2C). A mean difference of 2.66 ppFEV1 in subjects with ppFEV1≥70 % at screening (65 % less loss, p=0.069), 1.39 ppFEV1 difference in subjects taking CFTR modulators (81 % less loss, p=0.236), and 1.13 ppFEV1 difference in subjects taking ETI (60 % less loss, p=0.532). The a-priori planned analysis of the effect of pandemic confinement (pre/post) on the primary endpoint was non-significant (p>0.05).
3.2. Secondary endpoints
3.2.1. Pulmonary exacerbations
The incidence of PEx in the ITT population (overall IV-treated or post-hoc combined IV-or-oral-treated, occurring after Cycle 1 of study treatment) was lower than pre-randomization (Table 1) in both study arms (Supplement, Tables S3-S5), with 22.9 % and 13.3 % of subjects having IV-treated PEx, and for combined IV-or-oral-treated PEx, 41.0 % and 31.3 % of subjects, for LAU-7b and placebo, respectively. The PP population had similar low incidences. The mean incidence (SD) and relative risk (RR, 95 % confidence interval) of a LAU-7b subject to experience any type of PEx was comparable to placebo, 0.53(0.72) versus 0.47(0.82) events, (RR=1.16, 0.75 to 1.79), and was not significantly higher than placebo, 0.24(0.46) versus 0.18(0.57) events, for IV antibiotic-treated PEx (RR=1.30, 0.66 to 2.55); however, the study was not powered for this endpoint. Due to the large number of censored events in both treatment arms (subjects without PEx), the median time to first PEx could not be determined accurately.
In the post-hoc combined IV- or oral-treated PEx analysis, the mean number of PEx-related antibiotic treatments was 0.86 versus 0.81/subject, and the mean number of days of PEx-related antibiotics was 7.71 versus 8.34 days/subject, for LAU-7b and placebo, respectively. Similar trends were observed for the IV-treated PEx-related antibiotics; 0.53 versus 0.41 treatments/subject, p=0.200, and 3.8 versus 3.5 days of IV antibiotics/subject, p=0.747, for LAU-7b and placebo, respectively.
3.2.2. Changes in BW and BMI
No significant change in body weight or BMI occurred during the study at any visit in either study arm (Supplement).
3.2.3. Systemic biomarkers
Maximum relative changes from baseline in key fatty acids, biomarkers of inflammation, and oxidation in the ITT population are summarized in Supplement, Figs. S4-S6. The effect of LAU-7b on the levels of fatty acids AA and DHA, as well as the proportion of subjects reaching the range of normal healthy control subjects for AA, DHA and AA/DHA ratio were comparable to placebo while many subjects were already within the lipid’s normal ranges at baseline.
While a number of biomarkers of inflammation and oxidation exhibited differences between arms, statistical significance was not attained with the ITT datasets (Supplement). CRP and calprotectin increased over time in the placebo arm but remained stable in the LAU-7b arm, a difference reaching statistical significance at Week 24 in the PP population (p=0.029 and 0.046, respectively) but not in the ITT population (p=0.082 and 0.061, respectively).
3.2.4. Cystic fibrosis questionnaire-revised (CFQ-R)
The absolute changes from baseline in the CFQ-R respiratory domain for the ITT (PP) populations showed that LAU-7b treatment was associated with a decrease of 3.014 (2.831) points relative to placebo, p=0.167 (p=0.199), both below the minimum clinically important difference (MCID) [22] (Supplement, Tables S8-S9).
3.3. Safety results
While almost all subjects experienced a treatment-emergent adverse event (TEAE), a modestly higher number of TEAEs occurred with LAU-7b compared to placebo (673 vs 567 events) and the difference consisted mainly of expected ocular TEAEs of interest (Table 3). Nearly all TEAEs were non-serious (95 % on LAU-7b vs 96 % on placebo) and mild to moderate in severity (97 % on LAU-7b and 98 % on placebo). Most events were deemed possibly related, unrelated or of unknown causal relationship (90 % on LAU-7b and 98 % on placebo).
Table 3.
Summary of Safety including most common TEAEs by treatment arm (incidence ≥10 % in either trial arm) in the Safety Population.
| Treatment emergent adverse events * | LAU-7b (n=83) |
Placebo (n=83) |
|---|---|---|
| number of subjects (percent) | ||
| Subjects with at least one TEAE | 80 (96.4) | 79 (95.2) |
| Subjects with at least one TEAE by highest reported severity | ||
| Mild | 22 (26.5) | 27 (32.5) |
| Moderate | 45 (54.2) | 43 (51.8) |
| Severe | 13 (15.7) | 7 (8.4) |
| Life-Threatening | 0 | 0 |
| Subjects with at least one serious TEAE | 20 (24.1) | 15 (18.1) |
| Subjects with at least one TEAE leading to treatment discontinuation | 6 (7.2) | 3 (3.6) |
| LAU-7b: 3 withdrawals by PI (moderate cough, moderate loss of contrast sensitivity, mild QTC prolonged, all resolved) and 3 patient decisions. Placebo: 3 withdrawals by PI (severe neutropenia, moderate chest discomfort/dyspnoea, severe infective pulmonary exacerbation of CF, all resolved) | ||
| AE leading to death | 0 | 0 |
| Most common adverse events ** | number of subjects (percent) | |
| Infective pulmonary exacerbations of CF | 37 (44.6) | 32 (38.6) |
| Cough | 23 (27.7) | 24 (28.9) |
| Delayed dark adaptation | 22 (26.5) | 4 (4.8) |
| Night blindness | 15 (18.1) | 2 (2.4) |
| Headache | 14 (16.9) | 10 (12.0) |
| Upper respiratory tract infections | 13 (15.7) | 8 (9.6) |
| Haemoptysis | 11 (13.3) | 13 (15.7) |
| Diarrhoea | 11 (13.3) | 6 (7.2) |
| Fatigue | 10 (12.0) | 7 (8.4) |
| Delayed light adaptation | 10 (12.0) | 2 (2.4) |
| Dyspnoea | 10 (12.0) | 11 (13.3) |
| Glare | 9 (10.8) | 6 (7.2) |
| Visual impairment | 9 (10.8) | 2 (2.4) |
| Sputum increased | 7 (8.4) | 13 (15.7) |
Treatment emergent adverse events (TEAEs) are defined as AEs that increased in severity or appeared at or after the first dose of study drug and before or before or at the last follow-up. Each subject was counted only once within the greatest reported relationship/highest reported severity for a given AE term.
Shown are events that occurred in at least 10 % of the subjects in either trial group. Adverse events were coded using MedDRA version 24.0.
By highest reported severity, 13 (15.7 %; 19 events) and 7 (8.4 %; 9 events) subjects experienced at least one severe (grade 3) TEAE in the LAU-7b and placebo groups, respectively. No subjects experienced a life-threatening (grade 4) TEAE or died (grade 5) during the study. There were no suspected unexpected serious adverse reactions (SUSARs).
Twenty (24.1 %; 30 events) and 15 (18.1 %; 22 events) subjects reported at least one serious TEAE in the LAU-7b and placebo arms, respectively, almost all due to hospitalization. While infrequent compared to prior year, 34 of serious TEAEs were CF-related PEx requiring IV antibiotics (20 in LAU-7b and 14 in placebo). There was no change in study drug dosing for the majority of subjects (>90 %) in both arms, including those who underwent IV antibiotics for treating PEx.
The most commonly reported TEAEs included respiratory symptoms and eye disorders (Table 3). Respiratory symptoms were primarily related to CF and comparable in both arms. These TEAEs most frequently included PEx, cough, upper respiratory tract infections, haemoptysis, dyspnea or increased sputum.
Ocular disorders, mostly mild and subject-reported through vision questionnaires, were dark or light adaptation difficulties, difficulty seeing in darkness, and glare, and were more frequent in the LAU-7b group, as expected based on prior experience with fenretinide [25,26]. Similar ocular events in the placebo group could have been elicited by the informed consent details and frequent probing with vision questionnaires.
The ocular TEAEs of interest were mostly reported early in the course of study treatment, mainly during the first treatment cycle, and their reporting incidence dropped over the next cycles, following a pattern of tolerance, an observation common to prior long duration clinical studies [25,26] (FIg. 3A). There were 2 LAU-7b discontinuations resulting from ocular TEAEs of interest, both of which fully resolved before the next follow-up.
Fig. 3.
Time course of reporting of ophthalmological TEAEs of interest and corresponding plasma retinol/RBP, as well as ophthalmological examination outcomes (scheduled on-study or triggered by abnormal vision questionnaires). (A) Number of ophthalmological TEAEs of interest, mostly self-reported (delayed dark adaptation, reduced low light vision, glare and dazzling in bright light, yellowing of vision, spots in vision), by cycle of reporting with sample size and by treatment group, Safety Population. (B) Summary of scheduled and ad-hoc ophthalmological examinations with outcomes, NVQ – night vision questionnaire, Safety Population. Plasma retinol (C) and RBP (retinol binding protein) (D) concentrations (Mean ± SD), by visit with sample size and by treatment group, Safety Population.
A total of 240 scheduled on-study ophthalmological examinations were performed as objective assessments of visual health (113 in LAU-7b and 127 in placebo). These included tests of vision function under dim and bright light (electroretinography or dark adaptation). In 3 LAU-7b and 1 placebo subjects, all asymptomatic, the fundus examinations revealed mild abnormalities, all present at screening for LAU-7b and not present at screening for 1 placebo subject; one other placebo subject had a contrast sensitivity/amblyopia abnormal examination at all visits. (FIg. 3B) All other examinations were normal.
There were 26 ad-hoc examinations elicited after obtaining a night vision questionnaire with 2 or more abnormal answers (out of 3), 24 in LAU-7b and 2 in placebo (FIg. 3B). While none of the placebo subjects showed vision function alterations, 3 LAU-7b subjects had visual function alterations that confirmed their mild/moderate symptoms of dark adaptation delay. All returned to normal by the time of the last follow-up, confirming the transient nature of the effect.
As expected, plasma retinol and retinol binding protein (RBP) were lowest on Day 21 in the LAU-7b group, though within acceptable ranges, with no change in placebo (Figs. 3C, 3D). Subsequently, retinol and RBP increased over time in the LAU-7b group despite continued drug intake, indicative of hepatic compensation, and tended to return to baseline levels 4 weeks after last dose, accompanied by resolution of leftover ocular TEAEs, themselves poorly correlated with retinol concentrations.
4. Discussion
This Phase 2 trial of LAU-7b in adult PwCF showed a loss of lung function (primary endpoint of absolute change in ppFEV1 points) in both arms. Although the study did not meet its primary efficacy endpoint in the ITT population, the LAU-7b arm showed numerically and consistently smaller lung function losses relative to placebo, in ITT and PP populations and planned subgroups corresponding to the stratification factors. The treatment differences through 24 weeks met statistical significance in the PP population which underwent at least 5 treatment cycles, suggesting that LAU-7b can help preserve lung function in PwCF above current standard of care. These results passed sensitivity analyses, confirming the lack of impact of the higher-than-expected drop-out rate and missing data, more frequent for some visits set at a lower priority during the COVID-19 confinement.
Among the stratification factors/subgroups LAU-7b consistently showed less loss of lung function than placebo at 24 weeks, with the greatest treatment difference at Week 24 in the ITT subgroup with baseline ppFEV1≥70 % (steeper lung function decline in both arms, not statistically significant). The treatment effect was in the same direction in subjects receiving CFTR modulators including those on ETI. The loss of lung function in ETI-treated subjects in this study is in contrast with the 6-month ETI clinical trial data reported by Middleton [10] and open-label longer term extension studies as reported by Lee [27] and Daines [28]. Interestingly, our well-controlled, randomized double-blind study was performed using similar entry criteria to the randomized, controlled ETI studies (except for specific CFTR mutations in the ETI studies) and used standardized in-clinic, centrally-read spirometry measurements, concomitant CF care recording and data underwent comparable repeated measure analysis of variance statistics. Our study also experienced the same COVID-19 restrictions that affected the ETI extension study during the pandemic period. Thus, under comparable conditions, in our study sample, ETI-treated subjects tended to lose lung function over the 6-month period, though less when treated concurrently with LAU-7b.
While it was anticipated that LAU-7b, with its inflammation controlling mechanism of action, could reduce the rate of PEx relative to placebo, in contrast to some previous anti-inflammatory strategies for CF [29], the unexpectedly low rate of all types of PEx in both study arms interfered with the ability to detect benefit or lack thereof on the PEx endpoints. In contrast with the lack of any meaningful LAU-7b effect on several measured biomarkers, CRP and calprotectin remained stable with LAU-7b but rose in the placebo arm. Body weight, BMI, and CFQ-R respiratory domain score remained stable in both arms throughout the study.
LAU-7b was generally well tolerated with an acceptable TEAE profile, consistent with the large prior experience with fenretinide in other indications [25,26]. LAU-7b-associated TEAEs were mostly mild to moderate, many being common manifestations of CF, and this led to very few treatment discontinuations by Investigators; 3 per arm, and 3 subject decisions to withdraw due to TEAEs in LAU-7b arm). Compared with historical data, PwCF on LAU-7b experienced a similar incidence of reports of delayed dark adaptation or glare, mostly mild and transient in nature. Only 2 LAU-7b subjects discontinued treatment due to ocular TEAEs, in line with the large proportion of normal on-study ophthalmological examinations which included objective functional tests of vision. The extensive testing and probing about visual symptoms may have contributed to similar events reported by placebo-treated subjects.
The study had some limitations. Relatively wide and inclusive ppFEV1 criteria for this stage of development, small sample size of some a-priori-defined subgroups, higher than anticipated drop-out rate, and a limited 6-month duration of study intervention all may have contributed to the inability to identify statistically significant differences. Despite a changing therapeutic landscape following the introduction of ETI, the unexpected overlap of the study with the disruptions of the COVID-19 pandemic (both resulting in higher dropout rate) and inclusion of a generally healthier population at baseline, this study provides important information about the efficacy and safety of LAU-7b in adult PwCF.
Although the majority of PwCF are now eligible to receive HEMT, some PwCF are unable to tolerate it and not all PwCF exhibit stable ppFEV1 with such therapy, as observed in our study in those receiving CFTR modulators, including ETI, leaving some problematic aspects of CF in need of solutions.
In conclusion, this Phase 2 trial demonstrated that LAU-7b treatment was generally well tolerated and while it did not meet its primary endpoint in the ITT population, it showed evidence of potential benefit in preserving lung function through 24 weeks in the PP population and reductions in lung function loss were consistently observed across all treated subgroups. Given the concurrent acknowledged study limitations, these trends support the concept that LAU-7b may help preserve lung function in PwCF including those on CFTR modulators, subject to confirmation in carefully designed follow-up studies.
Supplementary Material
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2024.07.004.
Acknowledgments
We thank the subjects and their families for participating in this trial and the trial investigators and coordinators for their contributions to the trial. The complete list of trial investigators is present in the Supplement. We also wish to thank Ms. France Guay for chemistry and manufacturing oversight.
Source of funding
Funded by Laurent Pharmaceuticals. The US Cystic Fibrosis Foundation (CFF) provided grant support and assistance through the Therapeutic Development Network (TDN).
Footnotes
Subject descriptor number of manuscript
9.17 Cystic Fibrosis: Translational & Clinical Studies.
CRediT authorship contribution statement
Michael W. Konstan: Conceptualization, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing. Deepika Polineni: Investigation, Resources, Writing – review & editing. James F. Chmiel: Investigation, Resources, Writing – review & editing. Lara Bilodeau: Investigation, Resources, Writing – review & editing. Peter G. Middleton: Investigation, Resources, Writing – review & editing. Elias Matouk: Investigation, Resources, Writing – review & editing. Jean-Marie Houle: Conceptualization, Methodology, Validation, Formal analysis, Project administration, Visualization, Writing – original draft, Writing – review & editing. Radu Pislariu: Conceptualization, Funding acquisition, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing. Patrick Colin: Conceptualization, Methodology, Writing – review & editing. Irenej Kianicka: Conceptualization, Validation, Resources, Writing – original draft, Writing – review & editing, Visualization. Diane Potvin: Data curation, Formal analysis, Methodology, Resources, Software, Validation, Visualization, Writing – review & editing. Danuta Radzioch: Conceptualization, Visualization, Writing – review & editing. Tom Kotsimbos: Investigation, Resources, Writing – review & editing. Jonathan B. Zuckerman: Investigation, Resources, Writing – review & editing. Samya Z. Nasr: Investigation, Resources, Writing – review & editing. Theodore G. Liou: Investigation, Resources, Writing – review & editing. Larry C. Lands: Conceptualization, Methodology, Supervision, Visualization, Writing – original draft, Writing – review & editing.
Declaration of competing interest
MW Konstan, LC Lands, D Potvin and D Radzioch report receiving consulting fees from Laurent Pharmaceuticals; JM Houle, R Pislariu, P Colin, I Kianicka are employees of Laurent Pharmaceuticals; D Polineni, J Chmiel, L Bilodeau, PG Middleton, E Matouk, T Kotsimbos, JB Zuckerman, SZ Nasr, TG Liou report no conflict of interest related to this study.
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