We previously documented that regulatory T cells (Tregs) immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD), shifting the immune system toward a pro-inflammatory response. However, Tregs are a potentially restorable therapeutic target in AD. In this study, we evaluated the safety and efficacy of two dosing frequencies of low-dose Interleukin-2 (IL-2) in expanding Tregs to modify disease progression in AD individuals. In this phase 2a, randomized, double-blind, placebo-controlled study, 38 participants were assigned to receive subcutaneous IL-2 (10^6 IU/day) for five days, administered either every 4 weeks (IL-2 q4wks) or every 2 weeks (IL-2 q2wks), versus placebo, for 21 weeks, followed by 9 weeks of observation. The primary endpoints were the incidence and severity of adverse events. For the secondary endpoints, changes in Treg numbers and suppressive functions were evaluated. Exploratory endpoints included changes in plasma inflammatory mediators, CSF AD-related biomarkers, and clinical scales. Of the 38 participants, 9 received IL-2 q4wks, 10 received IL-2 q2wks, and 19 received placebo. All participants completed the trial with no serious adverse events or deaths. Both IL-2 dosing regimens increased Treg numbers and suppressive function, but IL-2 q4wks treatment exhibited superiority in enhancing Treg percentage and Foxp3 mean fluorescent intensity. In longitudinal analysis of 45 inflammatory mediators, IL-2 q4wks administration demonstrated greater efficacy in alleviating the plasma inflammatory mediators CCL2, CCL11, and IL-15, while enhancing IL-4 and CCL13 levels. A significant improvement in CSF Aβ42 levels (p = 0.045 vs. placebo) on Day 148 was observed following IL-2 q4wks administration, compared to placebo. While CSF NfL increased by 217 pg/ml in placebo recipients, it remained stable in the IL-2 q4wks group (p = 0.060, IL-2 q4wks vs. placebo). The adjusted mean change from baseline in the ADAS-cog score at week 22 indicated a trend toward slower clinical progression in IL-2 q4wks recipients compared to placebo (p = 0.061). The IL-2 immunotherapeutic strategy was safe and well-tolerated. IL-2 q4wks effectively expanded Treg populations, leading to modification in inflammatory mediators and CSF Aβ42 levels, while also showing promising trends on clinical scales. These findings provide a foundation for further investigation of low-dose IL-2 as a potential treatment for Alzheimer’s Disease. ClinicalTrials.gov Identifier: NCT06096090, Registration Date: 10-17-2023.

BACKGROUND:Epidermolysis bullosa (EB) is a group of rare and severe genetic disorders characterized by persistent skin fragility and open wounds. EB manifests as cutaneous and mucosal blistering, erosions and impaired wound healing. OBJECTIVES:To determine the long-term efficacy, tolerability and safety of Oleogel-S10 (birch bark extract) in dystrophic EB (DEB) and junctional EB (JEB) in the 24-month open-label phase (OLP) of the EASE study. METHODS:EASE was a double-blind randomized controlled phase III study consisting of two phases: a 90-day double-blind phase (DBP) and a 24-month OLP. Patients from both former treatment groups in the DBP entered the single-arm OLP (n = 205). Patients received Oleogel-S10 on all partial-thickness EB wounds. OLP endpoints included the incidence and severity/relatedness of adverse events (AEs), maximum wound infection severity, changes in body surface area percentage (BSAP) of wounds, EB Disease Activity and Scarring Index (EBDASI), pain, itch, disease severity and quality-of-life outcomes. RESULTS:The OLP data demonstrated that Oleogel-S10 target wound treatment adherence was > 99% and mean (SD) treatment duration was 584.7 (246.1 days). Seventy-two per cent of patients in the OLP were aged < 18 years and 86.8% had DEB; recessive DEB predominated (78.0%). AEs were reported in 77.1% of patients and were typically mild-to-moderate in severity. Severe and serious AEs were seen in 18.0% and 24.4% of patients, respectively. AEs resulted in the withdrawal of 7.8% of patients (n = 16), including three with treatment-related AEs. Nine deaths were reported; none were attributable to the treatment. The incidence of target wound infections was low (n = 7); five were mild-to-moderate in severity and two were severe. In patients treated with Oleogel-S10 throughout, mean (SD) BSAP changes from DBP baseline at 3, 12 and 24 months were -4.3% (8.1) (P < 0.001), -5.9% (8.6) (P < 0.001) and -3.7% (9.0) (P = 0.003), respectively. Similarly, significant changes in EBDASI skin activity score from DBP baseline were observed: -3.9 (8.3) (P < 0.001), -5.1 (8.2) (P < 0.001) and -3.0 (8.3) (P = 0.007) at 3, 12 and 24 months, respectively. CONCLUSIONS:These data support an encouraging long-term safety profile of Oleogel-S10 and a sustained reduction in wound burden over at least 24 months of Oleogel-S10 treatment.

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration.

Abstract Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self‐administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. Plain Language Summary Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation. We previously documented that Treg immunomodulatory mechanisms are compromised in people with Alzheimer’s disease (AD) and are associated with activation of peripheral monocytes and upregulation of inflammatory mediators. In this original study, we investigated the feasibility and potential impact of low-dose IL-2 immunotherapy on restoring Tregs and modifying inflammation in an AD clinical setting. Eight patients with mild-to-moderate AD dementia (MMSE:12-25) were enrolled in a phase 1, open-label, feasibility study of IL-2 treatment. The presence of elevated brain amyloid, as demonstrated by either CSF or amyloid positron emission tomography (PET) scan, was confirmed in all participants. Enrolled individuals received monthly five-day-courses of subcutaneous IL-2 (1 million units/day) for four months and were followed for an additional two months post-treatment. Treg immunophenotype and functional analysis were obtained serially at screening, day 1 (before IL-2 treatment) and day 8 (three days after the fifth dose) of each treatment cycle during therapy, and then at weeks 17 and 24. Two-sided paired t-tests were used to assess the statistical significance of changes in each analyte or clinical outcome at each timepoint. Overall, low-dose IL-2 immunotherapy was well-tolerated and all patients received the treatment as planned. The number of CD4 + CD25 high FoxP3 + Tregs increased two to three-fold after each IL-2 treatment cycle (p<0.01) and returned to baseline before the next cycle. Treg suppressive function on responder T cell (Tresp) proliferation also progressively increased through the four-month IL-2 treatment phase (p<0.01). IL-2 treatment down-regulated IL-1β, IL-6 and TNFa transcripts in circulating monocytes and modulated plasma pro-inflammatory chemokines and cytokines (IL-15, CCL2, CCL4, CCL11 and FLT3LG; p<0.01). Clinical benefits (mean change ± SE) were observed on the Mini-Mental State Exam (+2.25 ± 0.59, p = 0.007) and the Clinical Dementia Rating Sum of Boxes (-0.56 ± 0.24; p = 0.051). IL-2 immunotherapy restored peripheral Treg function and ameliorated systemic pro-inflammatory mediators in AD patients. The results of this study warrant conducting a well-controlled clinical study to further evaluate the safety and efficacy of low-dose IL-2 as a potential treatment for AD.

NCT03522129 https:// clini caltr ials.gov/ ct2/ show/ NCT03 522129.Investigational therapies for Alzheimer's disease (AD) target a wide range of mechanisms, yet promising disease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta (Aβ) is a toxic species contributing to AD through synaptic damage and neuronal toxicity [1].In support of this, Aβ oligomer reduction in an AD mouse model leads to memory preservation [2, 3], and clinical benefit was observed in trials of lecanemab, which targets Aβ oligomers and protofibrils [4], in AD patients, encouraging the continued development of Aβ oligomertargeting therapies.CT1812 is a novel, small-molecule, brain-penetrant sigma-2 receptor (S2R) modulator that selectively prevents and displaces Aβ oligomers from binding to neuronal synapses, thereby mitigating downstream toxicity.This is thought to occur through allosteric modulation

Objective: To determine the utility of quantitative wearable sensors in Multiple system atrophy (MSA). Background: Symptoms of MSA include parkinsonism, ataxia, and/or failure of the autonomic nervous system. Wearable sensors have potential to characterize motor impairment in an outpatient setting and to serve as clinical trial outcomes in MSA. Design/Methods: Participants enrolled in biomarkers of progression in MSA (bioMUSE) had early MSA (<3 years of motor symptoms) by clinical assessment. All completed neurologic exam, neuroimaging and biofluid assessments. The Unified MSA Rating Scale motor exam (UMSARS II), Parkinson Plus Scale (PPSm), and Tandem Walk (TW), were completed every 3 months. PAMSys actigraphy sensors were worn continuously for up to 12-months to assess gait (step count, bouts of walking, steps per bout, cadence, cadence variability), postures (minutes of sitting, lying, standing, walking, sedentary [sitting + lying]) and postural transitions (sit-to-stand) by averaging data over 14-days. Pearson correlation coefficients between clinical and sensor variables were estimated at each time point and two-sided p-values were calculated. Results: 12 participants (6 Female, mean age 64.2) with motor symptoms of 2.X years were followed for ≥ 6 months (n=9), and 12 months (n=5). Significant (P<0.05) correlations were observed between step count, bouts of walking, minutes walking and sit to stand transitions for UMSARS II, PPSm and TW. Significant correlations were most frequently observed at BL and months 3, 6 and 9. The strongest correlations (r>0.8) were observed at month 6 and 9. The PPSm had more frequent and stronger correlation with sensor parameters than UMSARS II. Conclusions: In early MSA, continuous actigraphy is feasible and demonstrates significant correlation with motor exam. The PPSm appeared to have stronger correlation with sensor variables than UMSARS II. Continuous motor assessments via wearable sensors may be a suitable endpoint for clinical trials in MSA. Disclosure: Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark . The institution of Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for HD Insights. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from Griffin Family Foundation. The institution of Dr. Claassen has received research support from Neurocrine. The institution of Dr. Claassen has received research support from Vaccinex. The institution of Dr. Claassen has received research support from AbbVie. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from Genentech/ Roche. The institution of Dr. Claassen has received research support from Prilenia. The institution of Dr. Claassen has received research support from Neurocrine/ HSG. Miss Iregui has nothing to disclose. Ms. Wynn has nothing to disclose. Charles Davis has nothing to disclose. Cynthia Wong has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics.

Trial registration ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic.clinicaltrials.gov/ct2/show/NCT05821153

BACKGROUND Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death. OBJECTIVES EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited. METHODS Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10-50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel - both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days. RESULTS A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01-2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe). CONCLUSIONS Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well -tolerated.

Epidermolysis bullosa (EB) is a rare, multisystem genetic disease that results in patients having severe wound burden and pain. EASE was a prospective, randomized, phase 3, double-blind, controlled study evaluating Oleogel-S10 (birch triterpenes) efficacy and safety vs control gel in EB (DEB and JEB). EASE met its primary endpoint with a higher percentage of patients having complete target wound closure by Day 45 with Oleogel-S10 vs control gel (P = .013). An exploratory analysis of the double-blind phase was carried out to determine a correlation between total wound burden (EBDASI and BSAP) and procedural pain (Wong-Baker FACES) in patients ≥4 years. At baseline, an association was observed between EBDASI skin activity and procedural pain. At each study visit (Day 30, 60, and 90) this remained the case with the strongest correlation being observed at Day 90, where a correlation between EBDASI and procedural pain was observed with Oleogel-S10 and control gel (Pearson: n = 78; r = 0.333; P = .003 and n = 80; r = 0.283; P = .011, respectively). In patients with RDEB a correlation between EBDASI and procedural pain was observed with Oleogel-S10 at Day 90 (Pearson: n = 66; r = 0.399; P < .001). The association with BSAP and procedural pain was weaker; however, it was most apparent at Day 90 in all patients and RDEB patients within the Oleogel-S10 arm (Pearson: n = 79; r = 0.240; P = .033 and n = 66; r = 0.300; P = .014, respectively). There is a correlation between total wound burden and procedural pain in patients with EB. Decreasing total wound burden is clinically meaningful for patients with this intractable disease.

Background: The impact of seizure clusters and the use of intermittent rescue therapy for clusters on the quality of life (QoL) of patients with epilepsy has not been widely studied. The present analysis assessed QoL as a secondary endpoint among adult patients with seizure clusters enrolled in a long-term, phase 3, open-label safety study (NCT02721069) of diazepam nasal spray (Valtoco (R)). The QoL aspect of patients in this study has not been previously published. Methods: The 12-month safety study of diazepam nasal spray enrolled patients aged 6-65 years with seizure clusters. Adults aged >= 18 years completed the Quality of Life in Epilepsy (QOLIE)-31-P at baseline (day 0) and days 30,150, 270, and 365. This instrument includes questions about patient health and daily activities with numeric values (1-100) assigned to responses; higher scores indicate better QoL. The QOLIE-31-P includes 7 subscales: Seizure Worry, Overall QoL, Emotional Well-Being, Energy/Fatigue, Cognitive Functioning, Medication Effects, and Social Functioning; an Overall Score is calculated as a weighted composite of the 7 subscales. Comparisons were made between subgroups of patients who had frequent (>= 2) and infrequent (<2) monthly dosing of diazepam nasal spray and those whose doses were administered by the patient or a care partner. This safety study was not powered to assess efficacy endpoints; descriptive statistics were calculated across time points. In addition, safety measures, including treatment-emergent adverse events, are reported. Results: Seventy-two adults who responded to the QOLIE-31-P were included in the analyses. Mean QOLIE-31-P scores were stable or increased across time points. The mean total scores increased from day 0 to day 365 by 5.2 among patients providing data for >= 1 time point (follow-up group) and 2.2 among patients providing data at all time points (QOLIE all-assessments subgroup). Subscale means for Seizure Worry and Social Functioning showed the greatest numeric increase from baseline. Mean QOLIE-31-P scores were similar in all subgroups. The safety profile in the follow-up group was similar to that seen in all study adults. Conclusions: Adults with refractory epilepsy who were treated with diazepam nasal spray for seizure clusters maintained or improved QOLIE subscale scores across the 12-month study period. Seizure Worry and Social Functioning subscale scores increased over time, suggesting improvement in these domains for this population with intractable epilepsy. Changes among subscale results suggest differences in sensitivity to the use of an intermittent treatment. The potential to improve patient function with treatment for seizure clusters warrants further study.

Objective Intermittent rescue therapy may be used for seizure clusters, which are clinical emergencies that may persist >= 24 h and increase risk of status epilepticus, emergency room visits, and reduced quality of life for patients with epilepsy. Beyond effectiveness for aborting seizure clusters, no data exist on how intermittent rescue therapy may impact the long-term natural course of seizure clusters. This novel analysis explores SEIzure interVAL (SEIVAL; time between seizure clusters) in patients from a long-term safety study of diazepam nasal spray (Valtoco) to assess SEIVAL changes with intermittent rescue therapy across time. Methods Patients were aged 6-65 years. Age- and weight-based doses of diazepam nasal spray were administered during a 12-month treatment period with an optional follow-up period. SEIVAL was evaluated in patients receiving two or more doses of diazepam nasal spray using 90-day periods. Results Of 163 treated patients, 151 had one or more SEIVALs. One hundred twenty had SEIVALs in Period 1 and one or more other periods. An increase in SEIVAL was noted from Period 1 compared with all subsequent periods (p <= .001). A consistent cohort (n = 76) had one or more SEIVALs in each of Periods 1-4 (360 days); mean SEIVALs increased significantly (p < .01) from 12.2 days (Period 1) to 25.7 days (Period 4). Similar SEIVAL patterns occurred when repeat doses within a seizure cluster were eliminated and irrespective of age group, treatment duration, and change to concomitant medications. In adults, Quality of Life in Epilepsy scores were maintained with increased SEIVALs. Significance Across 12 months, increases in SEIVAL were demonstrated in patients using diazepam nasal spray for seizure cluster treatment in a phase 3 safety study. Increased time between seizure clusters may reflect a previously unrecognized beneficial effect of intermittent rescue therapy. These results generate a range of biological and behavioral hypotheses and warrant exploration of the impact of intermittent rescue therapy.

: CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex with a novel disease-modifying mechanism of action against Alzheimer’s brain Aβ oligomers receptors three independent preclinical models of oligomer clearance the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. a phase 1b/2a clinical trial, CSF of A β oligomers, reduced concentrations of synaptic proteins fragments, and reversed expression of many of the AD-related proteins CSF results consistent data provide evidence of target engagement and impact on disease-related signaling pathways in AD patients, further development of restores the expression of neurogranin to normal vs. A β oligomers vs. A oligomers CT1812, n.s., ANOVA with Tukey’s hoc Synaptotagmin-1 is cause a 37% loss synaptotagmin-1 with CT1812 after addition Aβ blocks these losses and restores expression of synaptotagmin-1 levels (vehicle vs. post

Objective: Tolerance is a known consideration for maintenance use of benzodiazepines and other anti-seizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco (R)) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged >= 6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray. Methods: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2. Results: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was >= 12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use. Conclusions: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy. (C) 2021 The Author(s). Published by Elsevier Inc.

Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients’ brain tissue. We previously demonstrated that antagonists of the sigma‐2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma‐2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567).

L’épidermolyse bulleuse (EB) est un groupe de maladies rares et héréditaires affectant l’intégrité des tissus épithéliaux. L’étude prospective, randomisée, de phase 3, en double insu EASE (NCT03068780, Amryt Research limited) a comparé l’efficacité et l’innocuité d’Oleogel-S10 (triterpènes de bouleau) versus gel contrôle dans le traitement de l’EB. Les patients atteints d’EB dystrophique récessive ou dominante (EBRD, EBDD) ou jonctionnelle (EBJ) avec une plaie cible d’épaisseur partielle (10–50 cm2, depuis 21 jours à 9 mois) étaient éligibles. Le traitement était appliqué sur les plaies lors du changement de pansement (≤ 4 jours). Le critère d’évaluation principal était la proportion de patients présentant une première fermeture complète de la plaie cible dans les 45 jours. Les principaux critères d’évaluation secondaires comprenaient le temps de cicatrisation des plaies et la proportion de plaies cibles cicatrisées après 90 jours de traitement, l’incidence et la gravité de l’infection des plaies, l’évolution du fardeau total des plaies corporelles (score d’activité cutanée EBDASI), l’évolution des démangeaisons (échelles Itch Man et Leuven Itch) et les événements indésirables. Au total, 223 patients ont été inclus. Le critère d’évaluation principal a été atteint pour 41,3 % des patients traités avec Oleogel-S10 contre 28,9 % avec le gel contrôle (RR : 1,44 ; p = 0,013). Dans le groupe EBRD (n = 175), 44 % des patients sous Oleogel-S10 contre 26,2 % sous gel témoin ont atteint le critère d’évaluation principal (RR : 1,72 ; p = 0,008). Les proportions de fermeture des plaies cibles dans les groupes EBDD et EBJ n’étaient pas significativement différentes, tout comme le temps de cicatrisation des plaies pendant la période de double aveugle de 90 jours (test de log-rank, p = 0,302). À J90, 50,5 % des patients traités par Oleogel-S10 ont cicatrisé contre 43,9 % des témoins (p = 0,296). Une infection des plaies cibles est survenue chez 2 patients Oleogel-S10 et 5 contrôles. Le score d’activité cutané et le pourcentage de surface corporelle atteinte se sont plus améliorés dans le groupe Oleogel-S10 que le contrôle à J60 et J90. Les démangeaisons s’étaient qualitativement améliorées à la plupart des visites, sans différence cohérente entre les groupes. Les événements indésirables, en majorité légers ou modérés, étaient comparables dans les deux groupes. Oleogel-S10 a démontré qu’il permettait une cicatrisation accélérée des plaies dans les sous-types graves d’EB dans le plus grand essai randomisé en double-aveugle jamais exécuté chez ces patients. Oleogel-S10 est un traitement potentiel sûr et bien toléré pour ces patients.

Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016–002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. Results of the primary endpoint are anticipated to be available by H2 2019. ClinicalTrials.gov, NCT03068780 . EudraCT, 2016–002066-32. Registered on 3 March 2017.

Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.