52-week Extension Research Articles

Efficacy and safety of perampanel in patients with seizures associated with Lennox-Gastaut syndrome: A randomized trial.

The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS). Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and ≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures. Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p = .001) or all countable motor seizures (44.0% vs -.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients. This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.

Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation.

Mitochondrial disease is a group of rare conditions, with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This Phase 2b program, aiming at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety, and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100- or 50-mg sonlicromanol, or placebo twice daily (bid) for 28 days with ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study wherein they received 100-mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). 15 patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier Phase 2a study. The RCT primary endpoint (change from placebo in the attentional domain of cognition score [IDN: visual identification, Cogstate]) did not reach statistical significance. Using a categorisation of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (p=0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, p=0.0143), Cognitive Failure Questionnaire (CFQ, p=0.0113), and the Depression subscale of the Hospital Anxiety and Depression Scale (p=0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study (Test of attentional performance [TAP] with alarm, p=0.0102; TAP without alarm, p=0.0047; BDI somatic, p=0.0261; BDI Total, p=0.0563; SF12 physical component score, p=0.0008). Seven of nine domains of RAND-Short form-36 like SF-36 pain improved (p=0.0105). Other promising results were observed in Neuro QoL-Fatigue-SF (p=0.0036), MiniBESTest (p=0.0009), McGill Pain Questionnaire (p=0.0105), EQ-5D-5L-VAS (p=0.0213) and EQ-5D-5L-index (p=0.0173). Most patients showed improvement in the 5× sit-to-stand test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to one year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domains. Long-term treatment showed more pronounced changes from baseline.

Efficacy and safety of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, in adolescent and adult patients with alopecia totalis and alopecia universalis.

This post-hoc analysis of the ALLEGRO phase 2b/3 study (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral Janus kinase 3/TEC family kinase inhibitor, in patients with alopecia totalis (AT) and alopecia universalis (AU). Patients aged ≥ 12 years with alopecia areata (AA) and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg loading dose) or placebo for 24 weeks. In a subsequent 24-week extension period, the ritlecitinib groups continued their doses and patients initially assigned to placebo switched to ritlecitinib (200/50 or 50 mg daily). In this analysis, clinician- and patient-reported hair regrowth outcomes were assessed at weeks 24 and 48 in four AA subgroups: AT/AU, AT, AU, and non-AT/AU. Safety was monitored throughout. Of the 718 randomized patients, 151 (21%) and 147 (20%) were defined as having AT or AU, respectively. At week 24, Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp hair loss) response rates were higher in the ritlecitinib-treated AT/AU, AT, and AU groups (7%-14%, 7%-21%, and 4%-10%, respectively) vs the placebo group (0% in the AT/AU, AT, and AU groups). The proportions of patients with a SALT score of ≤20 increased through week 48 (AT/AU, 13%-31%; AT, 11%-27%; AU, 6%-41%). Additionally, at week 24, 25%-43%, 32%-42%, and 12%-50% of patients with AT/AU, AT, and AU, respectively, who received ritlecitinib achieved a moderately or greatly improved response based on the Patient Global Impression of Change scale. Response rates generally increased through week 48 and were similar across AA subgroups. In patients with AT/AU, ritlecitinib was well tolerated with a safety profile consistent with that of the overall AA population. Ritlecitinib demonstrated clinical efficacy, patient-reported improvement, and an acceptable safety profile in patients with AT and AU through week 48. A plain language summary of this study is available at https://doi.org/10.25454/pfizer.figshare.26879161. Clinicaltrials.gov: NCT03732807.

Efficacy and safety of cofrogliptin once every 2 weeks in Chinese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, phase 3 trial.

We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D). Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups. Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D. Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851).

Glycaemic outcomes in adults with type 2 diabetes over 34 weeks with the Omnipod® 5 Automated Insulin Delivery System.

The aim was to evaluate the effect of extended use of the Omnipod® 5 Automated Insulin Delivery (AID) System in adults with type 2 diabetes and suboptimal glycaemic control. Following an 8-week single-arm, multicentre, outpatient trial of AID in adults with type 2 diabetes and baseline HbA1c ≥ 8% (≥ 64 mmol/mol), participants were given the opportunity to continue use of the AID system in a 26-week (~6 month) extension phase. The primary safety endpoints were percentage of time with sensor glucose ≥ 250 mg/dL and < 54 mg/dL. Additional glycaemic measures, including percentage of time in range (TIR) (70-180 mg/dL) and HbA1c, were evaluated. The use of non-insulin anti-hyperglycaemic medications was permitted throughout the entire study. During the initial 8-week study, participants (N = 22) achieved a decrease in percentage of time ≥ 250 mg/dL from 27.4% ± 21.0% to 10.5% ± 8.8% (p < 0.0001), which further decreased to 9.7% ± 9.2% during the extension phase (p = 0.0002 vs. standard therapy). Percentage of time < 54 mg/dL remained low from standard therapy through extension (median [interquartile range] 0.00% [0.00%, 0.06%] vs. 0.02% [0.00%, 0.05%], p > 0.05). HbA1c decreased by 1.6% ± 1.2% (15.5 ± 13.1 mmol/mol, p < 0.0001) and TIR increased by 22.4% ± 19.2% (p < 0.0001) from standard therapy through extension with no significant change in body mass index and without an observed increase in total daily insulin requirements. These longer-term findings of Omnipod 5 AID System use demonstrate the potential value of AID in helping people with type 2 diabetes reach glycaemic targets.

7376 Efficacy and Safety of CAM2029 in Patients With Controlled or Inadequately Controlled Acromegaly on Standard-of-Care Treatment: Interim Data for the “New to CAM2029” Patient Subgroup in a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. G. Fidan Yaylali: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. E. Isaeva: None. A. Dreval: None. A. Gilis-Januszewska: None. E. Gezer: None. I. Bancos: Advisory Board Member; Self; Diurnal, Spruce, Neurocrine, Adrenas, Sparrow, Corcept, HRA Pharmaceuticals, Recordati, Xeris, AstraZeneca, Novo Nordisk. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is a rare, serious disorder characterized by overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). There is a need for new, convenient therapies that provide effective disease control. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration (ready-to-use syringe or injection pen). In a 24-week, Phase 3 trial (ACROINNOVA 1), CAM2029 was superior to placebo at attaining IGF-1 response (≤upper limit of normal [ULN] at week 22/24: 72.2% vs 37.5%; P=0.0018) in patients with acromegaly previously controlled under standard of care (SoC; octreotide long-acting repeatable [LAR]/lanreotide Autogel). Here, we report interim data from another Phase 3 trial of CAM2029 (ACROINNOVA 2; NCT04125836), focusing on the “New to CAM2029” subgroup of patients whose acromegaly was either controlled or uncontrolled under SoC. Methods: This 52-week, Phase 3, open-label trial (with a 52-week extension) enrolled patients who had received CAM2029 or placebo in ACROINNOVA 1 (reported separately) and “New to CAM2029” patients who were adequately or inadequately controlled (IGF-1 ≤2x ULN) on a stable dose of octreotide LAR/lanreotide Autogel for ≥3 months (data reported here). In the main part of the trial, new patients received once-monthly CAM2029 20 mg for up to 52 weeks. The primary endpoint was adverse events (AEs). Secondary endpoints included (i) the proportion of patients with IGF-1 ≤1x ULN (weeks 50/52 mean), (ii) the change from baseline in IGF-1, and (iii) the combined IGF-1 and GH response. Baseline values reflected SoC treatment. Data cutoff: May 23, 2023. Results: Eighty-one new patients were enrolled (mean age 51.8 years; 59.3% female). No new or unexpected safety signals were observed. The most common treatment-emergent AEs were injection site erythema (n=22) or swelling (n=13), and headache (n=12). AEs were mostly mild (grade 1/2); there were no serious or Grade 3 treatment-related AEs attributed to CAM2029. IGF-I response increased from 14.8% at baseline SoC (12/81) to 33.3% (20/60 patients with available data) at weeks 50/52. The estimated increase in IGF-1 response (linear probability model) from baseline at week 52 was 21.9% (95% CI: 9.6, 34.1). Biochemical control for both IGF-1 and GH improved over time: 30.0% of patients (18/60) had a combined IGF-1 and GH response at the end of the main part of trial, vs 11.7% (7/60) at baseline. Conclusion: CAM2029 was well tolerated with a safety profile consistent with that of SoC. Biochemical control rates improved from SoC baseline over 52 weeks of CAM2029 treatment in the “New to CAM2029” patients. These findings reinforce the efficacy and safety of CAM2029 in patients with acromegaly, including patients with uncontrolled disease with current SoC treatment (octreotide LAR/lanreotide Autogel). Presentation: 6/1/2024

Continuous glucose monitoring-based metrics and the duration of hypoglycaemia events with once-weekly insulin icodec versus once-daily insulin glargine U100 in insulin-naive type 2 diabetes: an exploratory analysis of ONWARDS 1

Continuous glucose monitoring (CGM) can provide a comprehensive assessment of glycaemic control. This exploratory analysis of the ONWARDS 1 trial assessed CGM-based metrics and CGM-derived hypoglycaemia duration in insulin-naive individuals with type 2 diabetes treated with subcutaneous once-weekly insulin icodec (icodec) versus once-daily insulin glargine U100 (glargine U100). ONWARDS 1 was a 78-week (52-week main treatment phase and a 26-week treatment extension phase plus a 5-week follow-up), randomised, open-label, treat-to-target, phase 3a trial done at 143 sites (outpatient clinics and hospital departments) across 12 countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c: 7·0-11·0%) who had not previously received insulin were randomly assigned (1:1) via an interactive web-response system to once-weekly icodec or once-daily glargine U100. Double-masked CGM data were collected during treatment initiation (weeks 0-4), midtrial (weeks 22-26), end of main phase (weeks 48-52), end of extension phase (weeks 74-78), and follow-up (weeks 78-83). Secondary and exploratory outcomes were CGM-based metrics, including the mean percentages of time in glycaemic range (TIR; sensor glucose 3·9-10·0 mmol/L [70-180 mg/dL]), time in tight range (TITR; 3·9-7·8 mmol/L [70-140 mg/dL]), time above range (TAR; >10·0 mmol/L [>180 mg/dL]), and time below range (TBR; <3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]), and CGM-derived hypoglycaemic episode durations (episodes defined by sensor glucose <3·9 mmol/L [<70 mg/dL for ≥15 consecutive minutes]). Analyses were done in the full analysis set (all randomly assigned participants). The ONWARDS 1 trial is registered with ClinicalTrials.gov, NCT04460885, and is complete. Participants were enrolled and randomly assigned in ONWARDS 1 between Nov 25, 2020, and Dec 1, 2022 (n=492 in each treatment group). During treatment initiation, we observed no statistically significant differences in the mean percentages of TIR, TITR, TAR, and TBR with icodec versus glargine U100. During the midtrial, end of main phase, and end of extension phase periods, the mean percentages of TIR and TITR were statistically significantly greater and the mean percentages of TAR statistically significantly lower with icodec versus glargine U100. The mean percentages of TIR met the internationally recommended CGM target (>70%) with icodec but not with glargine U100 during the three periods. TBR (<3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]) was low and below recommended targets (<4% and <1%, respectively) across all study periods in both treatment groups, with no statistically significant differences between treatment groups for the lower threshold (<3·0 mmol/L [<54 mg/dL]). During the follow-up period, mean percentages of TIR, TITR, TAR, and TBR did not statistically significantly differ with icodec versus glargine U100. The duration of overall hypoglycaemic episodes was similar between treatment groups throughout the trial (median duration ≤35 min). These CGM data support the long-term efficacy and safety of icodec versus glargine U100 during treatment and indicated no increase in the duration of individual hypoglycaemic episodes with icodec versus glargine U100 in insulin-naive individuals with type 2 diabetes. Novo Nordisk.

Evaluating Faricimab in Treatment-Naive Neovascular Age Related Macular Degeneration: A Retrospective Analysis of Real-World Data.

To evaluate the efficiency and safety of Faricimab on treatment-naive neovascular age related macular degeneration (nAMD) in a real world UK clinic. This single centre, retrospective note review was conducted on treatment-naive patients with nAMD. The data collected included demographics, best corrected visual acuity (BCVA), central macular thickness (CMT), total retinal fluid (TRF), the presence of intraretinal fluid (IRF) and subretinal fluid (SRF). A total of 66 eyes from 62 patients were analysed. The average age was 77 years (range 36-91) and 54% of patients were female. After the first dose of faricimab, the average BCVA improved by 0.05 LogMAR (+2.5 letters), the average CMT decreased by 65.9μm and 41% of patients were found to be inactive. The follow-up intervals after the third loading dose were divided into 2 subsets of 4 and 8week extensions. The 4week extension subset saw a smaller improvement in BCVA (+3 letters) than the 8week extension (+6 letters) while both had an average decrease in CMT by 86.6μm. The total retinal fluid decreased by 45% and 70.7%, leaving only 30% and 12.2% residual intraretinal fluid (IRF) and 30% and 24.4% residual subretinal fluid (SRF), respectively. Over a ten-month period, the average number of injections received was 6.6, including 3 initial loading doses. There was only one reported case of an adverse event out of 66 eyes (1/66, 1.5%). Three loading doses of Faricimab appear efficacious and safe for the treatment of nAMD.

Somapacitan in Children Born SGA: 52-week Efficacy, Safety, and IGF-I Response Results from the Phase 2 REAL5 Study.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in short children born small for gestational age (SGA). Evaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor-I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA. REAL5 is a randomized, multi-center, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension, and an ongoing 4-year safety extension (NCT03878446). Thirty-eight sites across 12 countries. Sixty-two GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment. Patients randomized (1:1:1:1:1) to somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously. Estimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4 and 10.7 cm/year for somapacitan 0.16, 0.20 and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I as well as peak IGF-I bioactivity were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modelling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups. A sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.

An Interim Report of a Phase 3, Long-Term, Open-Label Study to Evaluate Efficacy and Safety of Difamilast Ointment in Japanese Infants with Atopic Dermatitis.

Difamilast is the first selective phosphodiesterase 4 inhibitor approved for atopic dermatitis (AD) in Japan. A phase 3, 52-week, open-label study is ongoing to establish efficacy and safety of difamilast ointments in infants with AD aged 3 to < 24months because a clinical study has not been conducted in this population. This study consisted of a 4-week primary evaluation period in which difamilast 0.3% ointment was applied twice daily to Japanese infants aged 3 to < 24months (n = 41) and an ongoing 48-week long-term extension period in which difamilast 0.3% or 1% ointment was applied based on existing symptoms. The data on efficacy and safety of difamilast were obtained as of an interim report in the study period. The response rate in Investigator's Global Assessment score was 45.0% at week 1, which was maintained at 56.1% at week 4 and 63.4% at the interim report. Infants achieved the response rate in Eczema Area and Severity Index 75 (improvement of ≥ 75%) of 47.5% at week 1, which further improved to 82.9% at week 4 and 78.1% at the interim report. Adverse events (AEs) were reported in 22 (53.7%) infants in the primary evaluation period: of those the most frequent AE was nasopharyngitis (19.5%) followed by dermatitis contact (7.3%). As of the interim report, 36 (87.8%) infants experienced AEs: of those, nasopharyngitis (70.7%) and gastroenteritis (22.0%) were most frequently observed. The total AEs were mostly mild or moderate in severity. No investigational medicinal product-related AEs and no AEs leading to discontinuation were reported. Difamilast ointments applied twice daily to Japanese infants with AD aged 3 to < 24months is effective and well tolerated as of the interim report in the study period. The final results will be reported in the near future. Clinical Trials. gov identifier: NCT05372653.

Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10mg/kg or placebo every 4wk over 28wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

Adrenal suppression from vamorolone and prednisone in Duchenne muscular dystrophy: results from the phase 2b clinical trial.

Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD). To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD, and to assess cortisol thresholds using a monoclonal antibody immunoassay. Post-hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500nmol/L ("historical threshold") and <400nmol/L ("revised threshold"). Mean age at enrolment was 5.41±0.86 years (N=118). At Week 24, proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day=100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day=95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day=84.2% (16/19) and 47.5% (9/19); and placebo=20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48=0.83). AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.

Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0%(53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

Long-term efficacy and safety of difelikefalin in moderate-to-severe pruritus in Japanese hemodialysis patients: a 52-week open-label extension period of a phase 3 trial

BackgroundDifelikefalin, a potent and highly selective agonist of kappa opioid receptors, is used to treat moderate-to-severe pruritus in hemodialysis patients.MethodsThis was a 52-week, open-label phase 3 trial following a 6-week randomized double-blind placebo-controlled treatment period to investigate the efficacy and safety of difelikefalin in Japanese hemodialysis patients. Having completed the 6-week double-blind period, patients received difelikefalin 0.5 μg/kg three times per week intravenously for 52 weeks. Efficacies were assessed using numerical rating scale (NRS) scores, proportion of patients whose NRS score improved by ≥ 3 points and ≥ 4 points, Shiratori severity score, proportion of patients with a nighttime Shiratori severity score of ≤ 2, the Skindex-16 score, 5-D itch scale score, and patient global impression of change (PGIC). Safety was assessed on the basis of adverse events, clinical laboratory tests, vital signs, body weight, 12-lead electrocardiography, and dependency.ResultsThe number of patients who entered the extension treatment period from the difelikefalin (MR–MR) and placebo (P-MR) groups was 85 and 83, respectively. The weekly mean NRS scores (mean ± SD) in the MR–MR group at baseline, week 6, and week 58 were 6.57 ± 1.32, 4.04 ± 2.24, and 2.36 ± 1.86, respectively. The weekly mean scores in the P-MR group, at baseline, week 6, and week 58 were 6.42 ± 1.29, 4.85 ± 1.90, and 2.73 ± 2.14, respectively. In patients receiving difelikefalin, there was a decline in the score from treatment initiation, and this decline continued until week 58. Similarly, improvements were seen until week 58 in the proportion of responders, Shiratori severity score, proportion of responders based on the Shiratori severity score, the Skindex-16 score, 5-D itch scale score, and PGIC. A correlation was seen between the change in NRS and itch-related quality of life (QOL), including the Shiratori severity score, Skindex-16 score, 5-D itch scale score, and PGIC. Difelikefalin was well tolerated and safe even when used long term.ConclusionsDifelikefalin improved itching and itch-related quality of life during long-term treatment in hemodialysis patients with moderate-to-severe pruritus whose response to conventional medications had been inadequate. It also demonstrated excellent safety and tolerability.Trial registration: ClinicalTrials.gov; NCT04711603. Registered 15 January 2021, https://www.clinicaltrials.gov/study/NCT04711603?term=NCT04711603&rank=1.

Patient-Reported Satisfaction with Hair Regrowth in a Study of Ritlecitinib in Alopecia Areata: Results from ALLEGRO-2b/3.

Patients with alopecia areata (AA) report high levels of dissatisfaction with commonly used treatments. Patient-reported outcomes are essential to understanding patients' experiences with AA treatments. The objective of this study was to evaluate patient-reported satisfaction with hair growth among patients with AA receiving ritlecitinib or placebo and the correlation between clinician-assessed efficacy and patient-reported satisfaction. In the ALLEGRO-2b/3 (NCT03732807) trial, patients with AA and ≥50% scalp hair loss were randomized to daily ritlecitinib or placebo for 24 weeks, with a 24-week extension of continued ritlecitinib or switch from placebo to ritlecitinib. The Patient Satisfaction with Hair Growth (P-Sat) measure evaluated patients' satisfaction with hair growth in 3 domains: amount, quality, and overall satisfaction with hair growth. The prespecified analysis evaluated the proportion of patients who were slightly, moderately, or very satisfied with hair growth. Several post hoc analyses assessed the proportion of patients who were moderately/very satisfied and moderately/very dissatisfied and calculated polyserial correlations between change from baseline (CFB) in Severity of Alopecia Tool (SALT) and P-Sat scores at weeks 24 and 48. At week 24, the proportion of patients (N = 718) reporting satisfaction (slightly, moderately, or very satisfied) overall with their hair growth ranged from 36.4% in the ritlecitinib 10-mg group (evaluated for dose ranging only) to 67.5% in the 200/50-mg group versus 22.6% in the placebo groups. In patients randomized to ritlecitinib, the proportion who were satisfied increased or was maintained at week 48. A substantially greater proportion of placebo patients who switched to ritlecitinib reported satisfaction at week 48 than at week 24. Similar results were observed for patient satisfaction with the amount and quality of hair growth. In the post hoc analyses defining satisfaction as moderately/very satisfied and dissatisfaction as moderately/very dissatisfied, the benefit of ritlecitinib was also observed. All P-Sat domain scores strongly correlated with CFB-SALT scores at weeks 24 (range 0.73-0.76; p &lt; 0.05) and 48 (0.74-0.77; p &lt; 0.05). Patients receiving active ritlecitinib doses reported favorable results versus placebo in satisfaction with hair growth up to week 48. High concordance was observed between improvement in scalp hair growth evaluated by clinicians and patient-reported satisfaction.

SAT-203 Pegozafermin added to background GLP-1 therapy in patients with metabolic dysfunction-associated steatohepatitis with F2/F3 fibrosis: ENLIVEN 48-week extension data

SAT-203 Pegozafermin added to background GLP-1 therapy in patients with metabolic dysfunction-associated steatohepatitis with F2/F3 fibrosis: ENLIVEN 48-week extension data

Effectiveness and safety of polyacrylamide hydrogel injection for knee osteoarthritis: results from a 12-month follow up of an open-label study

ObjectiveThere are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data.MethodsThis multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0–100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs).Results49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (− 17.7 points (95% CI − 23.1; − 12.4); p < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI − 17.0; − 4.9), physical function (18.0 points; 95% CI − 19.1; − 10.6), and PGA (16.3 points; 95% CI − 23.1; − 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related.ConclusionThis open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection.Trial registration: Clinicaltrials.gov NCT04179552.

96-week retention in treatment with extended-release subcutaneous buprenorphine depot injections among people with opioid dependence: Extended follow-up after a single-arm trial

BackgroundThe most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting. MethodsThis study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N=100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension. ResultsOf 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P=0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P=0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P=0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment. ConclusionThis is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing. FundingIndivior

Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 100-Week Results from the Phase3 KEEPsAKE1 Randomized Clinical Trial.

Patients with psoriatic arthritis (PsA) require treatment providing durable long-term efficacy in different disease domains as well as safety. We present 100-week efficacy and safety results of risankizumab in patients with active PsA and previous inadequate response/intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). KEEPsAKE1 (NCT03675308) is a global phase3 study, including a 24-week, double-blind, placebo-controlled and ongoing open-label extension periods. Patients were randomized 1:1 to receive risankizumab 150mg or placebo at baseline and weeks4 and 16. After week24, all patients received open-label risankizumab every 12weeks thereafter. Patients were evaluated through 100weeks. Endpoints included achieving ≥ 20% reduction in American College of Rheumatology criteria for symptoms of rheumatoid arthritis (ACR20), minimal disease activity (MDA; defined as ≥ 5/7 criteria of low disease activity and extent), and other measures. Overall, 828/964 (85.9%) patients completed week100. For patients receiving continuous risankizumab, 57.3%, 70.6%, and 64.3% achieved ACR20 at weeks24, 52, and 100, respectively. For the placebo/risankizumab cohort, 33.5% achieved ACR20 at week24 but increased after switching to active treatment at weeks52 (63.7%) and 100 (62.1%). In ACR20 responders at week52, 81.2% of both treatment cohorts maintained response at week100. MDA was achieved by 25.0%, 38.3%, and 38.2% of the continuous risankizumab cohort at weeks24, 52, and 100. In the placebo/risankizumab cohort, 10.2% achieved MDA at week24, increasing at weeks52 (28.0%) and 100 (35.2%). MDA response was maintained at week100 in week52 responders in the continuous risankizumab (75.5%) and placebo/risankizumab cohorts (78.2%). Similar trends were observed for other efficacy measures. Risankizumab was generally well tolerated through 100weeks. For patients with active PsA who are csDMARD-IR, risankizumab demonstrated durable long-term efficacy and was generally well tolerated, with a consistent long-term safety profile. ClinicalTrials.gov identifier, NCT03675308.

A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.

To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.