Bimekizumab safety in moderate to severe plaque psoriasis: Rates of hepatic events and changes in liver parameters over 2 years in randomized phase 3/3b trials.

BACKGROUND: Patients with psoriasis are at increased risk of liver function abnormalities. OBJECTIVE: Explore rates of hepatic treatment-emergent adverse events (TEAEs) and changes in liver parameters in bimekizumab-treated patients with psoriasis. METHODS: Data are reported from 5 phase 3/3b trials over 2 years. Hepatic TEAEs, laboratory elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), and changes in clinical markers of liver fibrosis (Fibrosis-4 [FIB-4] Index and AST to Platelet Ratio Index [APRI]) are reported. TEAEs are presented using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). RESULTS: 2186 patients received ≥1 bimekizumab dose. Over 2 years, the EAIR of hepatic TEAEs was 3.5/100 PY and did not increase from first to second year. 2-year EAIRs of ALT/AST elevations >3x and >5x the upper limit of normal were 2.3 and 0.6/100 PY; rates were similar to placebo, adalimumab, secukinumab, and ustekinumab during controlled study periods. FIB-4 and APRI scores did not increase through 2 years, regardless of fibrosis risk at baseline. LIMITATIONS: Obesity, diabetes, dyslipidemia, chronic alcohol consumption, and medication changes are confounding factors for hepatic dysfunction. CONCLUSION: Rates of hepatic adverse events (AEs) with bimekizumab were consistent through 2 years; incidences of transaminase elevations were similar to comparators during phase 3/3b controlled study periods.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Current and Future Treatment of Retinitis Pigmentosa.

Retinitis Pigmentosa (RP) is a group of inherited retinal dystrophies (IRDs) characterised by progressive vision loss. Patients with RP experience a significant impact on daily activities, social interactions, and employment, reducing their quality of life. Frequent delays in referrals and no standard treatment for most patients also contribute to the high unmet need for RP. This paper aims to describe the evolving therapeutic landscape for RP including the rationale for advanced therapy medicinal products (ATMPs). A review of available data was conducted in three stages: (1) a search of publicly available literature; (2) qualitative research with physicians treating RP patients in France, Germany, Italy, Spain, and the UK; and (3) a review of leading candidates in the RP pipeline. Globally, there are currently over 100 drugs in development for RP; 50% of which are ATMPs. Amongst the 15 cell and gene therapies in late-stage development, 5 leading candidates have been selected to profile based on the development stage, drug target and geography: gene therapies AGN-151597, GS-030 and VMCO-1 and human stem cell therapies jCell and ReN-003. Hereditary retinal diseases are suitable for treatment with cell and gene therapies due to the accessibility of the retina and its immune privilege and compartmentalisation. Therapeutic approaches that aim to rescue photoreceptors (eg gene therapies) require that non-functional target cells are still present, whereas other therapies (eg cell therapies) are not reliant on the presence of viable photoreceptors. Gene therapies may be attractive as their fundamental goal is to restore vision; however, cell therapies will likely have a broader application and do not rely on genetic testing, which can delay treatment. Ensuring effective therapeutic options for RP patients across disease stages requires the continued diversification and advancement of the development pipeline, and sustained efforts to promote early patient identification and timely diagnosis.

Retinitis Pigmentosa: Burden of Disease and Current Unmet Needs.

Retinitis Pigmentosa (RP), a group of inherited retinal dystrophies characterised by progressive vision loss, is the leading cause of visual disability and blindness in subjects less than 60 years old. Currently incurable, therapy is aimed at restricting degeneration of vision, treating complications, and helping patients to cope with the psychosocial impact of their disease. Hence, RP is associated with a high burden of disease. This paper describes the current therapeutic landscape for RP and the disease burden for patients, caregivers, and society. A review of available data was conducted in three stages: (1) a literature search of publicly available information on all domains of RP; (2) a systematic literature review using Medline, Embase, the Cochrane Library and grey literature (GlobalData) on epidemiology and cost of RP; and (3) qualitative research with senior physicians treating RP patients in the EU4 and the UK to validate research findings from secondary sources. RP severely impacts the daily lives of over a million people worldwide. Progressive vision loss significantly affects the ability to perform basic daily tasks, to maintain employment, and maintain independence. Consequently, most patients will experience reduced quality of life, with a greater emotional and psychological impact than other conditions related to vision loss such as diabetic retinopathy or age-related macular degeneration. RP is also associated with a high level of carer burden, arising from psychological and financial stress. The therapeutic landscape for RP is limited, with few treatment options and minimal guidance for the diagnosis, treatment, and care of patients. A curative intervention, voretigene neparvovec (Luxturna®), only exists for 1-6% of patients. Although disease management can be successful in developing coping strategies, most patients live with this chronic, progressive condition without interventions to change the disease course. Innovative new therapies can transform the therapeutic landscape, provided appropriate clinical guidance is forthcoming.

Bimekizumab Safety in Patients With Moderate to Severe Plaque Psoriasis: Pooled Results From Phase 2 and Phase 3 Randomized Clinical Trials.

Importance: Psoriasis is a chronic disease requiring long-term management; understanding the long-term safety profiles of psoriasis treatments, such as bimekizumab, is important. Objective: To evaluate the 2-year safety profile of bimekizumab in patients with moderate to severe plaque psoriasis. Design, Setting, and Participants: Safety data were pooled from a cohort of patients from 4 phase 2 randomized clinical trials (BE ABLE 1, BE ABLE 2, PS0016, and PS0018) and 4 phase 3 randomized clinical trials (BE VIVID, BE READY, BE SURE, and BE BRIGHT) to include 2 years of study treatment. Data were obtained on adults with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index level ≥12, ≥10% body surface area affected by psoriasis, and an Investigator's Global Assessment score ≥3 on a 5-point scale) who were eligible for systemic psoriasis therapy and/or phototherapy. Interventions: Included patients received 1 or more doses of bimekizumab during the phase 2 or phase 3 trials. Main Outcomes and Measures: Treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation are reported using exposure-adjusted incidence rates (EAIRs) per 100 person-years. Results: A total of 1789 patients (1252 [70.0%] men; mean [SD] age, 45.2 [13.5] years) were treated with 1 or more doses of bimekizumab across the phase 2/3 trials and were included in these analyses; total bimekizumab exposure was 3109.7 person-years. TEAEs occurred at an EAIR of 202.4 per 100 person-years and did not increase with longer duration of bimekizumab exposure. The 3 most frequently reported TEAEs were nasopharyngitis (19.1 per 100 person-years; 95% CI, 17.4-20.9 per 100 person-years), oral candidiasis (12.6 per 100 person-years; 95% CI, 11.3-14.0 per 100 person-years), and upper respiratory tract infection (8.9 per 100 person-years; 95% CI, 7.8-10.1 per 100 person-years). Most oral candidiasis events were mild or moderate; 3 events led to discontinuation. The EAIRs of inflammatory bowel disease (0.1 per 100 person-years; 95% CI, 0.0-0.3 per 100 person-years), adjudicated suicidal ideation and behavior (0.0 per 100 person-years; 95% CI, 0.0-0.2 per 100 person-years), and adjudicated major adverse cardiac events (0.5 per 100 person-years; 95% CI, 0.3-0.8 per 100 person-years) were low. Conclusions and Relevance: In these pooled analyses of data from a cohort of patients from 8 randomized clinical trials, bimekizumab was well tolerated aside from an increased incidence of mild to moderate oral candidiasis. No safety signals were observed compared with previous reports, and there was no increased risk of AEs with longer duration of bimekizumab exposure.

CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD.

The Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII ß chain. This requires the Nedd4 family HECT E3 ubiquitin ligase Wwp2 and a tumor-suppressing transmembrane protein adaptor Tmem127. Here, through a proteomic screen of dendritic cells, we found that SteD targets the plasma membrane protein CD97 for degradation by a similar mechanism. SteD enhanced ubiquitination of CD97 on K555 and mutation of this residue eliminated the effect of SteD on CD97 surface levels. We showed that CD97 localises to and stabilises the immunological synapse between dendritic cells and T cells. Removal of CD97 by SteD inhibited dendritic cell-T cell interactions and reduced T cell activation, independently of its effect on MHCII. Therefore, SteD suppresses T cell immunity by two distinct processes.

Bimekizumab versus Adalimumab in Plaque Psoriasis.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with the tumor necrosis factor inhibitor adalimumab in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: We randomly assigned patients with moderate-to-severe plaque psoriasis in a 1:1:1 ratio to receive subcutaneous bimekizumab at a dose of 320 mg every 4 weeks for 56 weeks; bimekizumab at a dose of 320 mg every 4 weeks for 16 weeks, then every 8 weeks for weeks 16 to 56; or subcutaneous adalimumab at a dose of 40 mg every 2 weeks for 24 weeks, followed by bimekizumab at a dose of 320 mg every 4 weeks to week 56. The primary end points were a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score (PASI 90 response; PASI scores range from 0 to 72, with higher scores indicating worse disease) and an Investigator's Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (scores range from 0 [clear skin] to 4 [severe disease]), at week 16. The analysis of the primary end points tested noninferiority at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 614 patients were screened, and 478 were enrolled; 158 patients were assigned to receive bimekizumab every 4 weeks, 161 to receive bimekizumab every 4 weeks and then every 8 weeks, and 159 to receive adalimumab. The mean age of the patients was 44.9 years; the mean PASI score at baseline was 19.8. At week 16, a total of 275 of 319 patients (86.2%) who received bimekizumab (both dose groups combined) and 75 of 159 (47.2%) who received adalimumab had a PASI 90 response (adjusted risk difference, 39.3 percentage points; 95% confidence interval [CI], 30.9 to 47.7; P<0.001 for noninferiority and superiority). A total of 272 of 319 patients (85.3%) who received bimekizumab and 91 of 159 (57.2%) who received adalimumab had an IGA score of 0 or 1 (adjusted risk difference, 28.2 percentage points; 95% CI, 19.7 to 36.7; P<0.001 for noninferiority and superiority). The most common adverse events with bimekizumab were upper respiratory tract infections, oral candidiasis (predominantly mild or moderate as recorded by the investigator), hypertension, and diarrhea. CONCLUSIONS: In this 56-week trial, bimekizumab was noninferior and superior to adalimumab through 16 weeks in reducing symptoms and signs of plaque psoriasis but was associated with a higher frequency of oral candidiasis and diarrhea. Longer and larger trials are required to determine the efficacy and safety of bimekizumab as compared with other agents in the treatment of plaque psoriasis. (Funded by UCB Pharma; BE SURE ClinicalTrials.gov number, NCT03412747.).

Bimekizumab for patients with moderate to severe plaque psoriasis: 60-week results from BE ABLE 2, a randomized, double-blinded, placebo-controlled, phase 2b extension study.

BACKGROUND: Dual neutralization of both interleukin 17A and 17F with the monoclonal antibody bimekizumab may have greater efficacy in psoriasis than neutralization of interleukin 17A alone. OBJECTIVE: To provide longer-term efficacy and safety data for bimekizumab from a phase 2b extension study in patients with moderate to severe psoriasis (BE ABLE 2). METHODS: After the 12-week initial study (BE ABLE 1), patients who had a 90% improvement in Psoriasis Area and Severity Index (PASI 90) at week 12 received bimekizumab 64, 160, or 320 mg for an additional 48 weeks (60 weeks in total). The primary objective was safety. RESULTS: Across all dose groups (N = 217), initial PASI 90 responders generally maintained high levels of efficacy through week 60: PASI 90, 80% to 100%; 100% improvement in PASI, 69% to 83%; Investigator's Global Assessment score 0 or 1, 78% to 100% (all nonresponder imputation). Incidence of serious treatment-emergent adverse events was 15/217 (6.9%). No cases of inflammatory bowel disease, major adverse cardiovascular events, or suicidal ideation or behavior were reported. LIMITATIONS: Low numbers in the bimekizumab 64 mg group (n = 15). The majority of 60-week data reported here are primarily for the week 12 PASI 90 responders only. CONCLUSION: Bimekizumab response rates were maintained through week 60. A substantial proportion of patients achieved complete skin clearance. Bimekizumab was generally well tolerated.

Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled phase 2b trial.

BACKGROUND: Neutralizing interleukin (IL) 17F in addition to IL-17A might provide a more complete and specific approach to inhibiting inflammation. OBJECTIVE: Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate-to-severe plaque psoriasis. METHODS: Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg with 320 mg loading dose, 320 mg, 480 mg, or placebo. Primary endpoint was ≥90% reduction in Psoriasis Area Severity Index (PASI90) at week 12. RESULTS: There was a significant (P < .0001) dose-dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%-79.1%) than patients in the placebo group (0%; P < .0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 week 8, PASI75 week 12, PASI100 week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P ≤ .0003) compared with placebo. More bimekizumab-treated patients than placebo-treated patients achieved PASI100 (week 12) (27.9%-60.0% vs 0%; P ≤ .0002 all doses). Treatment-emergent adverse events were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients. LIMITATIONS: No active comparator. CONCLUSION: Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose-related safety findings.