Background and aim PF-07242813 (anti-CD1a) was designed to inhibit T-cell proinflammatory signaling. This analysis evaluated the safety and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses (MAD) of PF-07242813 in healthy participants and pharmacodynamics of a single dose in patients with atopic dermatitis. Methods In Part 1, healthy participants (18–55 years) received PF-07242813 intravenously (IV; SAD), subcutaneously (SC; MAD) or IV (MAD), or placebo. In Part 2, patients with moderate-to-severe atopic dermatitis (18–65 years) were randomized (2:1) to receive PF-07242813 1000 mg IV or placebo. Endpoints included safety and pharmacokinetic outcomes in healthy participants and efficacy endpoints in patients with atopic dermatitis. Results Of the 122 participants (SAD: n = 57; MAD: n = 40; atopic dermatitis: n = 25), 41 reported treatment-emergent adverse events (mostly mild); headache (4.9%) and alanine transaminase increased (4.9%) were most common. Peak serum PF-07242813 concentrations were 0.6–2 hours (IV, SAD) and 73–169 hours (SC, MAD). Overall, PF-07242813 did not demonstrate clinical benefit in patients with atopic dermatitis. Conclusions CD1a blockade is not sufficient to produce a clinical effect in patients with atopic dermatitis. PF-07242813 was well-tolerated and may be useful for CD1a pathway analyses. ClinicalTrials.gov Identifier NCT04668066

AIM:There is an unmet need for more effective therapies in inflammatory bowel disease (IBD). A single drug that blocks multiple distinct pathogenic pathways may offer therapeutic benefit superior to current monotherapies. PF-07261271, a bispecific antibody targeting both the p40 subunit of interleukin-12/23 and tumour necrosis factor-like cytokine 1A (TL1A), is being investigated as a potential new IBD therapy. This study evaluates the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PF-07261271 in healthy participants. METHODS:This phase 1, randomized, double-blind, placebo-controlled study assessed single ascending doses (SAD; intravenous 30-1000 mg) and multiple doses (MD; subcutaneous 300 mg once every 4 weeks) of PF-07261271 in healthy adults. Safety, PK, immunogenicity and exploratory PD serum biomarkers (total soluble TL1A [sTL1A] and p40) were evaluated. RESULTS:Thirty-five participants were enrolled (Part A: SAD, N = 27; Part B: MD, N = 8). PF-07261271 was generally safe and well tolerated; all treatment-emergent adverse events were mild/moderate. Following peak serum concentration, there was a multi-phase decline with a trend towards increased terminal half-life at the higher doses. For the MD cohort, the estimated bioavailability of PF-07261271 administered subcutaneously was 48%. Dose-dependent increases from baseline in serum total sTL1A and p40 levels were observed in participants receiving PF-07261271, demonstrating target engagement. There was no apparent impact of anti-drug antibodies on safety, PK or PD parameters. CONCLUSION:PF-07261271 demonstrated p40 and TL1A target engagement and a favourable safety profile. Further studies are warranted to evaluate its safety and efficacy in patients with IBD. CLINICALTRIALS:gov: NCT05536440.

Background:Crohn's disease (CD) has a high unmet need for treatment. Ritlecitinib (Janus Kinase [JAK]3/tyrosine kinase expressed in hepatocellular carcinoma [TEC] family kinase inhibitor) or brepocitinib (tyrosine kinase 2 (TYK2)/JAK1 inhibitor) are promising therapeutic targets. We aimed to evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ritlecitinib and brepocitinib versus placebo in patients with moderate-to-severely active CD. Methods:PIZZICATO was a multicentre, randomised, placebo-controlled, parallel-group, induction-maintenance, phase 2a study in patients with moderate-to-severely active CD. Eligible patients (18-75 years old) had an established diagnosis (endoscopic and histopathology) of ileal, ileocolonic, or colonic active CD at least 3 months before the study started and had documented treatment failure with at least one conventional CD therapy. This study was double-blind during the 12-week induction phase and was open label for the subsequent 52-week open-label extension (OLE) phase. Study participants were enrolled from 140 sites in 26 countries and were randomly assigned (1:1:1) to receive once-daily oral ritlecitinib (200 mg [8 weeks] followed by 50 mg [4 weeks]) or brepocitinib (60 mg [12 weeks]) or placebo in the induction phase, followed by a reduced dose of 50 mg ritlecitinib or 30 mg brepocitinib during the 52-week OLE phase. The primary efficacy endpoint was the proportion of patients who achieved Simple Endoscopic Score (SES) for CD (SES-CD 50; defined as ≥50% reduction from baseline) at Week 12 (ritlecitinib versus placebo; brepocitinib versus placebo), and was assessed in the full analysis set (FAS; all participants who received at least one dose of the study drug or placebo). The primary endpoint was changed from clinically-meaningful endoscopic improvement (CMEI) by protocol amendment during study execution. The safety profile of ritlecitinib and brepocitinib was assessed as a secondary endpoint during the induction phase and as a primary endpoint during the OLE phase. Safety was assessed in the safety analysis set (SAS; same as FAS). This trial was registered with ClinicalTrials.gov, NCT03395184, and EudraCT, 2017-003359-43. Findings:Between Feb 2, 2018, and Oct 19, 2023, 244 patients (median age: 33.0 [18, 71]) were randomly allocated into study groups (ritlecitinib n = 93; brepocitinib n = 72; placebo n = 79) and included in the FAS and SAS. Of 244 participants dosed in the induction phase, 217 (88.9%) completed the induction phase and entered the OLE phase; 216 were dosed in the OLE phase. Disease activity was generally similar across groups and the majority of participants were tumour necrotizing factor (TNF) inhibitor experienced. For the primary outcome at Week 12, a significantly higher proportion of participants achieved SES-CD 50 with ritlecitinib (difference versus placebo: 14.3% [90% CI 4.0-24.5]; p = 0.012) or brepocitinib (21.4% [10.0-32.9]; p = 0.0012) than did those receiving placebo. Regarding safety, during the induction phase, 146 (59.8%) patients reported 334 treatment-emergent adverse events (TEAEs); for the OLE phase, 169 (78.2%) patients reported 521 TEAEs. Most TEAEs were mild or moderate. Most common being severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positive (six patients, 6.5%). In the ritlecitinib 200/50 mg group, headache (five patients, 6.9%) in the brepocitinib group, and worsening of underlying CD (eight patients, 10.1%) in the placebo during the induction phase; and worsening of underlying CD in the ritlecitinib 200/50 mg to 50 mg (12 patients, 14.3%) and brepocitinib 60 mg to 30 mg (11 patients, 17.2%) group, and SARS-CoV-2 infection (six patients, 16.7%) in the placebo to ritlecitinib 50 mg group during the OLE phase. No deaths were reported. Interpretation:Ritlecitinib and brepocitinib showed significant improvement in the primary outcome versus placebo for treatment of moderate-to-severely active CD, with acceptable safety profiles. This should be considered as preliminary evidence of efficacy. It is not known how effective these treatments are likely to be in patients with milder disease. Further studies are required for both molecules and to better understand responder and non-responder populations. Funding:Pfizer Inc.

Evolving research landscapes warrant updates in drug development strategy. Collaborations between pharmaceutical industry and academic institutions are crucial for accelerating drug development, leveraging individual expertise in clinical trial conduct and pathophysiological investigations. This review highlights key collaborations between Pfizer and academic institutions in inflammation and immunology research, including dermatology, gastroenterology, rheumatology, and autoimmunity. These collaborations harness and enhance the development of innovative disease models, large clinical databases, registries, and novel clinical trial designs, and open new avenues in disease management to improve patient outcomes.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

BACKGROUND:TNF-like ligand 1A (TL1A) is an emerging therapeutic target for inflammatory bowel disease. We evaluated the safety and efficacy of multiple doses of afimkibart, a TL1A-directed antibody, in patients with moderately-to-severely active ulcerative colitis. METHODS:The multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b, TUSCANY-2 trial was conducted at 114 centres in 23 countries across North America, Europe, Asia, Africa, Australia, and South America. Adults (aged 18-75 years) with moderately-to-severely active ulcerative colitis (total Mayo score [tMS] 6-12, endoscopic subscore ≥2) were randomly assigned (2:2:2:2:2:3:1:1:1) to one of nine treatment sequences to receive subcutaneous afimkibart 50 mg, 150 mg, 450 mg, or matched placebo every 4 weeks during the 12-week induction period, and subcutaneous afimkibart 50 mg, 150 mg, or 450 mg during the treat-through 40-week maintenance period. Investigators and patients were masked to treatment. Study drugs were administered by masked site personnel following preparation by an unmasked pharmacist at the investigational site. Efficacy was assessed at weeks 14 and 56 in the intent-to-treat populations. The primary efficacy endpoint of clinical remission at week 14 by tMS (defined as tMS ≤2, with no individual subscore >1) was assessed in those who received at least one dose of drug or placebo during induction, excluding patients who had missing data due to complications resulting from COVID-19. Safety endpoints were also analysed in those who were randomly assigned and received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT04090411. FINDINGS:Between Dec 19, 2019, and Oct 25, 2022, 246 patients were randomly assigned treatment, of whom 245 were treated, 228 completed induction, and 178 completed maintenance. Median age was 39 years (IQR 30·0-51·0), 99 (40%) patients were female and 146 (60%) were male; median disease duration was 4·7 years (IQR 2·5-10·2). At week 14, the primary endpoint of clinical remission by tMS was reported in 12 (26%) of 47 patients in the afimkibart 50 mg group (risk difference vs placebo [RD] 13·9% [90% CI -0·2 to 27·7]; p=0·0545), 14 (23%) of 60 patients in the afimkibart 150 mg group (RD 11·7% [-1·7 to 24·1]; p=0·0823), and 21 (24%) of 88 patients in the in the afimkibart 450 mg group (RD 12·2% [-0·6 to 22·9]; p=0·0642) versus five (12%) of 43 patients in the placebo group. In alignment with updated US Food and Drug Administration guidance, clinical remission using the modified Mayo score at week 14 was reported in 14 (30%) of 47 patients in the afimkibart 50 mg group (RD 18·2% [90% CI 3·3 to 32·2]), 21 (35%) of 60 patients in the in the afimkibart 150 mg group (RD 23·4% [6·2 to 36·3]), and 28 (32%) of 88 patients in the in the afimkibart 450 mg group (RD 20·2% [3·2 to 31·3]) versus five (12%) of 43 patients in the placebo group. Overall, 117 (48%) of 245 patients in the induction phase and 132 (59%) of 224 patients in the maintenance phase reported at least one treatment-emergent adverse event; incidences of treatment-emergent adverse events during induction were similar with placebo and afimkibart. The most common treatment-emergent adverse events (occurring in ≥5% of patients) during induction were nausea, urinary tract infection, ulcerative colitis, anaemia, fatigue, headache, and pyrexia. Six serious adverse events were reported during induction in the active treatment groups and four in the placebo group. Two patients who completed induction and did not receive the study drug during maintenance had serious adverse events during safety follow-up. During the maintenance period, 12 (5%) of 224 patients had 13 serious adverse events. No deaths occurred. INTERPRETATION:Differences in the primary endpoint of clinical remission by tMS were not significantly different for any dose of afimkibart compared with placebo. However, secondary endpoints suggest that afimkibart was associated with a favourable benefit-risk profile, with clinically meaningful improvements in clinical remission with the modified Mayo score for patients with moderately-to-severely active ulcerative colitis. These results support the continued development of afimkibart. FUNDING:Pfizer, Roivant Sciences, and F Hoffmann-La Roche.

BACKGROUND:Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis. METHODS:This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA. Adults aged 18-80 years with skin-predominant dermatomyositis were enrolled during stages 1, 2, and 2a, and had to have a Cutaneous Dermatomyositis Disease Area and Severity Index-Activity (CDASI-A) score of 14 or more and at least one unsuccessful systemic treatment with standard of care; whereas those with muscle-predominant dermatomyositis were enrolled in stage 3 and had to have active moderate muscle involvement. Patients were randomly assigned using an interactive response technology system to dazukibart 600 mg or placebo in stage 1; dazukibart 600 mg, dazukibart 150 mg, or placebo in stage 2; dazukibart 600 mg then placebo, dazukibart 150 mg then placebo, placebo then dazukibart 600 mg, or placebo then dazukibart 150 mg in stage 2a; and dazukibart 600 mg then placebo or placebo then dazukibart 600 mg in stage 3. For stage 2a and stage 3, treatments were switched at week 12. Patients, investigators, outcome assessors, and funders were masked to the treatment assignment. Dazukibart and placebo were administered intravenously on day 1 every 4 weeks, up to and including week 8 (stages 1 and 2, and stages 2a and 3 for patients starting dazukibart), or on week 12 every 4 weeks, up to and including week 20 (stages 2a and 3 for patients who started placebo and switched to dazukibart). The primary outcome for the skin-predominant cohorts was the change from baseline in CDASI-A score at week 12 assessed in the full analysis set (FAS; stage 1) and the pooled skin FAS (stages 1, 2, and 2a), and safety in the muscle-predominant cohort. This study is registered with ClinicalTrials.gov, NCT03181893. FINDINGS:Between Jan 23, 2018, and Feb 23, 2022, 125 adults were assessed and 50 were excluded. 75 patients were randomly assigned and treated (15 to dazukibart 150 mg, 37 to dazukibart 600 mg, and 23 to placebo). Most patients were female (53 [93%] of 57 in the skin-predominant cohort vs 13 [72%] of 18 in the muscle-predominant cohort and four [7%] vs five [28%] were male). In the FAS in stage 1 at week 12, the mean change from baseline in CDASI-A for dazukibart 600 mg was -18·8 (90% CI -21·8 to -15·8; placebo-adjusted difference -14·8 [-20·3 to -9·4]; p<0·0001). In the pooled skin FAS at week 12, the mean change from baseline in CDASI-A for the dazukibart 600 mg group was -19·2 (-21·5 to -16·8; placebo-adjusted difference -16·3 [-20·4 to -12·1]; p<0·0001), whereas the dazukibart 150 mg group was -16·6 (-19·8 to -13·4; placebo-adjusted difference -13·7 [-18·3 to -9·0]; p<0·0001). Treatment-emergent adverse events occurred in 12 (80%) of 15 patients in the dazukibart 150 mg group versus 30 (81%) of 37 in the dazukibart 600 mg group versus 18 (78%) of 23 in the placebo group, with the most common being infections and infestations (two [13%] vs 12 [32%] vs seven [30%]). Four (11%) patients in the dazukibart 150 mg group and one (4%) in the placebo group reported serious adverse events. One patient in stage 3 received dazukibart 600 mg then placebo and died during follow-up due to haemophagocytic lymphohistiocytosis and macrophage activation syndrome. INTERPRETATION:Dazukibart resulted in a pronounced reduction in disease activity and was generally well tolerated, supporting IFNβ inhibition as a highly promising therapeutic strategy in adults with dermatomyositis. FUNDING:Pfizer.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease, promoting inflammation and intestinal fibrosis. Targeting TL1A with the anti-TL1A antibody RO7790121 showed significant endoscopic improvement and favorable safety in the phase IIa TUSCANY trial1 and the subsequent phase IIb TUSCANY-2 trial (NCT04090411) in patients (pts) with moderately to severely active ulcerative colitis (UC). Here we report histologic and endoscopic improvement and remission data from the phase IIb TUSCANY-2. Methods Pts aged 18–75 years with moderately to severely active UC (total Mayo score ≥6, endoscopic subscore [ES] ≥2) were enrolled in this multicenter, randomized, double-blind, treat-through, dose-ranging study. Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week, treat-through maintenance period. Histologic endpoints included histologic improvement (Geboes score [GS] ≤3.1) and remission (GS <2B.1), as well as histologic-endoscopic mucosal improvement (GS ≤3.1 and ES ≤1) and remission (GS <2B.1 and ES ≤1), assessed at Weeks 14 and 56. Results A total of 245 pts received ≥1 dose of RO7790121 or PBO; 228 pts completed the induction; 224 entered the maintenance period and 178 completed the maintenance period. At Week 14, the proportions of pts with histologic improvement (using Geboes histology score) were 40.0%, 39.6% and 32.9% with RO7790121 50mg, 150mg and 450mg, respectively, vs 12.2% with PBO, which were sustained through Week 56. Greater proportions of pts with histologic remission were also observed with any RO7790121 dose vs PBO at Week 14, sustained through Week 56 (Table). Additionally, 30.0%, 32.1% and 25.6% of pts treated with RO7790121 50mg, 150mg and 450mg, respectively, vs 4.9% with PBO experienced histologic-endoscopic mucosal improvement, which was sustained through Week 56. Greater histologic-endoscopic mucosal remission was also observed at any RO7790121 dose vs PBO at Week 14 and sustained through Week 56 (Table). Across the various endpoints, there was no apparent dose response. Conclusion Overall, higher rates of histologic improvement and remission were observed in pts treated with RO7790121 during induction, compared with PBO, and sustained through Week 56. Similarly, a higher proportion of pts treated with RO7790121 achieved histologic-endoscopic mucosal improvement and remission, sustained through Week 56. RO7790121 is currently being investigated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin Gastroenterol Hepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

OBJECTIVE:We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin-1 receptor-associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone. METHODS:This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C-reactive protein (DAS28-CRP) at week 12. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS:Overall, 460 patients were randomized. At week 12, zimlovisertib + tofacitinib demonstrated a greater magnitude of mean CFB in DAS28-CRP (-2.65; 90% confidence interval [CI], -2.84 to -2.46) versus tofacitinib (-2.30; 90% CI, -2.49 to -2.11; P = 0.032); mean CFB with zimlovisertib + ritlecitinib (-2.35; 90% CI, -2.54 to -2.15) was similar to tofacitinib. TEAEs were reported in 246 patients (53.5%), with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by 9 patients (2.0%) and 10 patients reported serious AEs. One patient receiving tofacitinib died because of severe COVID-19 infection. Safety profiles were similar across all treatment groups, with no evidence of additive/synergistic issues. CONCLUSION:Zimlovisertib + tofacitinib was more effective than tofacitinib for the primary endpoint, whereas the efficacy of zimlovisertib + ritlecitinib did not achieve statistical significance versus tofacitinib. All treatments were well tolerated.

PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP. In patients with AD, PF-06817024, in aggregate, reduced disease severity and improved symptoms, as demonstrated by greater percentage decrease from baseline in Eczema Area and Severity Index (EASI) scores and reduced pruritus numerical rating scores, compared with placebo. The efficacy in AD appeared to be bimodal with a sub-group of participants exhibiting high levels of improvement (EASI75 and EASI90) for a sustained period of time after dosing. In patients with CRSwNP, a consistent trend of decrease in eosinophil levels was observed in the PF-06817024 group, compared with placebo. Further research would be needed to confirm the clinical benefit and safety of PF-06817024 as a treatment for allergic diseases. Trial registration ClinicalTrials.gov, NCT02743871. Registered 15 April 2016, https://clinicaltrials.gov/study/NCT02743871?term=NCT02743871 rank=1 .

Successful and selective inhibition of the cytosolic protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off-target effects, or are otherwise limited by poor cellular permeability. Peptide-based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer-based proteomimetics. The protein-like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1-binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell-penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.

Abstract Background The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Methods This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18–70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03–6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3–10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. Results In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4–121.4 h (SAD cohorts) and 162.0–234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3%/62.4–98.7% [SAD] and 91.1–99.6%/89.5–98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. Conclusions These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. Trial registration ClinicalTrials.gov identifier: NCT03334851.