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Dual toll-like receptor (TLR) 7 and TLR8 inhibitor enpatoran is under investigation as a treatment for lupus and coronavirus disease 2019 (COVID-19) pneumonia. Population pharmacokinetic/pharmacodynamic (PopPK/PD) model-based simulations, using PK and PD (inhibition of ex vivo-stimulated interleukin-6 (IL-6) and interferon-α (IFN-α) secretion) data from a phase I study of enpatoran in healthy participants, were leveraged to inform dose selection for lupus and repurposed for accelerated development in COVID-19. A two-compartment PK model was linked to sigmoidal maximum effect (E

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo-controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG-based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient-level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non-Asian patients, supporting Asia-inclusive global SLE drug development. These results describe the first population approach to support a model-informed drug development framework in SLE.

Immunosuppressive drugs can alleviate debilitating symptoms of autoimmune diseases, but, by the same token, excessive immune suppression can result in an increased risk of infection. Despite the dangers of a compromised immune system, clear definitions of what constitutes excessive suppression remain elusive. Here we review the most common infections associated with primary antibody deficiencies (PADs), such as agammaglobulinemia, common variable immunodeficiency (CVID), and IgA deficiency, as well as infections that are associated with drug-induced or secondary antibody immunodeficiencies (SADs). We identify a number of bacterial, viral, and fungal infections (e.g., Listeria monocytogenes, Staphylococcus sp., Salmonella spp., Escherichia coli, influenza, varicella zoster virus, and herpes simplex virus) associated with both PADs and SADs, and suggest that diagnostic criteria for PADs could be used as a first-line measure to identify potentially unsafe levels of immune suppression in SADs. Specifically, we suggest that, based on PAD diagnostic criteria, IgG levels should remain above 2–3 g/L, IgA levels should not fall below 0.07 g/L, and IgM levels should remain above 0.4 g/L to prevent immunosuppressive drugs from inducing mimicking PAD-like effects. We suggest that these criteria could be used in the early stages of drug development, and that pharmacokinetic and pharmacodynamic modeling could help guide patient selection to potentially improve drug safety. We illustrate the proposed approach using atacicept as an example and conclude with a discussion of the applicability of this approach for other drugs that may induce excessive immune suppression. Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00706-z.

Objective Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Methods Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment Results Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. Conclusion At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

Signal transducer and activator of transcription 5 (STAT5) plays an important role in regulating gene expression in response to cytokines of the common (γc) chain family. In this capacity, STAT5 promotes CD8(+) effector and memory T cell survival and regulatory T cell development. However, its function in conventional CD4(+) T cells is less clear. In this study, the requirement of intact STAT5 signaling for CD4(+) effector and memory T cell generation and maintenance was investigated by using DO11.10 TCR transgenic T cells that are genetically deficient in STAT5A or B, as well as by transducing DO.11 T cells with a dominant-negative STAT5 to temporally block STAT5 function. We found that the presence of STAT5A or B alone was sufficient for primary CD4(+) effector T cell generation, but not for establishing a long-lived memory cell population. Similarly, blocking STAT5 signaling during priming did not prevent initial T cell activation, but inhibited the generation of memory cells. Surprisingly, blocking STAT5 post-priming did not impact the long-term survival of CD4(+) memory T cells in vivo. Mechanistically, intact STAT5B, but not STAT5A, was required for IL-7Rα re-expression in activated T cells, which is an important cytokine receptor for CD4(+) memory generation. These data show that fully functional STAT5 is essential to deliver an early, non-redundant signal for memory programming during the primary CD4(+) T cell response, while partial STAT5 signaling is sufficient for effector differentiation. Our results have implications for the precise use of STAT5 inhibitors to timely inhibit memory T cell responses.

Objectives Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

ObjectiveTo investigate the effects of abituzumab in systemic sclerosis–associated interstitial lung disease (SSc-ILD).MethodsSTRATUS was a phase II, double-blind, parallel-group, multicenter trial (ClinicalTrials.gov: NCT02745145). Adults (≤ 75 yrs) with SSc-ILD on stable mycophenolate were randomized (2:2:1) to receive intravenous abituzumab 1500 mg, abituzumab 500 mg, or placebo every 4 weeks for 104 weeks. The primary endpoint was the annual rate of change in absolute forced vital capacity.ResultsSTRATUS was terminated prematurely due to slow enrollment (n = 75 screened, n = 24 randomized), precluding robust analysis of efficacy. Abituzumab was well tolerated; no new safety signals were detected.ConclusionFurther investigation of abituzumab for treatment of SSc-ILD is required.

Immunosuppressive drugs can alleviate debilitating symptoms of autoimmune diseases, but, by the same token, excessive immune suppression can result in an increased risk of infection. Despite the dangers of a compromised immune system, clear definitions of what constitutes excessive suppression remain elusive. Here we review the most common infections associated with primary antibody deficiencies (PADs), such as agammaglobulinemia, common variable immunodeficiency (CVID), and IgA deficiency, as well as infections that are associated with drug-induced or secondary antibody immunodeficiencies (SADs). We identify a number of bacterial, viral, and fungal infections (e.g., Listeria monocytogenes, Staphylococcus sp., Salmonella spp., Escherichia coli, influenza, varicella zoster virus, and herpes simplex virus) associated with both PADs and SADs, and suggest that diagnostic criteria for PADs could be used as a first-line measure to identify potentially unsafe levels of immune suppression in SADs. Specifically, we suggest that, based on PAD diagnostic criteria, IgG levels should remain above 2-3 g/L, IgA levels should not fall below 0.07 g/L, and IgM levels should remain above 0.4 g/L to prevent immunosuppressive drugs from inducing mimicking PAD-like effects. We suggest that these criteria could be used in the early stages of drug development, and that pharmacokinetic and pharmacodynamic modeling could help guide patient selection to potentially improve drug safety. We illustrate the proposed approach using atacicept as an example and conclude with a discussion of the applicability of this approach for other drugs that may induce excessive immune suppression.

Background Low disease activity (LDA) and remission are important goals in the treatment of patients with SLE.1 2 Lupus Low Disease Activity State (LLDAS) is associated with reduced damage accrual,2 and has been shown to be a feasible clinical trial endpoint.3 In patients with high disease activity (HDA; SLEDAI-2K ≥10) enrolled in the ADDRESS II study, atacicept improved SLE responder index (SRI)-6 response rates and flare prevention at Week 24 vs placebo. Atacicept also demonstrated an acceptable safety profile.4 We present a post-hoc analysis of data from ADDRESS II and its long-term extension, describing 48-week LDA and remission rates in patients with HDA at Screening. Methods In ADDRESS II, patients were randomized (1:1:1) to weekly subcutaneous atacicept 75 or 150 mg or placebo for 24 weeks. Atacicept-completers continued at the same dose in the extension study, while placebo-treated patients were switched to atacicept 150 mg (placebo/atacicept 150 mg). This post-hoc analysis assessed: LDA (SLEDAI-2K ≤2), LLDAS (SLEDAI-2K ≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment [PGA] ≤1, prednisone-equivalent ≤7.5 mg/day, and stable immunosuppressants),2 and remission (clinical SLEDAI-2K=0, PGA Results Of 306 ADDRESS II patients, 158 (51.6%) had HDA at Screening. At Week 24, 42.4% achieved SRI-6, 23.4% attained LDA, 15.8% LLDAS and 10.8% remission. At Week 48, 52.5% achieved SRI-6, 26.6% attained LDA, 19.0% LLDAS and 10.8% remission. Among 83 patients with HDA at Screening who had an SRI-6 response at Week 48, 49.4% (n=41) attained LDA, 34.9% (n=29) LLDAS and 20.5% (n=17) remission. At 48 weeks, LDA, LLDAS and remission rates were higher in patients treated with atacicept 150 mg vs atacicept 75 mg and vs placebo/atacicept 150 mg (figure 1). Conclusions ADDRESS II patients with HDA at Screening who received atacicept 150 mg were more likely to attain LDA, LLDAS and remission at Week 48 than those treated with atacicept 75 mg or placebo/atacicept 150 mg. These endpoints were more stringent and discriminatory than SRI-6, confirming LLDAS, LDA, and remission to be robust and meaningful endpoints for SLE trials. In addition, these data further support future studies of atacicept in SLE. Funding Source(s): Merck KGaA, Darmstadt, Germany References Van Vollenhoven et al. Ann Rheum Dis 2017. Franklyn et al. Ann Rheum Dis 2016. Morand et al. Ann Rheum Dis 2018. Merrill et al. Arthritis Rheum 2018.

Purpose Atacicept targets the B-cell stimulating factors, BLyS and APRIL, and has shown evidence of clinical response in patients with SLE. The 24 week Phase II ADDRESS II (NCT01972568) Study and its long-term extension (LTE; NCT02070978) provided data on disease activity with up to 48 weeks of atacicept treatment. Methods In ADDRESS II, patients were randomised (1:1:1) to receive weekly atacicept (75 or 150 mg SC injection) or placebo (PBO) for 24 weeks. Those who completed treatment were eligible to enter the LTE, to either continue on the same atacicept dose (atacicept groups), or switch from PBO to atacicept 150 mg (PBO/150 mg). The SLE flare analysis from both studies are reported here. Results The ITT population of ADDRESS II included 306 patients; 158 of whom met the predefined high disease activity (HDA) criterion (SLEDAI-2K≥10 at Screening). Of the 262 patients who completed the ADDRESS II, 253 entered the LTE. At 24 weeks in the PBO-controlled trial, cumulative incidence of severe flare was significantly reduced with atacicept 75 mg vs PBO by BILAG A (HR 0.24; p=0.0186), and with atacicept 150 mg vs PBO by SFI (HR 0.18; p=0.002). There was no difference in moderate-to-severe flare by BILAG A/2B. In the HDA subpopulation, incidence of severe flare at 24 weeks was significantly reduced with both atacicept doses vs PBO by BILAG A (75 mg HR 0.08, p=0.002; 150 mg HR 0.32, p=0.038) and SFI (75 mg HR 0.33, p=0.029; 150 mg HR 0.19, p=0.004). Incidence of moderate-to-severe flare by BILAG A/2B was significantly reduced with atacicept 150 mg vs PBO (HR 0.34, p=0.032). At 48 weeks, risk of severe flare by SFI was significantly lower with atacicept 150 mg vs the PBO/150 mg in both the ITT and HDA populations (figure 1); significant flare reductions were seen with atacicept 75 mg by BILAG A, and with both atacicept doses by BILAG A/2B vs PBO/150 mg, in the HDA subpopulation. Conclusions In this 24 week, double-blind, PBO-controlled trial, atacicept treatment was associated with significant flare reductions compared with PBO. Rates of flare continued to be low in atacicept-treated patients between weeks 24–48. Most flares occurred in HDA patients in the PBO group.

Purpose Atacicept targets B-cell stimulating factors, BLyS and APRIL. ADDRESS II (NCT01972568) investigates the efficacy and safety of atacicept in SLE. Methods In this Phase IIb multicenter study, patients with active (SLEDAI-2K≥6), autoantibody-positive SLE on standard of care therapy received weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO) for 24 weeks. The primary endpoint was proportion of patients achieving SLE responder index (SRI)−4 response at week 24. Other endpoints included SRI-5 through SRI-8 response and low disease activity (LDA) attainment, defined as LDA-1 (SLEDAI-2K≤2), LDA-2 (SLEDAI-2K≤2 and prednisone-equivalent ≤7.5 mg/day), or LLDAS (SLEDAI–2K≤4 without major organ activity, no new disease activity vs previous visit, Physician’s Global Assessment≤1, prednisone-equivalent ≤7.5 mg/day, and stable maintenance doses of immunosuppressants). A pre-defined subset of patients was also evaluated, with high disease activity (HDA: SLEDAI-2K≥10 at Screening). Differences in clinical response between patients treated with atacicept and PBO at Week 24 were analysed using odds ratio estimated from logistic regression. Results The ITT population included 306 patients, and 158 had HDA. There was a trend towards improved SRI-4 response with atacicept vs PBO at Week 24 (p=ns in primary analysis; screening visit as baseline, BL). In a pre-specified sensitivity analysis using study day 1 as BL, a significantly larger proportion of patients on atacicept achieved SRI-4 response at week 24. In the HDA subpopulation, there were significant improvements in SRI-4,–5, −6,–7 and −8 response rates and attainment of LDA with atacicept 150 mg vs PBO (table 1). Atacicept was associated with increased serum C3 and C4, and decreased IgG, IgA, IgM and anti-dsDNA antibodies over time. Rates of treatment emergent adverse event (TEAE) and serious TEAEs were similar among groups. The most frequent serious TEAEs were infections but the incidence was not increased in the atacicept groups vs PBO. Conclusions Atacicept showed evidence of efficacy in SLE with a dose-dependent reduction of SLE disease activity in patients with HDA. Atacicept was associated with an acceptable safety profile. These results also suggest that more discriminatory endpoints will be useful for future SLE clinical trials.

Autoantigen-specific methods to prevent and treat Type 1 Diabetes (T1D) carry high hopes to permanently cure this disease, but have largely failed in clinical trials. One suggested approach to increase the efficacy of islet antigen-specific vaccination is to combine it with a modulator of the T cell response, with the goal of reducing effector differentiation and promoting regulatory T cells (Tregs). Here we asked if addition of antibodies that block the IL-7/IL-7Rα pathway altered the T cell response to islet antigen vaccination and prevented T1D in non-obese diabetic (NOD) mice. Anti-IL-7Rα monoclonal antibodies (mAbs) reduced the numbers of islet antigen-specific T cells generated after vaccination with islet peptides and alum. However, addition of anti-IL-7Rα antibodies to peptide/alum vaccination unexpectedly increased non-specific IFN-γ, IL-2 and IL-10 cytokine production and did not result in improved prevention of T1D onset. In a second approach, we used a conjugate vaccine to deliver islet autoantigens, using Keyhole Limpet Hemocyanin (KLH) as a carrier. Islet antigen-KLH vaccination led to a significant expansion of antigen-specific Tregs and delayed diabetes onset in NOD mice. These outcomes were not further improved by addition of anti-IL-7Rα antibodies. To the contrary, blocking IL-7Rα during vaccination led to non-specific cytokine production and reduced the efficacy of a KLH-conjugated vaccine to prevent T1D. Our study thus revealed that adding anti-IL-7Rα antibodies during autoantigen immunization did not improve the efficacy of such vaccinations to prevent T1D, despite altering some aspects of the T cell response in a potentially advantageous way. Further refinement of this approach will be required to separate the beneficial from the adverse effects of anti-IL-7Rα antibodies to treat autoimmune disease.

Fas drives activated T cell apoptosis in vitro, but lymphadenopathy and lupus development in Fas-deficient (lpr) mice cannot be explained only on the basis of the lpr T cell apoptotic defect. Unexplained also remains the in vivo hyperproliferation of T cells in lpr mice, including CD4+, CD8+ and CD4-CD8-TCR+ cells. To date, the effect of lpr T cell-hyperproliferation in both lymphadenopathy and lupus autoimmunity is not known. We investigate this point by generating T cell-specific p21-trangenic -lpr mice. p21, a cell cycle inhibitor and a lupus-like autoimmunity suppressor, regulates the expansion of memory but not of naïve T cells. p21 overexpression in lpr T cells did not affect primary T cell responses, but profoundly diminished lpr T cell proliferation after secondary activation, without affecting the compromised apoptotic cell death of lpr T cells. Importantly, in vivo, p21 overexpression restrains lpr T cell memory expansion, and results in reduced autoantibody production, glomerulonephritis and lymphadenopathy in lpr mice. p21 overexpression did not affect T cell memory in wt mice, pointing to a specialized role for p21 in hyperproliferating T cells. Overall we conclude that lpr T cell hyperproliferation is essential for the increased T cell memory, the autoimmunity and the lymphadenopathy development in lpr mice. Thus, decreasing the hyperproliferation of pathogenic T cells may be of therapeutic value for both Lupus and the Autoimmune Lymphoproliferative Syndrome.

Background Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing β-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Rα antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Rα administration. Results Anti-IL-7Rα antibodies were administered to prediabetic NOD mice for 3 weeks and blood samples were taken at the end of treatment and 2 weeks later to analyze changes in T cell phenotypes in response to IL-7Rα blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+ and CD8+ T cells from anti-IL-7Rα-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+ T cells was increased at the end of anti-IL-7Rα antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Rα-treated mice were more sensitive to co-inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics. Conclusions Together, our data show that short-term blockade of IL-7Rα induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Rα antibodies to modulate autoreactive T cell responses.