s7a 4 reduction of systemic lupus flares by atacicept in a randomised placebo controlled phase iib study address ii and its extension study

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

ps7 133 exposure response modelling and exposure safety modelling analyses in two phase ii studies of atacicept in sle

Purpose Atacicept targets the B-cell stimulating factors BLyS and APRIL, and has been shown to reduce SLE disease activity. Methods APRIL-SLE (NCT00624338) and ADDRESS II (NCT01972568) were phase II, multicenter studies in patients (pts) with autoantibody-positive SLE randomised (1:1:1) to weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO). In APRIL-SLE, pts had BILAG A/B flare at Screening that was reduced to BILAG C/D before randomization using corticosteroids; the primary endpoint was BILAG A/B flare over 52 weeks. In ADDRESS II, pts had SLEDAI-2K≥6 at Screening; the primary endpoint was SRI-4 response at Week 24. SLE responder index (SRI)−6 response was analysed post-hoc in high disease activity (HDA; SLEDAI-2K≥10) pts. Population pharmacokinetic (PK) model-derived exposure vs the probability of response (BILAG A/B flare, SRI-4, SRI-6), exploratory analysis of exposure vs safety, and population model simulations of serum IgG were analysed. Results Exposure-response modelling suggests a relationship between atacicept exposure and SLE clinical response [figure 1], including serum IgG changes from baseline. The optimal atacicept exposure was AUCtau,ss ≥~1 mg.hr/mL, which is more achievable with weekly SC doses of atacicept 150 mg than 75 mg across a range of body weights. Body weight-based dosing is unlikely to offer any value over a fixed 150 mg dose, based on comparable predicted clinical response. In HDA pts, greater reductions in serum IgG from baseline corresponded to a higher probability of SRI-6 response. Greater IgG reductions from baseline were associated with higher atacicept exposure; however, even at the highest exposure range, mean IgG reductions did not exceed ~40%. There was no association between serious/severe infections and exposure by PK quartile. Conclusions Exposure-response modelling indicated robust relationships between atacicept exposure and clinical response or IgG levels, supporting the proposed mechanism of action for atacicept. Atacicept 150 mg weekly SC is likely to provide an effective level of exposure with an acceptable safety profile. There was no evidence of an increased risk of severe or serious infections at higher exposures. Based on these results, the 150 mg dose merits further evaluation

s7a 5 sri response attainment of low disease activity and safety in patients with systemic lupus treated with atacicept in a phase iib study address ii

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

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

OBJECTIVES: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. MATERIALS AND METHODS: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. RESULTS: Thirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7–22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0–61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0–43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0–73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0–34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0–53.6%) in patients with low TMB. CONCLUSIONS: Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients

STRATUS, a Phase II Study of Abituzumab in Patients with Systemic Sclerosis-associated Interstitial Lung Disease

OBJECTIVE: To investigate the effects of abituzumab in systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: STRATUS was a Phase II, double-blind, parallel-group, multicenter trial (NCT02745145). Adults (≤75 years) with SSc-ILD on stable mycophenolate were randomized (2:2:1) to receive intravenous abituzumab 1500 mg, placebo, or abituzumab 500 mg every 4 weeks for 104 weeks. Primary endpoint: annual rate of change in absolute FVC. RESULTS: STRATUS was terminated prematurely due to slow enrolment (n=75 screened, n=24 randomized), precluding robust analysis of efficacy. Abituzumab was well-tolerated; no new safety signals were detected. CONCLUSION: Further investigation of abituzumab for treatment of SSc-ILD is required

Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer.

Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations

Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer

\ua9 2022, The Author(s). Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations