A Phase 1 Study to Evaluate the Safety and Pharmacokinetics following Administration of Single and Multiple Doses of the Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an anti-staphylococcal lysin, was administered intravenously as a 6 mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein.

REcovery and SURvival of patients with moderate to severe acute REspiratory distress syndrome (ARDS) due to COVID-19: a multicentre, single-arm, Phase IV Itolizumab Trial: RESURRECT

Objective: To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 ratio (PFR) ≤200 requiring oxygen therapy. Design: A multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days. Methods: Hospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200, oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19 specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90. Results: Day-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO2 without increasing FiO2. Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS and respiratory failure. No deaths were attributable to Itolizumab. Conclusion: Itolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.

Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis

Background Treatment-emergent adverse events (TEAEs) that occur close to treatment initiation may negatively affect overall tolerability and adherence. It is important to develop a clear understanding of potential early TEAEs after initiating treatment with cladribine tablets. Objective To identify TEAEs that begin early in the course of treatment in patients enrolled in CLARITY and ORACLE-MS studies. Methods This post hoc analysis of CLARITY and ORACLE-MS safety populations assessed the incidence of TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation in patients receiving cladribine tablets or placebo within 2, 6, and 12 weeks after treatment initiation. Results By Week 12, 61.3% of patients treated with cladribine tablets 3.5 mg/kg and 55.2% treated with placebo experienced a TEAE. More patients receiving cladribine tablets versus placebo experienced a drug-related TEAE by Week 12 (34.7% vs. 23.2%). The most common TEAEs reported with cladribine tablets were: headache (7.2%), lymphopenia (6.8%), and nausea (6.0%). Patients receiving cladribine tablets and placebo reported similar proportions of serious TEAEs (2.2% vs. 1.7%) and TEAEs leading to treatment discontinuation (1.6% vs. 1.4%). Conclusion Cladribine tablets were well tolerated during the first 12 weeks as evidenced by a low incidence of TEAEs leading to treatment discontinuation.

Results of the phase 2 MARCH Study: Oral ATG-010 (Selinexor) plus low dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma (RRMM) previously treated with an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI).

e20002 Background: ATG-010 is a novel, oral selective inhibitor of nuclear export inhibiting exportin 1. In preclinical and clinical studies, ATG-010 has demonstrated activity against multiple myeloma (MM). ATG-010 (80 mg biweekly) plus dexamethasone (20 mg biweekly) (Sd) was approved by US FDA for treatment of patients (pts) with penta-refractory MM in 2019 based on the STORM study. MARCH is a single arm, Phase 2 study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled pts have been previously treated with and refractory to PI, IMiD, and the last line of therapy. Sd is administered in 4-week cycles. Primary endpoint is overall response rate (ORR) per independent review committee. The total planned enrollment of 82 pts provides ̃80% power to test against H0 of 15% ORR at one-sided α of 0.025. This abstract provides data from a planned analysis of the first 60 treated pts. Results: As of 13 Oct 2020, 18 (30%) of the 60 pts were on treatment. Median follow-up was 9.5 months (mo) (range: 1.9-12.8). Median age was 61 years (range 43-82; 42% > 65). Pts had received a median of 5 (range 1-16) prior MM regimens, with following baseline risk factors: 72% R-ISS II/III, 70% cytogenetic abnormalities, 22% del (17p13),20% renal impairment, 15% prior CAR-T therapy, and 25% pre-treated with daratumumab (considered ‘triple-class exposed’). ORR was 26.7% (95% CI: 16.1, 39.7). Median DOR was 4.6 mo (95% CI: 1.42, NE). Median PFS was 3.7 mo (95% CI: 1.92, 4.66). Median OS was not reached; 9-mo OS rate was 68.5%. ORR was 33.3% in triple-class-exposed pts, and 44.4% in pts with prior CAR-T. ORR was generally consistent across subgroups. Common TEAEs of any grade included: thrombocytopenia (87%), nausea (87%), leukopenia (85%), anemia (85%), lymphopenia (78%), neutropenia (73%), weight loss (72%), hyponatremia (65%), decreased appetite (63%), asthenia (62%)/fatigue (17%), hyperglycemia (53%), vomiting (52%), hypocalcemia (38%), hypokalemia (30%), diarrhea (30%), pneumonia (27%). Common TEAEs of Grade ≥ 3 included: anemia (60%), thrombocytopenia (55%), leukopenia (42%), lymphopenia (42%), neutropenia (38%), hyponatremia (28%), and pneumonia (23%). Thirty pts (50%) had TESAEs, including (> 3%): thrombocytopenia (15%), pneumonia (15%), anemia (6.7%), hyponatremia (3.3%). Eight pts (13.3%) had TEAEs leading to treatment discontinuation, including (> 2%): thrombocytopenia (5%) and pneumonia (3%). Three fatal TEAEs were pneumonia, intracranial hemorrhage and sudden death (1 each). Conclusions: In Chinese RRMM pts refractory to both IMiD and PI, with a highly unmet medical need, MARCH confirms the efficacy of Sd as a promising new oral therapeutic option with a manageable safety profile, which is consistent with STORM. Clinical trial information: NCT03944057.

Copanlisib + rituximab versus rituximab + placebo in patients with relapsed follicular (FL) or marginal zone lymphoma (MZL): Subset analysis from the phase III CHRONOS-3 trial.

7510 Background: Rituximab (R) monotherapy is an approved treatment for patients (pts) with relapsed indolent NHL (iNHL) who have a prolonged progression-free and treatment-free interval after last R-based therapy or who are unwilling/unfit to receive chemotherapy. Copanlisib (C) is a PI3K inhibitor approved as monotherapy in pts with relapsed FL who have progressed after ≥2 systemic therapies. The recent Phase III CHRONOS-3 study in pts with relapsed iNHL treated with C+R vs placebo (P)+R (NCT02367040) met its primary endpoint with a significant 48% reduction in the risk of disease progression or death (Matasar et al. AACR 2021). We report here a pre-planned subset analysis in pts with relapsed FL or MZL. Methods: Pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after last R-based therapy or ≥6 mo if unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed progression-free survival (PFS) by Cheson 2014 criteria. Secondary endpoints included objective response rate (ORR), duration of response (DoR), complete response rate (CRR), time to progression (TTP), and treatment-emergent adverse events (TEAEs). All randomized pts were assessed for efficacy; pts were assessed for safety if they received ≥1 dose of C/P or R. The data cut-off date was August 31, 2020. Results: From a total dataset of 458 iNHL pts, 250 pts with FL/MZL (184 FL/66 MZL) were randomized to C+R and 120 (91 FL/29 MZL) to P+R. Median age was 62 years (range 28-91) and the arms were well balanced. With a median follow-up of 18.5 mo, C+R significantly reduced the risk of disease progression/death vs P+R (HR = 0.55 [95% CI 0.40, 0.76]; 1-sided p = 0.0001); median PFS was 22.2 mo (95% CI 19.1, 33.1) vs 15.4 mo (95% CI 11.0, 19.2), respectively. Median TTP was 27.5 mo for C+R vs 15.4 mo for P+R (HR = 0.500; 1-sided p = 0.00001). ORRs were 82.4% (CRR 37.6%) for C+R and 50.8% (CRR 18.3%) for P+R; median DoR was 23.9 mo vs 17.9 mo, respectively. Most common TEAEs (all grades [G]/G3+) in pts with FL/MZL receiving C+R (n = 249) were hyperglycemia (72.7%/59.0%), hypertension (53.8%/43.0% [all G3]), and diarrhea (35.3%/5.6% [all G3]). For pts receiving P+R (n = 116), the most common TEAEs were hyperglycemia (23.3%/7.8% [all G3]), hypertension (19.8%/8.6% [all G3]), neutropenia (18.1%/13.8%), and upper respiratory tract infection (18.1%/0%). Conclusions: C+R demonstrated superior efficacy vs P+R in pts with relapsed FL/MZL and had a manageable safety profile, consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed FL/MZL, representing a potential new therapeutic option. Clinical trial information: NCT02367040.

337 A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Analysis of Female Subgroup

Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.

335 Evaluation of Dose Transition From Zolpidem to Lemborexant Across 14 Weeks: Results From a Multicenter Open-label Pilot Study

Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.

Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

Abstract 13951: Safety, Tolerability and Efficacy of Single-dose Amg 890, a Novel Sirna Targeting Lp(a), in Healthy Subjects and Subjects With Elevated Lp(a)

Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of > 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.