The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) Study: Trial Design and Baseline Characteristics

<b><i>Introduction:</i></b> Despite optimal current care, up to 30% of individuals suffering from immunoglobulin A nephropathy (IgAN) will develop kidney failure requiring dialysis or kidney transplantation. The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study was designed to assess the benefits and risks of steroids in people with IgAN. We report the trial design as well as the baseline characteristics of study participants. <b><i>Methods:</i></b> It is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized trial of individuals with kidney biopsy-confirmed IgAN, proteinuria ≥1 g/day, and an estimated GFR of 20–120 mL/min/1.73 m², following at least 3 months of standard of care including maximum labelled (or tolerated) dose of renin-angiotensin system blockade. The original study design randomized participants 1:1 to oral methylprednisolone (0.6–0.8 mg/kg/day, maximum 48 mg/day) for 2 months, with subsequent weaning by 8 mg/day/month over 6–8 months, or matching placebo. The intervention was modified in 2016 (due to an excess of serious infection) to low-dose methylprednisolone (0.4 mg/kg/day, maximum 32 mg/day) for 2 months, followed by weaning by 4 mg/day/month over 6–9 months, or matching placebo. Participants recruited after 2016 also received prophylaxis against <i>Pneumocystis jirovecii</i> pneumonia during the first 12 weeks of treatment. <b><i>Results:</i></b> The study recruitment period extended from May 2012 to November 2019. By the time the excess of serious infections was observed, 262 participants had been randomized to the original full-dose treatment algorithm, and an interim analysis was reported in 2016. Subsequently, 241 additional participants were randomized to a revised low-dose protocol, for a total of 503 participants from China (373), India (78), Canada (24), Australia (18), and Malaysia (10). The mean age of randomized participants was 38, 39% were female, mean eGFR at randomization was 62.7 mL/min/1.73 m², and mean 24-h urine protein 2.54 g. The primary endpoint is a composite of 40% eGFR decline from baseline or kidney failure (dialysis, transplantation, or death due to kidney disease), and participants will be followed until the primary outcome has been observed in at least 160 randomized participants. Analyses will also be made across predefined subgroups. Effects on eGFR slope and albuminuria will also be assessed overall, as well as by the steroid dosing regimen. <b><i>Conclusions:</i></b> The TESTING study (combined full and low dose) will define the benefits of corticosteroid use on major kidney outcomes, as well as the risks of therapy, and provide data on the relative effects of different doses, in individuals with high-risk IgAN.

107. A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Oteseconazole (VT-1161) Oral Capsules versus Fluconazole and Placebo in the Treatment of Acute Vulvovaginal Candidiasis Episodes in Subjects with Recurrent Vulvovaginal Candidiasis (ultraViolet)

Background Recurrent vulvovaginal candidiasis (RVVC) affects nearly 138 million women globally each year. Currently there are no FDA approved treatments. The study was conducted to evaluate the efficacy of oral oteseconazole (VT-1161) in the prevention of culture-verified acute VVC episodes through Week 50 and compare the efficacy of oteseconazole and fluconazole in treatment of an acute VVC episode in RVVC subjects. Methods 219 subjects with history of RVVC (≥ 3 acute episodes within prior 12 months) were enrolled at 51 US sites. The study consisted of two phases. Induction Phase: Subjects who presented with a vulvovaginal signs and symptoms score of ≥ 3 and positive KOH test identifying Candida were randomized to either: • 600 mg oteseconazole on Day 1, 450 mg oteseconazole on Day 2 and matching placebo capsules; OR • 3 sequential 150 mg doses (every 72 hours) of over-encapsulated fluconazole together with matching placebo capsules Maintenance Phase: 185 subjects with resolved acute VVC infections (clinical signs and symptoms score of &lt; 3) on Day 14 received: • 150 mg oteseconazole or placebo weekly for 11 weeks • then 37-week Follow-up period Results Study achieved primary and secondary efficacy endpoints. Oteseconazole was superior to fluconazole/placebo in the proportion of subjects with ≥ 1 culture-verified acute VVC episode through Week 50 in the intent-to-treat (P &lt; 0.001). The average percentage of subjects with ≥ 1 culture-verified acute VVC episode through Week 50 was lower in the oteseconazole group (5.1%) compared to the fluconazole/placebo group (42.2%). Oteseconazole was noninferior to fluconazole in the proportion of subjects with resolved acute VVC infections at Day 14; 93.2% oteseconazole group, 95.8% fluconazole/placebo group. The percentage of subjects who had ≥ 1 treatment-emergent adverse event (TEAE) was similar; oteseconazole (54%), fluconazole/placebo (64%). Most TEAEs experienced were mild or moderate severity in both groups and no drug-related SAEs or adverse effects on liver function or QT intervals. Conclusion Oteseconazole was shown to be safe and effective in treatment of acute VVC, treatment of RVVC and prevention of recurrence of acute VVC episodes in RVVC subjects. Oteseconazole was non-inferior to fluconazole for treatment of acute VVC in subjects with RVVC. Disclosures Bassem Maximos, MD, Evofem Biosciences (Scientific Research Study Investigator, Speaker's Bureau)Mycovia Pharmaceutical (Scientific Research Study Investigator)Sage Therapeutics (Scientific Research Study Investigator, Speaker's Bureau) Thorsten Degenhardt, Ph.D, Mycovia Pharmaceuticals (Employee, Shareholder) Karen Person, M.S., Mycovia Pharmaceuticals, Inc. (Employee)Mycovia Pharmaceuticals, Inc. (Employee) Mahmoud Ghannoum, PhD, Mycovia Pharmaceuticals (Grant/Research Support, Research Grant or Support) Stephen Brand, Ph.D, Mycovia Pharmaceuticals (Employee)

Metastasiertes Melanom: Immuntherapie für Patienten ohne Krankheitsnachweis

<b>Background:</b> Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced – i.e., unresectable or metastatic – melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. <b>Methods:</b> We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. <b>Findings:</b> Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n = 56), nivolumab (n = 59), or placebo (n = 52). As of July 2, 2019, at a median follow-up of 28.4 months (IQR 17.7–36.8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12.4 months (95% CI 5.3–33.3) in the nivolumab group and 6.4 months (3.3–9.6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0.23 (97.5% CI 0.12–0.45; p &#x3c; 0.0001), and for the nivolumab group versus placebo group was 0.56 (0.33–0.94; p = 0.011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61.0–84.9) and at 2 years was 70% (55.1–81.0); in the nivolumab group, 1-year recurrence-free survival was 52% (38.1–63.9) and at 2 years was 42% (28.6–54.5); and in the placebo group, this rate was 32% (19.8–45.3) at 1 year and 14% (5.9–25.7) at 2 years. Treatment-related grade 3–4 adverse events were reported in 71% (95% CI 57–82) of patients in the nivolumab plus ipilimumab group and in 27% (16–40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment. <b>Interpretation:</b> Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3–4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease. <b>Funding:</b> Bristol-Myers Squibb.

Metastasiertes Melanom: Immuntherapie für Patienten ohne Krankheitsnachweis

<b>Background:</b> Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced – ie, unresectable or metastatic – melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. <b>Methods:</b> We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. <b>Findings:</b> Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n = 56), nivolumab (n = 59), or placebo (n = 52). As of July 2, 2019, at a median follow-up of 28.4 months (IQR 17.7–36.8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12.4 months (95% CI 5.3–33.3) in the nivolumab group and 6.4 months (3.3–9.6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0.23 (97.5% CI 0.12–0.45; p &#x3c; 0.0001), and for the nivolumab group versus placebo group was 0.56 (0.33–0.94; p = 0.011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61.0–84.9) and at 2 years was 70% (55.1–81.0); in the nivolumab group, 1-year recurrence-free survival was 52% (38.1–63.9) and at 2 years was 42% (28.6–54.5); and in the placebo group, this rate was 32% (19.8–45.3) at 1 year and 14% (5.9–25.7) at 2 years. Treatment-related grade 3–4 adverse events were reported in 71% (95% CI 57–82) of patients in the nivolumab plus ipilimumab group and in 27% (16–40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment. <b>Interpretation:</b> Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3–4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease. <b>Funding:</b> Bristol-Myers Squibb.

SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.

TPS1101 Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Concurrent use of luteinizing hormone-releasing hormone (LHRH) agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy (ET) and the disease is incurable. New therapies are needed to combat ET resistance, maintain patient quality of life (QoL), and delay the need for chemotherapy. AZD9833 (camizestrant) is an orally bioavailable, highly potent, next-generation SERD that demonstrated anti-cancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, 2020). A phase I study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor profile when administered alone or in combination with palbociclib, a CDK4/6 inhibitor (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ HER2− ABC who have not received any systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1,342 patients with de novo or recurrent ER+ HER2– ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive orally either (a) AZD9833 (75 mg, once daily), palbociclib (125 mg, once daily for 21 days followed by 7 days off treatment) and anastrozole-matching placebo (once daily) or (b) anastrozole (1 mg, once daily), palbociclib (same as active arm), and AZD9833-matching placebo (once daily). Premenopausal women and men will also receive LHRH agonists. The primary endpoint will be progression-free survival (PFS; up to 5 years). Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures. Enrollment began in January 2021. Acknowledgments: We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, UK, for providing medical writing assistance. Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04711252 .

Osilodrostat Is an Effective and Well-Tolerated Treatment for Cushing’s Disease (CD): Results From a Phase III Study With an Upfront, Randomized, Double-Blind, Placebo-Controlled Phase (LINC 4)

Background: In a prior Phase III, randomized-withdrawal study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid and sustained normalization of mean urinary free cortisol (mUFC) in most patients (pts) with CD. Now, we report efficacy and safety results from another Phase III study of osilodrostat in pts with CD that included an upfront, double-blind, randomized, placebo-controlled phase (LINC 4: NCT02697734). Methods: Adults with CD with mUFC &gt;1.3 x ULN were randomized 2:1 to osilodrostat 2 mg bid or matching placebo for a 12-week (W) double-blind period, with dose adjustments at W2, 5 and 8 (range 1-20 mg bid) based on efficacy and tolerability; dose matching and adjustments were managed by independent endocrinologists. From W12 to W48, all pts received open-label osilodrostat, with dose adjustments permitted (range 1-30 mg bid). At W48, pts could enter an optional extension. Primary endpoint: proportion of randomized pts in each arm who received ≥1 treatment dose with mUFC ≤ULN at W12. Results: 73 pts were randomized and received osilodrostat (n=48) or matching placebo (n=25; baseline median [range] mUFC 2.5 x ULN [0.7-12.5] vs 2.2 x ULN [0.2-18.9]). 77% of osilodrostat recipients achieved mUFC ≤ULN at W12 vs 8% of placebo recipients (OR 43.4; 95% CI 7.1-343.2; P&lt;0.0001). At W36, 81% (95% CI 69.9-89.1) of osilodrostat recipients had mUFC ≤ULN (key secondary endpoint). Median time to first controlled mUFC response was 35 days (95% CI 34‒52) for pts randomized to osilodrostat. Median duration of osilodrostat exposure at data cut-off (Feb 25, 2020) was 71.7 vs 62.3 weeks for pts randomized to osilodrostat and placebo (median [IQR] dose 4.7 [3.8-9.0] vs 6.0 mg/day [3.7-9.7]). Up to W12, 3 osilodrostat pts discontinued, 1 because of an AE (arthralgia), vs 0 with placebo. The most common (≥30%) AEs occurring by W12 were decreased appetite (38% osilodrostat vs 16% placebo), arthralgia (35% vs 8%) and nausea (31% vs 12%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 15% vs 0% and 44% vs 36% of osilodrostat and placebo pts; most were grade 1/2 and resolved with dose reduction/interruption and/or concomitant medication. During the overall study period, the most common (≥30%) AEs occurring on osilodrostat treatment were arthralgia (45%), decreased appetite (45%), fatigue (38%), nausea (37%) and headache (33%). Improvements in cardiovascular- and metabolic-related parameters, including systolic and diastolic blood pressure and HbA1c, were observed with osilodrostat treatment at W12 and W48. Conclusion: Osilodrostat was superior to placebo at normalizing mUFC levels at W12 (77% vs 8%). Improvements in mUFC levels were sustained at W36. Few pts discontinued because of AEs; hypocortisolism-related AEs were infrequent and manageable. We conclude that osilodrostat is a highly effective and well-tolerated treatment for pts with CD.

Immunotherapy to reduce frequency of urinary tract infections in people with neurogenic bladder dysfunction; a pilot randomised, placebo-controlled trial

Objective: To establish the feasibility of a randomized, placebo-controlled trial to investigate the effect of a specific immunotherapy bacterial lysate OM-89 (Uro-Vaxom®) in reducing the frequency of urinary tract infections in people with neurogenic bladder dysfunction. Design: A parallel-group, double-blind, randomized, placebo-controlled trial. Setting: Patients at home, recruited through out-patient contact, social media and patient support groups. Subjects: People with a spinal cord injury, multiple sclerosis, transverse myelitis or cauda equina syndrome who had suffered three or more clinically diagnosed urinary tract infections treated with antibiotics over the preceding 12 months. Interventions: All participants took one capsule of oral OM-89 immunotherapy (6 mg) or matching Placebo (randomisation ratio 1:1), once daily in the morning for 3 months. Main measures: The primary outcome was occurrence of a symptomatic urinary tract infection treated with an antibiotic, assessed at 3 and 6 months. Feasibility measures included recruitment, retention and practical difficulties. Results: Of 115 patients screened, 49 were recruited, one withdrew before randomization, and 23 were allocated to the control group receiving matching placebo. Six participants, all in the control group, discontinued the intervention; all participants provided full data at both follow-up times. Over 6 months, 18/25 active group patients had 55 infections, and 18/23 control group patients had 47 infections. Most research and clinical procedures were practical, and acceptable to participants. Conclusion: It is feasible to undertake a larger trial. We recommend broader inclusion criteria to increase eligibility and generalizability.

OP0234 MBS2320, A NOVEL SELECTIVE MODULATOR OF IMMUNE METABOLISM, IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY

Background:Despite the availability of several treatment options for Rheumatoid Arthritis (RA), many patients are classed as ‘non-responders’ who show little or no improvement. Hence, there remains a need for new therapies with a differentiated mechanism of action, to be used alone or in combination. MBS2320 is a selective modulator of immune metabolism displaying distinctive dual pharmacology: strong anti-inflammatory activity as well as a broader spectrum of osteoprotection than TNFα inhibition in preclinical models1.Objectives:To evaluate the safety, tolerability and efficacy of MBS2320 in patients receiving a stable dose of methotrexate (MTX).Methods:Patients with active RA on a stable dose of MTX were randomised 2:1 to receive MBS2320 (80mg) or matching placebo once daily for 4 weeks. Subject to a satisfactory safety and tolerability assessment, patients were escalated to a dose of 120 mg qd or remained on 80 mg qd for a further 8 weeks. Safety, efficacy, pharmacokinetics and pharmacodynamics were evaluated.Results:121 patients were randomised (Safety analysis set) to MBS2320 or matching placebo and 96 completed the study. Sixteen subjects were excluded from the efficacy analysis set due to evidence of poor compliance or absence of efficacy evaluations. Enrolled patients were mostly female (86.8%), white and with a mean (range) age at baseline (BL) of 52 (19-69) years.The study population had hard-to-treat, severe, active and erosive disease as indicated by high BL DAS28-CRP and DAS28-ESR, low Week-12 placebo ACR50 and DAS28-CRP responder rates (2.5% and 5% respectively) and a low ratio of synovitis-to-erosion volume despite treatment with DMARD(s).There were no serious treatment emergent adverse events (TEAEs). 15 patients (19%) randomised to MBS2320 withdrew due to TEAEs, predominantly of nausea. TEAEs were typically reported soon after dosing, were mostly mild in severity and resolved without treatment. Onset of TEAEs reduced as the study proceeded.Gastrointestinal disorders were the most frequently reported TEAEs (all causalities) with a higher incidence in patients receiving MBS2320 (68.8%) than placebo (14.6%). Nausea was most frequently reported during Week 1 (27.3% patients). Asthenia and/or fatigue was reported more frequently in the MBS2320 treatment group (23.8% patients) than with placebo (7.3% patients), with the majority being considered related to study drug. Infections were more frequently reported by patients receiving placebo (22.0%) than those receiving MBS2320 (12.5%). There were no clinically relevant treatment-related trends in the biochemistry, haematology, urinalysis, vital signs or ECG data.Higher ACR20 response rates were observed in patients receiving MBS2320 versus those receiving placebo at all time points and increased with time. At Week 12, ACR50 response rates with MBS2320 treatment were increased by >4-fold compared with placebo (11.6% vs 2.5%). Greater mean reductions from baseline in DAS28-CRP were also observed in patients receiving MBS2320 versus those receiving placebo at Week 12 (-18.6% vs -8.4%). DAS28-CRP responder rates were more than doubled with MBS2320 treatment compared to placebo (5% vs 14%). These changes were mirrored by improvements in tender joint counts, reduced hsCRP and improvements in Patient Reported Outcomes of pain VAS, Patients’ and Clinicians‘ Global Assessments of Disease Activity and Patients‘ Global Impression of Change.Conclusion:MBS2320 was generally well tolerated for up to 12 weeks in this RA study population. Nausea was the most common TEAE, was generally mild in severity and resolved without treatment. In this population of patients with hard-to-treat, severe, active, erosive disease MBS2320 showed evidence of a clinical benefit on both ACR20 responses and DAS28-CRP.References:[1]Patel et al, Ann Rheum Dis, 78, S2, 2019, A228Acknowledgments:Louise Jopling, Ian Anderson, Ian Gourley, Devenini Damayanthi,Disclosure of Interests:Lisa Patel Shareholder of: Istesso Ltd, Employee of: Istesso Ltd, Laurence Skillern Consultant of: Istesso Ltd, Martyn Foster Shareholder of: Istesso Ltd, Consultant of: Istesso Ltd, Andy Gray Shareholder of: Istesso Ltd, Consultant of: Istesso Ltd, Richard Leff Consultant of: Istesso Ltd, Sam Williams Shareholder of: Istesso Ltd, Employee of: Istesso Ltd

143 A Combination of Olanzapine and Samidorphan Has No Clinically Relevant Effect on QT Prolongation up to Supratherapeutic Doses

Background:ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM) in development for schizophrenia, is intended to mitigate olanzapine-associated weight gain. This thorough QT (tQT) study evaluated OLZ/SAM effects on electrocardiogram parameters.Methods:In this randomized, double-blind, parallel-group study, 100 patients with stable schizophrenia were randomized 3:2 to either receive OLZ/SAM 10/10 mg (therapeutic dose) on days 2–4, 20/20 mg on days 5–8, and 30/30 mg (supratherapeutic dose) on days 9–13 with moxifloxacin-matching placebo on days 1 and 14, or a single dose of moxifloxacin 400 mg and matching placebo on days 1 and 14 (nested crossover design). Drug concentration relation to change from baseline in Fridericia-corrected QTc (ΔQTcF) was evaluated using a linear mixed-effect concentration-QTc (C-QTc) model. Adverse events were assessed.Results:The slope (90% CI) of the C-QTc was not significant for olanzapine or samidorphan (0.03 [−0.01, 0.08] and 0.01 [−0.01, 0.04] msec per ng/mL, respectively). Predicted placebo-corrected ΔQTcF (90% CI) was 2.33 (−2.72, 7.38) and 1.38 (−3.37, 6.12) msec at the observed geometric mean maximal concentration of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL), respectively, on day 13. A clinically relevant QT effect (ie, placebo-corrected ΔQTcF ≥10 msec) can be excluded for olanzapine and samidorphan concentrations up to ≈110 and ≈160 ng/mL, respectively. Assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated.Conclusions:OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, was well tolerated and had no clinically relevant effects on electrocardiogram parameters, including QT interval, in patients with schizophrenia.Funding Acknowledgements:This study was funded by Alkermes, Inc.