BACKGROUND AND OBJECTIVES:Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA. METHODS:In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points. RESULTS:Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported. DISCUSSION:Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA. TRIAL REGISTRATION INFORMATION:This trial is registered with ClinicalTrials.gov (NCT03921528). CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

Background and ObjectivesCurrently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA.MethodsIn this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants >= 2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points.ResultsFifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported.DiscussionApitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA.Trial Registration InformationThis trial is registered with ClinicalTrials.gov (NCT03921528).Classification of EvidenceThis study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

SMA manifests progressive denervation weakness caused by genetic constraint of the SMN protein expression. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds proforms of myostatin thereby inhibiting myostatin activation. Apitegromab is intended to improve motor function by targeting the residual innervated muscle fibers in patients with SMA. The TOPAZ phase 2 trial (NCT03921528) was designed to identify clinical and protocol features that will best enable further study of its potential therapeutic effect, in patients with SMA. TOPAZ was conducted in subjects with Type 2 or Type 3 SMA (age 2-21 years). Patients received IV apitegromab Q4W, either as monotherapy or as an adjunct to nusinersen. 58 patients were dosed in 3 cohorts. Primary and secondary efficacy endpoints (assessment of motor function improvements via the Hammersmith scale scores) and safety results from TOPAZ were previously reported. Following the initial treatment period in TOPAZ, participants were offered the opportunity to enter an open label 12 month extension Period A, followed by a 12 month extension Period B. The TOPAZ study showed positive results in motor function scores at 12 months. Incidence and severity of AEs were consistent with the underlying patient population and background therapy. Of 58 subjects enrolled in TOPAZ, 55 continued in extension Period A. We will present here multiple efficacy endpoints and safety analyses of the extension Period A, after 2 years of apitegromab treatment. TOPAZ provided proof-of-concept that apitegromab has the potential to be the first muscle-directed therapy, complementary to SMN-augmenting therapy, in patients with SMA. TOPAZ extension B is ongoing and will provide further long-term efficacy and safety data of apitegromab in SMA patients. This information is helpful to the understanding of latent myostatin dynamics, apitegromab's therapeutic role for SMA, and the planning of future studies.

Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin—promyostatin and latent myostatin—thereby inhibiting myostatin activation.

Apitegromab is an investigational, fully human, monoclonal antibody that inhibits myostatin activation by specific binding to myostatin proforms, promyostatin and latent myostatin. We will present data, from the Phase 2 TOPAZ clinical trial (NCT03921528), on the relationships of pharmacokinetics (PK) and pharmacodynamic (PD) (marker of target engagement, latent serum myostatin levels) to apitegromab efficacy.

Apitegromab (SRK-015) is an anti-promyostatin monoclonal antibody under development to improve motor function in patients with spinal muscular atrophy, a rare neuromuscular disease. This phase 1 double-blind, placebo-controlled study assessed safety, pharmacokinetic parameters, pharmacodynamics (serum latent myostatin), and immunogenicity of single and multiple ascending doses of apitegromab in healthy adult subjects. Subjects were administered single intravenous ascending doses of apitegromab of 1, 3, 10, 20, 30 mg/kg or placebo, and multiple intravenous ascending doses of apitegromab of 10, 20, 30 mg/kg or placebo. Following single ascending doses, the pharmacokinetic parameters of apitegromab appeared to be similar across all dose groups, following a biphasic pattern of decline in the concentration–time curve. The mean apparent terminal t1/2 after single intravenous doses of apitegromab ranged from 24 to 31 days across dose groups. Dose-related increases were observed in Cmax following multiple ascending doses. Single and multiple apitegromab doses resulted in dose-dependent and sustained increases in serum latent myostatin, indicating robust target engagement. Apitegromab was safe and well tolerated, on the basis of the adverse event (AE) profile with no clinically meaningful changes in baseline vital signs, electrocardiograms, or clinical laboratory parameters and no anti-drug antibody formation. These results support continued investigation of apitegromab for the treatment of patients with milder forms (type 2 and 3) of spinal muscular atrophy.

Tuesday, April 28April 14, 2020Free AccessBaseline Characteristics of Participants of the SPARK Trial, a Phase 2 Study of the anti-alpha-synuclein antibody Cinpanemab (BIIB054) in Parkinson’s Disease (1579)Tara Fox, Andrew D. Siderowf, Hubert H. Fernandez, Caroline M. Tanner, Ronald B. Postuma, David K. Simon, Michael Byrne, … Show All … , Anthony E. Lang, David Brooks, Olivier Rascol, Eduardo Tolosa, Werner Poewe, Fabrizio Stocchi, Brit Mollenhauer, Nir Giladi, Beth Hirschhorn, Jesse M. Cedarbaum, George Nomikos, Laura Fanning, Minhua Yang, James Xiao, and Miroslaw Brys Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1579 Letters to the Editor

Background: Traditional randomized withdrawal studies have assessed the efficacy of antidepressants for reducing relapse and recurrence of major depressive episodes (MDEs) but have not compared dose reduction, increase, or maintenance within the same study. Methods: Here we present the development, implementation, and preliminary data from the open-label period of an ongoing phase 4, non-traditional, randomized withdrawal study. Designed to evaluate the efficacy of vortioxetine across its approved dose range for relapse prevention, the study enrolled adult patients with recurrent major depressive disorder (MDD), Montgomery-Asberg Depression Rating Scale (MADRS) >= 26, and history of >= 2 MDEs. After a 16-week, open-label, fixed-dose (vortioxetine 10 mg once daily) period, patients meeting response criteria 50% reduction in MADRS total score, Weeks 8-16) and remission criteria (MADRS total score <= 12, Weeks 14 and 16) were randomized to vortioxetine 5, 10, or 20 mg, or placebo in a 32-week doubleblind treatment period. Results: Of 1106 patients enrolled, 510 completed the open-label period (mean age: 45.7 years; mean MADRS = 5.0; predominantly female, white, and never smokers) and were eligible for randomization in the ongoing double-blind period. Limitations: Study is ongoing; only data from the open-label period are available for evaluation. Conclusions: Preliminary analysis suggests that patient baseline characteristics were not a factor in response to and stabilization with vortioxetine during the open-label period. The lack of flexibility in dosing, however, may have reduced the number of patients qualifying for randomization. This study design may provide useful information for optimizing the long-term efficacy and tolerability of vortioxetine treatment for MDD.

SAGE-217, a novel γ-aminobutyric acid A (GABAA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) studies to assess the safety and pharmacokinetics (PK) of SAGE-217 following administration as an oral solution. In the SAD study, subjects were randomized 6:2 to a single dose of SAGE-217 or placebo. Doses ranged from 0.25 to 66 mg across nine cohorts. In the MAD study, subjects were randomized 9:3 and received SAGE-217 (15, 30, or 35 mg) or placebo once daily for 7 days. In both studies, PK, maximum tolerated dose (MTD; against predetermined criteria), safety, and tolerability were assessed. A total of 108 healthy volunteers enrolled in the studies—72 subjects in the SAD study and 36 subjects in the MAD study. SAGE-217 was orally bioavailable, with a terminal-phase half-life of 16–23 h and a tmax of approximately 1 h. The MTDs for the oral solution of SAGE-217 in the SAD and MAD studies were determined to be 55 and 30 mg daily, respectively. In both studies, SAGE-217 was generally well tolerated, and no serious adverse events (SAEs) were reported. Most AEs were mild, dose-dependent, transient, occurred around the tmax, and related to drug pharmacology. SAGE-217 was generally well tolerated, and its PK profile was well characterized. Based on this profile, SAGE-217 has been advanced into multiple phase II clinical programs and pivotal studies of major depressive disorder and postpartum depression.

Objective: The objective of this work was to describe treatment-emergent sexual dysfunction (TESD) and tolerability following a switch from selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine, or sertraline) monotherapy to vortioxetine or escitalopram monotherapy in adults with well-treated major depressive disorder (MDD) and SSRI-induced sexual dysfunction. Methods: Data were analyzed from the primary study, an 8-week, randomized, double-blind, head-to-head study in which participants with well-treated depressive symptoms but experiencing TESD with SSRIs were directly switched to flexible doses (10/20 mg) of vortioxetine or escitalopram. Sexual functioning was assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), efficacy by the Montgomery–Åsberg Depression Rating Scale scores (MADRS) and Clinicians Global Impression of Severity/Improvement (CGI-S/CGI-I), and tolerability by adverse events. Efficacy and tolerability were assessed by pre-switch SSRI therapy where possible, and by participant characteristics. Results: Greater improvements in TESD were seen in the vortioxetine compared with escitalopram groups based on: participant demographics (≤45 years, women; P = 0.045), prior SSRI treatment ( P = 0.044), number of prior major depressive episodes (MDEs) (1–3; P = 0.001), and duration of prior SSRI therapy (>1 year; P = 0.001). Prior SSRI treatment did not appear to influence the incidence or severity of TEAEs, except for nausea. Regardless of prior SSRI, both treatments maintained antidepressant efficacy after 8 weeks. Conclusion: Results suggest that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age, and history of MDEs.

ObjectivesThis study aimed to evaluate the risk of suicidal ideation and behavior associated with vortioxetine treatment in adults with major depressive disorder (MDD).MethodsSuicide-related events were evaluated post hoc using 2 study pools: one short-term pool of 10 randomized, placebo-controlled studies (6–8 weeks) and another long-term pool that included 3 open-label extension studies (52 weeks). Evaluation of suicide-related events was performed using Columbia-Suicide Severity Rating Scale (C-SSRS) scores and treatment-emergent adverse events (TEAEs) data.ResultsAt baseline, the percentage of patients reporting any C-SSRS ideation or behavior events in short-term studies was similar between placebo (14.7%), vortioxetine (19.8%, 13.0%, 11.2%, and 13.7% for 5-, 10-, 15-, and 20-mg groups, respectively), and duloxetine active reference (13.2%) and did not change throughout the 6- to 8-week treatment period for placebo (17.0%), vortioxetine (19.3%, 13.5%, 12.6%, and 15% for 5-, 10-, 15-, and 20-mg groups, respectively), or duloxetine (11.3%). The incidence of suicide-related events for TEAEs in the short-term pool was 0.4% for placebo, 0.2% or 1.0% for vortioxetine 5 mg or 10 mg, and 0.7% each for vortioxetine 15 mg and 20 mg, as well as duloxetine. After 52-week treatment with vortioxetine, suicidal ideation based on C-SSRS was 9.8%, C-SSRS suicidal behavior was 0.2%, and the incidence of suicide-related events based on TEAEs was <1%. There were no completed suicides in any study.ConclusionsVortioxetine is not associated with increased risk of suicidal ideation or behavior in MDD patients.

INTRODUCTION:Sexual dysfunction is prevalent among patients with depression, but assessment of treatment-emergent sexual dysfunction (TESD), a common side effect of antidepressants, can be confounded by the treatment of depressive symptoms in some patients. AIM:To evaluate sexual functioning in healthy volunteers administered vortioxetine compared with paroxetine, an antidepressant known to cause sexual dysfunction, and placebo. METHODS:This phase 4, multicenter, randomized, double-blind, placebo-controlled, 4-arm, fixed-dose, head-to-head study compared sexual functioning in healthy volunteers administered vortioxetine (10 and 20 mg once daily [QD]), paroxetine (20 mg QD), or placebo for 5 weeks. Approximately equal numbers of men and women ages 18-40 years with normal sexual functioning (self-reported Changes in Sexual Functioning Questionnaire Short-Form [CSFQ-14] score > 47 for men; > 41 for women) were enrolled. Two modified full analysis sets adjusting for treatment non-compliance were prespecified. MAIN OUTCOME MEASURE:The primary endpoint was change in CSFQ-14 total score for vortioxetine (10 and 20 mg) vs paroxetine after 5 weeks. Additional endpoints included CSFQ-14 change scores vs placebo, CSFQ-14 subscales, and patient global impression. RESULTS:Of the 361 subjects enrolled (mean age, 28.4 years), approximately 57% were white, 34% black/African American, and 4% Asian. Vortioxetine 10 mg was associated with significantly less TESD than paroxetine (mean difference, +2.74 points; P = .009). Although vortioxetine 20 mg was associated with numerically less TESD than paroxetine (mean difference, +1.05 points), this difference did not reach statistical significance. Non-compliance appeared to influence results, particularly the paroxetine and vortioxetine 20 mg arms. Paroxetine, but not vortioxetine, was associated with statistically significantly more TESD vs placebo. Vortioxetine also had better outcomes than paroxetine in the 3 phases and 5 dimensions of sexual functioning measured by CSFQ-14. CLINICAL IMPLICATIONS:These data establish that vortioxetine is associated with less TESD than paroxetine in healthy individuals, suggesting that vortioxetine may be a drug of choice in managing depressive disorders when sexual functioning is a concern. STRENGTHS & LIMITATIONS:Conducting the study in healthy adults mitigated the risk of an underlying condition (eg, depression) confounding the results. Assay sensitivity was demonstrated by statistically significant TESD with paroxetine vs placebo. The single comparator, paroxetine, and short study duration limit the generalizability of these results. CONCLUSION:Vortioxetine is associated with less TESD than paroxetine in healthy adults across all phases and dimensions of the sexual response cycle. Vortioxetine was not significantly different from placebo on sexual functioning; however, the difference was significant between paroxetine and placebo, validating study results. Jacobsen P, Zhong W, Nomikos G, et al. Paroxetine, but not Vortioxetine, Impairs Sexual Functioning Compared With Placebo in Healthy Adults: A Randomized, Controlled Trial. J Sex Med 2019; 16:1638-1649.