SUMMARY

• In a post-hoc analysis of the TRANSFORM-1 and -2 studies in patients with treatment-resistant depression (TRD) not achieving an early response (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) by day 2 or by days 2 and 8, the proportion of patients with a response at day 28 was significantly higher in the SPRAVATO+oral antidepressant (oral AD) group vs the oral AD+placebo (PBO) group.¹
• A post-hoc analysis of patients with major depressive disorder (MDD) and active suicidal ideation with intent (MDSI) from the ASPIRE-1 and -2 studies found that those receiving SPRAVATO+standard of care (SOC) who did not meet the criteria for response within the first 24 hours or first week of treatment, had a higher likelihood of achieving response or remission predose on day 25 compared with those receiving PBO+SOC.²
• A post hoc subgroup analysis of the SUSTAIN-3 study reported similar response and remission rates in early and delayed responders throughout the optimization/maintenance (OP/M) phase.³
• A post hoc subgroup analysis of the SUSTAIN-3 study reported that a majority of patients who were partial responders or nonresponders at the end of the 4-week induction (IND) phase achieved response, remission, and clinically meaningful and substantial improvements in depressive symptoms by week 52 of the OP/M phase.⁴

CLINICAL DATA

TRANSFORM-1 AND 2 Trials in Patients with Treatment-Resistant Depression

Turkoz et al (2021)¹ conducted a post hoc analysis of the TRANSFORM studies^5,6, two 4-week phase 3, double-blind, placebo-controlled, multicenter studies of SPRAVATO. Adult patients with moderate-to-severe depression and nonresponse to ≥2 oral ADs in the current major depressive episode were randomly assigned to receive either SPRAVATO or PBO. In the SPRAVATO arm, patients were randomly assigned to receive 1 of 2 fixed doses (56 mg or 84 mg, TRANSFORM-1) or flexible doses (56 mg or 84 mg, TRANSFORM-2) of twice-weekly SPRAVATO. All patients, regardless of treatment arm, also received a newly initiated, open-label, oral AD taken daily for 4 weeks. The post-hoc analysis evaluated the response to SPRAVATO+oral AD at day 28 in patients with TRD who did not meet the response criteria during the first week of treatment.

In the complete study population, at each weekly visit (Day 2, 8, 15, 22, and 28), a significantly higher proportion of patients treated with SPRAVATO+oral AD met criteria for response as compared to those treated with oral AD+PBO (P<.05).

In patients without an early response (response defined as ≥50% decrease in MADRS score) by day 2 or by days 2 and 8, the proportion of patients with response at day 28 was significantly higher in the SPRAVATO+oral AD group than in the oral AD+PBO group (see Table: Response Rates by Study Visit and Treatment Among Patients Without an Early Response)

The odds of response using a stepwise logistic regression model at day 28 in patients who did not achieve a response at day 2 or at days 2 and 8 were 1.61 (95% confidence interval [CI], 1.09-2.40) and 1.56 (95% CI, 1.04-2.35), respectively. The repeated measures generalized linear mixed models also suggested a higher likelihood of achieving response with SPRAVATO+oral AD at day 2 (odds ratio [OR]=1.50; 95% CI, 1.10-2.00) and days 2 and 8 (OR=1.43; 95% CI, 1.04-1.91). Another multivariate adaptive regression splines model provided similar conditional probability of response estimates at day 28.

ASPIRE-1 and -2 Trials in Patients with MDD and Active Suicidal Ideation with Intent

Turkoz et al (2022)² conducted a post hoc, pooled analysis of the ASPIRE-1 and -2 trials^7,8 to assess response to, or remission with, SPRAVATO+SOC vs placebo PBO+SOC at 4 weeks in patients with MDSI who did not meet response criteria within the first week of treatment. Response was defined as ≥50% decrease in MADRS score and remission was defined as MADRS score ≤12. Early response was defined as ≥50% decrease in MADRS score at either 24 hours (day 1; 4 hours and 24 hours after the first dose) or within Week 1 (day 1 and day 8 [after 2 doses]). Response and remission rates were assessed predose on day 25 for patients who did not meet early response criteria.

In the complete study population, response and remission rates were achieved by a greater proportion of patients in the SPRAVATO+SOC group compared with the PBO+SOC group at each visit. Predose on day 25, 74.6% of patients in the SPRAVATO+SOC group and 58.3% in the PBO+SOC group attained response (P<0.001), and 52.2% of patients in the SPRAVATO+SOC group and 38.3% in the PBO+SOC group attained remission (P=0.007).

In patients without an early response, more patients in the SPRAVATO+SOC group vs the PBO+SOC group achieved response and remission predose on day 25. See Table: Response and Remission Rates Predose on Day 25 in Nonresponders.

Using multiple logistics models, the odds ratios (ORs) for a response predose at day 25 with SPRAVATO+SOC vs PBO+SOC among nonresponders at 24 hours and nonresponders at Week 1 were 1.89 (95% CI, 1.17-3.05) and 2.03 (95% CI, 1.22-3.40), respectively. The ORs for remission predose at day 25 with SPRAVATO+SOC vs PBO+SOC among nonresponders at 24 hours and nonresponders at Week 1 were 1.48 (95% CI, 0.93-2.35) and 1.63 (95% CI, 1.01-2.62), respectively.

SUSTAIN-3 Trial in Patients with TRD

Zajecka et al (2024)³ conducted a subgroup analysis to evaluate the response and remission rates in early (day 8) and delayed (week 8) responders in the SUSTAIN-3 study,⁹ a phase 3, open-label extension study that evaluated the long-term safety and efficacy of SPRAVATO in patients with TRD. Patients self-administered a flexible dose of SPRAVATO 2 times per week during the initial 4-week IND phase, followed by SPRAVATO administration once weekly, every other week, or every 4 weeks, based on Clinical Global Impressions - Severity scale and tolerability, in the variable-duration OP/M phase. Response was defined as a ≥50% improvement from baseline in MADRS or 9-item Patient Health Questionnaire (PHQ-9) total scores; remission was defined as MADRS total score ≤12 or PHQ-9 total score <5. Early and delayed responses were defined as achieving MADRS response by day 8 and week 8, respectively.

From a total of 1148 patients enrolled in SUSTAIN-3, 441 patients were included from the IND phase, in which 405 (91.8%) patients continued to the OP/M phase, and 258 (63.7%) completed the OP/M phase. The median duration of exposure to SPRAVATO was approximately 3.5 years (range, 1 day to 6 years).

Improvements in MADRS and PHQ-9 total scores were reported during the 4-week IND phase and were maintained in the OP/M phase (mean [SD] change from baseline in MADRS and PHQ-9 total scores in the IND phase, -12.9 [9.67] and -5.9 [5.77], respectively). At the IND endpoint, response and remission were achieved by 219 (50.0%) and 159 (36.3%) patients, respectively, based on MADRS. The rates of response and remission were sustained in the OP/M phase.

At the OP/M endpoint, early (n=65) and delayed (n=156) responders reported similar rates of response and remission. See Table: Response and Remission Rates per MADRS and PHQ-9 Total Scores in Early and Delayed Responders at the OP/M Endpoint and Figures: Response per MADRS Total Score During OP/M Among Early (Day 8) and Delayed (Week 8) Responders (LOCF) and Remission per MADRS Total Score During OP/M Among Early (Day 8) and Delayed (Week 8) Responders (LOCF).

Zajecka et al (2024)⁴ conducted a post hoc subgroup analysis of the SUSTAIN-3 study to evaluate the trajectory of first response and remission in patients who were nonresponders or partial responders during the 4-week IND phase. Response was defined as ≥50% improvement from baseline in MADRS total score, and remission was defined as MADRS total score ≤12. The subgroups were determined based on the response status at the end of the IND phase: IND full responders (≥50% improvement), IND partial responders (≥25% to <50% improvement), and IND nonresponders (<25% improvement).

A total of 405 patients were included in the analysis, of which 94 were IND nonresponders (mean age, 49.0 years; female, 60.6%), 93 were IND partial responders (mean age, 45.0 years; female, 67.7%), and 218 were IND full responders (mean age, 46.3 years; female, 74.8%). The mean (SD) baseline MADRS total score for the IND nonresponders was 26.1 (8.9); IND partial responders, 30.2 (7.3); and IND full responders, 30.0 (7.5). The median (range) duration of exposure to SPRAVATO for the IND nonresponders was 43.8 (0-72) months; IND partial responders, 41.8 (0-72) months; and IND full responders, 48.1 (0-78) months.

The mean (SD) change in MADRS total score from the IND baseline at week 52 of the OP/M phase in IND nonresponders was -6.5 (10.95); IND partial responders, -11.4 (8.37); and IND full responders, -14.7 (10.36).

For efficacy outcomes up to 52 weeks into the OP/M phase in the IND nonresponder and partial responder subgroups, see Table: Time to First Achievement of Efficacy Outcomes up to Week 52 of OP/M.

Safety and tolerability results in the subgroups were consistent with the established SPRAVATO profile, with no new safety signals being identified.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 October 2024.