A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide

Abstract

Background

Despite the prevalence of Major Depressive Disorder (MDD) and the propensity of affected individuals to eventually die by suicide, there is no therapeutic approved specifically for suicidal ideation and behavior (SI/B) in MDD. The NMDA receptor antagonist ketamine has been investigated for the treatment of depression and shown to have a rapid effect on symptoms. Spravato^® (esketamine) is approved by the FDA for use in treatment-resistant depression and Major Depressive Episodes with Suicidal Ideation based on studies conducted in adults also taking standard antidepressants. While esketamine was associated with a large reduction in suicidality indicators, the effects did not significantly exceed those associated with placebo. Racemic ketamine, a mixture of both esketamine and arketamine, may hold greater potential for the rapid alleviation of SI/B. SLS-002 was developed as an investigational intranasal racemic ketamine for the treatment of SI/B in individuals with MDD.

Methods

In part one of a two-part clinical trial, the safety, tolerability, and potential effectiveness of SLS-002 were evaluated in an open label study of 17 patients with MDD hospitalized with acute SI/B.

Results

Treatment with SLS-002 was associated with a significant reduction in depression and suicidality indicators on four clinical scales: the Montgomery-Åsberg Depression Rating Scale, the Sheehan-Suicidality Tracking Scale, and the Clinical and Patient Global Impression Scales for SI/B. SLS-002 was well tolerated with an acceptable safety profile.

Conclusions

The results of this open label study support the continued development of SLS-002. The randomized double-blind placebo-controlled part two of this trial was recently completed.

Introduction

Depression is the largest contributor to disability worldwide,¹ and the global lifetime prevalence of Major Depressive Disorder (MDD) is more than 10%.² It is estimated that as many as 15% of individuals with severe MDD will eventually die by suicide.³ Despite this burden, there is currently no therapeutic approved specifically for the treatment of suicidal ideation and behavior (SI/B) in individuals with depression. Conventional antidepressants may reduce symptoms over a period of weeks, but do not act rapidly enough to benefit individuals who are at imminent risk of suicide.

The anaesthetic drug ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been investigated for the treatment of depression and has been shown to have rapid and relatively large effects on depressive symptoms, even among some individuals who have not responded to conventional antidepressants.⁴ Ketamine’s activity in depression is thought to be through a number of mechanisms beyond antagonism of the NMDA glutamate receptor, such as impacting the AMPA glutamate receptor, opioid, GABA, and monoamine neurotransmitter signaling, and activating neurotropic factors.⁵ A meta-analysis of studies of intravenously administered ketamine showed comparably rapid and large effects on suicidal ideation.⁶ An intranasally delivered formulation of the S-enantiomer of ketamine (esketamine) has been tested and was approved by the US Food and Drug Administration (FDA) for treatment-resistant depression (TRD) and major depressive episodes with suicidal ideation (MDSI), but has not been approved for SI/B. Although intranasal delivery of esketamine holds some practical advantages over intravenous delivery, some evidence suggests that the racemic ketamine may hold greater potential for rapid treatment of SI/B.⁵ Therefore, SLS-002 was developed as an investigational intranasal racemic ketamine specifically for the treatment of SI/B in individuals with MDD.

The objectives of part one of this phase 2 study were to explore the hypothesis that SLS-002 may mitigate symptoms of depression and suicidality, as well as to explore its safety and tolerability, in an open-label setting. Part two of this trial assessed the safety and efficacy of SLS-002 in a randomized, double blind, placebo-controlled manner.

Materials and Methods

Rating Scales

Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Sheehan-Suicidality Tracking Scale–Clinically Meaningful Change Measure (S-STS CMCM), the Clinical Global Impression of Severity for Suicidal Ideation/ Behavior (CGIS-SI/B), and the Patient Global Impression of Severity for Suicidal Ideation/ Behavior (PGIS-SI/B). The MADRS is a 10-item scale with a score range of 0–60. Higher scores indicate more severe depression. The S-STS CMCM is a clinician-rated outcome measure that assesses SI/B on multiple patient and clinician-rated items including 13 suicidality items yielding a total score ranging from 0 to 52, higher scores indicate more severe suicidality. The PGIS- and CGIS-SI/B are 5-item patient- and clinician-rated measures, respectively, of suicidality-specific symptom severity, ranging from 1 to 5 (none to extremely severe). Dissociation-related side effects were assessed using the Clinician-Administered Dissociative States Scale (CADSS) and sedation was assessed using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S). CADSS is a 23 item scale with 0–4 points for each item, with total scores ranging from 0 to 92. A total score of > 4 indicates clinically meaningful dissociation. MOAA/S is a single item scale of 0–5 points, where lower scores indicate more sedation.

Subjects

Seventeen subjects diagnosed with MDD (based upon the DSM-5 criteria and confirmed by the Mini International Psychiatric Interview Version 7.02 for Suicidality Disorders [MINI], administered by a trained rater at the site) and requiring hospitalization due to significant risk of suicide were enrolled. All subjects were recruited from the hospital where they had sought treatment for their acute suicidal crisis. For inclusion, subjects were required to have a total MADRS score of ⩾ 28 points, a score of 5 or 6 on MADRS item 10 (regarding suicidal thoughts), a total score of ⩾ 15 points on the S-STS CMCM, and a history of previous suicide attempt(s), as identified by the C-SSRS, as defined by at least one actual attempt or, if the attempt was interrupted or aborted, judged to have been serious in intent.

Trial Design

A schematic depicting the trial design and dosing schedule is shown in Figure 1. Following informed consent and Baseline assessments, participants began study medication on day 1; all subjects were treated with standard of care (SOC) antidepressant therapy for the duration of the study. SLS-002, 90 mg intranasal, was dosed twice per week for a total of 5 doses across a 16-day treatment period. Participants could be discharged from the hospital as early as Day 6 if the site investigator or their designated physician sub-investigator confirmed that this was safe based on a number of factors including symptoms and home support network. The protocol specified that all participants would continue the study as outpatients. The treatment period concluded at Day 16, at which point a 2-week safety follow-up was conducted to determine maintenance of treatment effect and to monitor for any additional safety events.

Figure 1.

Study Design

Endpoints

The primary endpoint was the change in the MADRS total score from Baseline at 24 hrs following the initial dose. Key secondary endpoints were the changes from Baseline to Day 16 in MADRS total score, change at 24 hrs in the CGIS- and PGIS-SI/B, S-STS CMCM total score, and at Day 16 in the CGIS- and PGIS-SI/B, and S-STS CMCM total score. Additional secondary endpoints included the MADRS Response and Remission, MADRS item 10 response, and others. Safety endpoints included treatment-emergent adverse events (TEAEs), laboratory results and vital signs, electrocardiographs (ECG), CADSS, MOAA/S, the C-SSRS, and others.

Statistical Analyses

Results of efficacy analyses for Part 1 were summarized descriptively.

Results

Subjects and Demographics

Baseline subject demographics are presented in Table 1. Mean subject age was 39.8 years (SD 12.8 years); 10 (58.8%) were male and 7 (41.2%) were female. Nine (52.9%) were Black or African American and 8 (47.1%) were White. One (5.9%) was Hispanic or Latino, and 16 (94.1%) were not Hispanic or Latino. The mean Baseline body mass index (BMI) was 29.1 kg/m² (SD 5.2). Mean Baseline MADRS, S-STS CMCM, CGIS- and PGIS-SI/B scores are presented in the Clinical Improvements following SLS-002 Treatment table (Table 2). Four of the 17 subjects discontinued the trial prior to completion (two withdrew consent [on Days 8 and 19], one had an AE judged unrelated to study drug [withdrew on Day 14] and one was lost to follow-up [on Day 18]). All four were responders on the MADRS, and all had a clinically meaningful reduction in suicidal ideation and behaviors.

Table 1. Subject Baseline Demographics.

N		17
Mean Age: (SD), years		39.8 (12.8)
Sex: n (%)		M: 10 (58.8)
		F: 7 (41.2)
Race: n (%)		Black/African American: 9 (52.9)
		White: 8 (47.1)
Ethnicity: n (%)		Hispanic or Latino: 1 (5.9)
		Not Hispanic or Latino: 16 (94.1)
Mean BMI (SD): kg/m2		29.1 (5.2)

Table 2. Clinical Improvements Following SLS-002 Treatment.

		Baseline N = 17		24 hrs N = 17		Day 16 N = 14		Day 29/30 N = 13
MADRS Mean (SD)		39.4 (4.98)		14.5 (8.06)		7.4 (7.27)		6.3 (6.60)
Change from Baseline				−24.9 (8.34)		−31.6 (7.31)		−32.1 (7.40)
S-STS CMCM Mean (SD)		22.4 (4.76)		1.7 (5.80)		0.0 (0.00)		0.0 (0.00)
Change from Baseline				−20.6 (6.34)		−20.9 (3.66)		−21.1 (3.71)
CGIS-SI/B Mean (SD)		3.8 (0.64)		1.6 (0.94)		1.1 (0.27)		Not collected
Change from Baseline				−2.2 (0.90)		−2.7 (0.83)
PGIS-SI/B Mean (SD)		3.5 (0.80)		1.6 (0.80)		1.0 (0.00)		Not collected
Change from Baseline				−1.9 (0.86)		−2.3 (0.73)
MADRS Response,a n (%)		–		13 (76.5)		13 (92.9)		13 (100)
MADRS Remission,b n (%)		–		6 (35.5)		11 (78.6)		10 (76.9)
MADRS Item 10 Response,c n (%)		–		16 (94.1)		14 (100)		13 (100)

MADRS scale range 0–60, S-STS CMCM scale range 0–52, CGIS-SI/B and PGIS-SI/B range 1–5 with 1 not present and 5 extremely severe. Table includes observed cases. Change from Baseline is calculated as the mean of all the individual subjects’ (n = 14 at Day 16, n = 13 at Day 29/30) changes from Baseline. ^aMADRS response is defined as a total score with a reduction ⩽ 50% from Baseline. ^bMADRS remission is defined as a total score ⩽ 12. ^cMADRS item 10 is regarding suicidal thoughts and response is defined as a score ⩽ 3. The values shown are the numbers (and percent) of subjects who met the definition of response or remission.

Impact of Treatment on Depressive Symptoms and Suicidality

Subjects were assessed using four key scales (MADRS, S-STS CMCM, CGIS- and PGIS-SI/B) at Baseline and at up to 12 time points thereafter. Mean scores for all four scales decreased from Baseline by 24 hrs post-dose, with downward trends continuing for the duration of the study period (Figure 2). Mean scores and changes from Baseline for each scale at 24 hrs post-dose, Day 16, and Day 29/30 are listed below (Table 2).

Figure 2.

Clinical Improvements in Four Scales Over Study Duration

SLS-002 treatment was associated with clinical improvements across four key clinical scales: MADRS, S-STS, CGIS- and PGIS-SI/B. Subjects were assessed at Baseline and timepoints thereafter. Mean scores for all four scales decreased from Baseline by 24 hrs post-dose, with downward trends continuing for the duration of the study period.

Overall, clinical improvement was observed during treatment with the study drug across all four scales: the mean (SD) change from Baseline on the MADRS was −24.9 (8.34) at 24 hrs post-dose and −31.6 (7.31) at Day 16, on the CGIS-SI/B was −2.2 (0.90) at 24 hrs, on the PGIS-SI/B was −1.9 (0.86) at 24 hrs, and on the S-STS CMCM was −20.6 (6.34) at 24 hrs. At the final follow-up on Day 29/30, the mean MADRS score was 6.3 (6.60) and the mean S-STS CMCM score was 0.0 (0.00).

The proportions of subjects achieving MADRS response and remission at 24 hrs post-dose, Day 16, and Day 29/30 are also shown in Table 2. By study end, 100% of subjects met criteria for MADRS response, 76.9% experienced MADRS remission, and 100% experienced MADRS Item 10 response.

Safety and Tolerability

SLS-002 was found to be generally well tolerated, with a safety profile consistent with this class of therapeutics (Table 3). Eight subjects (47.1%) experienced at least one TEAE. There were no serious or severe TEAEs, and all were mild or moderate and short term or transient in nature. Five TEAEs were considered treatment-related per the investigator’s judgement. One TEAE (elevated ALT) led to the discontinuation of study drug, although this was judged to be unrelated to the study drug due to elevations at baseline. No other TEAEs led to the interruption or reduction of study drug, nor to withdrawal from the study. No TEAEs that were new or unique to the drug class were identified, and no vital sign or blood pressure related TEAEs were reported. No TEAEs led to death. The most common TEAEs (experienced by ⩾ two subjects each) were headache (n = 4, 23.5%), dizziness (n = 3, 17.6%), feeling abnormal (n = 2; 11.8%), sedation (n = 2; 11.8%), and nausea (n = 2; 11.8%). The mean change from Baseline on CADSS at all timepoints was lower than the threshold for clinically meaningful dissociation (> 4). The mean change from Baseline was highest on Day 1 at 40 minutes post dose (3.8) and lower at all timepoints thereafter. Overall, the results are consistent with expected outcomes from ketamine.

Table 3. Adverse Events.

Subjects with at least one		n (%)
TEAE		8 (47.1)
Serious TEAE		0 (0)
Treatment-related TEAE*		5 (29.4)
Serious treatment-related TEAE		0 (0)
Severe TEAE		0 (0)
TEAE leading to interruption or reduction of study drug		0 (0)
TEAE leading to permanent discontinuation of study drug**		1 (5.9)
TEAE leading to withdrawal from the study		0 (0)
TEAE leading to death		0 (0)

Discussion

Effective treatments for people in acute suicidal crises is a large unmet need. No therapeutic is currently approved for the treatment of acute SI/B in patients with MDD. Available treatments that are more broadly indicated for MDD have limitations including a possible weeks-long delay between treatment initiation and onset of effect, the need to switch between drugs before finding one that is effective, and partial response instead of full remission of symptoms.⁷ Furthermore, treatment with some compounds may even lead to worsening of SI/B.⁸ These limitations preclude the use of traditional antidepressants to address acute SI/B.

Ketamine is now widely used off label to treat people with various forms of difficult-to-treat depression and has been shown to rapidly alleviate suicidality.^9,10 In a systematic review and individual subject data meta-analysis of 10 separate studies, single doses of IV ketamine were shown to rapidly (i.e., within one day) reduce SI/B in patients with MDD, PTSD, or bipolar depression with SI/B at Baseline.⁶ Spravato^® (esketamine) is approved by the FDA for use in TRD (2019) and MDSI (2020); these studies were conducted in adults who were also taking standard antidepressants.^11,12 However, although the group receiving esketamine therapy experienced a large reduction in various indices of suicidality in the MDSI studies, these effects were generally not significantly greater than observed in the control condition who received antidepressant medication and placebo nasal spray.

SLS-002 is a racemic mix of both the S- and R-enantiomers of ketamine that was previously shown to be safe and well tolerated in two Phase 1 studies in healthy volunteers.¹² In this open label part one of the Phase 2 study, investigational SLS-002 appeared to generate rapid, large and sustained improvements across measures of depression and suicidality. Limitations of the study include the small cohort size and the open-label nature of the design; the benefits of ketamine were fairly well-known at the time this study was conducted and subjects were aware of their intervention. These results support the possibility that intranasal ketamine has the potential to treat SI/B in individuals with MDD, addressing an urgent unmet medical need.

SLS-002 was also found in this study to be well tolerated, with an acceptable safety profile and no new or unique safety signals identified. These results support the continuation of SLS-002 development with the double-blind placebo-controlled portion of this trial. Part two of this trial, which recently completed, assessed the safety and efficacy of SLS-002 in a randomized, double blind, placebo-controlled manner.

Conclusions

Intranasal racemic ketamine (SLS-002) was well tolerated by subjects with MDD who were hospitalized for acute suicide risk, and was associated with a reduction in measures of depression and SI/B. These results support the continued development of SLS-002 to treat SI/B in individuals with MDD.