MindMed ICPR 2024: Rapid and Durable Response to a Single Dose of MM120 (Lysergide) in Generalized Anxiety Disorder: A Dose-Optimization Study

Rapid and Durable Response to a Single Dose of MM120 (Lysergide) in

Generalized Anxiety Disorder: A Dose-Optimization Study

Authors: Paula L. Jacobsen, PhD; Jamie M. Freedman, BS; Jamileh Jamison, MD, MS; Sarah M. Karas, PsyD; Daniel R. Karlin, MD, MA; Reid Robison, MD

Introduction

GAD is one of the most common psychiatric disorders, with a prevalence of 10% among adults in the United States.1 GAD is a chronic condition that is characterized by persistent, excessive anxiety and worry about everyday life and difficulty controlling those worries.2 Individuals with GAD often experience somatic symptoms, including fatigue, muscle tension, irritability, and sleep disturbances, all of which significantly worsen individuals' functioning, productivity, and quality of life.2-4 In many cases, GAD is associated with comorbidities, including other anxiety disorders, MDD, chronic pain conditions, and other chronic medical conditions that add to patients' disease burden.5

While there are numerous treatment options for patients with GAD, many patients are unable to find sustained relief from their symptoms and continue to suffer from the disorder.6,7 With SSRIs as the most common first-line therapy, patients often experience undesirable and persistent side effects such as insomnia, nausea, agitation, and sexual dysfunction that add to the symptom burden and are a common reason for treatment discontinuation.8,9 Benzodiazepines may be acutely efficacious in some patients but have limited use due to the risks associated with misuse and dependence.6,10 Despite this, there has been little progress in developing effective, durable, and well- tolerated therapies in GAD.

MM120, a pharmaceutically optimized formulation of lysergic acid diethylamide (LSD), is a semisynthetic psychedelic drug of the ergoline family.11 LSD is a potent hallucinogen that was extensively studied from the 1940s to early 1970s as a potential therapy for neuropsychiatric disorders.12 Recently, there has been a resurgence of preliminary investigator-initiated LSD research in Europe.13 LSD has shown no evidence of addiction or dependence.12 MM120 has been shown to be relatively safe with no target organ toxicity at the proposed therapeutic dose levels.14 The doses evaluated in this dose range-finding study were previously evaluated in healthy volunteers.15

Objective

To assess the dose-response relationship, efficacy, safety, and tolerability of 4 doses of MM120 (25, 50, 100,

200 µg freebase-equivalent) in participants with moderate-to-severe GAD in the absence of any psychotherapy (NCT05407064).

Methods

This Phase 2b multicenter, randomized, double-blind,placebo-controlled,parallel-group,dose-finding clinical trial evaluated the effect of 4 doses of MM120 (25, 50, 100, or 200 µg) compared to placebo on anxiety symptoms in participants diagnosed with GAD. Eligible participants were randomized using a double-blind masking technique in a 1:1:1:1:1 ratio to receive one of the doses of MM120 or placebo.

The primary and key secondary outcomes determined the dose-response signal and relationship of 4 doses of MM120 as measured by the change in the HAM-A total score from baseline to weeks 4 and 8, respectively.

Other secondary outcomes included a change in HAM-A total score, MADRS, CGI-S, and PGI-S from baseline to weeks 1, 2, 4, 8, and 12.

Safety and tolerability were assessed throughout the study.

To ensure a mean power of over 87% for the generalized MCP-Mod Analysis, a total sample of 200 subjects was required to observe at least 180 endpoints after dropout. A threshold of 2.5 placebo-adjusted points on the HAM-A total score was used as the threshold for determining the minimally efficacious dose.

The secondary outcome of change from baseline in HAM-A was analyzed using an ANCOVA model that was adjusted for the baseline observation and treatment group assignment. No imputation was performed, and results were based on observed cases only. Results from the ANCOVA analyses were summarized using least squares means, least squares mean differences versus placebo and their associated confidence intervals. Cohen's d was calculated as the placebo-adjusted change from baseline divided by the pooled standard deviation of changes from baseline.

Other secondary outcomes, such as changes from baseline in CGI-S, MADRS, and PGI-S, were analyzed using a 2-samplet-test. Results were summarized using means, mean differences versus placebo, and their associated confidence intervals. Categorical data were summarized using the relevant number of observations and percentages.

Screening Period

Baseline and Dosing Period

Follow-Up Period

(Up to 30 days)

(1 to 5 days)

( ~ 12 weeks)

Randomization (visit 3A)

Dosing Session (visit 3B)

Subject is always under

MM120 200 μg single dose (n=40)

Key Eligibility

observation by dosing session

monitors until cleared for

MM120 100 μg single dose (n=40)

release by the Investigator

(I)

Male or female,

18 to <75 years old

Assessment for release begins

MM120 50 μg single dose (n=40)

at 8 hours post dose although

(II)

Diagnosis of generalized

subjects are required to

anxiety disorder

remain onsite for 12 hours

MM120 25 μg single dose (n=39)

Results (cont)

Results (cont)

0

0

Score

Score

-0.5

**p≤0.01

*p≤0.05

ChangeMeanLS(SEM) in HAM-A

-5

*p≤0.05

***p≤0.001

**

***

-3

***

***

**

*

**

ChangeMean(SEM) inCGIS-

**p≤0.01

-1

-10

*

***p≤0.001

*

-1.5

*

-15

-2

***

-20

-2.5

*

***

***

***

**

***

***

***

*

*

-25

*

Day Week

**

**

Week

Week

Week

Week

Baseline

1

2

4

8

12

Baseline

Week

Week

Week

Week

Week

2

1

2

4

8

12

25 μg

50 μg

100 μg

200 μg

Placebo

25 μg

50 μg

100 μg

200 μg

Placebo

Figure 3: Least-Squares Mean Change From Baseline in HAM-A	Figure 6: Mean Change From Baseline in CGI-S Total Scores
The clinical activity of MM120 100μg and 200μg was evident on day 2 as measured by the CGI-S scale.
The 100 and 200 μg doses demonstrated statistically and clinically significant reductions in HAM-A from baseline
to week 12.	• At day 2, the MM120 100μg and 200μg groups showed placebo-adjusted reductions of 1.1 (p≤0.001)
	and 0.8 (p≤0.05) points in the CGI-S score that were sustained through the end of the study

	MM120 100 μg	MM120 200 μg	Placebo	• From week 1 through week 12, there was a ≥2-point improvement in the CGI-S scores in both the
		Week 4
			MM120 100µg and 200µg groups
LS mean	-21.3	-19.2	-13.7
LS mean difference1	-7.6***	-5.5**
Effect size	-0.88	-0.64

Week 8

LS mean		-19.8		-20.9		-15.5			0								*p≤0.05
LS mean difference1		-4.3		-5.5*
					Score	-0.2								**p≤0.01
Effect size		-0.48		-0.60											***p≤0.001
						-0.4
				Week 12					PGI-S
								-0.6
LS mean		-21.9		-21.6		-14.2
LS mean difference1	-7.7**		-7.4**				in	-0.8	*
									(SEM)
Effect size		-0.81		-0.77				-1	**
*p≤0.05; **p≤0.01; ***p≤0.001								Change	-1.2
1Difference in mean change from baseline between MM120 and placebo.				-1.4
Table 2: Change From Baseline in HAM-A						Mean	-1.6
This study was not powered for pairwise comparisons other than the primary and key secondary outcomes due to	-1.8	***			**	*
low n numbers.													*
										-2	***		***	*
							**p≤0.01				Day							12
										Baseline			Week	Week		Week
							*p≤0.05				Week			Week
											2	1	2	4		8
90
						***p≤0.001
	78		78	78	78
80	75
70						68	70							25 μg	50 μg	100 μg	200 μg	Placebo
					65	63

Responders	60										58					56		Figure 7: Mean Change From Baseline in PGI-S Total Scores
		53	33
	51	50	54				51				49
														The MM120 100μg and 200μg doses showed clinically significant improvements in PGI-S scores from
	50							47
												44		44
																		weeks 1 to 4.
	40							38
%														31				31	31	• At week 4, the MM120 100μg and 200μg groups showed placebo-adjusted reductions of 0.5 (p≤0.05) and
30
	20																				0.6 (p≤0.05) points, respectively, in the PGI-S score
																				• Throughout the study, patients' self-reported anxiety continued to improve in the placebo group, while
	10
	0																				participants in the MM120 100μg group achieved consistent scores from weeks 2 through 12 with a slight
		Week 1				Week 2				Week 4		Week 8	Week 12		increase at week 8
							25 μg			50 μg				100 μg		200 μg		Placebo

(III) HAM-A total score				As part of the assessment for
≥20 at visits 1 and 2		release, subject must no
			Placebo single dose (n=39)	longer meet DSM-5 criteria for
				hallucinogen intoxication

Screening

Baseline

Day1/Randomization

Day 2

Week 2

Week 8

(visit 1)

(visit 2)

& Dosing Session

(visit 4)

(visit 6)

(visit 8)

(visits 3A & 3B)

30 days prior	1-5 days prior	Week 1	Week 4	Week 12
to baseline	to randomization	(visit 5)	(visit 7)	EOS (visit 9)

Figure 1: Study Design

Participants were excluded if they had contraindicated medical or psychiatric conditions or were taking concomitant medications, supplements, or other therapeutics that were contraindicated (eg, due to drug-drug interaction potential or anxiolytic or antidepressant function) and could not be paused.

Statistical Analyses: The primary and key secondary outcome measures were analyzed using the generalized multiple comparison procedure-modeling (MCP-Mod)method.16,17 Missing primary endpoint data were imputed using multiple imputations with 20 iterations. Missing observations due to the use of prohibited concomitant medications were imputed under a missing, not at-randomassumption by using referenced-basedimputation. All other instances of missingness were imputed under a missing, at-randomassumption by using treatment group-basedimputations.

Results

			MM120			Placebo
		25 µg	50 µg	100 µg	200 µg	(n=39)
		(n=39)	(n=36)	(n=40)	(n=40)
Mean age, years (SD)	38.0 (12.1)	45.3 (14.2)	42.7 (14.8)	42.1	(13.5)	38.7 (12.7)
Sex, n (%)
	Female	20 (51.3)	20 (55.6)	16 (40)	28	(70)	26 (66.7)
	Male	19 (48.7)	16 (44.4)	24 (60)	12	(30)	13 (33.3)

Figure 4: HAM-A Response Over Time

At week 12, 65% of participants with 100 μg and 62.5% with 200 μg achieved a HAM-A response, defined as a ≥50% reduction in the HAM-A total scores, vs. 30.8% with placebo.

											*p≤0.05
											**p≤0.01
	60										***p≤0.001
	50						50				48
Remission						43			45	45	45
40					38	35
	33	33	33		33	33	33		33
30	31
Achieving	26					28				28
					25
20					21				21	21
			15			18
%
	10
	0	Week 1		Week 2	Week 4		Week 8	Week 12
					25 μg	50 μg	100 μg	200 μg		Placebo

Figure 5: HAM-A Remission Over Time

At week 12, a total of 47.5% of participants with 100 μg and 45% with 200 μg achieved remission, defined as HAM-A total score of ≤7, vs. 20.5% with placebo.

						*p≤0.05
	0					**p≤0.01
Score					***p≤0.001
-5
MADRS
-10
(SEM) in
-15
Change
-20	*
Mean		*	*
	*	*
	*	**	*
	-25	1	2	4	8	**
	Baseline	12
	Week	Week	Week	Week	Week

Figure 8: Mean Change From Baseline in MADRS Scores

The MM120 100μg and 200μg groups showed clinically significant reductions in the MADRS score at all time points.

• The MM120 100μg group showed placebo-adjusted reductions of 5.7 (p≤0.05), 5.0 (n.s.), and 6.4 (p≤0.05) points in the MADRS scores at weeks 4, 8, and 12, respectively
• The MM120 200μg group showed placebo-adjusted reductions of 5.9 (p≤0.05), 6.4 (p≤0.05), and 7.6

(p≤0.01) points in the MADRS scores at weeks 4, 8, and 12, respectively

Race (White), n (%)	33 (84.6)	29 (80.6)	36	(90)	33 (82.5)	30 (76.9)
HAM-A score, mean (SD)	30.2 (6.1)	30.3 (5.7)	29.3 (6.4)	31.0	(7.0)	30.3 (6.6)
CGI-S score, mean (SD)	4.9 (0.8)	4.9 (0.6)	4.8	(0.7)	5.1 (0.7)	4.9 (0.6)
PGI-S score, mean (SD)	3.8 (0.6)	3.8 (0.6)	3.7	(0.7)	3.7 (0.7)	3.7 (0.6)
MADRS, mean (SD)	25.4 (7.6)	27.7 (8.3)	26.5 (8.0)	28.9	(8.3)	27.6 (9.7)

Table 1: Baseline Characteristics and Demographics

A total of 554 participants were screened for eligibility between August 24, 2022, and August 30, 2023. Of these, 198 participants were randomized to receive a single administration of MM120 at a dose of 25 (n=39), 50 (n=40), 100 (n=40), 200 µg (n=40), or placebo (n=39).

Changes	4
2
CI)	0

Safety and Tolerability

			MM120				Placebo
	25 µg	50 µg		100 µg		200 µg		(n=39)
	(n=39)	(n=40)		(n=40)		(n=40)
At least one TEAE, n (%)		36	(90.0)		39 (97.5)		40 (100)		22 (56.4)
30 (76.9)
Any treatment-related TEAEs, n (%)	29 (74.4)	32	(80.0)		38 (95.0)		40 (100)		16 (41.0)
At least one serious TEAE, n (%)	0	1	(2.5)		0		0		0
Any TEAEs leading to study	2 (5.1)	2	(5.0)		1 (2.5)		0 (0)		0 (0)
withdrawal, n (%)
Any TEAEs leading to death, n (%)	0 (0)	0 (0)		0 (0)		0 (0)		0 (0)

• The majority of these events occurred on dosing day and were mild to moderate in severity
• One serious AE, panic attack, occurred 97 days after dosing in a participant receiving 50 μg and was deemed unrelated to the study drug
• The most frequent AEs that occurred with 100 μg on dosing day were illusion (60%), nausea (40%), euphoric mood (27.5%), headache (25%), visual hallucination (22.5%), hyperhidrosis (22.5%), mydriasis (20%), altered state of consciousness (12.5%), anxiety (10%), increased blood pressure (10%), and abnormal thinking (10%)
• As assessed by C-SSRS and AE collection, following treatment with MM120, no participants engaged in self-injurious or suicidal behavior, nor was there endorsement of active suicidal ideation with intent or plan. Participants with a history of suicidal ideation showed no increase in severity of ideation and following treatment with MM120 reported ideation appeared less severe when compared to Baseline and Screening C-SSRS.
• As assessed by AE reporting, one participant each who received placebo and 25 μg reported moderate suicidal ideation. The participant with placebo reported this during the dosing session, although ideation was not present on C-SSRS at the session's end. The participant with 25 μg reported "non-specific active suicidal thoughts" at week 1 per C-SSRS. One participant each who received 50 and 100 μg reported mild passive suicidal ideation that correlated with C-SSRS item "wish to be dead." One participant who received 100 μg reported passive suicidal ideation at week 4; the participant was withdrawn from the study after week 4 due to starting a prohibited medication for ADHD.

Placebo−adjustedHAM−A	from Baseline(95%	−2
−4
−6
Modeled		−8
	−10
		Placebo	25	5056	85	100	200
		µg	.	.
		µg7	1		µg	µg
			µg	µg
					Dose
				Visit	Week 4		Week 8

Prespecified model estimates and observed responses drove dose selection for Phase 3 studies

Figure 2: MCP-Mod of HAM-A

The primary (week 4) and key secondary (week 8) endpoint analyses were met. MM120 demonstrated a statistically significant dose-response relationship at both 4 and 8 weeks, with the minimally efficacious dose (considered a placebo-adjusted change from baseline of 2.5 points) estimated to be between 56.7 μg and 85.1 μg. The 2.5-point change was needed to support an effective dose in the dose-response curves.

Conclusions

This trial was the first to assess the dose-dependent efficacy of LSD without concurrent psychedelic-assisted therapy. The study demonstrated that, for a single treatment with MM120, 100 µg is the optimal dose to bring forward into future research as it showed a clinically meaningful and statistically significant improvement in GAD and had a favorable AE profile compared to 200 µg.

This treatment effect was observed as early as the day following treatment (CGI-S) and sustained through the end of the study at week 12. The results of this study support progression toward pivotal trials of MM120 100 µg for the treatment of GAD to confirm efficacy and evaluate the durability of the effect. MM120 100 µg achieved the highest level of clinical activity at the primary endpoint with a 7.6-point reduction in HAM-A compared to placebo at week 4. In contrast, the week 4 HAM-A score reductions for 25, 50 and 200 µg were 3.4, 0.9, and 5.5. The HAM-A score reduction with 100 µg was more than twice that observed in clinical trials for other GAD treatments.18 Further, at week 4, MM120 100 µg exhibited an effect size of d=0.88, while a meta-analysis of 21 placebo-controlled trials for GAD revealed that current medications provide only modest benefits, with an overall d=0.39.19 Comparatively, benzodiazepines have shown acute efficacy in patients with GAD, but require repeat dosing to prolong effects and are associated with a risk for dependency and unwelcome side effects.20

Further, higher doses of MM120 also demonstrated improvement in depressive symptoms. Many patients with GAD have comorbid depressive symptoms;21 in our study, at week 1, the 100 µg dose showed a placebo-adjusted reduction of 6.6 points in MADRS from baseline. These improvements also had rapid onset compared to standard-of-care medications for depressive disorders.22

MM120 was well tolerated by most participants with AEs that were primarily mild and temporary, mainly occurring on dosing day, and were consistent with the drug class and prior studies. There were no serious AEs or suicide-related safety signals.

References

1. Ringeisen H, Edlund M, Guyer H, et al. Mental and Substance Use Disorders Prevalence Study (MDPS): Findings report. RTI International. 2023. 2. Patriquin MA, Mathew SJ. Chronic Stress (Thousand Oaks). 2017;1:2470547017703993. 3. Barrera TL, et al. J Anxiety Dis. 2009;23(8):1086-1090.4. Bandelow B, et al. Dtsch Arztebl Int. 2013;110(17):300-309.

1. Nutt D, et al. Eur Neuropsychopharm. 2006;16:S109-S118.6. Garakani A, et al. Focus (Am Psychiatr Publ) 2021;19(2):222-242.7. Ansara ED. Ment Health Clin. 2020;10(6):326-334.8. Gartlehner G, et al. Ann Intern Med. 2011;155(11):772-785.9. Kavan MG, et al. Am Fam Physician. 2009;79(9):785-791.10. Votaw VR, et al. Drug Alcohol Depend. 2019;200:95-114.

1. Jastrzębski MK, et al. Molecules 2022;27:7322. 12. Fuentes JJ, et al. Front Psychiatry. 2019;10:943. 13. Reiff CM, et al. Am J Psychiatry. 2020;177:5. 14. Tripp J, Smagin G, Silva R. 44th Annual Meeting. Int J Toxicol. 2024;43:73-115.15. Holze F, et al. Neuropsychopharm. 2021;46:537-544.16. Bretz F, et al. Biometrics. 2005;61(3):738-748.

1. Pinheiro J, et al. Stat Med. 2014;33(10):1646-1661.18. Fagan HA, et al. Expert Rev Neurother. 2023;23(6):535-548.19. Hidalgo RB, et al. J Psychopharmacol. 2007;21(8):864-872.20. Strawn JR, et al. Expert Opin Pharmacother. 2018;19(10):1057-1070.21. Newman MG, et al. Annu Rev Clin Psychol. 2013;9:275-297.22. Machado-Vieira R, et al. Pharmaceuticals. 2010;3:19-41.

Abbreviations:

AE, adverse event; CGI-S, Clinical Global Impression-Severity;C-SSRS, Columbia Suicide Severity Rating Scale; EOS, end of study; GAD, generalized anxiety disorder; HAM-A, Hamilton Anxiety Rating Scale;	Contact Email: [e-mail]
LS, least squares; LSD, lysergic acid diethylamide; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; PGI-S, Patient Global Impression-Severity;SD, standard deviation;
SEM, standard error of the mean; TEAE, treatment-emergent adverse event..
Disclosures:	Supported by funding from MindMed, Inc.
has stock ownership in Numinus. EF has no conflicts of interest to disclose.
SMK, RB, CC, JMF, PLJ, JJ, DRK, TS and MHW are employees of Mind Medicine, Inc. RR is employed by Numinus and