Study of safety, tolerability, pharmacokinetics and pharmacodynamics of MSD-001 in healthy participants

Temporary halt TH-82394

Halt date

2025-05-07

Planned restart

2025-05-14

Member states concerned

Netherlands

Publication date

2025-05-13

Reason

Safety related (clinical or pre-clinical results)

Explanation

A Dose Escalation Meeting was held on 02-May-2025, following the completion of Part 1 Cohort 4. During this meeting, the Safety Review Committee (SRC), composed of the principal investigator, study physician and representatives of the sponsor, reviewed all available safety- PD- and PK-data and selected a dose of 10mg MSD-001 for Part 1 Cohort 5.

On 07-May-2025, CHDR’s PK used the available PK data to extrapolate to the anticipated Cmax and AUC values that would be reached by administering a dose of 10mg MSD-001 in Part 1 Cohort 5.
Based on this analysis, it was predicted that the average Cmax and AUC for the cohort based on the proposed dose would be 65.6ng/mL and 336ng*h/mL, staying well below the exposure caps of 103ng/mL and 665ng*h/mL, respectively. However, the calculations show that the estimated probability of no participants reaching a maximum Cmax and AUC higher than the exposure cap would be 42.7%, and 60.5%, respectively.

This estimated probability, specifically with regards to the Cmax, leads to a temporary halt of dose escalation according to the precautions as defined in the protocol. Since it will be more likely than not that one or more participants dosed with 10mg MSD-001 in Part 1 Cohort 5 will reach a Cmax higher than the exposure cap as defined in the protocol, it is in conflict with stopping criterion #6 as defined in the protocol (version 2, p.23-25), which reads: “Observed individual Cmax and/or AUC0-24 values exceeding or predicted to exceed 103ng/mL and 665 ng*h/mL, respectively, in any subject.”

Following this temporary halt of dose escalation, a risk-benefit analysis was performed by the SRC and it was concluded that, the risk-benefit ratio for participants in the study would not be affected. Even if the exposure cap were to be exceeded in one or more individuals, this would still be significantly below the NOEL for convulsions, as the exposure cap is set factor 2 below the NOEL for convulsions. More importantly, these probability estimates do not translate to the probability of a seizure occurring, which was the intended aim when the stopping criteria were defined without having any experience with MSD-001 (which we now have), but have argued to be very low. As argued in the rationale for increasing the exposure cap in the substantial modification submitted in January, the risk of a healthy human developing a seizure following dosing with a 5-HT2A agonist is considered to be extremely small based on published data. The NOEL for convulsions, in contrast, has been determined based on preclinical studies in Beagle dogs, a species prone to (drug-induced) seizures. In addition, the uncontrolled human experience data, collected by Mindstate Design Labs, does not include any reports of seizures occurring following use of MSD-001, even at doses ≥10mg. Nor have there been any harbingers of seizure observed in the doses of up to 6mg MSD-001 administered in the study so far. Nonetheless, in the case of unforeseen occurrence of seizures or convulsions, sufficient safety precautions have been implemented in the current study to mitigate risk and to guarantee adequate medical management at CHDR.

Taken together, a dose of 10 mg MSD-001 is considered safe and rational by the SRC. In addition, PK predictions for the average maximal exposure at 10 mg, are consistent with the limits set in the study protocol, as Cmax and AUC for MSD-001 10 mg are predicted to reach 65.6ng/mL and 336ng*h/mL, respectively, which are below the exposure caps of 103ng/mL and 665ng*h/mL. Finally, as the SRC concluded that the conflict with stopping criterion #6 based on predicted PK data in the light of the arguments above does not change the risk-benefit ratio of the participants (art. 37 CTR), dosing will be resumed once the ethical committee has been informed.

Follow-up measures

No additional follow-up measures are needed.

Benefit-risk balance changed

No

Treatment stopped

No