First-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of VTX-PID in healthy male volunteers

Temporary halt TH-31072

Halt date

2024-06-10

Member states concerned

Germany

Publication date

2024-06-25

Reason

Safety related (clinical or pre-clinical results)

Explanation

Dosing of further subjects in Study Vivet VTX-PID_CLN_001 has been paused because one of the predefined stopping rule criterion has been met: “One or more subjects experience increased alanine aminotransferase or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) with total bilirubin > 2 x ULN or increased AST > 3 x ULN accompanied by alkaline phosphatase (ALP) > 1.5 x ULN”. The peak values observed for subject RDN403 of cohort 4, who received the IMP, were ALT: 306.5 IU (ref. 0-50), i.e. 6.2 x ULN; AST: 174 IU (ref. 0-50) i.e. 3.5 x ULN; ALP: 219.4 IU (ref 30-120) i.e. 1.8 x ULN; GGT: 233 IU (ref. 0-55 IU), while total bilirubin remained unchanged and in the normal range.
The event happened after 5/8 subjects of the last cohort of the dose escalation had been dosed with VTX-PID 0.6 mg/kg.
A hepatologist expert in drug-induced liver toxicity has been consulted on the matter and concluded that, although the threshold for considering a potential DILI occurred in this case, this is not the main issue; indeed, the liver involvement here is considered to be a biochemical hepatic alteration in the setting of a systemic inflammatory response syndrome, rather than a primary toxic effect of the IMP on the liver for the following reasons:
• Two similar cases of elevated LFTs occurred in the study (subjects 403 and 204 (1), one of which reached the per protocol DLT definition), which does not match with the very rare frequency of idiosyncratic DILI in general;
• The lab results did not show any increase of bilirubin, indicating that the AE does not meet the Hy’s Law criteria;
• The LFT elevations (mild, considering the International DILI Expert Working Group DILI severity classification (Aithal et al Clin Pharmacol Ther 2011), with preserved hepatic function and coagulation parameters) of both subjects were accompanied with several other symptoms, as well as signs of inflammation; this indicates that the events were not primary hepatic, but secondary to another cause, which may be linked to an immunological reaction to the product or an infection (the AE were clearly unrelated to the concomitant medications, i.e. amoxicillin, paracetamol, loratadine);
The expert indicated that dosing of further subjects may resume:
• Once additional exams to investigate etiology e.g. infections, have been completed on new samples or already existing samples,
• and possibly after amending the protocol to use prophylactic prednisone ≥ 0.5 mg/kg.
The principal investigator temporarily halted the trial while investigations are ongoing and decisions are made on the appropriate mitigation to be implemented in the protocol.
(1). RDN204 from Cohort 2 dosed with VTX-PID 0.15 mg/kg previously presented with a similar event, albeit not reaching the threshold of the stopping rule.

Follow-up measures

1) Since the AE was reported, the treatment of the next subjects screened has been postponed. No additional subjects have been dosed since 04JUNE2024, day of dosing of subject RDN403. VTX-PID is a single dose administration, all subjects already dosed and still in the study will continue according to the planned follow-up.
2) Subject RDN403: was discharged as planned from phase I unit on 12JUNE2024 since his liver enzymes improved quickly, ultrasound examination did not reveal any relevant findings and he was clinically well. He came back (ambulatory visit) on 17JUNE2024 to perform D14 visit and the additional exams requested. At that date ALT, AST values had returned within normal ranges. ALP had decreased close to normal range (124.6 IU; ref 30-120), GGT had significantly decreased to subnormal values (82.8 IU; ref 0-55 IU).
3) Subject RDN203: had previously been discharged as planned without additional follow-up measures. He has completed the study on 21MAY2024.
4) Once available, all data will be reviewed by the safety review committee of the study to decide on the restart of the study, and if the protocol needs to be amended.

Benefit-risk balance changed

Yes

Treatment stopped

Yes