Good question, to which I don't have a great answer.
So the negative RCT I cited was actually for sepranolone (isoallopregnanolone), a GABAA receptor modulating steroid antagonist - it's a stereoisomer of allopregnanolone which (confusingly) has antagonistic effects to allopregnanolone at the GABAA receptor.
The rationale was that fluctuations in allopregnanolone results in symptoms of PMDD due to its action at GABAA receptors so blocking this will treat symptoms.
Some possible explanations for the negative RCT:
1. Dosing issues. The timing of dosing was complicated, sub/cut administered injections every 48 hours during the luteal phase, up to a maximum of 14 days. Perhaps the timings were off. 10mg also seemed to work better than 16mg - the pharmacokinetics of these drugs are complicated.
2. Power issues. The trial retained slightly less than they had anticipated for their power calculation - 143 vs 150. Maybe a bigger phase III trial would show statistically significant effects?
3. Is sepranolone doing what we want it to do in vivo? A phase II trial in menstrual migraine also failed to beat placebo.
4. Maybe there are other mechanisms at play rather than allopregnanolone. After all, adding back oestradiol in PMDD leads to a recurrence of symtpoms, so it can't be the full story.
Final thought - getting new drugs to market is hard!
Good question, to which I don't have a great answer.
So the negative RCT I cited was actually for sepranolone (isoallopregnanolone), a GABAA receptor modulating steroid antagonist - it's a stereoisomer of allopregnanolone which (confusingly) has antagonistic effects to allopregnanolone at the GABAA receptor.
The rationale was that fluctuations in allopregnanolone results in symptoms of PMDD due to its action at GABAA receptors so blocking this will treat symptoms.
Some possible explanations for the negative RCT:
1. Dosing issues. The timing of dosing was complicated, sub/cut administered injections every 48 hours during the luteal phase, up to a maximum of 14 days. Perhaps the timings were off. 10mg also seemed to work better than 16mg - the pharmacokinetics of these drugs are complicated.
2. Power issues. The trial retained slightly less than they had anticipated for their power calculation - 143 vs 150. Maybe a bigger phase III trial would show statistically significant effects?
3. Is sepranolone doing what we want it to do in vivo? A phase II trial in menstrual migraine also failed to beat placebo.
4. Maybe there are other mechanisms at play rather than allopregnanolone. After all, adding back oestradiol in PMDD leads to a recurrence of symtpoms, so it can't be the full story.
Final thought - getting new drugs to market is hard!