The rare childhood epilepsy space has a new contender. On the back of positive phase II data, Ovid Therapeutics’ and Takeda’s novel cholesterol 24-hydroxylase inhibitor, soticlestat, should soon go into late-stage testing.
But the win was not as emphatic as it could have been. The Elektra study showed a benefit with soticlestat in Dravet syndrome, but the project looks to have fallen short of the efficacy bar set by Zogenix’s Fintepla. And soticlestat stumbled in Lennox-Gastaut syndrome (LGS); Ovid is evaluating its next steps here.
Ovid’s stock, which climbed as much as 50% during premarket trading, ended up down 3% yesterday, perhaps as these doubts hit home. It also might not have helped that the company wasted no time in announcing a $50m fundraising.
Elektra shines…or does it?
Ovid was no doubt following the old biotech mantra of raising money when you can rather than when you need it, given that Elekta was, on the face of it, a success.
The trial enrolled both Dravet and LGS patients, who received either soticlestat or placebo over an eight-week dose optimisation period, followed by a 12-week maintenance period. The primary endpoint was the median change from baseline seizure frequency, across both epilepsy types, during the maintenance phase.
Elekta hit this endpoint, showing a 28% reduction in seizures in soticlestat-treated patients, versus a 3% increase in the placebo group. This was statistically significant with a p value of 0.0007.
However, delving into the different epilepsy subtypes paints a different picture for Dravet and LGS.
Soticlestat showed a benefit in Dravet, and Ovid now plans to move into phase III here. However, a look at the placebo-adjusted numbers suggests that soticlestat’s efficacy falls short of that seen with a higher dose of Zogenix’s Fintepla, which was approved for Dravet in June. At least the Ovid/Takeda project looks better than GW Pharmaceuticals’ Epidiolex.
|Cross-trial comparison in Dravet syndrome|
|Project||Company/ies||Placebo-adjusted reduction in convulsive seizure frequency|
|Fintepla 0.2mg/kg||Zogenix||23 points|
|Fintepla 0.7mg/kg||Zogenix||56 points|
|Epidiolex||GW Pharmaceuticals||26 points|
|*Figure given for full 20-week treatment period. Source: Ovid presentation; Lancet publication of Fintepla phase III results; Epidiolex label.|
The above numbers represent the absolute differences between the response rates in the treatment and placebo arms.
Obviously, caution applies when making such cross-trial comparisons. One major difference between the trials was the variable responses seen with placebo. Notably the phase III trials of Fintepla found a 19% reduction in seizure frequency in the placebo group.
Conversely, in Elekta soticlestat was flattered by a low placebo response. Ovid executives admitted during a conference call yesterday that the increase in seizures in the placebo arm had surprised them: they had been expecting a 10-20% reduction in seizures with placebo, in line with other trials in rare epilepsies.
This could spell trouble for phase III, if more typical placebo responses are seen.
But even if soticlestat continues to fall short of Fintepla there could still be a place for it, especially given Fintepla’s cardiovascular side effects.
Soticlestat’s adverse event profile looked fairly clean, with the most common side effects being lethargy and constipation.
This raises the possibility that soticlestat, with its different mechanism of action, could be used in combination with the other agents. Rare epilepsy patients are often treated with multiple drugs and enrolees in Elektra were on up to four concomitant medications, including Epidiolex. Fintepla was not included because the drug was not approved at the time the trial was recruiting, the Ovid execs said.
Soticlestat’s chances in LGS look more doubtful. In these patients Elekta showed a 21% reduction in drop seizures over 20 weeks, versus a 6% reduction in the placebo arm. This was not statistically significant (p= 0.1279).
The Ovid execs said they were encouraged by the trend in LGS, pointing out that it is a more heterogeneous disease and noting that certain patients appeared to do better than others.
Epidiolex is approved for LGS; Fintepla is behind here, but Zogenix reported a phase III win in February.
Ovid’s chief medical officer, Amit Rakhit, concluded that there are “still possibilities to move forward with LGS”, but that the company wants to make sure it has a good handle on data before it announces plans.
Soticlestat is forecast to bring in $268m by 2026, according to EvaluatePharma. Fintepla and Epidolex are expected to make $807m and $1.3bn the same year.