Positive phase II results with Neuroderm’s 24-hour version of ND0612, a subcutaneous formulation of levodopa/carbidopa, have taken it a step closer to approval in Parkinson’s disease. Should upcoming studies go to plan, the group aims to submit ND0612 to US and European regulators in the second half of 2018.
However, the small, 38-patient trial failed to show a benefit with a more convenient 14-hour dosing schedule. Neuroderm is only taking the 24-hour regimen forward, and it will now need to prove the therapy in a much larger, placebo-controlled study – at least if it wants to get approval in Europe.
This did not seem to temper the enthusiasm of investors, who sent Neuroderm’s stock up 27% yesterday. Analysts were particularly impressed by a complete reduction of “off” time in 42% of patients in the 24-hour therapy group, albeit in a post-hoc analysis. This will obviously need to be replicated in phase III, and the company has tweaked the design of its study accordingly.
Also a plus is a relatively easy path to approval in the US: Neuroderm has previously said it only needs to carry out pharmacokinetic trials there, which do not appear to have started yet, as well as finishing the ongoing Beyond long-term safety study, due to read out in 2018.
Meanwhile, approval in Europe could be tricker. After a meeting with the EMA, Neuroderm has tweaked its plans, abandoning the 009 pharmacokinetic trial and resurrecting the suspended Indigo study. It had previously hoped that 009 would be enough for approval by demonstrating equivalence to Abbvie’s marketed Duopa levodopa/carbidopa gel.
The company tried to put a positive spin on the development, saying Indigo might help ND0612 get a broader label than would have otherwise been the case.
According to Mr Lieberman, approval based on pharmacokinetic studies would have left ND0612 “boxed into the [EU] label for Duopa”, which restricts its use to patients with severe motor fluctuations who are not responding to oral treatment. Neuroderm hopes that ND0612 could be used to treat any patients on levodopa with motor fluctuations.
ND0612 might also be more patient-friendly than Duopa, which is pumped directly into the duodenum via a permanent tube over 16 hours. Neuroderm’s project, meanwhile, delivers the drugs subcutaneously via a small pump worn on the belt, which the company describes as “minimally invasive”.
As part of its European approval strategy Neuroderm has changed the design of Indigo to incorporate a high-dose group, as well as the planned low-dose and placebo arms, increasing the number of patients from 150 to 240. It has also added new endpoints including a responder analysis – no doubt on the back of the promising response rates seen in a phase II study, 006.
Trial 006 only tested a high-dose version, known as ND0612H. As well as a 24-hour infusion, it evaluated 14-hour administration during the day, complemented by a morning oral dose of levodopa/carbidopa.
The 24-hour therapy group met the primary endpoint of change in “off” time, which was reduced by 2.8 hours versus baseline. There was a non-significant reduction of 1.3 hours in the 14-hour treatment group.
This was in line with what the company had expected, said its chief medical officer, Sheila Oren. The company had always intended ND0612 to be delivered over 24 hours, but “when we were planning the study we were asked to look into day only versus day and night, because clinicians believed some patients might prefer a daytime only therapy [plus] a pill in the morning.”
As it turned out, the 24-hour infusion looked more effective “and patients didn’t complain” that night-time dosing was inconvenient, she said.
While the 006 results look promising there are reasons for caution, including its small size and the fact that one dosing regimen failed. If it wants to get the go-ahead in Europe, Neuroderm will need to prove ND0612’s benefit in the larger and more rigorous Indigo study.
|Beyond (012) long-term safety trial||NCT02726386|