Upcoming events – Zogenix and Mallinckrodt look to rare diseases

Welcome to your weekly digest of approaching regulatory and clinical readouts. Data from Zogenix’s second phase III trial of ZX008 in Dravet syndrome are due this quarter; the first was positive, but as the drug contains fenfluramine investors will be watching closely for any hints of a cardiac safety signal. 

Also by mid-year Mallinkrodt will report phase II/III data for VTS-270 in Niemann-Pick C disease. In an earlier single-arm trial the cholesterol modulator showed signs of efficacy, but the latest study is placebo controlled, presenting a higher hurdle. However, the severe lack of available treatments means that the FDA might be lenient.

Second chance

The Zogenix data expected soon are from Study 1504, in Dravet syndrome, a rare form of childhood epilepsy. The ZX008 has completed two phase III trials, 1501 and 1502, and the resulting data were pooled into what is referred to as Study 1. 

Results from Study 1 showed that ZX008 0.8mg/kg/day cut mean convulsive seizure frequency – the trial’s primary endpoint – by 63.9% versus placebo between baseline and 14 weeks. The lower dose, 0.2mg/kg/day, also hit statistical significance, sending Zogenix’s shares up 172% (Dravet hit makes Zogenix another September biotech winner, September 29, 2017).

Study 1504 has enrolled 80 patients whose background epilepsy medications include stiripentol, which is approved for Dravet syndrome in the EU. Study 1 excluded such patients. Because stiripentol can elevate the concentration of concomitantly administered drugs 1504 tests a lower dose of ZX008 – 0.5mg/kg/day.

Safety will be scrutinised because ZX008 contains low-dose fenfluramine, half of the Wyeth Fen-Phen anti-obesity combo that was withdrawn in 1997 after being linked to heart valve problems. Cardiac safety monitoring throughout ZX008’s Study 1 demonstrated no clinical or echocardiographic evidence of cardiac valvulopathy or pulmonary hypertension.

However, in December Zogenix reported that five patients on placebo, seven on the low dose and nine on the high dose had trace mitral or aortic regurgitation. Despite clinical guidelines categorising absent and trace echocardiogram findings as normal investors sent shares down 11%.

Studies 1 and 1504 will be used for a filing later this year, but Zogenix still lags GW’s Epdiolex, a cannabinoid that had a positive panel for Dravet and Lennox Gastaut syndromes and is due a US regulatory decision by June 27.

Rare disease

Niemann-Pick C (NPC) disease is a rare genetic condition in which lipid accumulates in the brain, liver and spleen, leading to progressive loss of brain function, motor control, hearing, speech and cognition. It is often fatal within 15 years.

Mallinckrodt gained VTS-270 through its $1.2bn acquisition of Sucampo at the end of 2017, and phase II/III data should emerge by mid-year.

In an open-label single-arm phase I/II trial, 14 patients aged 4-24 were given monthly spinal injections of VTS-270 at doses 50-1,200mg. NPC Neurological Severity Scores (NNSS) were used to compare disease progression. For treated patients the scores increased, meaning the disease worsened, at 1.2 points per year, compared with 2.9 points for historical control, and the greatest improvements were seen in gait, cognition and speech.

One issue with the treatment was increased hearing loss, also a symptom of NPC, which was compensated with the use of hearing aids. This adverse effect was expected as it was evident in animal models.

In the phase II/III study 51 patients will receive VTS-270 every two weeks for 12 months. The trial is sham controlled and initially tests 900-1,800mg doses in nine patients for eight weeks. One dose will then be chosen for the remainder of the study.

NNSS will again be used to measure disease progression, but unlike the single-arm trial will only include four major components: ambulation, fine motor, cognition and swallowing. The hearing endpoint is excluded but hearing loss will be closely monitored.

The study is 90% powered to show a difference between treatment and sham. Leerink analysts note the lack of approved agents in the US; J&J’s Zavesca has NPC on its label in Europe but not in the US, where it is only approved in Gaucher’s disease. There is likely some off-label use, but Zavesca has limited efficacy and causes high rates of diarrhoea, abdominal pain and nausea.

To contact the writer of this story email Joanne Fagg in London at [email protected] or follow @ByJoFagg on Twitter