Welcome to your weekly digest of approaching regulatory and clinical readouts. A US advisory committee will meet on November 14 to discuss Vanda Pharmaceuticals' tasimelteon, indicated for the treatment of non-24-hour sleep-wake disorder in blind individuals.
There is no approved treatment for this disorder, but tasimelteon showed efficacy in a small phase III trial and in a subsequent maintenance study. However, with controversy over changes to primary endpoints, questions remain over the validity of the results and the project's potential for approval.
Non-24 is a chronic circadian rhythm disorder, whereby the body fails to synchronise with the 24-hour day-night cycle. It affects individuals who lack light sensitivity, as light perception is needed to reset the circadian rhythm and control the release of the hormones melatonin and cortisol. Dysregulation leads to significant disruption of the sleep-wake cycle.
Tasimelteon, which has the proposed brand name Hetlioz, is a dual melatonin receptor agonist with selective activity at melatonin receptors MT1 and MT2. It has orphan drug designation in the US and Europe. While there is no approved treatment for non-24, oral melatonin therapy, which is used for insomnia, can be given but has had varying success.
Two phase III studies, called Set and Reset, were completed. 84 totally blind individuals were recruited into the Set study, and were given oral tasimelteon daily for 6 months. Reset was a withdrawal trial to test the maintenance effect of tasimelteon, and 20 individuals who took part in Set were recruited into the second study.
In Set the primary endpoints were "entrainment", defined as resetting the body clock by measuring urinary melatonin and cortisol, and clinical response. The rate of entrainment was 20% for the tasimelteon group and 2.6% for placebo, with a p value of 0.0171. In Reset entrainment rate was 90% versus 20% for placebo (p=0.0026).
However, an article published by The Street in June cast significant doubt on the trial, causing Vanda's shares to fall 22%. This noted that multiple changes had been made to the primary endpoint, which had originally been set as average night-time total sleep, over the course of the trials. Furthermore, the new endpoint was determined just one month before results were published last December.
The article notes that enrolment was hindered because totally blind patients with non-24 could not be identified. Meanwhile, a benefit in the clinical response endpoint was only demonstrated in trials thanks to combining data from the two phase III studies. After its publication shareholder lawyers began investigating complaints against the company.
Despite the concerns Vanda shares bounced back 44% in July when the FDA granted tasimelteon a priority review, setting a PDUFA date of January 31 next year. An advisory committee notification was given last month, with intense scrutiny likely on endpoints and the drug's unmet need.
Vanda Pharmaceuticals in licensed tasimelteon from Bristol-Myers Squibb back in 2004 for $41m, and earlier this year Bristol waived its option to re-acquire rights.
While Vanda notes that 65,000 and 90,000 totally blind individuals in the US suffer from the disorder, Jefferies analysts only assume market penetration of <6.5%, or <5,000 patients, at peak in 2022. EvaluatePharma consensus is for sales to reach $402m in 2018, but estimates vary very widely.
Two tasimelteon safety studies are recruiting, with primary completion dates next year. Vanda is also looking beyond non-24-hour disorder to Smith-Magenis syndrome, a developmental disorder that includes disturbed circadian rhythms, and paediatric patients with anophthalmia or microphthalmia – rare developmental defects of the eyes.
The company’s only marketed product is Fanapt, for which it receives royalties in the US and Canada. Sales have been disappointing as the drug struggled to make headway in the crowded schizophrenia market. The patent for Fanapt is due to expire in 2017, making the approval of tasimelteon a much-needed catalyst.
|Trial details||Name||Trial ID|
|Safety and efficacy study||Set||NCT01163032|
|Withdrawal study to demonstrate maintenance effect, 20 patients from Set study||Reset||NCT01430754|
|Open-label safety study, 1-year dosing, recruiting 140||-||NCT01218789|
|Open-label safety study, 24 month dosing, recruiting 200||-||NCT01429116|
All information is sourced to analyst notes and the EvaluatePharma Calendar of Events tool.