Changing endpoints in the middle of pivotal trials can cast doubt over a drug’s efficacy and approvability. Such is the case with Chelsea Therapeutics’ hypotension therapy Northera, and despite the company's best efforts to shine a positive light on yesterday's news its stock has dropped nearly 20% since then, trading at $5.
Preventing falls in patients with the low blood pressure condition neurogenic orthostatic hypotension (NOH) – the new primary endpoint – is arguably a highly relevant measure, given that the main reason NOH sufferers end up in hospital is because of injuries sustained from a fall. However, this second pivotal change-of-tack Chelsea has made with Northera has observers questioning whether the drug is approvable and raises the worrrying prospect that the FDA will ask for further trials (Chelsea soars as it gets positive result second time round, September 20, 2010). As it stands, the company will file this year for NOH, with a view to launching in the second quarter of next year, when it expects to report topline results for the bigger prevention of falls indication.
The biggest outcome
Northera is a formulation of droxidopa, designed to replace epinephrine, and is already sold for low blood pressure in Japan.
NOH is a condition of dangerously low blood pressure associated with dizziness and fainting when standing up, and the resulting falls can cause serious injuries. A complication of about half of Parkinson’s disease cases, Chelsea says it is the most common reason for Parkinson’s patients being hospitalised.
However in an ongoing pivotal trial in Parkinson's patients, called 306, Chelsea had designated a patient questionnaire on the severity of symptoms – the Orthostatic Hypotension Questionnaire (OHQ) - as the primary endpoint, falls was only a secondary measure. An interim analysis revealed the study was heading towards failure on the OHQ measure, prompting the company's plans to amend the trial design.
Simon Pedder, Chelsea's chief executive, said that for elderly patients with Parkinson’s the questionnaire approach was too subjective, and blamed the outcome on an unprecedentedly high placebo effect. Preventing falls would be a more objective outcome, he said. Northera reduced the number of weekly falls by 60%, two to three times as effective than placebo, the unblinded data from 306 showed.
“The biggest clinically meaningful outcome in this indication is the prevention of falls. It is the most troublesome worry for patients that have this disease,” he said during a conference call.
The company is currently discussing with the FDA the proposed change, and Chief Medical Officer William Schwieterman confidently postulated that the FDA could “be very excited about it.”
An amended protocol will be submitted in coming weeks. Chelsea plans to split the 306 trial into 306a and 306b, to measure outcomes in unblinded and then blinded patient cohorts, and hopes to achieve a 40% reduction in falls.
Why the company did not pursue falls as a primary outcome in the first place appears to stem from the very first 301 trial of Northera, preventing dizziness in NOH patients, which failed. At the time, and coming as a surprise to observers, the FDA allowed a redesign of 301 using OHQ as the primary endpoint, which eventually passed muster.
This, however, was clearly not reading through to 306.
Interestingly Northera did also improve Parkinson’s symptoms during 306, which could help Northera’s approvability without having to endure another trial; furthermore no safety issues were reported.
The FDA has previously agreed that Northera can be filed for NOH under an accelerated procedure, based on the results of 301 and another study, 302, in symptomatic NOH patients with primary autonomic failure. Chelsea will also file with some preliminary unblinded data from the new 306 study.
Chelsea expects an approval this time next year, with a launch in the second quarter of 2012.
At that time, it also expects a preliminary read-out in the potentially more lucrative setting of Parkinson’s disease-associated NOH, from the modified 306 trial.
Chelsea recently raised $38m through a public share issue and has enough cash to run until the anticipated approval point and Chelsea now seems keen to bring partners on board before turning to the public market again.
The results for preventing falls are certainly significant, though investors and potential partners could be put off by the overall inconsistency of pivotal data and the general to-ing and fro-ing by Chelsea. That said, if Northera continues its good performance in a new, arguably more relevant orphan indication, both regulators and partnership prospects could be sufficiently appeased.
|Trial name||Study 301||Study 302||Study 306|