NeuroSearch experienced both the heady heights of clinical success and the painful fallout from an embarrassing data blunder last year. Hopes for another about turn in fortune were dashed last month when the FDA confirmed that another trial of its Huntington’s disease treatment, Huntexil, would be required for US approval.
With the possibility of a similar demand emerging from European regulators in the next couple of months the Danish company has some crucial decisions to make, not least over partnerships and financing, made no easier by a share price testing eight year lows. New chief executive Patrik Dahlen tells EP Vantagewhile the company’s prize drug could be back in the clinic before the end of the year, all options to get it there are still very much on the table.
Ups and downs
Last year was certainly eventful for NeuroSearch. It started off well with highly encouraging phase III data on Huntexil, a dopaminergic stabiliser. The prospect of a drug with a real impact on the debilitating movement and mobility problems caused by the degenerative neurological condition caused the stock to more than double in value, reaching Dkr220, and propelling the company's market value towards $1bn (NeuroSearch redeems itself with impressive Huntington’s phase III data, February 3, 2010).
The news turned sour only two months later when the company had to admit the trial, called MermaiHD, had actually missed its primary endpoint, a disastrous event that claimed top level scalps, including former chief executive Flemming Pedersen (NeuroSearch data blunder dents confidence, April 28, 2010).
After a second phase III trial, called Hart, also failed the company performed a meta-analysis of the two studies in an attempt to win approval on a successful secondary endpoint; the thumbs down from the FDA in March suggest another trial is on the cards.
Mr Dahlen says the company is still awaiting the official feedback from the US regulator on the clinical path, but their position is relatively clear. The opinions of European regulators should be known by the end of June, and the company hopes to be able to run one trial to satisfy both agencies.
“If they have the same view, we will consolidate their input and come up with a new study plan; that’s what we are focusing on right now,” he says. “All things being equal and provided we get similar advice, we could look to be up and running before the end of this year.”
Huntington’s is caused by a genetic defect which causes a mutant form of the Huntingtin protein to be produced. Its presence causes degeneration in the brain, particularly in an area associated with both voluntary and involuntary movements, cognition and emotion. Symptoms usually manifest when a patient reaches their 30s or 40s, and life expectancy from when they start is 15 to 20 years.
Specifically, the disease is caused by a repeated or longer than normal section of part of the Huntingtin gene. This so-called CAG repeat is linked to the severity of the illness in individual patients – more repeats can mean earlier onset, more severe symptoms and faster degeneration.
Adjusting the MermaiHD results to take CAG repeat length into account caused all the problems for NeuroSearch last year. The first announcement declaring the trial a success had adjusted for this difference in patients’ genetic disposition – an adjustment the company at the time argued was clinically relevant. Unfortunately this was not part of the trial protocol, and when the data was run without the CAG repeat adjustment, the primary endpoint was missed.
Mr Dahlen says the company has not decided yet whether the CAG adjustment will be used in the next pivotal study, pending further feedback from regulators.
“We will collect the data – it is true that there is some correlation between longer CAG repeat and severity. But we are not going to hitch the study on finding a CAG related relationship (for Huntexil),” he says. “We would like to move forward with Huntexil where all eligible Huntington patients could be coming on the drug without needing to do a genetic test.”
What he does expect is for a successful secondary endpoint to become the primary measure this time round.
Both MermaiHD and Hart were primarily seeking to show a significant improvement on the modified motor score mMS. This was chosen because it was thought Huntexil mainly had an impact on voluntary movements, and mMS allows these to be measured specifically.
The secondary endpoint chosen was total motor score (tMS), which measures all motor symptoms, voluntary and involuntary. Both trials unexpectedly performed much better on this measure.
As well as utilising tMS, Mr Dahlen expects any new trial to take approximately 26 weeks, recruit around 450 patients and use the two times daily 45mg dose – all pending final regulatory feedback.
To deal or not to deal
Perhaps a more important decision facing Mr Dahlen is whether to sign up a partner, and what any deal should look like. He says that decision has yet to be taken.
“Any management in a company like NeuroSearch would need to evaluate partnership opportunities on a drug like Huntexil, even though we have said our primary objective is to take drug to market ourselves,” he says. Ex-European deals in particular are being considered, he says.
“We have interested parties and we continue to move those interested parties to a point where we could have proposals to evaluate.”
Investors are unlikely to be happy if NeuroSearch decides to go it alone. Shares in the company were trading at Dkr53.50 today, giving a market value of Dkr1.30bn ($253m). Raising funds would be highly dilutive and many shareholders would prefer to see a partner help fund the study. Currently, the company has enough cash to last until the end of 2012.
Mr Dahlen admits promoting a share sale would be hard, although he believes he could find support if necessary. The fact the stock has fallen 25% since the company announced another trial was required in the US suggests he will need to mount a persuasive argument.
However, the failure of Pfizer’s Dimebon in Huntington’s this week highlights the need for treatments for this illness, with only Lundbeck’s Xenazine on the market and very little in the pipeline (Dimebon is Medivation's frustration once again, April 11, 2011). This fact, plus the convincing efficacy seen so far, highlights the promise in Huntexil.
"We see the value of it. The Huntington’s patients that have been in the trial see the value, the key opinion leaders that have evaluated the data see the value. When in a 26 week trial you improve [total motor score], which corresponds to something more like seven or eight months of decline, it’s difficult to see this would not be an important drug,” Mr Dahlen says.
More evidence that Huntexil works is still required. If NeuroSearch gets a partner on board, investors would be more easily persuaded to stick around.