Clive Ballard on Pimavanserin for Treatment of Hallucinations, Delusions Associated with Dementia-Related Psychosis

Clive Ballard, MD, professor of age-related diseases and Dean of the University of Exeter Medical School

Clive Ballard, MD

At the 2018 Alzheimer's Association International Conference in Chicago, Illinois, Clive Ballard, MD, presented the results from a phase II trial designed to evaluate the safety and efficacy of pimavanserin in participants with Alzheimer disease psychosis.

Since safe and effective treatments for Alzheimer disease psychosis are an urgent priority for this patient population, NeurologyLive sat down with the professor of age-related diseases and Dean of the University of Exeter Medical School to discuss the study results.

Pimavanserin has been granted breakthrough therapy designation by the FDA for dementia-related psychosis and researchers are currently conducting HARMONY, a phase III trial, to evaluate the safety and efficacy of pimavanserin for treatment of hallucinations and delusions associated with dementia-related psychosis.

NeurologyLive: Can you speak to the results of the phase II trial you conducted looking at pimavanserin for treatment of psychosis in patients with Alzheimer disease?

Clive Ballard, MD: We conducted a phase II trial of pimavanserin, which is a 5-HT _2A inverse agonist for the treatment of psychosis, that's been licensed for treating psychosis in people with Parkinson disease in the US, based on a study we were previously involved with. In the UK, we conducted a phase II study looking at Alzheimer psychosis with pimavanserin. This was a predominantly a 6-week randomized control trial comparing pimavanserin to placebo in 179 people and then we had an extra 6-week follow-on to look at safety type issues in the study.

The main study we completed was published in Lancet Neurology a couple of months ago and showed significant benefit in the improvement of psychosis at the primary endpoint at 6 weeks, which has now led on to a phase III trial which is commencing predominantly in the United States—so we’re very excited about that and we’re excited to see what the results of that will be.

What we presented here in the poster was a further secondary analysis looking at the people within that study who had more severe psychosis. These were people who scored more than 12 in total on the 2 main NPI psychosis items, like [clinical] delusions and hallucinations, so this is pretty intense psychosis and about 40% of the study population had psychosis at that level. The interesting thing was those individuals did much better than the overall trial population, and they saw much more benefit and if you look at that in terms of a standardized effect size, in the study overall the standardized effect size wasn't bad it was Cohen's d= -.32, which compares very favorably with antipsychotics and other currently used medications which have effect sizes of about .2, so we're very pleased with the initial study. If you look in the subgroup with more severe psychosis, the effect size actually goes up to Cohen’s d= -.077, which is potentially spectacularly good, but clearly you need to be cautious because this is a secondary analysis, that wasn't the primary outcome.

I think what's really encouraging about the results is that these are the patients we really feel we need to treat with pharmacological therapies, so those are the patients that we want to really improve and respond, so it was a really good signal that those were the patients who were doing really well with the pimavanserin treatment.

If this gets approved later down the line, what would pimavanserin mean for this patient population?

CB: Well at the moment there's a huge unmet need in treating psychosis in people with Alzheimer disease. It's a common symptom in people with Alzheimer disease depending on the stage of the illness, somewhere between 20%—40% of people will have these symptoms and over the course of the illness it's the majority. The symptoms are distressing for the person themselves or for caregivers, they accelerate in placement in nursing homes and other types of institutionalization and they're associated with more rapid decline, so they're not just distressing they actually have a major impact on disease outcome for individuals as well. At the moment we don't have any licensed pharmacological treatments, and unlike others neuropsychiatric symptoms in people with Alzheimer disease, like agitation which respond well to non-pharmacological interventions, there's really not much evidence that psychosis does respond to those non-drug approaches.

So currently what's happening is people are being prescribed atypical antipsychotics off-label but the effect sizes of these treatments is very marginal and they have a lot of harms, they're almost double the mortality rate, they’ve significantly increased stroke, falls, fractures, deep vein thrombosis. We've been in a very difficult position where they've been the only available pharmacological treatments but even then they're off-label and they’re associated with a lot of harms, so actually if pimavanserin does turn out to be a more effective and safer alternative that would be a great step forward in treating these distressing symptoms.

What are you most excited about in the Alzheimer space?

CB: I think a lot of things have been quite good. We’ve seen a lot more treatments for psychiatric, neuropsychiatric symptoms like psychosis and agitation beginning to come through and that’s been a huge unmet need and we’ve been in the same sort of void for 20 years, so it’s great to see more stuff coming into that space. Obviously, we’ve all been looking for disease-modifying therapies, you know that’s been a space that’s been a little bit disappointing, we’ve not seen any real breakthroughs for a long time, but I think there are 1 or 2 things at this conference which are looking encouraging, so it’s not quite the job done but it’s creating a little bit more optimism and enthusiasm, so that’s good. I think the other area for me that’s a real opportunity is prevention. From some work that we’ve done, and others have done over the last couple years, it seems clear that about 45% of the risk for Alzheimer disease is potentially modifiable, and we’re beginning to understand some of the lifestyle and medical risk factors that might contribute to that. And we’re already seeing in large epidemiological studies that perhaps things like better treatment of hypertension in midlife is beginning to reduce the incidence in specific age bands, so I think there’s a lot of opportunity there and really actually do things that are proper and effective prevention interventions, so I think again that’s going to be an exciting space over the next 5 years.

What do you think is the most challenging aspect?

CB: Well probably several levels, I think it’s been the disease-modifying therapy trials that have been challenging and that’s partly finding the right therapies but also we’re increasingly realizing that perhaps it’s going to be important to identify people at a much earlier stage of illness, possibly even before they have obvious preclinical symptoms, even though that might be the right scientific thing to do, how to actually find a way of doing that, and a way that’s manageable and deliverable is actually a real challenge. For me personally, the other bit that’s frustrating is right at the other end of the spectrum when we’re looking at people with more severe Alzheimer in nursing home care. We’re beginning to find a lot of evidence that certain training programs that promote person-centered care, that promote approaches that are more focused on the individuals and helping them live better can actually really improve peoples’ lives, but the frustrating thing is those programs aren’t being implemented anywhere and when we reviewed what was actually happening in the UK, 97% of the training programs that are being used aren’t evidence-based and it just feels almost criminal. It feels worse in a way than the disease-modifying drug situation because that’s frustrating, but when we actually know what will help and we’re not doing it, that feels even worse.

Transcript edited for clarity.

REFERENCE

Ballard, C, Banister C, Khan Z. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2,

randomised

, placebo-controlled, double-blind study. The Lancet Neurology. 2018;17.

doi

: 10.1016/S1474-4422(18)30039-5.