Scrip Intelligence: AAN REVIEW: Snapshots of new Parkinson’s and Alzheimer’s therapies

By Mandy Jackson

March 25, 2013

Parkinson's and Alzheimer's disease presentations at the 65th American Academy of Neurology (AAN) Annual Meeting in San Diego from 16 to 23 March tended toward imaging and biomarker studies rather than clinical trial data for therapeutics, but some drug trial results were presented at the week-long conference.

The amount of new data for Parkinson's and Alzheimer's drugs paled in comparison to results for multiple sclerosis therapies, but that may reflect plans to present data at specialized conferences  later in 2013 rather than a lack of development in those diseases. Still, efforts are under way to encourage investment in new therapies given the progressive nature and growing number of patients with Parkinson's and Alzheimer's diseases.

About 5.4 million Americans have Alzheimer's disease and as many as 16 million people may be diagnosed by 2050, according to the Centers for Disease Control and Prevention.

Datamonitor estimates that Alzheimer's drug sales in the US, Japan and five largest EU markets (France, Germany, Italy, Spain, and the UK) will grow from $5.3 billion in 2011 to $12.5 billion in 2021, representing a compound annual growth rate (CAGR) of 9.1%.

It is believed that about one million people in the US and five million worldwide suffer from Parkinson's disease, according to the Michael J Fox Foundation.

Baseline data from the Fox Foundation's Parkinson Progression Marker Initiative (PPMI) were presented at the AAN meeting. PPMI will identify biomarkers and look for ways to standardize analyses of biomarkers so that the data can aid in Parkinson's drug clinical trials.

As of October, 298 Parkinson's patients and 155 healthy volunteers had volunteered for screening. Information from the online PPMI database has been downloaded from the internet more than 32,300 times.

"We were really excited by the rate of recruitment. It's a credit to the clinical investigators and the patient community," Fox Foundation CEO Todd Sherer said in an interview with Scrip.

Dr Sherer did not attend the AAN meeting, but the foundation had staff at the conference to survey Parkinson's research presented in San Diego.

The first biological and neuroimaging markers from the PPMI project are coming into focus. Patient recruitment will end in the next month or so and data from the initiative are being made available online in real time.

"We're starting to get to the point where we can unwrap the presents on Christmas morning," Dr Sherer said.

Parkinson's therapies

Data for nine Parkinson's drugs that treat the disease and its symptoms were presented at the AAN meeting, but clinical trial results from a larger selection of therapies are anticipated at the Movement Disorder Society's annual conference in Sydney, Australia from 16 to 20 June and at the Fox Foundation's annual conference in the fall.

Among the standouts at AAN were San Diego-based Acadia Pharmaceuticals' pimavanserin for Parkinson's psychosis. The once-daily, oral small molecule selectively blocks the 5-HT2A receptor involved in psychosis.

Acadia announced in November that patients who took 40mg daily doses of pimavanserin in the Phase III -020 clinical trial had a 5.79-point improvement in the nine-point Scale for the Assessment of Positive Symptoms for Parkinson's disease (SAPS-PD) versus a 2.73-point improvement in the trial's placebo group (p=0.001), marking a highly statistically significant difference for the study's primary endpoint ( scripintelligence.com, 28 November 2012).

Clinical investigator Jeffrey Cummings, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, presented detailed data at AAN from the Phase III -020 clinical trial at AAN showing significant improvements in all secondary efficacy measures, including the Clinical Global Impression Severity (CGI-S) scale (p<0.001), the Clinical Global Impression Improvement (CGI-I) scale (p=0.001) and CGI-I responder analyses (p=0.002).

Newron Pharmaceuticals and partner Zambon presented data from Phase III studies in which the alpha-aminoamide known as safinamide was evaluated as add-on therapy to a dopamine agonist in the MOTION clinical trial and as an add-on to levodopa in the SETTLE trial ( scripintelligence.com, 20 March 2013).

The companies intend to file for marketing approval in the US and EU by the fourth quarter of 2013 based on the Phase III results. Safinamide showed improvements over dopamine agonists alone in Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores for patients with early Parkinson's disease and improved "on-time" without dyskinesia compared with levodopa alone in patients with advanced Parkinson's.

In the treatment of levodopa-induced dyskinesia, Phase IIa data presented at AAN for Addex Therapeutics' dipraglurant showed improvements compared with placebo in clinician-observed measures and patient evaluations.

The clinical trial was supported by a $900,000 Fox Foundation grant. The organization recently provided a $1 million grant to support additional analyses of the available data.

The intent is to attract a partner that can help Addex complete development for dipraglurant - an oral, small molecule allosteric modulator that selectively inhibits the metabotropic glutamate receptor 5 (mGlu5).

"We were interested in continuing to move that project forward as quickly as we can. The ultimate goal is to find a partner to help accelerate it through the later stages of development," Dr Sherer said. "We're working with them to continue to do studies to make that case and augment the data to try to attract partners."

In terms of targeting Parkinson's symptoms that emerge as levodopa drugs wear off, Phase II data were revealed by Orion Corporation and BioTie Therapies at AAN.

Orion shared positive results from its Phase II clinical trial for ODM-101, which is under investigation as a Stalevo (levodopa plus entacapone and carbidopa) replacement ( scripintelligence.com, 22 March 2013).

BioTie reported Phase IIb data for its adenosine A2a receptor antagonist tozadenant (SYN115) with partner UCB ( scripintelligence.com, 22 March 2013).

Dr Sherer said it is important for researchers and drug developers to continue seeking improvements for existing dopamine-based therapies, because those medicines are effective in controlling Parkinson's symptoms. He noted that there are innovative therapies in development as well, and said the PPMI project's search for biomarkers should aid in some of those efforts.

Datamonitor estimated in mid-2012 that the Parkinson's disease drug pipeline had grown by 28% since December 2010 to 168 development programs, but 67% of the therapeutic candidates were in the preclinical stage.

Alzheimer's data

Companies and clinical investigators profiled seven investigational therapies for Alzheimer's disease at AAN, but data from two high profile monoclonal antibodies - Eli Lilly's solanezumab and the recently failed Pfizer/Elan/Janssen effort bapineuzumab - were minimal.

A bapineuzumab poster and a scientific presentation reviewed amyloid-related imaging abnormalities (ARIA) observed in Phase III studies, which showed that ARIA - much like bapineuzumab therapy - had no significant effect on cognitive measures.

Solanezumab data in a poster session showed validation of the amyloid hypothesis in terms of targeting beta-amyloid to slow or stop cognitive declines. And in a separate scientific session, data from the two Phase III EXPEDITION studies reviewed previously announced signs of efficacy for cognitive measures assessed in patients with mild Alzheimer's disease ( scripintelligence.com, 26 August 2012).

Solanezumab is moving forward in a third Phase III clinical trial in patients with mild Alzheimer's disease ( scripintelligence.com, 13 December 2012), but development for bapineuzumab ended last year after Pfizer, Elan and Janssen discontinued two Phase III trials for the anti-amyloid antibody ( scripintelligence.com, 7 August 2012).

Lilly also presented Phase I safety and tolerability data in a poster at the AAN meeting for its beta-amyloid precursor protein site-cleaving enzyme (BACE) inhibitor LY2886721, which was taken daily for 14 days by healthy volunteers. The drug is in Phase II testing with mild Alzheimer's patients, but Merck's BACE1 inhibitor MK-8931 is slightly ahead of Lilly with a Phase II/III clinical trial ongoing ( scripintelligence.com, 5 December 2012).

The Alzheimer's Association International Conference (AAIC) from 13 to 18 July in Boston should provide a much clearer snapshot of therapies in development for the disease.

Certainly, AAIC will be a venue to discuss the US FDA's new willingness to consider accelerated approval for Alzheimer's drugs that improve cognitive impairment in the early stages of the disease before dementia becomes acute ( scripintelligence.com, 14 March 2013).

Alzheimer's Drug Discovery Foundation executive director and chief scientific officer Dr Howard Fillit told Scrip that the shift in strategy unveiled earlier this month in the New England Journal of Medicine will benefit Alzheimer's drug development, "because it recognizes mild cognitive impairment."

The FDA previously sought both functional and cognitive improvements from new Alzheimer's therapies to show clinically meaningful effects. But Dr Fillit said the agency's policy change is a response to current drug research, since many clinical trials are evaluating treatments for early stages of the disease in which functional impairments are not yet a concern for patients.

However, the FDA guidance itself is in early stages. It's not yet clear which kinds of cognitive tests can be used to show clinically meaningful effects and which types of biomarkers may be used to help establish efficacy.

The agency has said it will not approve Alzheimer's therapies based on biomarkers alone.

But even without clarity on cognitive tests and biomarkers, Dr Fillit is optimistic that the FDA's willingness to approve therapies based on cognitive improvements alone will encourage investment in the field.

"The hurdles are a little lower now. I hope it will encourage investment in early-stage projects," he said.