An Armamentarium of Alzheimer's Drugs in 10 Years' Time?

July 27, 2017

LONDON — Despite negative findings from the only two phase 3 trials of new drugs on last week's program at the Alzheimer's Association International Conference (AAIC) 2017 in idalopirdine (Lundbeck) and nilvadipine (Archer Pharmaceuticals), experts in the field are still hopeful several new agents for Alzheimer's will become available in the next few years.

"It has been frustrating in recent years, but there is growing investment from industry in the field of Alzheimer's, with more than 60 drugs in late clinical development," David Morgan, professor of molecular pharmacology and physiology, University of South Florida, Tampa, told Medscape Medical News.

Dr Morgan presented data from Researchers Against Alzheimer's (RA2), which reported an 18% increase in phase 2 drugs (from 49 to 58) and a 7% increase in phase 3 drugs (from 30 to 32) in development from 2016 to 2017.

The report optimistically suggests that 27 Alzheimer's disease (AD) drugs in phase 3 clinical trials and eight drugs in phase 2 trials may launch in the next 5 years. It also points out that the current drugs in clinical development have many different mechanisms of action, with 23 targeting amyloid buildup in the brain and 28 focusing on neurotransmitter activity.

"We've gone from this very amyloid-centric view in terms of pharmacology to one that is including many different approaches. Alzheimer's is a complex disease, so there will be many potential targets and it is likely that none of these on its own will be successful," said Dr Morgan.

He noted that it was "only when we put a few options together that we got an effect" in HIV/AIDS treatments, with similar findings in other conditions. "I think we are in the very early stages, but I am encouraged by the development pipeline, and I think we're going to have an armamentarium in the next 10 years," he said.

Dr Morgan also pointed out that development is shifting to a focus on earlier disease, specifically in patients who have not yet developed symptoms. "We are definitely looking earlier now, and that's a big step forward; prevention is always easier than treatment."

Phase 2 studies of several new drugs were also presented at the AAIC meeting and showed some signs of benefit. These included bryostatin (in development by Neurotrope Biosciences), which is a new drug targeting growth of new synapses, and a new formulation of the cytokine GM-CSF (Leukine).

However, the news on the latest phase 3 trials was not good. There were two such programs scheduled to be presented at the AAIC meeting: one on idalopirdine, which was previously announced as negative, and the other on the calcium channel blocker nilvadipine (the Nilvad trial).

Nilvadipine Negative

The Nilvad trial presentation was actually withdrawn at the last minute, but the abstract concluded that "The pre-specified primary analysis for this study was negative, and the results do not indicate benefit of nilvadipine as an add-on treatment" for patients with mild to moderate AD.

The abstract notes that in preclinical studies, nilvadipine was shown to enhance cerebral blood flow and reduce amyloid levels, as well as to have anti-inflammatory and anti-tau properties.

The Nilvad trial was an 18-month, randomized controlled study conducted at 23 centers in Europe and included 511 patients with mild to moderate AD. These participants received either once-daily slow-release nilvadipine 8 mg or placebo.

The coprimary outcomes were progression on the AD Assessment Scale Cognitive-12 (ADAS-Cog12) and on the Clinical Dementia Rating Scale sum of boxes in the intention-to-treat population, in a three-stage gated analysis strategy. The prespecified primary analyses failed to show any treatment benefit on change in ADAS-Cog12 score compared with placebo (P = .44). Secondary outcomes showed no effects of further interest.

Lead investigator of the Nilvad trial Brian Lawlor, MD, Trinity College, Dublin, Ireland, told Medscape Medical News the presentation was withdrawn because the data analysis had not been finalized.

"The paper describing the results is in preparation for submission and will provide more comprehensive information than was in the withdrawn abstract," he said. "We anticipate that presentation of the results at another time is highly likely."

Idalopirdine Post Mortem

The final results from three phase 3 trials with idalopirdine (STARSHINE, STARBEAM, and STARBRIGHT) were also presented at the meeting by Alireza Atri, MD, from the California Pacific Medical Center, San Francisco.

"One of the largest drug development programs in mild to moderate Alzheimer's has not shown overall effectiveness," he said. "Although favorable safety and tolerability were shown, we could not replicate efficacy results shown in the earlier proof-of-concept study."

The trials tested the 5HT6 antagonist at doses of 10 to 60 mg per day in 2500 patients with mild to moderate AD, all of whom had scores of 12 to 22 on the Mini-Mental State Examination (MMSE).

Results showed no clear difference overall between placebo and drug on primary endpoints of changes on ADAS-Cog and global ADCS-CGIC scores. There was some suggestion of benefit in STARBRIGHT in more severe patients (MMSE scores, 12 - 19), but there was no effect in the milder group (MMSE scores, 19 - 22).

Dr Atri was visibly emotional when ending his presentation. "This doesn't happen without an incredible amount of people working so hard for many years; all of us have cried over this. This has taken 10 years' work, but we have to keep going."

He said the negative results of the idalopirdine studies have "weakened support for the approach of using 5HT6 antagonists in Alzheimer's. But there are still other drugs of this type at different doses still being tested."

Dose Questioned

Dr Morgan, who was co-chair of the session, commented to Medscape Medical News that the idalopirdine results "are a big disappointment," particularly as there were promising phase 2 results.

"I think part of the problem may have been they reduced the dose from 90 mg in phase 2 to 10, 30, and 60 mg in phase 3. Given that, it is plausible that they didn't have enough drug on board," he said. "I think they mentioned liver enzyme elevations at higher doses in phase 2, but there are a lot of drugs that elevate liver enzymes; look at the statins, for example."

The other cochair, Eric Karran, PhD, AbbVie Inc, US, said it was unusual to see such a range of doses in a phase 3 study and questioned Dr Atri as to whether receptor occupancy studies had been conducted to target the appropriate dose.

Dr Atri replied that a study like that had been done in younger people without Alzheimer's. From that, it appeared that a 30- to 60-mg dose per day would give at least 80% occupancy for 24 hours.

Dr Morgan explained that the 5HT6 antagonist drugs are being positioned as symptomatic agents for AD, similar to memantine and the cholinesterase inhibitors. Although such agents are not necessarily targeting the cause of the condition, he believes there is still value in agents focusing on improving memory.

"L-dopa has been the mainstay of therapy for Parkinson's for years and shows that symptomatic drugs can have a long-term benefit," he said.

GM-CSF: Promising Preliminary Results

Among phase 2 studies, early results with a formulation of the cytokine recombinant human GM CSF (Leukine) in 13 patients with mild to moderate AD showed improvement through mean changes on scores from the MMSE and the Activities of Daily Living compared with 19 patients receiving placebo. Leukine was given at a subcutaneous dose of 250 mg/m2 per day, 5 days a week, for 3 weeks.

The randomized controlled study, presented as a poster at the AAIC meeting, is still underway. It is based on observations that patients with rheumatoid arthritis and upregulated levels of GM-CSF have a reduced risk for developing Alzheimer's and that daily injections of the cytokine have reduced Alzheimer's pathology by more than 50% and completely reversed the cognitive impairment of transgenic Alzheimer's mice.

In addition, bone marrow transplant patients treated with GM CSF for leukopenia showed significantly improved cognition at 6 months compared with those who received GM-CSF alone or no treatment at all.

Commenting on the current study, lead investigator Huntington Potter, MD, from the University of Colorado, Denver, told Medscape Medical News: "We are cautiously optimistic about these preliminary positive results. We did not expect to see an improvement in any cognitive measure in only 3 weeks of treatment.

"Clearly we must continue to study the effect of Leukine in a longer trial to see if the results hold up," Dr Potter added. "We have partial funding for such a longer, 6-month trial from the Alzheimer's Association and hope to start that trial in a few months."

Bryostatin

In another phase 2 study, some possible preliminary evidence of improved cognition was shown for bryostatin.

The compound, a protein kinase C epsilon activator, has been shown to induce the growth of new synapses and prevent neuronal death in preclinical studies. It represents a new therapeutic strategy for AD because of the hypothesis that synaptic loss has a major effect on cognitive deficits in the condition, lead investigator Martin Farlow, MD, from Indiana University School of Medicine, Indianapolis, reported.

The 13-week study randomly assigned 147 patients with moderate to severe AD 20 or 40 μg bryostatin or placebo. The drug is only available as an injectable formulation at present and was given as seven doses by intravenous infusion during a 12-week period.

Results showed improvements with the 20-μg dose in the primary cognitive endpoint of score change on the Severe Impairment Battery. Scores for the secondary functional endpoint, the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Severe Impairment Version, also showed improvement with the 20-μg dose.

There was no therapeutic signal observed with the 40-μg dose, which was also associated with an unacceptable level of adverse events, Dr Farlow reported.

"In this exploratory study evaluating a novel mechanism of action, we see an encouraging therapeutic signal in late-stage Alzheimer's patients with the 20-μg group, which was maintained across time points with relatively minimal toxicity and good tolerability," he said.

"It is important now to determine if these effects can be maintained and enhanced over a longer period of time."

In a press release, Neurotrope said the lack of signal at the higher 40-μg dose was not entirely unexpected, based on the in vitro dose response features of bryostatin-induced protein kinase C epsilon activation. "As seen with the 40-μg dose, the obligatory downregulation phase appears to override the initial activation phase, thereby mitigating the desired clinical effect," the company noted.

During the discussion, session co-chair Dr Karran suggested this profile was likely to lead to a limited therapeutic window, which might produce pharmacokinetic problems.

"Yes, if the dose goes too high we get inhibition of the enzyme," replied Dr Farlow. "We need a subcutaneous or oral formulation and to do more work on studying this."

Shares in Neurotrope fell by 30% in May when it first released top-line details of these results. Dr Farlow suggested the investment community had interpreted this as a later stage phase 2 study. Instead, it should be considered as a much earlier dose-finding proof of concept study and, as such, showed some promising findings, he said.

The NILVAD trial is funded by the European Commission Framework 7 Programme Health Theme collaborative project. Dr Atri has received personal compensation for activities with Lundbeck. Dr Potter is named as an inventor on three patents owned by the University of South Florida on the use of GM-CSF for AD. Dr Farlow has acted as a consultant for Neurotrope Biosciences.

Alzheimer's Association International Conference (AAIC) 2017: Abstracts P3-011, P4-572, DT-02-01, and DT-02-02. Presented July 18 and 19, 2017. Abstract DT-02-04, withdrawn.

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