At AAIC, Yet Another Phase 3 Flop While Phase 1 Trials Forge Ahead

Series - Alzheimer's Association International Conference 2017:

Part 1 of a three-part story.

At this year’s Alzheimer's Association International Conference, held July 16–20 in London, researchers reported negative data from three Phase 3 trials of the 5HT6 antagonist idalopirdine. It came as no surprise, since topline data released last year had already deemed one of the trials to have fallen short. In contrast, Phase 2 data for VX-745, a kinase inhibitor, and leucine, a recombinant human cytokine, hint that they may slow cognitive decline. Safety and tolerability data from Phase 1 trials appeared to give a green light thus far for everything from small molecules such as BACE inhibitors to passive immunotherapies for Aβ and tau (see Part 2 and Part 3 of this story). Read on for a summary of the latest clinical data.

Once Again, Phase 3 Brings Down a Rising “Star”
Alireza Atri from the California Pacific Medical Center, San Francisco, reviewed three Phase 3 clinical trials of H. Lundbeck’s 5HT6 antagonist idalopirdine. This drug is thought to enhance neurotransmission in several neuronal subtypes in the brain, including cholinergic and glutamatergic. Phase 2 data had suggested to its sponsors that idalopirdine and the acetylcholinesterase inhibitor donepezil together slowed cognitive decline in people with moderate Alzheimer’s disease better than donepezil alone did (Jun 2012 news), and the company launched a Phase 3 program of three trials all dubbed STAR.

Alas, already last September, topline data from the STARSHINE study dimmed idalopirdine’s luster. Among 932 patients taking 10 mg donepezil daily, those who also took 30 or 60 mg of this study drug performed no better on the ADAS-Cog over 24 weeks (Sep 2016 news). At AAIC, Atri presented data from STARSHINE as well as from its sister trials STARBRIGHT and STARBEAM. The latter tested 10 and 30 mg of the drug versus placebo in combination with 10 mg donepezil among 858 patients, while STARBRIGHT tested a combination of 60 mg idalopirdine or placebo with any approved AD treatment in 734 patients. Atri did not report data from an ongoing extension trial.

Overall, the 5HT6 antagonist had no effect. Of 4,000 patients who were screened for inclusion and exclusion criteria, the three trials enrolled about 2,500. On average, they were around 74 years old and had been diagnosed with AD 2.2 years prior. They had a mix of mild and moderate AD; 40 percent scored between 19 and 22 on the MMSE, while 60 percent scored between 12 and 18.

Atri showed plots of treatment and placebo data for the 24 weeks of each trial. In all three trials, scores for the ADAS-Cog, the ADCS-Activities of Daily Living, and the Clinician Global Impression of Change (CGIC) followed the same trajectory in both the treatment and placebo groups. In STARSHINE there was a possible trend toward a signal in the CGIC, said Atri.

Breaking down the data by disease severity at baseline exposed hints of an effect in people with moderate AD, Atri said. This prespecified analysis covered patients with MMSEs of 12 to18, which resembled the baseline scores in the positive Phase 2 proof-of-concept study. In STARBRIGHT, moderate AD patients in the treatment group did better on the ADAS-Cog, with a p value of 0.03. There was also a trend for efficacy on the ADCS-ADL. In STARSHINE, a trend for efficacy on the CGIC also emerged. Patients with MMSEs of 19–22 did no better than placebo on any outcome measure in any of the trials.

Atri said the drug seemed safe and well-tolerated. Patients on drug and placebo reported similar adverse events, such as diarrhea, nausea, vomiting, falls, and headaches. They were a tad more common in the 30 and 60 mg doses.

Researchers at AAIC were disappointed but congratulated Atri, calling the trials a considerable effort. Some questioned if the Phase 2 trial had been robust enough to warrant a Phase 3 program, given the lack of a benefit on the ADCS-ADL. Others wondered if the dosing was high enough. Atri said dose occupancy tests had been done, though not in AD patients but in young healthy controls. Nonetheless, Atri said he expected 80 percent target occupancy over 24 hours with the doses used. He did acknowledge that having no biomarker selection was a limitation of the program. He said some of the patients likely had no brain amyloid and therefore were misdiagnosed as having AD. 

Atri did not review data from an ongoing extension trial that monitors 1,500 patients on 60 mg of the drug for an additional 28 weeks.

A Neuroinflammation Target? Kinase Inhibitor and Cytokine in Phase 2
Niels Prins, VU University Medical Center, Amsterdam, outlined cognitive results of two small trials of the p38 MAP kinase inhibitor neflamapimod, a.k.a. VX-745. It is purported to reduce harmful inflammation and improve neural plasticity while stimulating microglia to phagocytose amyloid. Two tiny AD trials on this compound have been done. In one, 16 patients took either 40 mg or 125 mg of it twice daily for 12 weeks. In a second, nine-week trial, five people took 40 mg, and one person took 125 mg. The primary outcome measure, a change in plaque burden as judged by quantitative PiB PET, suggested that the drug stimulated plaque removal. Philip Scheltens from VU Amsterdam outlined those results at CTAD last December (Dec 2016 conference news). 

In London, Prins said that when patients in the 12-week trial sat for the Wechsler Memory Scale, their average scores for its immediate recall composite increased by 5.7 points at four weeks and by 10 points at the end of the trial, a significant improvement. Delayed recall scores also improved, from 13.2 at baseline to 18.2 and to 22 at four and 12 weeks, respectively. The nine-week trial used the Hopkins Verbal Learning Test-Revised. It also indicated significant improvement in delayed recall, with participants scoring on average 5.4 at baseline and 7.5 at day 40.

Researchers at AAIC expressed concern that there was no placebo group for comparison in these studies. They wondered why Prins assumed there would be no practice effect in the memory test, which could confound interpretation of the data. Prins said that prior literature has shown no strong practice effects with these tests. He also said pharmacokinetic data bolstered the idea that the improvements were drug-related. This analysis indicated a correlation of 0.7 between the drug’s concentration in plasma and combined immediate and delayed recall tests in the 12-week trial.

Prins said they were planning a six-month double-blind, placebo-controlled trial.

In their poster, researchers led by Huntington Potter, Jonathan Woodcock, and Tim Boyd at the University of Colorado Anschutz Medical Campus, Aurora, and Ashok Raj at the University of South Florida, Tampa, showed preliminary analysis of a Phase 2 trial to test the safety, tolerability, and efficacy of leukine in patients with mild or moderate AD. This is a recombinant form of human granulocyte-macrophage colony stimulating factor (GM-CSF) made by Genzyme/Sanofi. The FDA has approved this drug for treating bone marrow transplant (BMT) patients to beef up their blood cell counts. Potter had reported that in a BMT clinical trial, GM-CSF improved neuropsychological test scores, indicating that the cytokine improved cognition (Jim et al., 2012). Other hints that the cytokine might benefit AD come from patients with rheumatoid arthritis. They have elevated levels of GM-CSF in their blood, explained Potter, and they also have lower risk of developing Alzheimer’s. To investigate this correlation, the researchers gave injections of GM-CSF daily to transgenic mouse models of AD for 20 days. The treatment halved the amyloid burden in the mice and improved their navigational skills (Boyd et al., 2010). 

In the Phase 2 trial, volunteers were injected subcutaneously with placebo or 250 μg/m2 leukine five days a week for three weeks. Patients were examined at baseline, at the end of the trial, and again 45 and 90 days later for safety and with a battery of cognitive and functional tests. Potter reported data for13 people on drug (six men) and 19 on placebo (10 men). Those in the randomized treatment arm had an average MMSE score of 16.46 at baseline, versus 20.63 for those on placebo, a significant difference. ADL scores were also lower—54.61 for treatment group and 63.16 for placebo.

The drug seemed well-tolerated. The poster listed no serious adverse events and reported no signs of ARIA, or amyloid-related imaging abnormalities. Plots of MMSE and ADL scores suggested that patients on the drug benefitted at the end of the three-week treatment period. At this point the treatment group scored about 1.5 points higher in MMSE than at baseline, while the placebo scores had not changed. Similarly, the ADL score rose about 1.5 points at the end of treatment but then fell by about the same margin in treatment and placebo arms, respectively. No differences emerged between the two groups at later time points. No significant difference emerged at any time between treatment and placebo arms on the ADAS-Cog, CDR-sb or MOHS tests. Given these results, the authors wrote that the “Part the Cloud” 24-week trial of leukine in patients with mild to moderate AD is warranted. Clinicaltrials.gov list a Sanofi-sponsored Phase 2 trial of leukine, a.k.a. sargramostim, as “withdrawn.”—Tom Fagan

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References

News Citations

  1. At AAIC, Encouraging Safety Data on a Variety of Small-Molecule Candidates
  2. High-Dose Aβ and Tau Immunotherapies Complete Initial Safety Tests
  3. Therapy Reported to Boost Cognition in Phase 2 Clinical Trial
  4. STARSHINE Trial Loses its Luster
  5. Emerging Alzheimer’s Therapies Test the Waters at CTAD

Therapeutics Citations

  1. Idalopirdine
  2. Donepezil
  3. Neflamapimod

Paper Citations

  1. Jim HS, Boyd TD, Booth-Jones M, Pidala J, Potter H. Granulocyte Macrophage Colony Stimulating Factor Treatment is Associated with Improved Cognition in Cancer Patients. Brain Disord Ther. 2012;1(1) PubMed.
  2. Boyd TD, Bennett SP, Mori T, Governatori N, Runfeldt M, Norden M, Padmanabhan J, Neame P, Wefes I, Sanchez-Ramos J, Arendash GW, Potter H. GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis. 2010;21(2):507-18. PubMed.

Other Citations

  1. leukine

External Citations

  1. STARSHINE
  2. STARBRIGHT
  3. STARBEAM
  4. Phase 2 trial
  5. Phase 2 trial

Further Reading

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