At CTAD, Early Failures and Hints of Success, from Small Trials

Series - Clinical Trials on Alzheimer's Disease 2019:

Though Aβ-targeted therapies hogged the limelight at this year’s Clinical Trials on Alzheimer’s Disease meeting, held December 4–7 in San Diego, California, a large handful of smaller studies had findings to report, as well. These studies evaluated drugs trained against a variety of targets, including telomerase, serotonin receptors, nuclear receptors, and neurotrophic factors. Some clearly flopped, while others posted positive results that, according to their presenters, justify larger trials.

  • GV1001, rasagiline, gemfibrozil, NDX-1017 study met primary endpoint.
  • Masupirdine, neflamapimod fell short.

Rasagiline
A Parkinson’s disease drug showed some signs of efficacy in people with AD, according to results from a small proof-of-concept study of rasagiline presented by Dawn Matthews of ADM Diagnostics in Northbrook, Illinois. The drug inhibits monoamine oxidase B (MAOB), an enzyme that promotes the breakdown of dopamine and thus boosts dopaminergic activity in people with PD. Elevated MAOB levels have been detected around Aβ plaques in the AD brain, and the enzyme reportedly generates reactive oxygen species and even promotes amyloidogenic processing of APP, casting it as a candidate target.

Run at the Cleveland Clinics in Las Vegas and Cleveland, the trial enrolled 50 people with diagnoses of mild to moderate AD, who had an AD-like pattern of metabolic dysfunction as indicated by FDG-PET. No Aβ- or tau-based biomarkers were used to confirm their diagnoses at screening. Participants took 0.5 mg rasagiline or placebo for the first four weeks, followed by 1 mg rasagiline, or placebo, for 20 weeks. Forty-three people completed the trial, which used change in FDG-PET from baseline to 24 weeks as its primary endpoint. Exploratory measures included tau PET and several cognitive measures.

The trial met its primary endpoint, Matthews reported. In the placebo group, glucose metabolism waned in prespecified frontal, anterior cingulate, and striatal regions over the 24-week trial. Metabolism slipped significantly less, or hardly at all, in these regions in the rasagiline group. On clinical measures, the rasagiline group posted significant improvements on the Quality of Life-AD (QOL-AD) test. They also trended toward better performance on six out of seven other cognitive tests, including the Controlled Oral Word Association Test (COWAT), the ADAS-Cog, MMSE, CGIC, Digit Span, and NPI.

Matthews reported interactions between some of the outcome measures, saying that quality-of-life improvement correlated with FDG-PET uptake in the anterior cingulate, while improvement on the COWAT and digit span tests correlated with improved metabolism in the middle frontal regions. A higher tau PET burden at baseline correlated with the degree of subsequent slippage on the MMSE for those in the placebo group, and with a larger treatment effect for those in the rasagiline group. Matthews said the findings warrant a larger trial.

NDX-1017
Hans Moebius of Athira Pharma in Seattle presented early stage trial results on the regenerative compound NDX-1017. This small molecule activates the hepatocyte growth factor (HGF)/MET receptor, which is normally expressed in the CNS but less so in AD cortex and hippocampus. Receptor activity promotes LTP and is necessary for learning and memory. It also boosts neuronal survival, neurogenesis, and dendritic outgrowth, and dampens neuroinflammation. In animal models, HGF/MET receptor activation lessened cognitive impairment caused by Aβ and prevented onset of Parkinsonian symptoms (Takeuchi et al., 2008; Koike et al., 2006). 

At CTAD, Moebius reported findings from Phase 1a and 1b studies completed in the U.S. and France. A single-ascending-dose (SAD) study enrolled 48 healthy young volunteers and tested doses from 2 to 90 mg. In the multiple-ascending-dose (MAD) study, 29 healthy elderly and 11 AD patients received NDX-1017 for nine days, at doses ranging from 20 to 80 mg. The drug was well-tolerated, with four of the 88 participants experiencing some pain or itching at the injection site. There were no other adverse events deemed related to drug.

Because of the drug’s activity on synapses, the researchers used EEG measures as a readout for target engagement and potential efficacy. The power of gamma waves wanes in people with AD, and in animal studies an increase in gamma power associates with improved learning and memory. Conversely, another EEG measure—the event-related potential latency, aka E300 wave—increases in AD.

In the SAD study, gamma power rose after a single dose of 20 mg or more NDX-1017, indicating target engagement. The increase was dose-dependent and statistically significant in the 90 mg dose group, Moebius reported. In the MAD study, 40 mg NDX-1017 increased gamma power on day four and day eight in all seven AD patients who received the drug. In addition, p300 latency dropped, and this change was significant by day eight. The four AD patients taking placebo had no EEG changes. The trial did not include cognitive tests to determine if these electrophysiological changes would translate into a benefit in thinking or memory.

A Phase 2/3 trial is set to start in 2020. It will enroll 120 people with mild to moderate AD, who will take NDX-1017 for 26 weeks, followed by a six-week washout period to see if any improvement stays or fades. The trial will compare several doses and use EEG as an exploratory outcome measure. The primary outcomes will be the Global Statistical Test and safety; the widely used outcomes ADAS-Cog11, ADCS CGIC, and NPI are secondary outcomes in this trial design.

Gemfibrozil
Gregory Jicha, University of Kentucky, Lexington, presented results from a Phase 2 study of gemfibrozil, a member of a class of drugs known as fibrates. They activate peroxisome proliferator-activated receptor-α (PPARα), nuclear receptors involved in lipid metabolism. Fibrates reduce triglyceride levels, and are prescribed to control cholesterol. Some studies have linked the use of fibrates to reduced AD risk (Defouil et al., 2005). The drugs also purportedly increase expression of miR-107 (see grant abstract). This microRNA itself controls expression of BACE, and is reduced in the AD brain (Feb 2008 news; Nelson and Wang, 2010). 

At CTAD, Jicha presented data from an NIA-funded trial that evaluated a 48-week regimen of 600 mg gemfibrozil versus placebo in 75 people, including 48 who were cognitively normal and 24 with MCI. The former were at increased risk for dementia based on family history, and half of them had abnormal CSF Aβ42, indicative of brain amyloid, Jicha said.

On safety—the primary outcome measure of the trial—the drug passed. Jicha also reported a dip in the plasma concentration of miR-107, although levels of the microRNA in CSF were too minute for detection. The scientists only detected BACE1 in the CSF of about half the participants, and so were unable to conclude whether the drug affected CNS levels of the Aβ-producing enzyme.

Gemfibrozil did appear to reduce change in CSF Aβ42, p-tau, and the p-tau/Aβ42 ratio between baseline and 48 weeks; however, these biomarker trends were not statistically significant. Those in the treatment group had less brain atrophy, better scores on some tests of memory, and reduced plasma levels of the pro-inflammatory cytokine TNF-α. Again, these effects trended in the right direction but none were statistically significant, Jicha reported. He said the findings warrant future trials with adequate power to detect changes on cognitive, MRI, and CSF measures. Finally, Jicha pointed out that at just pennies per dose, gemfibrozil could make a cheap treatment. For this trial, the placebo cost more than the drug, he said.

GV1001
Seong-Ho Koh of Hanyang University Guri Hospital, South Korea, showed topline results from a Phase 2 trial of GV1001 in people with clinical diagnoses of moderate to severe AD. GV1001 is a peptide drug against telomerase reverse transcriptase. Developed by GemVax & KAEL in Daejeon, South Korea, GV1001 kicks up an immune response against a form of telomerase that is known to be over-represented in cancer cells; it also interacts with heat shock protein 90 (Hsp90). GemVax is evaluating this drug for multiple types of cancer. Scientists have reported anti-inflammatory and anti-viral effects as well (Kim et al., 2016; Kim et al., 2018; Moon et al., 2018); and at CTAD, Koh described the first trial to test GV1001 in people with AD. It enrolled 90 participants, who were randomized equally to three groups who received four weekly subcutaneous injections of 0.56 mg or 1.12 mg of GV1001, or placebo, followed by biweekly injections for 24 weeks, making for a total of 14 injections.

Koh said the trial met its primary endpoint, which was improved performance on the Severe Impairment Battery between baseline and week 24. While those in the placebo group dropped by 7.23 points on the SIB, scores stabilized in both treatment groups, ultimately slipping by an average of 0.12 points. To the chagrin of audience members, Koh showed no results on any of the trial’s numerous secondary endpoints, noting that they would be released within the coming month. The trial ended in June 2019, according to clinicaltrials.gov. Others noted a particularly steep decline of the placebo group, wondering how that contributed to the apparent treatment effect.

“It’s not very often that we see positive results like this for an AD trial,” said Mike Weiner of the University of California, San Francisco, who co-chaired the session. He asked if Koh attributed the effect to a symptomatic or disease-modifying mechanism. Koh said that GemVax plans to investigate this question further with a Phase 3 trial of the drug in South Korea. The company has listed a Phase 2 trial in 90 people with moderate AD in the U.S. on clinicaltrials.gov.

Masupirdine
Jeffrey Cummings of the Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas reported that a Phase 2 trial evaluating the 5-HT6 receptor antagonist masupirdine missed its primary outcome. According to a previous report from the drug’s developer, Suven Pharma Inc., the Delaware-based subsidiary of Indian company Suven Life Sciences, this serotonin receptor antagonist boosted acetylcholine levels and improved brain oscillations in rats.

The trial enrolled 543 people with a clinical diagnosis of moderate AD, 60 percent of whom carried an ApoE4 allele. All participants took both donepezil and memantine, and were equally randomized to a 26-week course of 50 mg or 100 mg masupirdine, or placebo. Cummings reported no difference between placebo and treatment groups on ADAS-Cog, the primary outcome measure. Numerous secondary measures told a similar story.

The trial failure marks the latest in a string for this class of drugs (Sep 2017 news; Jan 2018 news). Some researchers at CTAD questioned why the trial was done in the first place. Cummings said previous studies had left open the possibility that dosing could have been higher, noting that this latest study truly tested the maximum dose for a 5HT6 antagonist. “I think we are done testing these drugs for effects on cognition,” Cummings said.

Neflamapimod
Philip Scheltens of VU University Medical Center, Amsterdam, presented the results of another negative Phase 2 trial. Unlike the masupirdine trial, however, this one, of the p38a inhibitor neflamapimod, did end with a hint that it might have worked had a higher dose been used.

At CTAD in 2016, Scheltens had reported that in a small pilot study without placebo, the drug had safely lowered amyloid-PET at a twice-daily dose of 40 mg, although, strangely, a higher dose of 125 mg had not budged amyloid deposition. In a subsequent study, researchers reported that higher doses of the drug were associated with anti-inflammatory effects, leading researchers to speculate that higher doses may have hobbled the plaque-clearing prowess of microglia (Dec 2016 news). 

This year at CTAD, Scheltens presented the results of a placebo-controlled, Phase 2b clinical study that evaluated a 24-week course of twice-daily 40 mg doses neflamapimod, or placebo, in 161 people with MCI or mild AD. Participants had CSF Aβ42 levels indicative of brain amyloid accumulation.

The drug appeared safe and well-tolerated, but missed its primary endpoint of change on the Hopkins Verbal Memory Test. Participants in the treatment and placebo groups tracked together on this measure, and also across all secondary cognitive endpoints. The drug did appear to budge some CSF biomarkers—reducing an uptick in the placebo group in total tau and p-tau-181 between baseline and 24 weeks, and trending toward reduction of neurogranin.

In a prespecified analysis to explore dose-response relationships of the drug, the researchers found that participants with the highest quartile of plasma neflamapimod at 21 days fared better on the HVLT as well as on the Wechsler Memory Scale than did people whose drug exposure was lower. The apparent benefit among those with highest plasma exposure was most striking among people who were on a background therapy of acetylcholinesterase inhibitors.

Overall, Scheltens said, the findings suggest that neflamapimod might boost cognition at a 50 to 100 percent higher dose. Despite the unmet primary in this study, he believes future studies are warranted.—Jessica Shugart

Comments

  1. It is easy to forget in the excitement around the amyloid studies that clinical trial results with alternative approaches have been presented, some with impressive results. In particular, the small NA-831 (traneurocin) Phase 2 trial showed an impressive difference with placebo of close to four points on ADAS-Cog after 14 weeks in a double-blind placebo controlled study of 56 patients.

    This effect is reminiscent of a symptomatic therapy; however the compound is presented as an AMPA modulator with pleiotropic effects on BDNF and synapse functioning. Granted, this is a small study. It underscores the importance to focus again on the synapse as the key player in cognitive deficits associated with Alzheimer’s disease, as was proposed almost 30 years ago by the late Bob Terry. Many proposed pathological processes, such as amyloid, tau, oxydative stress, metabolic dysfunction, likely converge on synapse dysfunction, which in turn is strongly correlated with functional outcome.

    References:

    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80. PubMed.

    View all comments by Hugo Geerts

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References

Therapeutics Citations

  1. Rasagiline
  2. Gemfibrozil
  3. Masupirdine
  4. Neflamapimod

News Citations

  1. Number 107: MicroRNA Gets to First BACE in AD Brain
  2. Intepirdine Joins the Ranks of Failed Alzheimer’s Drugs
  3. RIP: Serotonin Receptor 5-HT6 Antagonist
  4. Emerging Alzheimer’s Therapies Test the Waters at CTAD

Paper Citations

  1. Takeuchi D, Sato N, Shimamura M, Kurinami H, Takeda S, Shinohara M, Suzuki S, Kojima M, Ogihara T, Morishita R. Alleviation of Abeta-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model. Gene Ther. 2008 Apr;15(8):561-71. PubMed.
  2. Koike H, Ishida A, Shimamura M, Mizuno S, Nakamura T, Ogihara T, Kaneda Y, Morishita R. Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease. Gene Ther. 2006 Dec;13(23):1639-44. Epub 2006 Jun 22 PubMed.
  3. Dufouil C, Richard F, Fiévet N, Dartigues JF, Ritchie K, Tzourio C, Amouyel P, Alpérovitch A. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology. 2005 May 10;64(9):1531-8. PubMed.
  4. Nelson PT, Wang WX. MiR-107 is reduced in Alzheimer's disease brain neocortex: validation study. J Alzheimers Dis. 2010;21(1):75-9. PubMed.
  5. Kim H, Choi MS, Inn KS, Kim BJ. Inhibition of HIV-1 reactivation by a telomerase-derived peptide in a HSP90-dependent manner. Sci Rep. 2016 Jul 1;6:28896. PubMed.
  6. Kim JW, Yadav DK, Kim SJ, Lee MY, Park JM, Kim BS, Kim MH, Park HG, Kang KW. Anti-cancer effect of GV1001 for prostate cancer; function as a ligand of GnRHR. Endocr Relat Cancer. 2018 Oct 1; PubMed.
  7. Moon KT, Yoo TK, Kwon SY, Ha JY, Byun SS, Kim JH, Chung JI, Kim TH, Moon HS, Kim SJ, Lee KS. A randomised, placebo-controlled, multicentre, Phase 2 clinical trial to evaluate the efficacy and safety of GV1001 in patients with benign prostatic hyperplasia. BJU Int. 2018 Aug;122(2):283-292. Epub 2018 May 4 PubMed.

External Citations

  1. cholesterol
  2. grant abstract
  3. GV1001
  4. clinicaltrials.gov
  5. clinicaltrials.gov

Further Reading

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