21 Nov 2020

If at first you don’t succeed, try, try again. This adage seemed to pay off for the clinical development of the drug neflamapimod. After failing to curb cognitive decline in people with AD, the drug appears to have done just that in people with dementia with Lewy bodies (DLB), according to results from a small Phase 2 trial presented at this year’s virtual Clinical Trials on Alzheimer’s Disease (CTAD) meeting, held November 4-7. John Alam of EIP Pharma, Boston, reported that participants who took three 40 mg capsules of the drug per day posted improvements in a neuropsychological test battery focused on executive function and attention—two cognitive domains most affected in people with the disease.

Neflamapimod inhibits the alpha isoform of p38 MAP kinase. In preclinical studies, the drug stemmed damaging pro-inflammatory responses in the brain and protected synapses. More recently, researchers have tied its beneficial effects to inhibition of Rab5, a small endosomal GTPase that causes endosomal dysfunction when overactive, as observed in AD (Germann and Alam, 2020). A forthcoming paper in Cell Reports, led by Ralph Nixon at New York University, found that overactivation of Rab5 leads to an AD-like neurodegenerative phenotype in mice, in the absence of Aβ.

In 2016, Alam and Philip Scheltens from VU Amsterdam reported findings from two small Phase 2a trials of neflamapimod, without placebo groups, in people with MCI or mild AD (Dec 2016 conference news). Participants in the first trial received twice-daily doses of either 40 or 125 mg of the drug, and only those on the lower dose had a reduction in amyloid. The findings suggested that higher doses of the drug may have squelched neuroinflammatory processes needed to mop up Aβ.

Alas, a subsequent, placebo-controlled Phase 2b trial testing the twice-daily 40 mg dose in people with MCI or mild AD missed its primary cognitive endpoint in 2019 (Dec 2019 conference news). Tantalizingly, Scheltens reported that participants with the highest plasma levels of the drug outperformed those with lower exposure on cognitive tests, hinting that slightly higher doses may have benefitted patients.

Might people with DLB respond better to the drug than those with AD? At CTAD, Alam reported positive results from a Phase 2 trial, called AscenD-LB, addressing this question (see clinicaltrials.gov). Conducted at 22 centers in the United States and two in the Netherlands, the placebo-controlled trial tested the efficacy of neflamapimod in people who had a clinical diagnosis of mild to moderate probable dementia with Lewy bodies, as well as reduced dopamine transporter protein as measured by a DAT scan. Participants were split 1:1 to receive either 40 mg neflamapimod or placebo. Participants who weighed less than 80 kg took two capsules per day, while those who weighed 80 kg or more took three.

At baseline, the study enrolled 91 participants, including 45 in the placebo group (including 18 who took two capsules and 27 who took three per day), 26 in the twice-daily (BID) neflamapimod group, and 20 who took neflamapimod three times per day (TID). Alam noted that participants in the twice-daily groups started the study with lower scores on several cognitive tests, suggesting they had slightly more advanced disease. These lower-weight participants were represented in both the treatment and placebo groups.

The primary outcome of the 16-week trial was a combined score on six measures within a neuropsychological test battery. The researchers had customized it to probe executive function and attention, the cognitive domains most impaired in DLB. Participants took the tests every four weeks, and the final outcome used a statistical model for repeated measures, using participants’ scores at every visit to determine efficacy.

The trial met its primary endpoint in participants who took three 40 mg capsules of neflamapimod per day. Their scores improved above baseline starting at four weeks, and held steady throughout the 16-week trial, Alam reported. For those in the placebo or neflamapimod BID groups, scores did not improve during the trial.

The eight-week visit was affected by the COVID-19 pandemic, which prevented 40 percent of participants from coming to the clinic. Therefore, this timepoint had less data. Even so, with a p value of 0.015 and an effect size of 0.52, the treatment benefit observed in the 40 mg TID group compared to the 40 mg BID or placebo groups was significant, Alam said. The significance and effect size improved slightly when the researchers imputed missing data at the eight-week timepoint, by carrying forward data from the previous visit. The researchers also conducted a series of sensitivity analyses to assess whether bodyweight, as opposed to dosage, dictated the treatment effects. These analyses suggested that the dosage of the drug, not the participants’ weight, was responsible for the treatment effect.

The trial included many secondary endpoints, some of which showed favorable trends for the neflamapimod TID group. One, the “timed up and go” test, showed a statistically significant benefit. It measures the time it takes a person to stand up from a chair, walk to a line three meters away, return to the chair, and sit down again. While the test clearly measures mobility, it also requires cognitive sharpness to complete quickly, Alam said. At the trial’s start, participants clocked in at an average of 13 seconds, indicating mild impairment. While people in the neflamapimod BID and placebo groups slowed down by an average of 1.5 seconds throughout the 16-week trial, those in the neflamapimod TID group sped up by 1.5 seconds.

The neflamapimod TID group trended toward improvement on the 10-item neuropsychiatric inventory throughout the trial, with benefit in less-severe depressive symptoms and hallucinations. People taking the drug three times a day trended toward improvement on the CDR-SB.

The international shopping list test, a measure of episodic memory, showed no significant differences between groups, though the neflamapimod TID group trended better than the others. Episodic memory deficits are less pronounced in people with DLB.

Alam presented no findings from the trial’s two additional secondary outcomes—the MMSE, and change in quantitative electroencephalogram (EEG) patterns associated with DLB. Alam said that while the neflamapimod TID group trended toward improvement on the MMSE, the findings were complicated by differences in scores between participants who took the test remotely and in-clinic. The EEG data are still being analyzed.

Neflamapimod was safe and well-tolerated. Ten participants dropped out of the trial early on, but no discontinuations were due to adverse events associated with the drug, Alam said. He believes these findings support evaluation in late-stage trials for people with DLB. Alam told Alzforum that EIP Pharma will soon meet with the FDA to discuss next steps. If all goes well, he expects a Phase 3 trial in DLB to begin in a year.

What about AD? That participants in the DLB study who took three, but not two, daily capsules of the drug saw a benefit is in agreement with pharmacokinetic data from the REVERSE-SD trial, Alam said. It suggested that a ~40 percent higher dose might be effective in people with AD. The findings therefore support the idea of giving the drug another try in people with that disease.

Alam called neflamapimod’s dose-finding saga a reality of developing drugs for the brain, where the inability to directly measure drug levels poses a major hurdle. “With the data we have gathered over last few years, in four different trials, I believe we now have a good handle on the dose response, and the reason why we were able to succeed in the DLB Phase 2 study,” Alam said.—Jessica Shugart

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References

Therapeutics Citations

1. Neflamapimod

News Citations

1. Emerging Alzheimer’s Therapies Test the Waters at CTAD 30 Dec 2016
2. At CTAD, Early Failures and Hints of Success, from Small Trials 29 Dec 2019

Paper Citations

1. Germann UA, Alam JJ. P38α MAPK Signaling-A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease. Int J Mol Sci. 2020 Jul 31;21(15) PubMed.

External Citations

1. clinicaltrials.gov

Further Reading

No Available Further Reading