15 Dec 2017

Confirming once again that not only anti-amyloid therapeutic approaches struggle to score a win in Alzheimer’s and related dementias, the 10th CTAD conference, held November 1–4 in Boston, featured rest-in-peace presentations on a range of investigational drugs. They stumbled over safety in Phase 1, or fell short on efficacy in Phases 2 and 3.

Abeotaxane
Adam Boxer, University of California, San Francisco, presented his center’s Phase 1 trial of TPI 287. Also known as abeotaxane, this small-molecule taxol derivative stabilizes microtubules. TPI 287 accumulates in the brain, and has been tested primarily to treat central nervous system tumors. Its application to tauopathies grew out of work showing beneficial effects of the microtubule stabilizer epothilone D in tau transgenic mice (Zhang et al., 2012). Testing of epothilone D in AD patients started in 2012 but was discontinued for lack of efficacy.

Boxer’s group examined the safety and tolerability of TPI 287 in 44 people with the primary four-repeat tauopathies cortical basal degeneration (CBD) or progressive supranuclear palsy (PSP), and in 33 people with AD. Participants received abeotaxane by intravenous infusion once every three weeks for nine weeks, with an option for open-label extension up to three months.

In recruiting for the CBD cohort, Boxer screened with amyloid PET to exclude people with AD and to limit the treatment group to people with pure tau pathology. Of 55 diagnosed with CBD, Boxer excluded seven based on positive amyloid scans. He also used CSF biomarkers to confirm diagnoses: AD patients had lower Aβ42 and higher total tau and phospho-tau levels than CBD/PSP group members, who showed elevations in neurofilament and a higher neurofilament light (NfL)/phospho-tau ratio than the AD group.

Participants received tailored doses of 2, 6.3, or 20 mg/meter² TPI 287, or placebo.

AD patients tolerated the treatment poorly. Boxer told the CTAD audience that he had to stop the high-dose arm because two participants suffered anaphylactoid hypersensitivity reactions, most likely to the diluent for the active compound. In all, seven people in the AD group discontinued treatment. Curiously, the CBD/PSP group tolerated the drug well, even at the highest dose. They suffered no hypersensitivity reactions, and most participants stuck with the trial even through the open-label extension. However, in CBD and PSP patients, the drug caused more falls, a serious concern.

On the exploratory cognitive endpoints, the researchers saw a hint of stabilization of MMSE scores in the AD group, but no change in the ADAS-Cog, and the CBD/PSP cohort had a dose-related worsening on the Clinical Dementia Rating-sum of boxes at three months.

Boxer has no future plans for the drug, except to complete the analyses of pharmacokinetics and MRIs. He told Alzforum that investigators learned a lot from the trial. “It shows the importance of testing potential treatments in different tauopathies," he said. “Animal models don't tell the whole story, and we have to look at different conditions in humans," he said.

Edonerpic
Previously known as T-817, this compound is thought to protect neurons, possibly by activating sigma receptors. An earlier Phase 2 trial had a difficult time recruiting and high dropouts, yet the trial’s overall null result looked to the sponsor, Toyama Chemical, as if a treatment benefit for more advanced patients might be had with higher doses. The company contracted the Alzheimer’s Disease Cooperative Study (ADCS) to run another trial. At CTAD, Lon Schneider of the University of Southern California, Los Angeles, presented results of that trial.

In short, this Phase 2 study also delivered a null result, where the treatment failed to outperform placebo on the primary outcome, the ADAS-cog, or any of the secondary outcomes. On the upside, Schneider told the audience, “We can now trust this result because this was a well-designed and well-run study.”

For one, the trial included frequent assessments to make the outcome measurements more precise. For another, even though the trial did not require biomarker positivity as an inclusion criterion to ensure participants truly had AD, CSF samples taken for exploratory measurement of edonerpic’s effects on Aβ and tau confirmed that 98 percent of the study participants indeed were positive for the CSF AD signature at baseline. In other words, the clinical AD diagnosis used in this trial worked.

Conducted at 52 sites, the trial enrolled 476 people with a diagnosis of probable AD and an MMSE of between 12 and 22, and randomized them to either placebo or 224 mg or 448 mg of edonerpic once daily for a year. Outcomes were measured at 12, 24, 36, 44, and 52 weeks. MRI of the whole brain, ventricles, and hippocampus, and CSF measurement of Aβ40/42 and total and phospho-tau formed part of the trial.

Dropouts in the placebo, low dose, and high dose were 11.4, 29.5, and 24.1 percent, respectively. Some biomarkers showed changes but the changes did not all trend in the same direction. For example, CSF p-tau dropped on the high dose, hippocampal shrinkage slowed on the low dose, and different MRI analysis techniques yielded different results. “We need better neurodegeneration markers when we evaluate drugs that are presumably neuroprotective,” Schneider said.

S47445
This drug is a positive allosteric modulator of AMPA glutamate receptors. The French company Servier has been evaluating it for people with Alzheimer’s disease who also have symptoms of depression (see Therapeutics database). At CTAD, Maria Pueyo told the audience that Servier decided to end its work with this drug in Alzheimer’s. That’s because its latest, six-month, Phase 2 trial of 520 people with mild to moderate Alzheimer’s showed no significant differences between the drug and placebo groups on the primary outcome, the ADAS-cog, or on secondary measures of daily function or depression for either of the three doses used.

“Safety was good but we had no efficacy on cognition or function,” Pueyo said. The drug did get into the CSF and increased glutamate in the brain, Pueyo said in response to audience questions, but still achieved none of the desired benefit. Curiously, symptoms of depression improved in both drug and placebo groups, perhaps as a consequence of receiving the added care and attention that come with participating in a clinical trial.

Tricaprilin
Samuel Henderson of Accera Inc. in Boulder, Colorado, explained negative results for tricaprilin, Accera’s latest formulation of caprylic triglycerides to boost ketone body metabolism with a dietary aid. Nourish-AD was a Phase 3 trial conducted at 61 sites in the U.S., in 413 people who met the NINDS-ADRDA diagnosis of probable AD.

At the end of the trial, the treatment and placebo groups performed equally on the primary outcome measure, cognition as per the ADAS-cog, and the secondary outcome measure, overall function as per the ADCS-CGIC. As with prior formulations of this dietary approach, adverse events included nausea, vomiting, and gastrointestinal discomfort.

At CTAD Henderson ascribed the negative result to low exposure and bioavailability, saying this new formulation generated insufficient amounts of ketone bodies in the brain. As happens frequently in six-month trials in AD, the tricaprilin trial, too, was further hobbled by a relative lack of cognitive decline in the placebo group.

Henderson noted the company still has faith in the rationale behind ketone body therapy for treating neurologic disease, and has developed yet another formulation for its approach.—Pat McCaffrey and Gabrielle Strobel

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References

Therapeutics Citations

1. TPI 287
2. Epothilone D
3. Edonerpic
4. S47445
5. Tricaprilin

Paper Citations

1. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB, Lee VM, Brunden KR. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci. 2012 Mar 14;32(11):3601-11. PubMed.

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