22 Nov 2019

Treatment with the antibiotic minocycline failed to slow cognitive decline or functional impairment in patients with mild Alzheimer’s disease, according to a November 18 paper in JAMA Neurology. Researchers led by Robert Howard, University College London, reported that neither the standard nor a double dose slowed cognitive decline when given over two years. The results argue against repurposing minocycline for Alzheimer’s disease. “This definitively rules out efficacy,” Howard told Alzforum. “The trial was large and long enough to have been able to detect a disease-modifying effect if there was one.”

Some preclinical data suggested minocycline for Alzheimer’s.

Alas, two years of the drug failed to slow cognitive decline in mild AD.

Could this simple trial be a model for future testing of repurposed drugs?

To AD researchers, the results came as no shock. “In light of dozens of therapeutic failures … prior negative minocycline trials for other neurological disorders, and absent of a clear, validated drug target for Alzheimer disease, minocycline’s lack of effectiveness was not surprising,” wrote Lon Schneider, University of Southern California, Los Angeles, in an accompanying editorial.

That said, the trial was also pragmatic, which in this instance means that it used simple clinical procedures and outcomes in an uncomplicated design that was cheap to execute. “This minocycline trial is an example of an efficient use of resources, a potentially rapid way to bring a re-purposed drug forward and to get an answer,” wrote Schneider.

Same Same. On measures of cognition (left) and daily living (right), patients taking minocycline declined just as much as those on placebo. [©2019 American Medical Association.]

Much evidence suggests inflammation and microglia are primary contributors to Alzheimer’s disease. As such, minocycline has been suggested as a possible disease-modifying drug (Corbett et al., 2012). This tetracycline-derived antibiotic has been reported to cross the blood-brain barrier, inhibit proinflammatory microglia and, in vitro, prevent Aβ fibrillization and cell death (Familian et al, 2006). In transgenic mice, minocycline was reported to protect against tau phosphorylation and neuronal death, and to help maintain hippocampal neurogenesis (Seabrook et al., 2006; Noble et al., 2009; Biscaro et al., 2012). It also prevents learning impairments in rats (Choi et al., 2007).

Minocycline has been trialed in several neurological disorders already. No benefits emerged in Huntington’s disease, multiple-system atrophy, or schizophrenia (Schwarz et al., 2010; Dodel et al., 2010; Deakin et al., 2018). While minocycline appeared to have a short-term benefit for people with multiple sclerosis, it hastened decline in amyotrophic lateral sclerosis (Metz et al., 2017; Gordon et al., 2007). In traumatic brain injury, it reduced microglial activation but increased neurodegeneration (Scott et al., 2018).

Based on cell-based and animal data, some groups argue for repurposing minocycline and other tetracycline derivatives in Parkinson’s disease (Bortolanza et al., 2018; Cankaya et al., 2019). In 2004, minocycline was tested in 66 PD patients in a Phase 2 trial for Parkinson’s. It did not work, though the data from this cohort was later published in a paper on PD progression (Parashos et al., 2014).

“These trials are worth doing even though they are long shots, because they offer a shortcut to therapy,” wrote John Hardy, University College London, to Alzforum.

Except for one tiny trial in five people, no one has directly tested minocycline in people with Alzheimer’s, so Howard and colleagues designed a large Phase 2B trial.

The two-year trial began in May 2014. Howard recruited 544 patients with mild AD from National Health Service memory clinics around England and Scotland. People could enroll as long as they were older than 50, had a clinical diagnosis of possible or probable AD, and scored at least 24 on the standardized mini-mental state examination (sMMSE), which would indicate mild dementia. Patients were randomized to 200 mg or 400 mg of minocycline, or placebo. Every six months, the researchers assessed performance on the sMMSE and the Bristol Activities of Daily Living Scale.

At 24 months, neither the 200 mg nor 400 mg dose had slowed cognitive or functional decline relative to placebo. The combined cohort of minocycline-treated participants dropped 4.1 points on the MMSE, compared with 4.3 points in the placebo group (see image above). Scores on the BADLS also fell similarly in all groups.

If there was no treatment effect, there was a compliance effect. Almost two-thirds of the people taking 200 mg or placebo completed the trial, whereas more than two-thirds in the 400 mg group dropped out, mostly because of gastrointestinal, skin-related, or dizziness problems.

The authors called the negative findings disappointing, given the role of neuroinflammation in AD. Other anti-inflammatories, notably ibuprofen and naproxen, have also proven ineffective and possibly even harmful for AD patients (Apr 2019 news).

“It is unsurprising that the minocycline trial was negative; it was only powered to see a very substantial effect,” wrote Paul Aisen, University of Southern California, Los Angeles, to Alzforum. He noted that without biomarker confirmation of diagnosis, the sample likely included many people without AD pathology.

The drug may also have been given too late, wrote Claudio Cuello, McGill University, Montreal, to Alzforum. Cuello thinks that inflammation in early preclinical AD could be different from that in symptomatic AD (Cuello, 2017 ). It’s possible that anti-inflammatory drugs given 10 years before symptoms may delay or prevent clinical presentations, but not in mild AD. Epidemiological data support this idea (McGeer and McGeer, 2013). The current work cannot rule it out, said Howard, but testing it would require a decades-long trial and thousands of patients.

Howard said that this trial could inspire future pragmatic AD trials to cheaply assess whether a drug works. By simplifying entry criteria to keep screen failures at a minimum, skipping biomarkers, and using familiar cognitive/functional tests that require no extra training, Howard kept the study’s cost to about $2 million, he told Alzforum.

Schneider agreed that pragmatic designs could be used to check the potential of other repurposed, often inexpensive drugs that have preclinical or clinical evidence to support a rationale for use in Alzheimer disease. “Even when supported by preclinical science, it is difficult to fund these trials because of the lack of profit potential,” Schneider wrote.—Gwyneth Dickey Zakaib