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The Phase II/III GAIN Trial: atuzaginstat for mild-moderate Alzheimer’s disease

Atuzaginstat, a novel small-molecule bacterial protease lysine gingipain inhibitor, is currently under investigation as a first-in-class treatment to slow or halt the progression of Alzheimer’s disease. Based on the ginigpain hypothesis, the drug targets the major causative agent of periodontitis to reduce neuronal damage. Read on to learn more…

Atuzaginstat: a novel approach to treating Alzheimer’s based on the gingipain hypothesis


The GAIN trial (NCT03823404) is a Phase II/III double-blind, placebo-controlled clinical trial evaluating the safety and clinical activity of atuzaginstat (COR388), a novel bacterial virulence inhibitor, in patients with mild-moderate Alzheimer’s disease (AD). It is thought that the investigational oral drug may slow or halt the progression of AD by reducing damage in the brain caused by the bacteria Porphyromonas gingivalis (P. gingvalis). P. gingvalis is commonly associated with gum disease but can infect the brain and it has been hypothesized to be an influential factor behind the onset of AD.1

Atuzaginstat was developed based on the gingipain hypothesis, proposing that P. gingivalis infection of brain tissue causes Alzheimer’s disease through the secretion of gingipains (cysteine proteinases) which promote neuronal damage.2 P. gingivalis resides in vacuoles within human cells and they are unique in that they feed off proteins. These features mean they cannot be targeted with currently available antibiotics. By targeting gingipains, atuzaginstat aims to prevent the damage caused to cells by these proteases, as well cutting off food supply to the bacteria.



“The proteases are going round chopping up everything inside the cell. They’re a little bit like having termites in your brain cell or your gum cell. So we’ve developed small molecules which bind covalently to these gingipain proteases and deactivate them.”


Targeting P. gingivalis infection to treat Alzheimer’s: the evidence



Micheal Detke, MD, PhD, shares an overview of the key pre-clinical and early phase data from past investigations using atuzaginstat. Post-mortem tissue analysis has shown the presence of gingipains in a statistically significantly higher proportion of Alzheimer’s brains compared to age-matched controls (p<0.0001).2 Furthermore, the level of gingipains was found to correlate with other biomarkers of Alzheimer’s severity, including tau and ubiquitin levels. Another study showed that when healthy mice were infected with P. gingivalis through their gums, the bacteria were able to infiltrate the brain and induce downstream Alzheimer’s pathology; amyloid beta production, microglial activation, and hippocampal neurodegeneration were observed.3 When atuzaginstat was introduced to this model, it blocked these changes.2

Following on from the promising findings demonstrated in preclinical studies, a first in human single ascending dose study (NCT03331900) was carried out, which demonstrated atuzaginstat to be well tolerated. A Phase I multiple ascending dose study of atuzaginstat (NCT03418688) was then initiated in 24 healthy older adults and 9 patients with AD. Analysis revealed a favorable pharmacokinetic profile, rapidly reaching therapeutic levels in the cerebrospinal fluid (CSF).4 Adverse events were infrequent and transient, with no serious adverse events reported. The findings of the study indicated that there were trends towards improvement in memory tests and measures of cognitive performance for atuzaginstat-treated Alzheimer’s patients, compared to the placebo-treated patients.4


“So all in all these data in our Phase I study were very encouraging and led us to go on to the larger Phase II study, Phase II/III potentially pivotal GAIN trial. We’re really excited about this molecule, the efficacy we’ve seen so far, the safety we’ve seen so far, and not only that, but the convergence of data. I’ve walked you through some of the data, but there are all sorts of other things that this Pg hypothesis explains.”


Phase II/III GAIN trial of a novel lysine-gingipain inhibitor for the treatment of Alzheimer’s


Dr Detke shared the latest details of the Phase II/III GAIN trial presented at the Alzheimer’s Association International Conference (aaic) 2021 meeting in July, which assessed the efficacy, safety, and tolerability of 2 dose levels (high and low dose) of atuzaginstat in 643 participants with a clinical diagnosis of mild to moderate AD.5 The primary study endpoints were the mean change in ADAS-Cog 11 and ADCS-ADL from baseline to 48 weeks, with biomarkers of Alzheimer’s disease and P. gingivalis infection being investigated as exploratory endpoints. CSF, saliva, and blood will be analyzed for measurements of AD biomarkers and neuroinflammation, and to detect the presence of P. gingvalis DNA and gingipains. The trial also includes a sub-study of 233 participants for evidence of efficacy of atuzaginstat in periodontal disease.6

The trial has been statistically powered to have a 90% chance to see a 50% reduction in the decline accompanying Alzheimer’s. A positive outcome could improve the quality of life for many patients with Alzheimer’s as well as others affected by the disease.



“The study was started in early 2019. We completed all enrollment in September of 2020. And we are expecting top-line data in this next quarter… this would be a very significant improvement for people with Alzheimer’s and obviously family members and all the many others who are impacted so significantly by Alzheimer’s.”

-Michael Detke, MD, PhD

Written by Gabby Ward


  1. Cortexyme Presents Data Linking P. Gingivalis to Elevated Levels of Phospho-tau217 Reinforcing Evidence of Pathogen as Causative Agent of Alzheimer’s Disease at AAIC 2021 [Press Release]. July 2021.
  2. Dominy S, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. Jan 2019; 5(1):eaau3333.
  3. Ilievski V, Zuchowska P, Green S, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. Oct 2018; 13(10):e0204941.
  4. Kaba S, Lynch C, Raha D, et al. A Randomized, Placebo-Controlled, Repeat Dose Phase 1 Study of COR388 in Older Healthy Volunteers and Patients With Alzheimer’s Disease [Conference poster]. Clinical Trials on Alzheimer’s Disease, October 24-27, 2018
  5. Detke M, Kapur S, Sabbagh M, et al. An update and baseline data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease [Conference poster]. Alzheimer’s Association International Conference, July 26-30, 2021.
  6. GAIN Trial: Phase 2/3 Study of COR388 in Subjects With Alzheimer’s Disease – [online] Available at: 2021.