Early Clinical Development of Synapse-Focused Agent SPG302 for Alzheimer Disease

Peter Vanderklish, PhD, chief science officer at Spinogenix

The prevalence of Alzheimer disease (AD), a progressive neurodegenerative disorder, has increased in the currently rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. There have been some positive steps in drug development with the introduction of a class of novel treatments that target amyloid plaques, a hallmark of the disease.

Earlier this month, Spinogenix, a clinical-stage biopharmaceutical company, announced that enrollment is open in Australia for its phase 2 clinical trial (NCT06427668) evaluating its investigational agent SPG302 as a treatment for patients with AD. SPG302, a once-a-day pill, has a unique ability to restore synapses, which are the key connections between neurons that allow patients to think, plan, remember, and control motor functions. It may serve as a first-in-class approach to treating AD, for which there are no approved therapies that operate on synaptic function.

Following the announcement, Peter Vanderklish, PhD, chief science officer at Spinogenix, gave comment on the newly initiated study and the promise behind SPG302. He spoke specifically about some of the ins and outs of the trial, the mechanism of action of the drug, and the expanded literature on the effect of synapses in AD. Furthermore, he also provided perspective

NeurologyLive: What are some of the main parameters of this phase 2 study clinicians should understand? What goes into enrollment?

Peter Vanderklish, PhD: The Phase 2 study of SPG302, a once daily pill, is currently enrolling adult participants with mild-to-moderate Alzheimer’s disease.

To evaluate safety and efficacy of SPG302 in patients with mild-to-moderate Alzheimer’s disease, this trial consists of two parts. Part A is a pilot, placebo-controlled, randomized safety and preliminary efficacy cohort designed to assess preliminary safety, tolerability, pharmacokinetics, and pharmacodynamics. Part B will use insights from Part A to inform the evaluation of clinical efficacy of SPG302 in a larger group of Alzheimer’s patients.

The primary efficacy endpoints for Part A include changes in resting state electroencephalogram (EEG) and auditory-evoked P300, which are sensitive to synaptic density and provide insights into the CNS impact of SPG302. Additionally, changes in cognitive function and quality of life scales frequently used in Alzheimer’s clinical trials will be assessed to evaluate the preliminary clinical efficacy of SPG302 for treating AD. Secondary endpoints include monitoring for safety, adverse events (AE), blood chemistry, blood biomarkers and clinical assessments.Part B of the study may evaluate many of the same endpoints, as informed by directional changes detected in Part A, in an expansion cohort with greater number of patients, and potentially a modification of dose as determined in Part A.

Why does SPG302’s mechanism of action seem promising for the treatment of AD?

SPG302 is a small molecule that has synaptic regenerative properties and has been developed as a once-a-day pill.

It’s well appreciated that the loss of glutamatergic synapses is a key driver of Alzheimer’s disease early on and throughout its progression. SPG302 has demonstrated the ability to regenerate lost glutamatergic synapses in multiple animal models of injury and neurodegenerative disease, including a mouse model of AD, two mouse models of ALS and a very defined and highly quantitative rat model of cervical spinal cord injury. In the NIH- supported mouse model of AD, large deficits in synapses and memory were reversed by SPG302. Being able to regenerate synapses in patients with Alzheimer’s disease could potentially restore function, and ultimately reverse cognitive deficits.

The synaptic regenerative effects of SPG302 stem from a novel mechanism of action at the molecular level and are remarkable in several respects. In preclinical models, we’ve observed that new glutamatergic synapses are formed within hours in vitro, and in vivo, within weeks of daily dosing we observe benefits on synaptic density and cognitive and motor function. Moreover, new synapses formed during SPG302 treatment stay within physiologically relevant limits in terms of the numbers and shapes of synapses, which may be a factor in the favorable safety and tolerability profile observed thus far in the clinical and in preclinical studies.

No currently approved therapies for Alzheimer’s disease regenerate synapses to reverse the course of dementia. In addition, many treatments today are “biologics”, which can require complex administration and careful monitoring for side effects. In a disease where we thus far, at best, slowed progression but not restored function, a regenerative and easy to administer small molecule approach could really be a game changer if successful.

How has the literature on the role of synapses in AD evolved over the years?

The appreciation that synapse loss is an early and fundamental driver of AD actually emerged quite some time ago. Early histological studies revealed large declines in synaptic markers in hippocampal and cortical regions, prompting the idea that any successful treatment would have to stop or even reverse the course of synapse loss. The case for AD being a synaptopathy has only gotten stronger over the years as various histological, PET imaging and functional studies have all pointed to large and progressive declines in glutamatergic synapses. An equally compelling line of evidence is the finding that “cognitive reserve” in patients who have normal cognition despite high AD-like amyloid pathology is associated with greater dendritic spine synapse density. Synapse loss also appears to be a key pathological impact of neuroinflammation and aberrant microglial activity. Intriguingly, new studies suggest that disease-causing mutations in AD genes such as APP and presenilin may compromise synaptic structural integrity. In our own preclinical studies, we have shown that SPG302 as a synaptic regenerative therapy can improve cognition and motor behaviors in multiple animal models of neurodegenerative disorders, including AD.

Do we believe this drug could potentially have synergistic effects with other approved novel therapies? Considering AD will most likely not be treated with 1 treatment.

While we believe that synaptic regeneration may be very effective as a monotherapy, there is clearly the possibility that SPG302 may have powerful synergies with other therapeutic interventions. There are a number of exciting new therapeutic approaches in development for AD that could slow or halt specific disease-causing molecular and cellular events. However, few if any of these have regenerative potential, and it is unlikely that, in the aged brain, endogenous regenerative potential will replete lost synapses. SPG302’s unique synaptic regenerative effects may thus offer a powerful synergistic approach to virtually any new AD treatments aimed at slowing the disease, which could lead to the restoration of cognitive function in Alzheimer's disease patients. Such combinations could help address the heterogeneity of AD at the mechanistic level. The synaptic regenerative activity of SPG302 and its potential to complement a wide range of other therapies set it apart from other emerging therapies in the treatment landscape.