EVANSTON, Ill.—Recently, Aptinyx Inc. announced positive preclinical data on its novel NMDA receptor modulator NYX-458, demonstrating reversal of cognitive deficits in a non-human primate model of Parkinson’s disease. The data were presented at the 14th International AD/PD conference on Alzheimer’s & Parkinson’s Diseases in Lisbon, Portugal.
“With up to half of all people with Parkinson’s disease experiencing cognitive impairment and very few therapeutic options addressing these cognitive deficits, the unmet need in Parkinson’s cognitive impairment is immense,” said Dr. Norbert Riedel, president and CEO at Aptinyx.
As Nick Smith, senior director of corporate development at Aptinyx, tells DDNews, “NYX-458 is a novel, orally administered, synthetic small molecule that exhibits a very unique, subtle modulatory mechanism against the NMDA receptor, which we believe allows it to restore the normal function of the receptor. We have demonstrated that NYX-458 engages with the receptor, leading to conformational (structural) changes to the receptor, increased expression of receptors at the cell surface, and changes in gene and protein expression, ultimately leading to long-term potentiation and enhanced synaptic plasticity—i.e., enhancements in processes associated with neuronal communication, learning and memory.”
“We know that NYX-458 … binds in a previously uncharacterized domain on the NMDA receptor that is distinct from the binding sites of other molecules known to act on NMDA receptors,” Smith continues. “To our knowledge, there are no other known ligands of the NMDA receptor that bind in this domain.”
In the preclinical study, healthy non-human primates were trained on cognitive tests that are components of the Cambridge Neuropsychological Test Automated Battery to establish a baseline. Once the baseline cognitive performance was established, a neurotoxin called MPTP was administered chronically at low doses to deplete dopaminergic neurons and induce cognitive deficits similar to those experienced by people with Parkinson’s disease. When a stable deficit was established, the primates received a single dose of placebo and showed no improvement in cognitive performance. Following the placebo period, the primates were given a single dose of NYX-458 and assessed on the cognitive tests.
Administration of NYX-458 resulted in rapid, robust and long-lasting improvements in cognitive performance across the tests. In the Variable Delayed Response assay, an assessment of attention and working memory, the effects observed were statistically significant (p < 0.05) on day 1 following a single administration of NYX-458, and remained significant at day 21. NYX-458 was also shown to induce statistically significant cognitive improvements, following a second course of MPTP dosing administered to deplete additional dopaminergic neurons and re-induce cognitive deficits.
In the Simple Discrimination Reversal assay, an assessment of cognitive flexibility, administration of NYX-458 resulted in statistically significant improvements in discrimination reversal (p < 0.05). The robust improvements observed on cognitive performance were consistent across the tests, were maintained with daily oral administration of NYX-458, and endured for approximately three months after dosing was discontinued.
“We are most excited about the potential to address a significant aspect of Parkinson’s disease with which patients and caregivers struggle,” notes Smith. “While the movement symptoms of PD are very well characterized and tend to be the primary symptoms that PD therapies target, there is an increasing recognition that the cognitive symptoms have a major impact on patients and caregivers.”
A separate study evaluated the effects of NYX-458 on motor symptoms and the anti-Parkinsonian effects of levodopa, the standard of care. A separate cohort of non-human primates was dosed with high doses of MPTP and levodopa to cause Parkinson’s-like motor impairments and levodopa-induced dyskinesia. After motor impairments were established, the primates were dosed with NYX-458 and assessed on scales measuring activity, Parkinsonian disability and dyskinesia.
NYX-458, as a monotherapy or in combination with levodopa, had no adverse effects on motor symptoms and didn’t interfere with the effects of levodopa. These results further reinforce the suitability of NYX-458 as a potential treatment for Parkinson’s-related cognitive impairment, and support further development. Both studies observed no evident tolerability issues with NYX-458.
“We have evaluated many different compounds and mechanisms in this model, and the benefits exhibited by NYX-458 are among the most compelling I have seen,” mentioned Dr. Jay Schneider, professor of pathology, anatomy and cell biology at Thomas Jefferson University who worked with the research organization, Atuka Inc., on the studies. “Based on these results, it will certainly be interesting to evaluate this compound in patients to determine whether the cognitive benefits observed in this model can be replicated in patients.”
The data indicate that NYX-458’s novel modulation of NMDA receptors may be an effective approach to addressing cognitive impairment associated with Parkinson’s disease without worsening motor symptoms or interfering with levodopa therapy.
“To date there has been only one pharmacotherapy approved for the cognitive symptoms of Parkinson’s disease: rivastigmine (Exelon) … The data for rivastigmine and other drugs working through this mechanism show that it is not a very effective therapy in PD and often comes with burdensome side effects,” adds Smith. “The data we presented at the recent AD/PD conference, showing robust cognitive effects in a non-human primate model with MPTP-induced dopaminergic cell depletion, suggest the mechanism of NYX-458 is particularly well suited to treat these cognitive deficits in Parkinson’s disease.”
Aptinyx is completing a Phase 1 study evaluating the safety, tolerability, pharmacokinetics and CNS exposure of NYX-458. Smith confirms that the company is on track to report data from that study in the first half of 2019.
“Following the Phase 1 study and based on the robust results we have seen in numerous preclinical models, we expect to initiate a Phase 2 study in patients with Parkinson’s disease cognitive impairment in the second half of this year. In this study, we will evaluate the safety and tolerability of multiple dose levels of NYX-458 in people with cognitive impairment associated with Parkinson’s disease, as well as explore the potential benefit of NYX-458 across multiple cognitive measures,” Smith concludes.
