‘All drugs that are prescribed for schizophrenia patients treat the well-known symptoms: hallucinations, delusions and paranoia, for example, which are called “positive symptoms”’, says Kynexis CEO Kees Been. Despite the side effects, they work quite well. ‘However, about eighty percent of the patients suffer from Cognitive Impairment Associated with Schizophrenia [CIAS, ed.], the cognitive symptoms for which there is currently no treatment. Paying attention, simple shopping, remembering things or living independently are all problematic.’ This is a huge burden to themselves and to society, and even with antipsychotics, people with schizophrenia need a lot of help.

That’s where Kynexis comes in. In November 2023, the Dutch startup hit the ground running in a Series A financing of $61 million to pursue its clinical development plan of KYN-5356, a drug compound that is aimed to treat the cognitive symptoms. ‘Even if patients are successfully treated for their positive symptoms, they still have these cognitive problems, even though they think they’re “cured”’, Been explains. ‘Our drug will be complementary to the antipsychotics, and we hope that it can improve patients’ awareness and recognition of their disease state so they will be more compliant with their anti-psychotic medication, while the improvement of cognition will enable them to have a functional life again, have jobs, develop relationships.’

Brain function

What causes cognitive symptoms? ‘An excess of kynurenic acid [KYNA, ed.] has been found in the brains of schizophrenia patients’, says Been. ‘KYNA is a known inhibitor of the cholinergic and glutamatergic networks. Specifically, it inhibits the α7 nicotinic receptor and the NMDA receptor. Both networks are critical for normal brain function.’

‘If we can improve cognitive function by normalising KYNA levels, the same normalisation might apply to other cognitive diseases’

‘KYNA is derived from tryptophan in the diet, which is metabolized to kynurenin’, Been continues. ‘Kynurenin is like a central node from which many different branches radiate. Our interest is in the conversion of kynurenin to KYNA.’ The Kynurenin Amino Transferase (KAT-II) enzyme is responsible for this conversion. ‘So, the scientific rationale is: if you can inhibit KAT-II and normalise KYNA levels, you can normalise cognitive function.’

In animal studies conducted by Mitsubishi Tanabe Pharma Company (MTPC), which is who Kynexis licensed their compound from, its highly selective and brain penetrant KAT-II inhibitor KYN-5356 was tested at very high doses and there were no adverse effects.

Clinical trial

This year, the start-up company started its phase 1 clinical trial. ‘First, we’ll do a single ascending dose, followed by a multiple ascending dose. The most important factor we are monitoring is the safety and tolerability of the drug.’ If all goes well, a phase 2A study will be conducted in 2025, looking at biomarkers in schizophrenia patients. ‘We will test our compound’s ability to lower KYNA levels in the Central Spinal Fluid, the most proximal biochemical biomarker of target engagement with the KAT-II enzyme, as well as seek to normalize certain deficient EEG patterns, to establish proof of mechanism.’

If the tests are successful, there could be other applications. Been: ‘You can imagine that if we can improve cognitive function by normalising KYNA levels, the same normalisation might apply to other cognitive diseases, such as Alzheimer’s or bipolar disorder. We’re also looking at animal studies for this idea.’

All in all, there’s a lot to be excited about. ‘Firstly, our compound is based on a very solid scientific rationale’, Been says. ‘Secondly, we have a clear path to clinical translation, that is translating the scientific rationale into a response in the relevant patient population based on biomarkers. And finally, there is a huge need, because eighty percent of schizophrenia patients have cognitive impairment. These are the three things that get me up in the morning to be ready for work.’