Self-described precision neuroscience company Cadent Therapeutics hauled in $40 million in a series B financing led by Cowen Healthcare Investments and Atlas Venture with participation from Qiming Venture Partners, Access Industries, Clal Biotechnology Industries, Novartis Institutes for Biomedical Research and Slater Technology Fund.

The round is designed to support the company's lead program, CAD-1883, a selective positive allosteric modulator of the small conductance calcium-activated potassium (SK) channel to treat essential tremor (ET) and spinocerebellar ataxia. The company has a phase I dose-escalation study of the oral small molecule underway in individuals with ataxia that has been well-tolerated at all doses with no adverse effects observed to date. By year-end, Cadent plans to initiate an open-label, non-randomized, single group assignment, interventional phase IIa trial to evaluate the safety, tolerability and efficacy of CAD-1883 in approximately 20 adults with ET, according to Michael Curtis, president and CEO.

SK channels are ion channels that regulate the amount of potassium that enters a cell. In preclinical disease models, CAD-1883 showed the ability to regulate neuronal firing, improve motor control and reduce tremor in individuals with ET. The condition is characterized by uncontrollable shaking or tremor in different parts of the body, including the head, arms, hands, neck and chin, and among the most common movement disorders, affecting 10 million people in the U.S. alone, Curtis pointed out. Nevertheless, no improvements in the standard of care have occurred in more than 40 years.

All told, the round "enables us to run potentially three phase II proof-of concepts – two in movement disorder and one in our second program for cognitive impairment in schizophrenia – over the next two years," Curtis told BioWorld.

The schizophrenia program is testing NR2B positive allosteric modulators, subunit selective N-methyl-D-aspartate (NMDA) receptor modulators (SNRMs), for the ability to reverse NMDA receptor hypofunction and restore cognitive balance in people with schizophrenia. Proper functioning of NMDA receptors in the brain is critical for learning, memory and neuroplasticity, and its dysfunction is a significant contributor to cognitive impairment in individuals with schizophrenia. In preclinical studies, Cadent's approach showed the ability to restore auditory novelty detection in a model of NMDA receptor hypofunction.

The B round attracted "a lot of interest," Curtis said, not just for the company's clinical stage programs but also for the diversity of its pipeline, offering "relatively near-term value creators if any one of those phase II studies is positive," since all represent indications with high unmet medical need.

The financing also represented a sort of coming out party for Cadent, which has lain low since its formation.

The backstory began in 2010 when Mnemosyne Pharmaceuticals Inc. was formed by a medicinal chemist and two ex-Pfizer Inc. neuroscientists. That company spent its formative years testing SNRM candidates preclinically for their ability to enhance the activity of the NR2B subtype most prominent in schizophrenia. The goal was to mitigate not only the cognitive symptoms associated with schizophrenia – those least likely to respond to existing antipsychotic drugs – but also to show a therapeutic benefit in the positive and negative symptoms associated with the disease, with fewer side effects than existing antipsychotics.

In 2012, the work attracted a $5.4 million in a Series A financing led by Access Bridgegap Ventures that included the Slater fund as an existing investor. (See BioWorld Today, Feb. 16, 2012.)

In 2015, Mnemosyne relocated from Providence, R.I., to Cambridge, Mass., recruited neuroscience R&D veteran Timothy Piser as chief scientific officer (CSO) and was renamed Luc Therapeutics Inc. – short for lucidity – to reflect the company's focus on synaptic plasticity-oriented drug development. Piser had two decades of biopharma leadership, notably at Astrazeneca plc and Forum Pharmaceuticals Inc.

Meanwhile, in 2013 Atlas had formed Cambridge, Mass.-based Ataxion Inc. based on promising assets once held by now-defunct Neurosearch A/S. In 2011, Denmark-based Neurosearch decided to focus on a Huntington's disease program – one that would later fail in phase III – and offload its earlier-stage CNS-targeted assets into spinouts. Atlas found the unmet need in ataxia, combined with the biology and the resources already invested in the program, sufficiently compelling to seed the newco.

Rather than attacking individual genetic causes of ataxia, Ataxion was seeking to alleviate the symptoms of a broad range of ataxias by targeting neurons in the cerebellum that are degenerating. In 2014, the company raised $17 million in a series A round from Atlas and Biogen Idec Inc. (now Biogen Inc.). (See BioWorld Today, March 31, 2014.)

In March 2017, Ataxion merged into Luc, with a combined focus on precision medicine for neurological and psychiatric diseases and three development programs in the pipeline, including an existing partnership between Luc and Novartis AG testing NR2B subtype selective negative allosteric modulators for rapid, ketamine-like relief of treatment-resistant depression without the ketamine-like side effects. That program subsequently moved into phase I development.

'We're leveraging really powerful biology'

Late last year, Luc quietly rebranded as Cadent, which better reflects the company's mission to restore harmony to neuronal "rhythms," effectively re-wiring the brain to treat movement and cognitive disorders, explained Curtis, whose career has taken him from small-molecule and biologics development at Bristol-Myers Squibb Co. through leadership positions at Genzyme Corp., Infinity Pharmaceuticals Inc. and Catabasis Pharmaceuticals Inc.

In addition to Curtis and Piser, who remains CSO, Cadent's management team includes big pharma veteran Bob Dagher – most recently senior medical director for clinical development services in neuroscience at Covance Inc. – as newly hired chief medical officer and Ataxion alum Gregg Keaney as vice president of product development.

Atlas partner Peter Barrett chairs the company's board, which also includes David Grayzel from Atlas, Cowen's Tim Anderson, Paul Wotton of Access and Qiming's Mark McDade.

As the CNS space heats up, three factors set Cadent apart, according to Curtis.

"First, we're leveraging really powerful biology, and doing that in a safe way," he said, noting that the company's use of allosteric modulators, while not new as a mechanism, is being applied in a novel manner. NMDA receptors represent strong and well-validated targets, Curtis added.

"If you take a step back, we're using a dimmer-switch approach," he explained. "In the case of movement disorders and cognitive impairment, we want to turn up the current through the ion channels, and we're doing that through positive modulators. In the case of depression, we want to turn it down."

Recognizing that individuals with essential tremor, ataxia and cognitive impairment may be more different than alike, Cadent also is trying new approaches to patient selection. In ataxia, the company is using a genetic approach that identifies the target population through sequencing. On the cognition side, "the novelty that we bring is an endpoint that allows us to select patients by employing an EEG," Curtis said.

That EEG endpoint also is important to evaluate treatment.

"That's why we love the cognition program so much," Curtis said. "We're going to use an EEG endpoint that allows us to select patients, we're going to use that endpoint also to look at drug response, and that endpoint has been shown to correlate with cognitive impairment. We have a quantitative, measurable biomarker."

Cadent is integrating body sensors and related technologies to build quantitative, objective measures of response into its movement disorder programs. In both cases, the company is confident it can detect early elements of response to its candidates even in relatively small phase II studies.

Although, "at the end of the day, we're still going to have to show that we've improved quality of life" for individuals across its CNS development programs, the FDA is on board with the company's strategy, Curtis said. In fact, the company is working with the agency to qualify its biomarkers and, on the cognition side, is in the early stages of assembling a consortium around its EEG biomarker.

With 10 employees, Cadent remains small but expects to ramp up as its internal programs and partnership with Novartis progress. Curtis predicted the company could have 15 employees by year-end and up to 25 by the end of next year.

After that, "we'll see where the clinical data takes us and where we find the best value for the company," he said.

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