Jodie MorrisonJodie Morrison
Cadent Therapeutics’ first-in-class selective positive allosteric SK channel modulator, CAD-1883, has been granted an orphan drug designation from the FDA for the treatment of spinocerebellar ataxia, a condition without available treatment, the company has announced.1

The therapy is currently in a phase 1 dose-escalation trial, and according to Cadent, has thus far been well tolerated at all doses, with subjects experiencing only transient adverse events. It operates by increasing the calcium sensitivity of the SK channels and thus a flow at lower calcium concentrations, potentially restoring neuronal firing regularity and improving motor function.

A plan for a phase 2a trial is underway, with an anticipated start date in the second half of 2019.2

“We are pleased to obtain Orphan Drug Designation for CAD-1883 in SCA, a progressively debilitating disease for which there are currently no approved treatments,” said Jodie Morrison, CEO, Cadent Therapeutics, in a statement. “This deeply underserved patient population deserves new therapies, and we look forward to advancing CAD-1883, our therapy that holds great potential for addressing their unmet needs.”

Spinocerebellar ataxia is estimated to impact somewhere between 6000 and 11,000 individuals in the US, with genetic testing a major identifier. Most patients carry poly-Q expansions similar to that of Huntington disease, and the progressive condition impacts motor control and balance. It has 4 identified genotypes which impact more than 50% of the patients with spinocerebellar ataxia. A progressive loss of coordination, abnormal speech, involuntary eye moment, and cognitive dysfunction all characterize the condition.

In animal models, the therapy was shown to modulate Purkinje firing in wild-type mouse cerebellar slices, in addition to regularizing chaotic Purkinje neuron firing in cerebellar slices from spinocerebellar ataxia-2 58Q mice, reducing ataxic symptoms in episodic ataxia 2 (EA2) mice, and reducing tremor in the rat harmaline model of essential tremor. The data ultimately showed that CAD-1883 reduced the firing rate of Purkinje cells by approximately 40%, consistent with the anticipated therapeutic mechanism of positive allosteric modulation of SK channels. As well, sequential bath application of 1 or 3 µM CAD-1883 resulted in a partial reversal of the increased coefficient of variation of the interspike interval which was seen in cerebellar slices from 11-month-old spinocerebellar ataxia-2 58Q mice.3

The lead drug discovery program for Cadent has sought to optimize the chemical matter of positive allosteric modulation of the SK channels, and according to the company, hundreds of analogs were profiled, with CAD-1883 demonstrated the most exceptional properties through all studies. As a result, CAD-1883 emerged quickly as a candidate thanks to a number of factors, including its “high SK potency, improved stability, reduced off-target liabilities, high cross-species oral bioavailability, and notable efficacy in a variety of in vivo and ex vivo models of ataxia and tremor,” Keaney et al. detailed in a poster from the National Ataxia Foundation 2019 annual conference.3

Cadent Therapeutics is also exploring the SK channel modulator for the treatment of essential tremor. As such, the company is currently recruiting patients for a phase 2 clinical trial (NCT03688685) of CAD-1883 in essential tremor, evaluating its safety, tolerability, and efficacy when administered orally, twice daily to adult patients.
REFERENCES
1. Cadent Therapeutics Announces FDA Orphan Drug Designation for CAD-1883 for Spinocerebellar Ataxia [press release]. Cambridge, MA: Cadent Therapeutics; Published May 29, 2019. businesswire.com/news/home/20190529005434/en/Cadent-Therapeutics-Announces-FDA-Orphan-Drug-Designation. Accessed June 3, 2019.
2. CAD-1883 for treatment of essential tremor and spinocerebellar ataxia. Saniona website. 2019. saniona.com/pipeline/cad-1883. Accessed June 3, 2019.
3. Keaney G, Foster K, Curtis M, Piser T. CAD-1883, a clinical-stage positive allosteric modulator of the small conductance calcium-activated potassium channel (SK channel): effects on cerebellar Purkinje neuron firing, ataxic gait, and tremor in animal models. Presented at: National Ataxia Foundation 2019 annual conference; March 29-30, 2019; Las Vegas, NV. Poster 1495. saniona.com/media/1495/cad-1883-naf-poster.pdf.