Praxis Precision Medicines Inc. CEO Marcio Souza told BioWorld that the line figuratively walked by PRAX-114, a GABAA positive allosteric modulator in major depressive disorder (MDD), means upside relief without the downside of adverse effects.

“You want a little bit of the synaptic effects and a lot of the extra-synaptic effects” in order to dose high enough to get results, Souza said, and PRAX-114 preferentially works six times more on extra-synaptic GABAA. “Having the right balance there is quite important and targeting the right patients.” The unmet need in MDD already is sizeable, and “I would even argue that with COVID-19, if you look into the preliminary numbers in China or in Europe, the rate of depression and traumatic stress in general is huge,” he said. “The awareness is only going to grow after this,” along with the demand for a drug that can act in days rather than weeks.

Marcio Souza, CEO, Praxis

Among the failures in MDD is AV-101, an NMDA receptor antagonist developed by Vistagen Therapeutics Inc., of South San Francisco, which late last year fell short of separating from placebo in the phase II study called Elevate. In general, “when you’re looking into drugging the different targets in depression – while they have been, I would say, easy to identify – the toxicity has been holding them back,” Souza said. PRAX-114 completed phase II development in MDD; just begun is a phase II experiment in perimenopausal depression. “We’ve known for a while that it’s a hormonal dysfunction that happens” in that condition, often accompanied by depression, he said. “Our hypothesis here is that we would [also] be able to reduce the more classic menopausal symptoms like hot flashes, for example.”

The Cambridge, Mass.-based firm is working on a raft of therapies that involve genes linked to the imbalance of excitation and inhibition of neuronal circuitry at the core of multiple central nervous system disorders. Next in the pipeline is PRAX-944, a T-type calcium channel blocker for essential tremor (ET), also at the phase II stage, with data due later this year. ET is the most common movement disorder. “We talk a lot about Parkinson’s [disease (PD)] and rightly so,” Souza said. “I don’t think we talk enough about ET.” Characterized by involuntary, rhythmic shaking, especially in the hands, ET is distinguished from tremor that results from other disorders such as PD or known causes. ET typically turns up alone, without other neurological signs or symptoms, according to the NIH, though some experts believe that it can include other features, such as mild balance problems.

Between 3 million and 6 million people in the U.S. are afflicted with ET, and no adequate therapies exist, Souza said. Sometimes patients are sedated, and stimulation of certain areas of the brain has been tried. T-type calcium channels “are not that druggable,” he said. “The genesis of this product came from understanding the biology of another disease,” namely epilepsy. By studying electroencephalograms, “it’s very easy to see if the drug is engaging with the mechanism or not,” and using that approach in phase I helped to determine dosing, so that PRAX-944 could be given “in a way that you do not over-block the channel,” he said. “If you completely block the channel, you’re going to create a number of liabilities.” Praxis, with backup molecules, is studying epilepsy in parallel with ET. How epilepsy ultimately will fit into the picture “is an ongoing discussion,” he said.

Farther back in the pipeline are PRAX-562 at the phase I stage for genetic epilepsies and pain disorders; PRAX-222, undergoing IND-enabling work for genetic epilepsies; and preclinical PRAX-020/021, also for genetic epilepsies. Other programs will be disclosed soon. Some of Praxis’ candidates were developed in-house and others in-licensed.

Before joining Praxis as president and CEO, Souza worked at PTC Therapeutics Inc., of South Plainfield, N.J., where he served in leadership roles since 2014, most recently as chief operating officer. Praxis has 40 employees and will grow “quite dramatically” over the next few years, he said. “We’re hiring right now and we’re going to continue to expand.” The idea for the firm was generated in 2016, and Praxis – which takes its name from the Greek word meaning practice (as separate from theory), or “getting things done” in his words – was officially founded a little over three years ago. It has added more than $100 million to the coffers since then. Regarding the COVID-19 pandemic, he said, Praxis has not felt the impact as much as many in the industry, though “it would be silly for me to say it has had no effect. To some extent, it’s better to be lucky than smart,” he said, and conducting a degree of its research in Australia, one of the lesser-hit countries, meant the company has been “pretty much up and running all the time. We actually started one of the trials after we were in lockdown in the U.S.”

Backing of Praxis is led by founding investor Blackstone Life Sciences (via prior Clarus funds in 2016) as well as Novo Holdings, Vida Ventures, Eventide and others.

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