EXPERT INSIGHT: Engrail Therapeutics: Addressing the Need for Safer, More Effective Medicines to Treat Anxiety Disorders

/ EXPERT INSIGHTS

Engrail Therapeutics: Addressing the Need for Safer, More Effective Medicines to Treat Anxiety Disorders

Vikram Sudarsan, PhD

Founder and CEO

Engrail Therapeutics

(May 2024)

Anxiety is a mental health problem of epic proportions, affecting more than 300 million people worldwide, according to the World Health Organization (WHO).

“The numbers are staggering,” said Vikram Sudarsan, PhD, founder and CEO of RiverVest portfolio company Engrail Therapeutics, when we met with him at our home office in St. Louis in May 2024.

Moreover, the symptoms can be devastating, affecting people’s ability to sleep, concentrate, and make decisions, which can impede their ability to work and care for themselves and their families.

Despite the prevalence and impact of anxiety disorders, there is a lack of safe, effective medical treatments, which is the significant unmet medical need that Engrail Therapeutics is addressing with its portfolio of precision neuroscience transformational therapies.

For this Expert Insight, RiverVest spoke with Dr. Sudarsan about the company he founded and about ENX-102, the company’s lead drug candidate for treating general anxiety disorder (GAD), in particular.

Please describe the scope of the anxiety epidemic.

There are currently about five-and-a-half million patients on treatment for GAD. There are an additional nine million patients with unspecified anxiety and an additional one-and-a-half million patients with co-morbid depression and anxiety. So, it’s a huge problem affecting up to 15 million patients here in the US.

Anxiety has become such a problem that the United States Preventive Services Task Force recommends that all adults age 64 and under be routinely screened for anxiety. That’s really important because the ability to identify and diagnose early will lead to much better management of generalized anxiety disorder and other anxiety disorders as well as other psychiatric conditions where anxiety plays a large role including depression and post-traumatic stress disorder.

What causes anxiety disorders?

The fear centers in the brain largely drive anxiety, specifically, the amygdala. Both genetic factors as well as environmental factors contribute to the development and worsening of anxiety.

Scientifically, that may be somewhat unsatisfying because there may not be a single common etiology to anxiety. But that’s a true reflection of the disease. There could be a predisposition to anxiety that may be caused by genetic factors, with environmental insults over time contributing to its worsening.

Engrail is studying ENX-102 specifically in patients with generalized anxiety disorder. What differentiates GAD from other forms of anxiety?

GAD refers to chronic, debilitating anxiety that significantly reduces a person’s quality of life. To be diagnosed with GAD, a person must be expressing excessive anxiety and worry accompanied by physical symptoms, including irritability, concentration impairment, muscle tension, insomnia, and so on, for at least six months.

Sometimes, patients with GAD are unable to leave their beds or go to work or school. They may not interact well with people. They may have a tremendous fear of being out there doing things that are otherwise considered normal. There are also increased rates of suicide ideation and suicide attempts with GAD. These are some of the typical phenotypes.

Is it possible to manage anxiety through lifestyle changes rather than pharmaceuticals?

I think the management of anxiety requires both behavioral intervention as well as pharmaceutical management. There are forms of anxiety that may be episodic or less severe that can certainly be managed with the right type of behavioral care. Patients with chronic, very debilitating conditions, such as GAD, however, may require medication to improve quality of life.

What pharmaceutical options are currently available to patients with GAD?

Treatment guidelines recommend using selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) as first-line options for the treatment of GAD, which are drugs that were originally developed as antidepressants. These are well-known drugs and have been around for a long time.

The problem with SSRIs and SNRIs is that they aren’t very effective for treating anxiety. They can take up to 12 weeks to have an anxiolytic effect in a patient, and often, that's too long to wait. Another problem is that many patients who are taking SSRIs experience sexual dysfunction. Whether due to lack of efficacy or tolerability, many patients do not experience adequate response.

After SSRIs or SNRIs, guidelines recommend adding or switching to benzodiazepines, which are gamma-aminobutyric acid (GABA) modulators initially discovered in the 1950s. GABA is the most important inhibitory neurotransmitter in the brain and plays a central role in regulating anxiety. Modulation of the GABA_A receptor is a well-validated approach for controlling GAD symptoms. In fact, over 30 drugs have been approved that target the GABA_A channels inspired by the benzodiazepines, representing one of the most successful drug classes in pharmaceutical history.

Benzodiazepines are highly effective, and they act very quickly; even with the first dose of a benzodiazepine, the patient can have an anxiolytic effect. The problem with benzodiazepines is that they are limited to short-term use due to their abuse liability and significant side effects, including withdrawal effects, cognitive and motor impairment, and sedation.

Image courtesy of Engrail Therapeutics, Inc.

Successful treatment of GAD is clearly challenging for many patients. In fact, when you look at how patients cycle through lines of therapy, we can see that more than 60% of patients move on to later lines of treatment, which include medications that are not very effective and are often used off-label.

No new treatments for GAD have been approved in more than a decade, so there is a high unmet need for better medications for the management of chronic anxiety.

How is Engrail addressing the need for better anxiety treatments?

At Engrail, we leverage our deep experience in precision neuroscience to identify and develop novel therapeutics with clinically validated mechanisms of action and properties that position them to potentially be best-in-class.

For example, we have applied our scientific expertise in GABA_A receptor pharmacology and neurocircuitry to the development of precision-targeted therapies that maximize the clinical benefits of GABA modulation while minimizing the undesirable side effects and risks associated with benzodiazepines. Benzodiazepines non-selectively activate GABA_Areceptors containing α1, α2, α3, and α5 subunits – with α1 activation seen as the major driver behind many of their negative effects.

Engrail’s lead-stage clinical compound ENX-102 is a precision-targeted GABA_Apositive allosteric modulator (PAM) developed to enhance neurotransmission through GABA_Areceptors containing α2, α3, and α5 subunits while blocking α1. In other words, ENX-102 is expected to deliver the efficacy of a benzodiazepine but without the concerns of abuse potential, cognitive impairment, and sedation.

Engrail CEO Vikram Sudarsan, Ph.D. describes the mechanism for ENX-102, the company’s next-generation therapy for treating GAD

What are the next steps in the development of ENX-102?

Following the positive safety and pharmacodynamic results seen in our Phase 1 studies, ENX-102 advanced into a Phase 2 study as a monotherapy treatment for patients with GAD. The ENCalm study is an ongoing, multi-center study in which we are testing our best dose from the Phase 1 study against a placebo. The two-arm study is intentionally designed with a variable-blinded placebo lead-in and follow-out to overcome the potential bias of a “placebo response.”

Because of the extent of the biomarker engagement we saw in the Phase 1 study, we anticipate this drug will be highly efficacious and fast-acting. It has a fabulous pharmacokinetic property, with a 60-hour half-life, so it should be associated with its own in-built taper and withdrawal, which is vital because patients on benzodiazepines can develop physical dependence.

The potential for the ENX-102 mechanism is vast; beyond GAD, it may have application in the treatment of panic disorder, social anxiety disorder, and other anxiety symptoms, as well as a variety of neurologic diseases. So we’re very excited to advance this compound in GAD and further explore its potential in additional diseases over the coming years.

What is Engrail’s outlook as a company?

It is a very exciting time in mental health, with renewed interest in neuroscience. Engrail recently completed a $157 million financing, and it was an absolute pleasure to work with RiverVest managing directors Niall O’Donnell, Ph.D., and Isaac Zike, Ph.D., who were extremely thorough in their diligence. They asked deep and probing questions to ensure they understood our pharmacology and what we want to achieve as we advance our neuropsychiatry portfolio.

Beyond ENX-102, we have built a diversified, precision-targeted neuroscience pipeline. Several Phase 1 studies for our compound targeted at depression will begin this year. Also in development are treatments for PTSD and a rare, fatal disease called Menkes Disease. We have been very intentional in our development plans for our large, very exciting pipeline. We have a very experienced leadership team and supportive investors that position the organization well for significant growth and pipeline advancement.

About Engrail

Engrail is a clinical-stage pharmaceutical company with the aspiration of becoming a leader in neuroscience. Its purpose is to deliver transformational therapies that improve the lives of patients with neuropsychiatric and neurodevelopmental diseases.

In March 2024, the company closed on an oversubscribed $157 million Series B financing round co-led by new investors F-Prime Capital, Forbion, and Norwest Venture Partners, with participation from RiverVest Venture Partners, Red Tree Venture Capital, funds managed by abrdn Inc., Ysios Capital, Longwood Fund, Eight Roads Ventures, and existing founding investor Pivotal Life Sciences. Since its inception in 2019, the Company has raised over $220 million.

About RiverVest

RiverVest Venture Partners is a leading venture capital firm building life science companies to address significant unmet needs of patients and deliver consistently strong returns to investors. With headquarters in St. Louis and offices in San Diego and Cleveland, RiverVest accesses forward-thinking research and clinical expertise at leading institutions across the country to found and fund biopharma and medical device companies.