Fueled With $100M, Autobahn Therapeutics Gears Up for Depression Drug Clinical Trials

When prescription depression drugs fall short in efficacy, there’s an off-label way to help them work better: add-on doses of thyroid hormone. Clinicians have long known about this approach and some of them practice it, but the additional treatment is not problem-free. Autobahn Therapeutics’ science improves on the targeting of thyroid hormone receptors to treat depression and the startup has unveiled $100 million in financing to bring its lead drug candidate into mid-stage clinical testing.

The idea of targeting thyroid hormone receptors to treat depression comes from physicians, not pharma companies. Decades ago, doctors noticed that patients who received hormone replacement therapy for underactive thyroid glands also experienced improvement in mood, Autobahn CEO Kevin Finney said, speaking in an interview earlier this year. Psychiatrists picked up on the observation, and proceeded to prescribe thyroid drugs to help some patients when depression does not adequately respond to antidepressants.

Thyroid hormone drugs are synthetic versions of the hormone. The problem with administering synthetic thyroid hormone to patients who don’t have low thyroid levels is that these doses can elevate central and peripheral levels of the hormone, which in turn increases the risk of cardiovascular problems and other adverse effects, Finney said. San Diego-based Autobahn designed its small molecule, ABX-002, to selectively hit its target receptors in the brain.

“We’re trying to build a better version of what’s already been done by doctors,” Finney said.

Thyroid hormone plays a role in increasing metabolic rate. In drug research, targeting the receptor for this hormone is better known for applications in metabolic diseases. Rezdiffra, the Madrigal Pharmaceuticals small molecule approved earlier this year for metabolic dysfunction-associated steatohepatitis (MASH), targets and activates thyroid hormone receptor beta in the liver. A Viking Therapeutics drug candidate addresses this target to treat the fatty liver disease. Even so, hypothyroidism has been associated with depression for years, though the strength of that link remains a point of debate.

The science of Autobahn is based on thyroid hormone research from Thomas Scanlan, a co-founder of the startup and a professor of chemical physiology and biochemistry at Oregon Health & Science University. ABX-002 is a prodrug, a molecule that’s inactive until it converts into an active therapeutic inside the body. The Autobahn drug is designed to penetrate the blood-brain barrier. Inside the brain, an enzyme converts the molecule into an active drug, Finney explained. By selectively activating thyroid hormone receptor beta in the brain, Autobahn’s drug is intended to affect mood without causing complications elsewhere in the body.

Last November, Autobahn reported results from a Phase 1 study that enrolled 48 healthy adult volunteers. The data showed ABX-002 was safe and well tolerated. No adverse effects were observed and no patients dropped out of the study. Furthermore, in the top multiple-ascending dose cohort, there was clinical evidence in two participants indicating the drug engaged its target in the brain, leading to mood alteration. The company said these observations are evidence of the drug’s activity in the central nervous system.

With the newly raised capital, Autobahn plans to run two Phase 2 trials to demonstrate proof of concept of ABX-002 as an adjunct treatment for major depressive disorder and bipolar disorder depression. The company expects to begin both studies in the second half of this year.

Depression represents a strategy shift for Autobahn. When the startup launched in 2020, it was developing ABX-002 for multiple sclerosis and adrenomyeloneuropathy. Both diseases are characterized by deterioration of myelin, the protective sheath covering nerves. For these indications, activating thyroid hormone beta receptor is intended to stimulate the regenerative process of remyelination. In 2022, Autobahn raised $32.7 million financing to support its change in strategy, prioritizing the development of ABX-002 for treatment-resistant depression in which a patient’s disorder does not adequately respond to at least two approved antidepressants.

MS could still be on Autobahn’s radar, but with a different drug. ABX-101 is a small molecule that leverages the company’s brain-targeting technology to modulate the sphingosine 1-phosphate (S1P) receptor. This drug could become a treatment for immunologic and inflammatory disorders of the brain. The class of approved S1P modulators includes multiple sclerosis medicines Zeposia from Bristol Myers Squibb, Ponvory from Johnson & Johnson, and Mayzent and Gilenya from Novartis.

S1P receptors are found throughout the body and drugs in this class are also approved for ulcerative colitis. Finney said Autobahn can stand apart from other S1P modulators by selectively hitting S1P receptors in the brain. Preclinical research so far suggests Autobahn’s drug is achieving strong exposure in the brain, Finney said. With the new financing, Autobahn plans to advance ABX-101 through the preclinical research that could support an investigational new drug application.

The Series C round announced Wednesday was led by Newpath Partners. Other participants in Autobahn’s financing include new investors Canaan Partners, Monograph Capital, and Insight Partners. All of the company’s earlier investors participated in the round, including founding investors Arch Venture Partners and Blue Owl Healthcare Opportunities. They were joined by BVF Partners, Invus, Samsara BioCapital, Biogen, Bristol Myers Squibb, Pfizer Ventures, Section 32, Alexandria Venture Investments, and GT Healthcare Capital Partners.

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