Investigational treatment named US, EU orphan drug for scleroderma

A Phase 2 trial will explore effect of AM1476 on skin thickness, lung function
by Andrea Lobo, PhD | February 6, 2024

AM1476, AnaMar’s investigational anti-fibrotic medication, has been granted orphan drug status by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating scleroderma.

To get this designation, a medication must be intended to treat a life-threatening rare disease that affects fewer than five in 100,000 people in Europe or under 200,000 people in the U.S. The designation provides certain incentives, including regulatory fee reductions and the potential for extensive market exclusivity — seven years in the U.S. and 10 in the European Union — if approved.

The company plans a Phase 2 clinical trial to evaluate the treatment in people with scleroderma and interstitial lung disease (ILD), a group of diseases marked by lung scarring. The study will evaluate AM1476’s effects on skin thickness and lung function in 60 patients with diffuse cutaneous scleroderma and ILD over a year.

“This is a significant milestone and underscores the significant unmet need for novel medicines to prevent, heal, and slow organ scarring from fibrotic diseases, which are often progressive and can have a poor prognosis,” Ulf Ljungberg, PhD, AnaMar’s CEO, said in a company press release.
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Scleroderma, also known as systemic sclerosis, is marked by inflammation and fibrosis, or uncontrolled tissue hardening and scarring, in the skin and even the heart, kidneys, and lungs. Up to 80% of people with SSc may develop ILD, which leads to reduced lung function and breathing problems.

​What is AM1476 expected to do in scleroderma?
The disease process in SSc features the overactivation of the immune system, particularly of macrophages, a type of cell involved in scar tissue formation and wound healing. Fibroblasts, cells that play a key role in fibrosis are also activated.

AM1476 is a small molecule given as an oral tablet to block a receptor protein, called 5-HT2B, which helps drive fibrosis. It may be used alone or in combination therapies, according to AnaMar. Blocking 5-HT2B receptors means AM1476 reduces cellular processes related to fibrosis and inflammation, minimizing side effects and interactions with other therapies.

The therapy was effective in preclinical models of fibrosis and was generally safe and well tolerated with  a favorable pharmacological profile in a Phase 1 clinical trial (NCT04691115) in 97 healthy people.
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“There is great potential in AM1476 as a unique dual-action approach to treat skin and lung manifestations of systemic sclerosis,” Ljungberg said.
The company is also developing biomarkers and a new genetic marker approach to identify who is more likely to respond to treatment.