AI Therapeutics begins dosing in Phase 2 trial of LAM-001

LAM-001 is a potential disease-modifying therapy for pulmonary arterial hypertension

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by Steve Bryson, PhD |

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AI Therapeutics has begun dosing in a clinical trial testing inhaled LAM-001, a potential disease-modifying therapy for pulmonary arterial hypertension (PAH).

The 24-week, open-label Phase 2 study (NCT05798923) is recruiting 15 adults at Brigham and Women’s Hospital in Boston, Massachusetts. All participants should have advanced PAH and be symptomatic despite standard therapy.

“Recognizing that there is still an acute need to offer additional treatments for this population, we are excited to have begun dosing in our Phase 2 LAM-001 study in PAH,” Brigette Roberts, MD, AI Therapeutic’s CEO, said in a press release.

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PAH is a progressive lung disorder characterized by remodeling and narrowing of the arteries that supply the lungs, leading to high pulmonary blood pressure. Symptoms include shortness of breath, fatigue, chest pain, and fainting episodes.

Current therapies work by widening the blood vessels to reduce blood pressure and help with symptoms, but do not address the underlying disease processes in the pulmonary arteries. Despite these treatments extending survival, most people with PAH still progress to lung failure.

“Currently available therapies for PAH provide relief to patients predominantly through the reversal of vasoconstriction, but do not directly address the cellular remodeling that constitutes the underlying pathophysiology [processes] of the disease,” said Aaron Waxman, MD, PhD, the trial’s principal investigator and director of the pulmonary vascular disease program at Brigham and Women’s Hospital.

LAM-001 is an inhaled dry powder formulation of rapamycin, also known as sirolimus, an oral medication first approved to treat kidney transplant rejection.

How rapamycin works

Rapamycin blocks the activity of mTOR, an enzyme essential for cellular growth and function, which is activated in the small blood pulmonary arteries in PAH patients. By blocking mTOR, rapamycin can potentially prevent the excessive growth of cells that leads to arterial thickening.

The therapy also rescues the BMPR2-mediated dysfunction of the endothelial cells that line the pulmonary arteries. More than 70% of familial and 20% of sporadic PAH cases carry mutations that lower BMPR2 production. Low BMPR2 activity is linked to the excess growth of muscle cells in pulmonary arteries, causing them to narrow.

“By modulating both the mTOR and BMPR2 pathways, LAM-001 has the potential to reduce smooth muscle cell hyperproliferation [excess growth] and ameliorate endothelial cell dysfunction in the pulmonary vasculature, thereby altering the long-term course of disease,” Waxman said.

“Even as new disease modifying agents become available, because of its unique mechanism of action, LAM-001 may become an important addition to our growing armamentarium of drugs used to treat this devastating disease,” Waxman said.

Rapamycin’s potential as a PAH treatment is supported by a case study and a small clinical trial that tested a related mTOR-blocker. Treated patients saw their lung function, blood flow, and walking endurance improve.

LAM-001 may alleviate side effects

Despite these features, oral rapamycin has been associated with side effects, such as cold symptoms, fever, nausea, mouth sores, muscle aches, chest pain, and dizziness. According to AI Therapeutics, an inhaled rapamycin formulation that can deliver lower therapeutic doses directly to the lungs may help alleviate some of these side effects.

“LAM-001 offers an innovative solution to delivering sirolimus directly to diseased lungs, thereby potentially minimizing systemic exposure,” Roberts said. “Systemic toxicities have heretofore precluded the widespread adoption of oral sirolimus in certain promising indications despite strong signals of clinical benefit. PAH represents one such orphan pulmonary disorder.”

The Phase 2 study will assess LAM-001’s safety and efficacy in adults with advanced PAH who still experience symptoms despite treatment. Participants will receive standard care plus LAM-001 once daily for 24 weeks, or about six months. Those who show improvements can continue receiving the treatment for one year.

The study’s primary goals are safety, tolerability, and change in peak oxygen uptake (VO2 max), an indicator of lung function, after 24 weeks, as recorded by exercise testing. Secondary goals include various measures of blood pressure, blood flow, heart function, and physical abilities, as well as LAM-001’s pharmacological properties.

LAM-001 was granted orphan drug status in the U.S. for PAH, a designation to support experiential treatments for rare diseases via financial incentives for development and commercialization.

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