A19-01 An Open Label Phase 2a Exploratory Study of Inhaled Sirolimus (LAM-001) for the Treatment of Pulmonary Hypertension

Abstract Rationale Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling and proliferation. Despite therapeutic advances, many patients experience ongoing clinical deterioration.Sirolimus, a potent mTOR inhibitor, reverses pulmonary vascular remodeling in preclinical PH models. LAM-001 is a novel inhaled formulation delivering 100-µg of sirolimus daily via dry powder inhaler at 1/20th the standard oral dose. This approach enables targeted pulmonary delivery while reducing systemic exposure and minimizing toxicity associated with oral sirolimus therapy. Methods This multicenter, phase 2a, single-arm, open-label, exploratory study (NCT05798923) evaluated LAM-001 as add-on therapy to standard of care in adults with WHO Functional Class III PH (Group 1 or Group 3). All patients were on at least 2 background PH medications (ambrisentan, epoprostenol, macitentan, riociguat, selexipag, sildenafil, tadalafil, and/or treprostinil). Assessments at baseline and 24-weeks included safety monitoring, pulmonary functional tests, 6-minute walk distance (6MWD), plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and invasive cardiopulmonary exercise testing (iCPET). Results Ten patients were enrolled and treated (mean age 63.1±10.1 years; 6 females, 4 males). Six patients completed 24-week assessments (evaluable population: mean age 60.3±6.42 years; 2 females, 4 males; Group 1, n = 2; Group 3, n = 4). LAM-001 was well tolerated with no drug-related SAEs or withdrawals, and no clinical worsening. At 24 weeks, the median increase in 6MWD was 60.1 meters (IQR: 155.6; 26.2% mean improvement); NT-proBNP decreased by a median of -35.5 pg/mL (IQR: 129.5; 29.0% mean reduction); % predicted forced vital capacity (FVC) improved by a median of 3.5% (IQR: 8.0); resting supine PVR decreased by a median of 164.6 dynes-sec/cm5 (IQR: 187.7; 28.2% mean reduction); peak exercise PVR decrease by a median of 106.0 dynes-sec/cm5 (IQR 279.3; 25.5% mean reduction); and % predicted VO2max increased by a median of 5.0 percentage points (IQR: 5.0). The Group 3 population (mean age 60.3±7.66 years; 1 female, 3 males) had similar changes in these endpoints. All patients improved to at least FC II by week 16, with one achieving FC I; two patients showed FC improvement within four weeks. Conclusions LAM-001 demonstrated favorable safety and tolerability in adults with WHO FC III Pulmonary Hypertension, with improvements in exercise capacity, cardiac biomarkers, and functional class. These findings support further investigation of LAM-001 as a novel disease-modifying therapy for Pulmonary Hypertension. This abstract is funded by: OrphAI Therapeutics