Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study

Abstract

Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day −1 escalated to 10 mg·day −1 ) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (−111-132) and 114 mL (11-217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL −1 to 934.5 pg·mL, and 103 ng·mL −1 to 80.5 ng·mL, respectively. Adverse events were mostly grade 1−2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe. @ERSpublications Everolimus improved some lung function measures and reduced serum biomarkers in patients with LAM http://ow.ly/MkQQK

Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

“…Patients with TSC typically have comorbidities that reflect the involvement of multiple organs. Unlike a neurosurgical procedure, mTOR inhibitor therapy may cause regression of other lesions, such as angiomyolipomas (kidney), angiofibromas (skin), and lymphangioleiomyomatosis (lung) 12, 22, 23, 24, 25…”

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

“…daily) (13,19), or (f) mTOR inhibitor rapamycin (0.5 to 20 mg/kg i.p. daily) (27,28). None of the vehicles used for these agents had a measurable effect on amount of lymphangiectasia in this model ( Figure 2C).…”

“…Our rationale for comparing the efficacy of six therapeutic strategies for reversing established lymphangiectasia was based on published reports of their use in prevention or treatment of lymphatic malformations, hemangiomas, and related conditions (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Inhibition of VEGFR-2 and VEGFR-3 signaling by function-blocking antibodies prevents lymphatic growth in inflammation and in CCSP/VEGF-C mice (6,13).…”

The changing face of a rare disease: lymphangioleiomyomatosis

“…The efficacy results after 26 weeks of treatment were compared with the 6-month data in the placebo-controlled group from the MILES study showing a slightly larger increase in FEV1 and a lower improvement in FVC than the absolute difference seen between sirolimus and placebo in the MILES study. However, a difference between the patient populations including a greater number of Asian patients and a greater severity of disease in the MILES placebo group may affect the comparison [136].…”

“…Infection occurred in 65% of patients on everolimus without grade 4 infectious events. The results of an exploratory, open-label, non-randomised, within-subject dose escalation trial of everolimus in patients with LAM have just been published [136]. Primary end-points were safety and tolerability, pharmacokinetics, and VEGF-D levels; secondary end-points were measures of lung function.…”