mTOR treatment in lymphangioleiomyomatosis: the role of everolimus

SUMMARY

The orphan lung disease lymphangioleiomyomatosis (LAM) has until recently been untreatable other than by lung transplantation. However, improved understanding of underlying disease mechanisms has revealed the central role of constitutive up-regulation of the mammalian target of rapamycin (mTOR) pathway in this disease. Although other pathways exist and are under investigation for treatment, several mTOR inhibitors are currently available and emerging information suggests that these may have some efficacy in preventing loss of lung function in LAM. This paper summarizes current understanding of treatment with mTOR inhibitors in LAM, and everolimus in particular. It outlines pharmacokinetics and pharmacodynamics relevant to the clinician, recent clinical studies, and issues with potential side effects. mTOR treatment is not yet available in most countries for LAM, but current data for treatment efficacy are impressive, and it is hoped that mTOR inhibition will soon be recognised as an important treatment of this disease.

KEYWORDS:

• Everolimus
• lymphangioleiomyomatosis (LAM)
• mTOR inhibition
• pneumothorax
• lung function
• tuberous sclerosis complex

Financial and competing interests disclosure

D H Yates has received funding from Novartis for an investigator-initiated research study into LAM and also for conference organization, speaking and chairing. She is a member of the Novartis advisory board. She is also a member of the TSC and LAM Australia advisory boards and has spoken at several national meetings on these topics. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Everolimus has encouragingly good clinical efficacy in LAM but a stronger evidence base is needed.

• Prospective data gathering is required to elucidate issues of clinical importance such as

  • long term efficacy and side effects;

  • effects on fertility and pregnancy;

  • need for cessation during infections or surgery;

  • interactions with other medications and vaccinations;

  • effect on incidence of pneumothorax and long term decline in lung function;

  • optimal dosage for efficacy particularly at low dose.

• The cost of the medication is high.

• Regulatory recognition is needed in all countries for prescription in LAM within the country’s health system.