Sirolimus (Rapamune) for lymphangioleiomatosis (LAM), a very rare lung disease

Last Updated on June 7, 2015 by Joseph Gut – thasso

June 07, 2015 – The U.S. Food and Drug Administration (FDA) resently approved Sirolimus (Rapamune) to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This is the first drug approved to treat the disease.

So, what is LAM in the first place? Lymphangioleiomyomatosis (LAM) is a condition that affects the lungs, the kidneys, and the lymphatic system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body. LAM is found almost exclusively in women. It usually occurs as a feature of an inherited syndrome called tuberous sclerosis complex. When LAM occurs alone it is called isolated or sporadic LAM.

Signs and symptoms of LAM most often appear during a woman’s thirties. Affected women have an overgrowth of abnormal smooth muscle-like cells (LAM cells) in the lungs, resulting in the formation of lung cysts and the destruction of normal lung tissue. They may also have an accumulation of fluid in the cavity around the lungs (chylothorax). The lung abnormalities resulting from LAM may cause difficulty breathing (dyspnea), chest pain, and coughing, which may bring up blood (hemoptysis). Many women with this disorder have recurrent episodes of collapsed lung (spontaneous pneumothorax). The lung problems may be progressive and, without lung transplantation, may eventually lead to limitations in activities of daily living, the need for oxygen therapy, and respiratory failure. Although LAM cells are not considered cancerous, they may spread between tissues (metastasize). As a result, the condition may recur even after lung transplantation. Women with LAM may develop cysts in the lymphatic vessels of the chest and abdomen. These cysts are called lymphangioleiomyomas. Affected women may also develop tumors called angiomyolipomas made up of LAM cells, fat cells, and blood vessels. Angiomyolipomas usually develop in the kidneys. Internal bleeding is a common complication of angiomyolipomas.

Sporadic LAM is estimated to occur in 2 to 5 per million women worldwide. This condition may be underdiagnosed because its symptoms are similar to those of other lung disorders such as asthma, bronchitis, and chronic obstructive pulmonary disease.

There are some genes are involved in the aetiology of inherited LAM. Mutations in the TSC1 gene or, more commonly, the TSC2 gene, cause LAM. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. Within cells, these two proteins likely help regulate cell growth and size. The proteins act as tumor suppressors, which normally prevent cells from growing and dividing too fast or in an uncontrolled way. When both copies of the TSC1 gene are mutated in a particular cell, that cell cannot produce any functional hamartin; cells with two altered copies of the TSC2 gene are unable to produce any functional tuberin. The loss of these proteins allows the cell to grow and divide in an uncontrolled way, resulting in the tumors and cysts associated with LAM.

Sirolimus (Rapamune), which is available as both a tablet and an oral solution, was originally approved in 1999 as an immunosuppressive agent to help prevent organ rejection in patients 13 years and older receiving kidney transplants. Because Rapamune’s sponsor demonstrated that the drug may offer a substantial improvement over available therapies, it received breakthrough therapy designation. It also received a priority review, which provides for an expedited review of drugs that have the potential to provide a significant improvement in safety or effectiveness in the treatment of a serious disease or condition. Rapamune also received orphan product designation for this indication because LAM is a rare disease or condition. Development of this drug was also supported in part by the FDA Orphan Products Grants Program which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

The safety and efficacy of Rapamune for treatment of LAM were studied in a clinical trial that compared Rapamune with an inactive drug (placebo) in 89 patients for a 12-month treatment period, followed by a 12-month observation period. The primary endpoint was the difference between the groups in the rate of change in how much air a person can exhale during a forced breath in one second (forced expiratory volume in one second or FEV1). The difference in the average decrease in FEV1 during the 12-month treatment period was approximately 153 mL. After discontinuation of Rapamune, the decline in lung function resumed at a rate similar to the placebo group.

The most commonly reported side effects associated with Rapamune for the treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.