FDA approves lipodystrophy drug metreleptin

February 25, 2014

DALLAS - Feb. 25, 2014 - Dwanna Swan has a lean, muscular physique many women would envy. Inside, however, a rare metabolic disease called lipodystrophy was wracking her body, resulting in severe diabetes, high blood pressure, and dangerously elevated triglyceride levels that could kill her.

But there was help at UT Southwestern Medical Center, thanks to researchers probing treatments for the disease and testing a new drug, metreleptin.

"Without metreleptin, I could have developed life-threatening issues, such as heart attack or stroke," said Mrs. Swan, who has been taking the injectable drug for 14 years as part of the first clinical trial to test leptin treatment for lipodystrophy, conducted by researchers at UT Southwestern.

Last night, the U.S. Food and Drug Administration approved metreleptin, which is the drug form of the hormone leptin, for treatment of generalized lipodystrophy.

"Many lipodystrophy patients have benefited from leptin therapy. While it is not a cure, leptin does help manage complications that can include diabetes, high blood lipids, and accumulation of fat in the liver," said Dr. Abhimanyu Garg, Chief of the Division of Nutrition and Metabolic Diseases at UT Southwestern and the leading expert worldwide on lipodystrophy treatment and research. Dr. Garg initiated the first trial in collaboration with the National Institutes of Health (NIH).

The disorder, which has been reported in just 300 to 500 people worldwide, can be inherited or acquired and is characterized by near-complete absence of fat tissue from birth or disappearance of fat during childhood. Those with lipodystrophy are deficient in the hormone leptin, which is made by fat cells and regulates energy intake and expenditure.

Until now, standard treatment for lipodystrophy has consisted of high-dose insulin plus triglyceride- or lipid-lowering medications. Metreleptin curbs the appetite and normalizes the lipodystrophy patient's metabolism, offsetting the metabolic abnormalities common in these patients.

Mutations in the gene that cause Mrs. Swan's disorder were first identified by a team led by Dr. Garg, whose research on lipodystrophy began nearly three decades ago, when he was a postdoctoral fellow. In 1986, he met Mrs. Swan, who was taking part in a UTSW study to pinpoint the cause of her diabetes and severe insulin resistance.

"She was a patient who had no fat on her body, but she was extremely insulin-resistant, which is almost contradictory. What intrigued me was the lack of understanding of the underlying metabolic mechanism," said Dr. Garg.

Leptin's potential as a lipodystrophy therapy evolved from experiments of UTSW Nobel Laureates Dr. Michael Brown and Dr. Joseph Goldstein. As part of their research on cholesterol metabolism, the pair accidentally created a leptin-deficient mouse model of generalized lipodystrophy. When they injected the mice with leptin, the rodents ate less and their insulin resistance, diabetes, and fatty liver improved.

That's when the pair suggested Dr. Garg test leptin as a therapeutic, since he had been treating and studying this unusual metabolic disorder. UT Southwestern teamed up with investigators at NIH's National Institute of Diabetes and Digestive and Kidney Diseases and pharmaceutical company Amgen to launch the first national clinical trial of leptin for treatment of lipodystrophy. Mrs. Swan was the first of nine women and girls enrolled in that trial, after which other clinical trials for leptin followed. In a landmark study reported in the February 2002 issue of the New England Journal of Medicine, the NIH investigators and Dr. Garg's team reported that leptin replacement therapy not only controlled severe insulin resistance and lowered triglyceride levels in patients with severe generalized lipodystrophy but also decreased fat accumulation in the liver.

"Some of the patients came off of insulin therapy. At the time, Dwanna was taking at least 700 units of insulin to control her diabetes. Now she no longer requires high-dose insulin," said Dr. Garg.

Two daily shots of metreleptin for life is a prescription that Mrs. Swan said she can live with. Without metreleptin, the alternative she faced with her disease was potentially worsening diabetes, heart disease, or liver damage. And even though she'll always maintain the muscular features characteristic of lipodystrophy, Mrs. Swan said she now feels healthy, and most importantly, comfortable in her skin.

That hasn't always been the case, though the McKinney woman credits her family for providing support during her childhood and not treating her differently from her four siblings. In grade school, she was called names for looking different. As an adult, she gets looks from strangers who often assume she's an overzealous body builder.

"I like being me. I'm used to being me," said the feisty 45-year-old founder and CEO of a Dallas-based provider of health services for people with special needs. "I'm at an age of life where I'm comfortable with who I am, and I don't care if you don't like me."

Dr. Garg, who has been sought by patients worldwide because of his expertise on lipodystrophy, holds U.S. and European patents in collaboration with NIH and Amgen for use of leptin to treat lipodystrophy. He is a paid consultant to Bristol-Myers Squibb, which in partnership with AstraZeneca makes the drug metreleptin. In 2006, the Bristol-Myers Squibb subsidiary Amylin Pharmaceuticals acquired rights to the leptin molecular franchise and program (including metreleptin) from Amgen.
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To obtain more information on clinical trials and treatments for metabolic diseases such as lipodystrophy at UT Southwestern, contact the Division of Nutrition and Metabolic Diseases at 214-648-5610.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 91,000 hospitalized patients and oversee more than 2 million outpatient visits a year.

This news release is available on our home page at utsouthwestern.edu/home/news/index.html

UT Southwestern Medical Center

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