Nancy A. Melville

October 07, 2015

CHICAGO — 3,4-Diaminopyridine (DAP), an orphan drug long used in the treatment of Lambert-Eaton myasthenic syndrome (LEMS) on a compassionate use basis, shows strong efficacy for treating weakness associated the disease, new trial results show.

"This randomized, double-blind, placebo-controlled withdrawal study provides unequivocal evidence of the efficacy of 3,4-DAP in LEMS," said principal investigator Vern C. Juel, MD, a neurologist with Duke University Medical Center in Durham, North Carolina.

LEMS is a rare autoimmune disorder characterized by muscle weakness and frequently associated with small cell lung cancer. While some previous studies have demonstrated DAP's efficacy in the treatment of LEMS, as well as congenital myasthenic syndrome, none have been designed as the current study to meet US Food and Drug Administration (FDA) standards for approval.

The results were presented here at the American Neurological Association (ANA) 2015 Annual Meeting.

For new study, 52 patients older than age 18 years who had been treated with DAP for LEMS for more than 3 months were randomly assigned to continue treatment (n=14) or withdraw from DAP while tapering to placebo (n=18).

For inclusion, patients had to demonstrate responsiveness to DAP, assessed by a change in the triple timed up-and-go test (3TUG).

"We chose to modify the timed up-and-go procedure, which has long been used in assessment of elderly and patients with Parkinson's disease because it exploits the muscles that are the most frequently weak in LEMS and provide the most functional problems," Dr Juel said.

Mean ages were 50.7 years in the continued DAP group and 59 years in the taper-to-placebo group. The mean duration of disease for both groups was 6.7 years.

The results showed significantly greater declines in the taper-to-placebo group in 3TUG times compared to baseline (P < .0001) and a sharp return to the same levels as the DAP group on day 5.

The study met its primary outcome of a greater than 30% increase in 3TUG time, with 0% of patients in the DAP group having the increase during the study and 72% having the increase in the taper-to- placebo group (P < .0001).

Changes in the self-assessment of LEMS-related weakness were highly significant (P < .0001), while changes in compound muscle action potential amplitude also were consistent with the primary endpoint.

Rescue medication was meanwhile required for recurrent symptoms in 7 of the 18 taper-to-placebo patients (38.9%) and just 2 of the 14 (14.2%) patients who continued DAP.

DAP is unique in that it doesn't target the immune system but rather enhances the function of nerve terminals that boost the signal to the nerve to contract, said Eric Sorenson, MD, from the Mayo Clinic's Department of Neurology, Rochester, Minnesota.

"By doing so, the patients get stronger," he told Medscape Medical News. "Unfortunately the drug's half-life is only a few hours and so to get a sustained effect one has to take the drug multiple times a day. Most, however, don't mind because in many the drug's effects are substantial."

Known potential adverse effects from the medication include seizures, but none were reported in the current study.

Another concern surrounding 3,4-DAP is the potential for the type of price gouging that generated controversy when pharmaceutical company Biomarin obtained approval for the drug in Europe and the price for an annual course of the drug skyrocketed from between $1280 and $3200 to approximately $64,000 a year or more.

The incident prompted top British neurologists to publish an open letter to British Prime Minister David Cameron and to officials calling for action to prevent such massive price increases.

"It has been very controversial and everyone here in the States is nervous the same thing will occur once approval through the FDA happens," Dr Sorenson said.

Jacobus Pharmaceuticals supported the study and provided research support to Dr Juel. Dr Sorenson is the sponsor of the Mayo Clinic's IND compassionate use protocol for 3,4-DAP in LEMS with the FDA.  The center uses the drug supplied currently by Jacobus Pharmaceuticals, which was also used in the current study.

American Neurological Association (ANA) 2015 Annual Meeting. Abstract S613. Presented September 27, 2015.

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