New FDA Orphan Drugs: Droxidopa, LX201, Marqibo

Yael Waknine

January 30, 2007

January 30, 2007 — The US Food and Drug Administration (FDA) has granted orphan drug designations for L-threo-dihydroxyphenylserine for the treatment of symptomatic neurogenic orthostatic hypotension in patients with primary autonomic failure; a cyclosporine A–eluting ocular implant for the prevention of acute rejection in corneal transplant patients; and vincristine sulfate liposomes injection for the treatment of adults with acute lymphoblastic leukemia.


Orphan Drug L-Threo-DOPS (Droxidopa) for Symptomatic NOH

On January 22, the FDA granted orphan drug designation for L-threo-dihydroxyphenylserine (L-threo-DOPS; Droxidopa, made by Chelsea Therapeutics International, Ltd) in the treatment of symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure, a group of diseases that includes Parkinson's disease, pure autonomic failure, and multiple systems atrophy.

According to a company news release, symptomatic NOH affects an estimated 300,000 patients in the United States and European Union combined. In the United States alone, approximately 72,000 patients experience chronic, symptomatic NOH.

Midodrine (ProAmatine tablets, made by Shire Laboratories, Inc) is currently the only FDA-approved treatment for orthostatic hypotension. Midodrine must be taken 3 times daily, fails to treat the underlying cause of symptomatic NOH, and is limited by adverse events such as the risk for supine hypertension.

In contrast, L-threo-DOPS is an orally active synthetic precursor of norepinephrine that increases the deficient supply of norepinephrine in patients with NOH, thereby improving orthostatic blood pressure and alleviating associated symptoms of lightheadedness, dizziness, blurred vision, and syncope. According to the news release, the once-daily formulation's safety and tolerability should provide significant improvement in long-term treatment for the condition.

A double-blind, placebo-controlled safety and efficacy study of L-threo-DOPS is planned at multiple sites in the United States and Europe during the second half of 2007, the company said. The primary end point will be defined as improvement in orthostatic blood pressure over time.

L-threo-DOPS is currently under consideration for orphan drug status by the European Agency for the Evaluation of Medical Products. It was first approved in 1989 by Japan's Ministry of Health and Welfare (MHW) for the treatment of frozen gait and dizziness on standing associated with Parkinson's disease, and for the treatment of orthostatic hypotension, syncope or dizziness on standing associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy. In 2000, the MHW approved use of L-threo-DOPS for the prevention of vertigo, dizziness, and weakness associated with orthostatic hypotension in hemodialysis patients.


Orphan Drug Cyclosporine A–Eluting Ocular Implant (LX201) for the Prevention of Corneal Transplant Rejection

On January 8, the FDA approved orphan drug designation for a cyclosporine A–eluting ocular implant (LX201, made by Lux Biosciences, Inc) in the prophylaxis of acute rejection in corneal transplant patients.

According to a company news release, the silicone matrix ocular implant is placed in the subconjunctival space under the eyelid. The implant steadily releases therapeutic doses of cyclosporine A locally to the eye for 1 year.

Although cyclosporine A is commonly used as systemic therapy to prevent rejection of solid organ transplants, no drugs are currently FDA-approved to prevent rejection in corneal transplantation. Pivotal clinical trials of the product in the corneal transplant setting are expected to begin during the first quarter of 2007.

The implant was previously granted orphan drug status by the European Agency for the Evaluation of Medical Products.


Orphan Drug Vincristine Sulfate Liposomes Injection (Marqibo) for ALL

On January 8, the FDA approved orphan drug designation for vincristine sulfate liposomes injection (Marqibo, made by Hana Biosciences, Inc) in the treatment of adults with acute lymphoblastic leukemia (ALL).

Because vincristine activity is dependent on duration of drug exposure, the formulation is designed using sphingosome encapsulated technology, yielding a rigid liposome that allows the drug to leak out slowly, thereby maintaining vincristine levels for prolonged periods of time.

According to a company news release, the improved pharmacokinetic profile of the product, which mimics a continuous vincristine infusion, may yield greater activity in rapidly dividing cancers.

Vincristine activity is also typically limited by its short half-life and neurotoxic effects at doses higher than 2 mg. In contrast, the liposomal formulation has demonstrated a significantly longer half-life in phase 1 and 2 trials, and patients have been able to tolerate doses twice as high as those conventionally used.

A pivotal clinical trial of the liposomal vincristine formulation in patients with ALL is expected to begin during the first half of 2007, the company said.

Vincristine sulfate injection is approved by the FDA for the treatment of acute leukemia. It can also be used in combination with other oncolytic agents in Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor.

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