Treprostinil is a therapy manufactured by United Therapeutics and approved by the U.S. Food and Drug Administration (FDA) to pulmonary arterial hypertension (PAH). It is commercialized in three different forms: an inhaled form (brand name Tyvaso), an oral form (brand name, Orenitram), and an injectable infusion (brand name, Remodulin).
It is currently being studied to treat digital ulcers in people with systemic scleroderma.
How treprostinil works
Scleroderma is a rare disease characterized by the scarring and thickening of the connective tissue in the skin and other organs. As the disease progresses, the thickening of connective tissue around small blood vessels, called capillaries, results in poor blood flow and can lead to complications that include digital ulcers and PAH.
Treprostinil is a man-made form of the natural hormone prostacyclin, which is produced by cells in the walls of blood vessels. When it binds to receptors found on the surface of cells lining the walls of the pulmonary artery, blood vessels that supply the lungs, prostacyclin triggers signaling pathways that cause these blood vessels to relax and widen. Prostacyclin also prevents blood cells called platelets from clumping and blocking vessels.
Treprostinil is designed to relax blood vessels by mimicking these two mechanisms, helping blood flow through the lungs more efficiently. This should increase the availability of oxygen throughout the body, improving patient symptoms.
Treprostinil in clinical trials
The pharmacokinetics (movement in the body), safety, and tolerability of oral treprostinil for scleroderma were first tested in a Phase 1 clinical trial (NCT00848939). In the study, 19 systemic scleroderma patients with digital ulcers received up to 4 mg of treprostinil twice daily. Researchers verified that oral treprostinil was effectively absorbed and was associated with improved cutaneous perfusion (passage of fluid through the circulatory system to the skin) in the short-term. These results were published in the Arthritis Research & Therapy journal.
A Phase 2 trial (NCT00775463), called DISTOL-I, evaluated the effectiveness of oral treprostinil compared to placebo on digital ulcers in 148 patients with systemic scleroderma. Its primary outcome ws change in “net ulcer burden,” defined as new, active, or “indeterminate” digital ulcers that develop in treated patients at 20 weeks compared to study start and placebo. Completed in 2011, it failed to meet its goal of reduced burden. Researchers concluded that oral treprostinil was not an effective treatment, and a planned open-label extension (NCT00848107) study was terminated.
But an analysis of data collected from that Phase 2 study and post-treatment follow-up showed an improvement in Raynaud’s phenomenon, another condition associated with scleroderma. Results, presented at the 2014 ACR/ARHP annual meeting showed a beneficial effect of oral treprostinil on the vascular complications of scleroderma, with the total digital ulcer burden increasing significantly after therapy discontinuation in the 51 patients in this analysis.
A Phase 1/2 study (NCT03120533) is currently recruiting patients to confirm the tolerability of treprostinil hydrogel delivered topically by cathodal iontophoresis in healthy volunteers and scleroderma patients with digital ulcers. Iontophoresis delivery means that the medicine is delivered across the skin using a voltage gradient. The trial aims to recruit up to 36 participants in France, and it is expected to finish collecting data in February 2019.
United Therapeutics is also evaluating the effect of oral treprostinil in the treatment of calcinosis (calcium deposits) in patients with systemic scleroderma in a pilot Phase 2 trial (NCT02663895). Up to 12 patients will receive treprostinil for 12 months, with follow-up evaluations every three months. Its goal is to determine whether oral treprostinil is safe and effective in reducing calcinosis in these patients. The trial, which concludes in June 2020, is currently recruiting at Stanford University in California.
Common side effects of treprostinil include reactions or pain at the injection site, headache, diarrhea, nausea, jaw pain, and swelling.
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