Pfizer’s Tikosyn (dofetilide) has been available since 1999 to help treat patients with irregular heartbeats. Now, years after the drug has gone generic, scientists at Georgetown University have found a potential new use for it—treating pulmonary arterial hypertension (PAH).
Tikosyn works in cardiac arrhythmia by targeting Kv11.1, a group of potassium ion channels that acts as an important regulator of the heart’s pace. In a new study published in The American Journal of Pathology, the Georgetown team showed the channels also affect lung tissue and that their increased expression is linked to changes in the pulmonary vascular system.
In rats with PAH, Tikosyn successfully inhibited pulmonary vascular remodeling, which helped to lower high blood pressure in the lungs, the team reported.
PAH and chronic obstructive pulmonary disease (COPD)-associated hypertension are marked by the narrowing of the arteries in the lung. In control rats and healthy humans, the researchers found that Kv11.1 channels are expressed in the smooth muscle cell (SMC) layer of large-diameter pulmonary arteries (PAs), but not in the SMCs of small PAs.
But in rats with experimentally induced PAH and samples from patients with COPD, researchers observed significantly increased Kv11.1 levels. The same phenomenon occurred in small PAs, too. As a result, the PA walls were thickened, leading to narrower blood vessels.
The investigators found that rats treated with Tikosyn experienced a reduction in wall thickness and an increase in the diameter of the interior of blood vessles—with both measures reaching the level seen in healthy rats. Animals that got only a drug solvent agent, by contrast, didn’t experience those benefits, the team reported.
There is no cure for PAH, which has become hot area of interest among biopharma companies. Last year, United Therapeutics shelled out $800 million upfront to license Arena’s candidate ralinepag, which the companies believe could even be a better therapy than Johnson & Johnson’s fast-growing Uptravi (selexipag), an oral prostacyclin receptor agonist.
PAH drug development has also seen its fair share of failures. United itself recently scrapped esuberaprost after it failed in a phase 3 test. GlaxoSmithKline’s GSK2586881, a recombinant form of human angiotensin-converting enzyme 2, didn’t make it out of phase 2 in PAH and acute lung injury.
The Georgetown team believes blocking Kv11.1 channels with dofetilide may offer a new way to treat PAH.
“Specifically, we have shown that dofetilide, which is already FDA-approved as an antiarrhythmic and therefore has passed all of the drug safety requirements, can be considered for repurposing for treatment of patients with PAH,” Tinatin Brelidze, the study’s senior author, said in a statement.