An investigational compound called ITI-214, which is being investigated in clinical trials for Parkinson’s disease, may also be effective in strengthening the heart, according to an animal study recently published in the journal Circulation.
ITI-214, being developed by Intra-Cellular Therapies, is a potent and selective inhibitor of an enzyme known as phosphodiesterase 1 (PDE1), which mediates the breakdown of cAMP and cGMP. These messenger molecules act within the cells of the nervous system in response to various signals, but they also play an important role in cardiac myocytes, a cell type found in the heart muscle.
Changes in PDE1 activity have been reported in both neurological and cardiovascular diseases, and the use of PDE1 inhibitors is intended to block the breakdown of cAMP and cGMP to re-establish normal function in these conditions.
An ongoing Phase 1/2 trial (NCT03257046) is evaluating ITI-214’s safety, tolerability, and pharmacological profile in Parkinson’s patients. Participants are still being recruited, for an estimated total of 40 patients. The trial is expected to conclude sometime this month.
ITI-214 is also being tested in a Phase 1/2 clinical trial (NCT03387215) in patients with heart failure at Johns Hopkins Medicine and Duke University. The compound successfully passed Phase 1 safety trials in healthy individuals.
Heart failure develops as a result of the heart becoming weakened or stiff, which may lead to inefficient ability to pump blood to the rest of your body. Although patients may benefit from available medications that boost the strength of cardiac contractions — such as dobutamine — these therapies may lead to an irregular heartbeat and other complications.
Prior studies have shown that PDE1 inhibitors can ease the abnormally thick heart muscle in mice. However, because mice have a different form of PDE1 than humans, PDE1 inhibitors may cause different effects. Based on this, Johns Hopkins Medicine researchers in this study used dogs and rabbits, which have a PDE1 composition more similar to humans.
The dogs underwent surgeries to implant sensors and pacemakers. The effects of different doses of ITI-214, both oral and intravenous, were tested before and after inducing heart failure.
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Results showed that oral ITI-214 at 10 mg per kilogram of body weight increased the amount of blood pumped out by the heart per minute by 50% in healthy hearts and by 32% in failing hearts. This was associated with a nearly 30% increase in the strength of the heart’s contractions with blood vessels dilation. Intravenous ITI-214 had similar but more rapid effects.
“To my knowledge, no study had reported increased heart contraction strength from a PDE1 inhibition before,” David Kass, MD, the study’s senior author, said in a press release. He also noted that the similar composition of PDE-1 in larger mammals and humans may have led to the positive results.
Kass added that ITI-214 also raised the heart rate of healthy dogs by approximately 40 beats per minute, which may be dangerous for heart failure patients. However, dogs with failing hearts did not show an ITI-214-induced change in heart rate.
Importantly, the strengthened heart contractions were not linked to the development of irregular heartbeats, as observed with dobutamine and inhibitors of a different PDE — PDE3 — such as Primacor (milrininone).
Since ITI-214 produced many of the same effects as PDE3 inhibitors, the investigators tested them side by side, Kass said.
Comparisons in isolated muscle cells from rabbit hearts showed that both PDE3 inhibitors and ITI-214 caused the cells to contract more strongly. However, unlike PDE3 inhibitors, ITI-214 did not increase calcium levels, suggesting a different mechanism that may spare the severe alterations in heartbeat.
“Our results are intriguing because so far it’s been largely uncharted territory to come up with a way of increasing contractility that doesn’t ultimately hurt patients,” Kass said.