There are a large number of potential new antiarrhythmic agents for atrial fibrillation being studied in different levels of investigation. John Camm, London, UK presented an update of the main drugs under investigation at the Venice Arrhythmias conference, in Venice, Italy.
Today, according to Camm, there are 94 studies regarding atrial fibrillation agents registered with Clinicaltrials.gov: 30 of them are presently recruiting, eight have yet to recruit, 31 are completed, and the remainders are suspended, terminated or not recruiting for some other reason.
“So there are 38 trials that are now active or about to be active in some way. Most of those concern amiodarone, a few concern betablockers, one Coumadin, and another, magnesium. There are very few registered clinical trials involving so called new antiarrhythmic agents. And yet we have a large number of new antiarrhythmic molecules,” Camm added.
Camm described first the new class III agents. “Some of you will not know much about the new amiodarones; one called nexterone, which can be given by an intravenous push, very quickly, does not cause any hypertension and no phlebitis since you only give it over the space of a few seconds. The other is called budiodarone.
Budiodarone has enhanced safety, significantly shorter biological half-life, avoids safety issues due to organ accumulation, and avoids drug interactions. In the phase IIb PASCAL (Paroxysmal atrial fibrillation study with continuous atrial fibrillation logging), 72 patients who had DDD pacemakers received budiodarone doses (200, 400, 600mg bid) compared to placebo. Reduction on atrial fibrillation burden was seen in all groups receiving budiodarone, with 83% reduction at three months for the patients who received the highest dose. “Budiodarone obviously need more studies to get anywhere.”
Camm showed a slide where Vernakalant, dronedarone, ranolazine, and celivarone classified as multichannel blockers.
“Some of these have moved into this box since this figure was first designed. Dronedarone is obvious to all of you, and a derivative of that, celivarone, is very similar to dronedarone. Vernakalant started of life as a so called atrial repolarising delay agent, but it truly is a multi-channel blocker and I feel it should sit where it does now. Ranolazine is from an electricphysiological stand point quite similar to vernakalant.”
Vernakalant, an important ion channel-blocking drug, has a major physiological effect of slowing conduction. It has been studied in a series of studies, according to Camm, “with encouraging but not spectacular results.”
Dronedarone is now approved in the US, Switzerland, Canada, and was recommended for approval in the European Union. Phase IV studies are being planned.
Moving on to talk on the novel drugs, Camm said that some of them are already in the clinic or at least in pharmacological investigation. He mentioned ryanondine receptor modulator, connexin modulator, Na+/H+ inhibitor, Na+/Ca2+ inhibitor, SAC blockers, IKur blockers, and IKACh blockers. “I think we have available to us many drugs that could eventually come to clinical trials but there are very few ongoing at the moment.”
There are many potential new antiarrhythmic drugs. Dronedarone is now approved. Celivarone is derivative of that, and is very similar to dronedarone. Ranolazine is approved for ischaemia and phase III atrial fibrillation studies have been performed or are being planned.
Vernakalant is being considered by agencies worldwide (AVRO study ongoing) but has been rejected by FDA pending a further study (ACT V). Budiodarone and oral vernakalant have phase II studies and phase III (pivotal studies) are planned. Xention 101 is in early phase II and NTC-801 in early phase I.
Camm said that it is uncertain whether celivarone or rotigaptide have any future as atrial antiarrhythmic agents. He called for more studies on new agents for atrial fibrillation.