Inflammation plays a major role in the development of cardiovascular disease (CVD) and has been a missing link in how cardiologists prevent and treat atherosclerotic plaques that can cause heart attacks or strokes. But now, after a priority review, the U.S. Food and Drug Administration (FDA) has approved Agepha Pharma USA's version of the drug colchicine, sold and marketed under the name Lodoco. It is the first anti-inflammatory medication approved by the FDA to treat CVD.
Studies leading to the drug's market clearance demonstrated it can reduce coronary inflammation and the risk of myocardial infarction (MI), stroke, coronary revascularization and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for CVD. The drug was shown to reduce the risk of cardiac events by 31% on top of statin medications, the current standard of care.[1]
Agepha anticipates its colchicine drug will be available for prescription in the U.S. in the second half of 2023.
“Approval by the FDA of the first drug to target cardiovascular inflammation is an important step forward for the care of our patients,” Paul Ridker, MD, MPH, a professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, said in a statement. Ridker has been instrumental in researching the role of inflammation in CVD for more than two decades. “To treat coronary disease effectively, cardiologists must aggressively reduce inflammation and cholesterol. For appropriate patients already taking a statin, adding the anti-inflammatory drug colchicine at a dose of 0.5 mg daily has been proven to significantly lower risks of recurrent heart attack and stroke.”
Clinical evidence of colchicine for heart attack and stroke prevention
The effectiveness and safety of colchicine in preventing heart attack and stroke is supported by randomized trial data reported in the New England Journal of Medicine, Circulation, Journal of the American College of Cardiology, and European Heart Journal.[1-4]
A multi-national, randomized, double-blind, placebo-controlled clinical trial was conducted among 5,522 patients with chronic coronary disease all of whom were taking guideline-directed medical care including high-intensity statins. In the trial, 0.5 mg colchicine was found to significantly reduce the overall risk of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization by 31% in comparison with the placebo group when added to high-intensity statins and other cardiology prevention therapies.[1]
Treating inflammation may offer a new era of cardiac patient care
It has been long understood that inflammation, as well as high cholesterol, increases cardiovascular risks, but up until now only cholesterol has been treated. Inflammation plays a critical role in atherosclerotic cardiovascular disease (ASCVD). Patients with ASCVD, the leading cause of morbidity and mortality in the United States, and are at high risk for acute cardiovascular events.[5,6]
Inflammation can be measured through high-sensitivity C-reactive protein (CRP or HS-CRP) testing, but it has not been widely used, Ridker told Cardiovascular Business in an interview at the American College of Cardiology (ACC) 2023 this past spring. He presented results of a late-breaking study at ACC on the residual inflammatory risk in contemporary statin-treated patients. The study focused on data from nearly 32,000 patients in the PROMINENT, REDUCE-IT and STRENGTH trials.[7]
"The data are very clear cut—CRP really matters. And it is really surprising to me how few of my colleagues measure CRP at all ... You measure LDL so you know what you are doing and you measure blood pressure so you know what you are doing. If you are not measuring CRP, you don't even know who in the clinic has this residual inflammatory risk problem," Ridker explained to Cardiovascular Business. "You need to measure CRP just like you measure LDL and blood pressure."
Until this FDA approval of colchicine, Ridker said there were not any indicated drugs to treat the inflammation. He said statins can help lower CRP, but the addition of colchicine will help lower risks of MIs and strokes even lower.
"If we do not attack the inflammation, we just are not going to get the best outcomes for our patients," Ridker said. "We in the cardiology community have done a great job on the LDL side, we just to focus on the other half of the inflammation piece."
Colchicine reduces coronary plaque inflammation and plaque formation
The formation of atherosclerotic plaque, in which inflammation plays a substantial role, contributes to the development and progression of ASCVD.[8] Colchicine inhibits microtubule assembly and has multiple anti-inflammatory mechanisms.[9,10] Cardiologists can now use HS-CPR to determine if the addition of colchicine can help lower patient risks.
“For the first time, patients with residual inflammatory risk, as measured by hs-CRP, will have an FDA-approved treatment option demonstrated to reduce the risk of cardiovascular disease by targeting the inflammatory pathways that influence major cardiac events,” Michael Blaha, MD, MPH, director of clinical research and professor of medicine at the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, said in the same statement. “The cardiovascular research community has demonstrated that focusing on unmet patient medical needs and addressing the long-standing challenge of reducing cardiac inflammation can translate into meaningful risk reduction in the incidence of cardiac events.”
Cardiovascular Business spoke with Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention, and a professor at Brigham and Women's Hospital, about coronary plaque inflammation, why it is important, how it can be detected and ways to treat it. He presented a late-breaking study on residual inflammatory risk in contemporary statin-treated patients at ACC.23, and discussed the role for colchicine as a therapy.
Colchicine has been used to treat gout for past decade
The anti-inflammatory properties of the colchicine were first tested in trials to treat gout. The Mutual Pharmaceutical Company gained FDA approval for its brand name drug Colcrys to treat gout in 2009. Avion Pharmaceuticals gained FDA approval for Gloperba in 2019 for the same indication.
Oral colchicine has been used as a drug since the 1800s, but was not fully regulated in the U.S. until the 2010, when the FDA announced it would be banning unapproved oral colchicine products. This came after the regulatory clearance of Colcrys.
Colchicine is also used to treat familial Mediterranean fever (FMF), a chronic, rare autoinflammatory disease. Another anti-inflammatory drug canakinumab also has FDA clearance for treating FMF. Ridker led the CANTOS trial, published in 2017, using canakinumab to determine if it also could be used to treat coronary artery plaque inflammation.[11]
Drug and safety information for colchicine
Lodoco tablets are formulated as a once-daily, continuous-use oral treatment for adults and can be used safely alone or in combination with standard-of-care lipid-lowering medications and other therapies.
Patients with kidney failure or severe liver disease should not take this drug. Patients should temporarily stop taking colchicine if prescribed certain drugs like azithromycin or ketoconazole as these medications should not be taken simultaneously.
Fatal overdoses have been reported with colchicine in adults and children.
Patients should not take Lodoco if they:
• Take strong CYP3A4 inhibitors or P-glycoprotein inhibitors. Taking certain medicines with Lodoco may cause the patient's level of of the drug to be too high and cause life-threatening side effects or death.
• Have severe kidney or liver problems.
• Are allergic to colchicine.
Lodoco may cause serious side effects, including:
• Low red blood cell counts, low white blood cell counts and low platelet counts, which can be life-threatening.
• Muscle weakness due to neuromuscular toxicity.
The most common side effects of Lodoco include diarrhea, vomiting and abdominal cramping.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: dfornell@innovatehealthcare.com