The much anticipated cholesterol blockage control drug Muvalaplin reduces lipoprotein (a) by up to 85% within twelve weeks. Last June we reported that Muvalaplin researchers had published encouraging phase I clinical trial results. This January, Victorian Heart Institute scientists led by John H. Krege, MD announced in a JAMA research article that the drug has passed the next hurdle on its way to the pharmacy. Read on to find out how muvalaplin fared against lipoprotein (a) in phase II clinical trials. You can find background information about the drug and lipoprotein (a) here.
Around the world in 84 days
Australian researchers based at Monash University collaborated with a global network of clinicians to perform a randomized double blinded placebo controlled clinical trial to test how well the cholesterol carrier busting drug worked.
Two hundred and thirty-three patients over 40 years old with serum lipoprotein (a)
concentrations of 175 nmol/L or greater were recruited at 43 centres across the world. The participants located in Australia, Brazil, China, Germany, Hungary, Japan, the Netherlands, and the United States had a history of type 2 diabetes, heart problems (coronary artery disease, ischaemic stroke, peripheral arterial disease) or familial hypercholesterolaemia that put them at risk of cardiovascular events.
By testing the drug in Asia, Latin America, North America and Europe, in addition to Australia, doctors were able to see how the lipoprotein (a) busting drug fared in different contexts. They were able to challenge the medication against different genetic backgrounds, different diets and differing approaches to heart health. The researchers found that the drug performed better than the placebo regardless of these factors.
A Randomized Double Blind Placebo Controlled Trial for Muvalaplin
Split into groups randomly, participants took a twelve-week course of oral Muvalaplin at dose 10 (34 participants), 60 (63 participants), or 240 mg (68 participants), or placebo pill (67 participants). Neither doctors nor patients knew which medication each party used. The researchers tested a range of doses to find out whether there was a ‘dose dependent effect’ – does the drug work better if you take more? – , and to determine whether side effects appear at higher doses.
Every four weeks the researchers gave the recruits a blood test to see how their lipoprotein (a) levels were responding to each treatment. The doctors collected data to quantify how lipoprotein (a) concentrations changed after 12 weeks. They also examined whether levels dropped below 125 nmol/L, how apolipoprotein B and hs-CRP quantities changed and whether participants had experienced adverse effects or cardiovascular events during the trial.
Lipoprotein (a) levels dropped
At the end of the twelve-week study, the researchers crunched the blood test data. They discovered that while patients who took the placebo saw no real change in their numbers (-0.5% after three months), the Muvalaplin treatment groups saw significant changes in their lipoprotein (a) levels. Patients benefitted from the drug at all three doses, with 10 mg yielding a 47.4% reduction up to 81.6% lower at 60 mg and 85.7% reduction at 240 mg. The changes happened over time, researchers saw the drug treatment group’s cholesterol levels falling at each testing point.
Average starting lipoprotein levels were 216.8 nMol/L. By the end of the trial, however, 13 (38.9%) members of the 10 mg group were at 125 nMol/L or below, likewise 49 (81.9%), and 53 (77.4%) of the 60 mg and 240 mg dose groups. In contrast only 2 (3.6%) of the placebo group had lipoprotein (a) levels lower than 125 nMol/L.
Apolipoprotein B levels also went down by a small amount in a dose-dependent manner, while hs-CRP concentrations were unchanged.
Safety and tolerability
Patients who used Muvalaplin reported side effects or adverse events at the same frequency as the group who used the placebo pill. In fact, the placebo group reported more serious adverse events than those in the Muvalaplin groups. It seems that at least within 12 weeks, the dug performs well with no significant side effects.
While these results are encouraging, the trial lasted only twelve weeks. Phase III clinical trials of Muvalaplin are needed before doctors can confidently say that the drug works to lower lipoprotein (a) in the long term. Given that there is currently no widely available treatment for high lipoprotein (a), ongoing trials will also deliver key information about whether lipoprotein (a) really contributes to cardiovascular problems and to what extent.
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