麻豆传媒

An investigational antisense drug targeting LPA gene expression successfully reduced levels of lipoprotein(a), or Lp(a), in a dose-ranging study aimed at informing a future outcomes trial.

People randomized to one of five dosing regimens of APO(a)-LRx had large drops in Lp(a) by the sixth month, the reduction ranging from 35% from baseline (at a dose of 20 mg every 4 weeks) to 80% (at 20 mg every week) compared with a 6% drop in the saline placebo arm (P=0.003 and P<0.001, respectively).

Lp(a) lowering was dose-dependent and observed as early as the first month, reaching near-maximal effect by week 16, according to the AKCEA-APO(a)-L_Rx Study team, led by Sotirios Tsimikas, MD, of the University of California San Diego and Ionis Pharmaceuticals (majority owner of Akcea Therapeutics, maker of the APO(a)-L_Rx drug).

Full results from the phase II trial were published Wednesday in the ; some were previously presented at the American Heart Association meeting in late 2018.

Genes determine the plasma concentration of Lp(a), an atherogenic and thrombogenic low density lipoprotein. APO(a)-L_Rx works as a subcutaneous injection that blocks Lp(a) production in hepatocytes via an antisense mechanism aimed at disabling LPA mRNA.

"Most LDL-lowering drugs do not substantially lower lipoprotein(a), and statins often have a neutral or modest lipoprotein(a)-increasing effect," Tsimikas' group wrote, adding that the patients in the FOURIER outcomes trial who could not achieve very low LDL cholesterol on PCSK9 inhibition tended to have elevated Lp(a).

A whopping 98% of patients in the highest APO(a)-L_Rx dosing group (20 mg every week) achieved Lp(a) levels of 50 mg/dL or under by 6 months.

Patients also had drops in proinflammatory oxidized phospholipids on apolipoprotein B and apolipoprotein(a), as well as LDL cholesterol and apolipoprotein B.

"Elevated levels of lipoprotein(a) are a cardiovascular risk factor for which no effective pharmacological therapy currently exists. In this trial, we found that APO(a)-L_Rx provided potent reductions in levels of lipoprotein(a) in patients with cardiovascular disease," Tsimikas and colleagues concluded.

The 80% Lp(a) reduction in the present study would be expected to provide a significant, incremental benefit over currently available therapies, commented Deepak Bhatt, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, who was not involved with the study.

Gordon Huggins, MD, of Tufts Medical Center in Boston, also told 麻豆传媒 that this magnitude of effect would suggest that the drug is "robust" and "might translate into improved cardiovascular health."

A good outcomes trial may look to the PCSK9 trials as a model where patients already treated with maximally effective therapies are enrolled, targeting people who have very high Lp(a) to begin with, Huggins suggested.

Indeed, the pivotal phase III plans to include 7,680 patients with established cardiovascular disease and Lp(a) ≥70 mg/dL over 4-5 years of monthly APO(a)-L_Rx or placebo injections. The trial is sponsored by Novartis, which from Akcea in 2019, and is expected to start in about 2 weeks. It's anticipated to finish in April 2024.

The phase II study was conducted as a randomized double-blind trial assigning patients to 6-12 months of APO(a)-L_Rx (at various doses) or placebo on top of their usual lipid-lowering medications.

Study participants were 286 adults with established atherosclerotic cardiovascular disease and Lp(a) levels at least 60 mg/dL at baseline. Exclusion criteria included recent acute coronary syndrome, major cardiac surgery, or stroke; uncontrolled hypertension; and impaired kidney function.

The cohort averaged age 60 and was over 30% women. Median Lp(a) ended up ranging from 205 to 247 nmol/L across groups. At trial entry, about 80-90% of patients were on statins, half were on ezetimibe, and 20% were on a PCSK9 inhibitor.

The AKCEA-APO(a)-L_Rx investigators noted that these patients were generally younger than the ones included in other cardiovascular trials, consistent with Lp(a) being genetically determined and "therefore a lifelong risk factor."

Most study participants experienced adverse events, the most common ones being injection-site reactions (such as myalgia, arthralgia, and post-injection general discomfort). Serious adverse events were noted in 10% and 2% of the APO(a)-L_Rx and placebo arms, respectively. Events were not dose-dependent.

Platelet counts, liver and renal measures, and influenza-like symptoms were no different between the experimental and control groups.

That nearly all of the patients were white is a limitation of the trial, the authors cautioned.

Nevertheless, Bhatt said, "This appears to be a very promising approach to cardiovascular risk reduction. The mechanism of action is fascinating. These data show excellent effectiveness at lowering Lp(a), with very good safety as well."

Noted Steven Nissen, MD, of the Cleveland Clinic and chairman of the upcoming phase III trial, "We have no therapy whatsoever for this disorder that affects 20% or so of the population. That's 1.5 billion people with high Lp(a). A therapy that reduces levels up to 80% is a really important development and has enormous [clinical] potential. That will, of course, need to be proven in an outcomes trial."

"I'm very optimistic and very hopeful," Nissen said. "This is one of the last really important frontiers in cardiovascular risk reduction."

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