Regeneron to File for Evinacumab in Climate Where Cost Is the First Question Asked Despite Results

With early results out about Regeneron Pharmaceuticals’ evinacumab for a rare form of deadly high cholesterol, how will payers react if the drug is eventually approved by the FDA?

Adding evinacumab to other anticholesterol medications reduced low-density lipoprotein (LDL) cholesterol by 49% in patients with homozygous familial hypercholesterolemia (HoFH), a rare, genetic form of life-threatening high cholesterol, the company said last week.

Regeneron said it will submit an FDA application in 2020 after releasing the positive phase 3 results for evinacumab, an investigational angiopoietin-like 3 (ANGPTL3) antibody.

“Currently HoFH patients face limited choices in reducing their LDL cholesterol, including therapies that are time-consuming like LDL apheresis, or that may have side effect concerns,” George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron, said in a statement. "Despite recent therapeutic advances, there is still a significant unmet need to lower the LDL cholesterol of many patients with HoFH. On average, evinacumab reduced patients’ LDL cholesterol in half and was generally well-tolerated in the trial."

Writing in Forbes, pharmaceutical executive John LaMattina wrote that, if approved, the first question payers and others will likely ask about evinacumab is one of cost. Pricing strategies are not currently known, but he noted apheresis costs at least $8000 a month.

In 2015, when the FDA approved 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Regeneron's alirocumab (Praluent) and Amgen's evolocumab (Repatha), they both carried annual prices of about $14,000, creating payer resistance. The drugs have since seen price cuts and now have with an annual cost of $5850. A recent study found that patients were 16% more likely to have a heart attack or stroke if their prescription was rejected than if their prescription was covered and filled for approximately 1 year. If a prescription was covered but a patient failed to fill it, the patients were 21% more likely to have a cardiovascular event.

Another study found that prior authorization requirements for PCSK9 inhibitors were so stringent that they were seen as hindering patient access.

Patients with HoFH have severely elevated levels of LDL cholesterol and often experience early atherosclerotic disease, sometimes as early as the teen years. More than one-third of the patients in the randomized, double-blind, placebo-controlled trial had the most severe form of HoFH, called “null/null,” which often does not respond to other treatment. The average age of patients entering the trial was 42 years, with ages spanning from 12 to 75.

The trial, called ELIPSE HoFH, is an ongoing, parallel-group trial evaluating the efficacy and safety of evinacumab 15 mg/kg administered intravenously every 4 weeks in 65 patients (43 evinacumab, 22 placebo). The trial is not powered to evaluate the effect of evinacumab on cardiovascular events.

On average, patients entered the trial with LDL cholesterol levels of 255 mg/dL, despite treatment with other lipid-lowering therapies, including statins, PCSK9 inhibitors, ezetimibe, LDL apheresis, and lomitapide. A cholesterol level of 255 mg/dl is more than twice the CDC’s recommended level of 100 mg/dl, Regeneron said in a statement.

The majority (98%) of the patients were on statins, while 82% were taking PCSK9 inhibitors, and 75% were on ezetimibe, a cholesterol-busting drug often prescribed with statins. A little more than one-third were on LDL apheresis and 26% were on lomitapide.

Researchers saw LDL cholesterol drop from the first assessment at week 2, and it was maintained throughout the 24-week double-blind treatment period. At week 24, the evinacumab group met its primary end point, cutting LDL cholesterol 49% from baseline when added to other statin therapies, compared with placebo (47% reduction for evinacumab compared to a 2% increase for placebo, P <.0001), the primary end point.

There was 132 mg/dL absolute change in LDL cholesterol from baseline, compared with placebo (135 mg/dL reduction for evinacumab compared to a 3 mg/dL reduction for placebo, P <.0001). Within the evinacumab group, 47% achieved LDL cholesterol levels less than 100 mg/dL, compared with 23% for placebo (nominal P = .0203). Similar levels of LDL cholesterol-lowering were also observed in the most difficult-to-treat patients who often don’t respond to certain other therapies, described as “null/null” or “negative/negative” patients.

In addition, evinacumab also reduced apolipoprotein B (ApoB), non-HDL cholesterol, and total cholesterol compared to placebo.

“These results raise the potential that evinacumab may have value for other patients with severe, refractory hypercholesterolemia, where we have a trial ongoing,” Yancopoulos said.

A little more than 80% of patients in the placebo group experienced an adverse event (AE) compared with 66% of those in the evinacumab group. AEs that occurred in at least 5% of patients and more commonly with evinacumab were influenza-like illness (11% evinacumab, 0% placebo) and rhinorrhea (7% evinacumab, 0% placebo). There was no difference in the incidence of nausea, abdominal pain or diarrhea between treatment groups, and there were no deaths, major adverse cardiovascular events or hepatic disorders.

In 2017, the FDA granted Breakthrough Therapy designation for evinacumab. for the treatment of hypercholesterolemia in patients with HoFH, which affects about 1300 people in the United States.

ANGPTL3 blocks lipoprotein lipase and endothelial lipase, and appears to play a central role in lipoprotein metabolism. It is also in phase 2 trials for refractory hypercholesterolemia and severe hypertriglyceridemia.