FDA Passes on Inclisiran, Citing Manufacturing Site Problems

The manufacturer specified that the FDA did not have safety or efficacy concerns, but needed facility conditions resolved.

FDA Passes on Inclisiran, Citing Manufacturing Site Problems

In a surprise move, the US Food and Drug Administration has opted to not approve the novel LDL cholesterol-lowering drug inclisiran, citing problems with a European manufacturing site. The complete response letter was sent last week and cited “unresolved facility inspection-related conditions” as the reason for the decision and not “any concerns related to the efficacy or safety of inclisiran,” a Novartis press release notes.

That stance is in contrast to the decision by European regulators, who approved the twice-yearly, subcutaneous, small interfering RNA (siRNA) earlier this month. The drug is now indicated for patients with hypercholesterolemia or mixed dyslipidemia already taking a statin or other lipid-lowering therapies who have not met LDL-cholesterol goals outlined in the European guidelines, as TCTMD reported.

According to Novartis, the issues are being conveyed to the European manufacturing site, which is a “third-party facility”; the FDA-stipulated conditions will need to be resolved before a New Drug Application can be approved. Of note, no on-site inspection has yet been conducted by the US regulator, and COVID-19 may complicate matters, the press statement notes. “If it is determined that a facility inspection is needed to approve the application, the FDA will define an approach for scheduling once safe travel may resume based on public health need and other factors.”

The evidence supporting the approval of inclisiran, which will be sold as Leqvio in Europe, comes from the ORION series of trials. ORION-9 tested inclisiran in 482 patients with clinical or genetic evidence of heterozygous familial hypercholesterolemia, ORION-10 tested the drug in 1,561 patients with atherosclerotic cardiovascular disease (ASCVD), and ORION-11 included 1,617 patients with ASCVD or ASCVD-risk equivalents. The mean placebo-adjusted reduction in LDL cholesterol at 17 months ranged from 48% to 52%.

The ongoing ORION-4 study, not expected to wrap up for several more years, is a 15,000-patient outcomes trial looking at whether inclisiran on top of guideline-directed medical therapy lowers the risk of major adverse cardiovascular events (coronary heart disease death, MI, stroke, or urgent revascularization) in a broader group of patients with ASCVD.

Photo Credit: Novartis

Shelley Wood is the Editor-in-Chief of TCTMD and the Editorial Director at CRF. She did her undergraduate degree at McGill…

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