Evolocumab (PCSK9 Inhibitor) in Hereditary Spastic Paraplegia Type 5

Background: Hereditary spastic paraplegia type 5 (SPG5) is an ultra-rare neurogenetic axon-degenerative disease. The absence of treatment to prevent disease progression represents a major unmet clinical need. With a greater understanding of the pathophysiological basis of SPG5, opportunities have emerged for providing a targeted mechanistic therapy. The aims of this preliminary study were to investigate the efficacy of a PCSK9 inhibitor, Evolocumab, as a cholesterol-lowering therapy for reducing the accumulation of neurotoxic oxysterols and to evaluate the effects on axonal degeneration. Methods: This was as an open-label, evaluator-blind, single-center pilot study in which 23 SPG5 patients each received a single subcutaneous injections of 420 mg Evolocumab. Clinical data, CSF and blood were collected for analysis at enrollment and subsequent day 30. Induced pluripotent stem cells (iPSCs) were generated from the fibroblasts of a SPG5 patient to assess the mechanism of PCSK9 inhibitor’s effect on treatment. Findings: This trial is the largest sample-size prospective study among any treatment trial for SPG5. In this relatively homogeneous group of SPG5 patients (96% carried the same known nonsense mutation c.334 C>T; the median age was 34 years; disease duration was 16 years), we found that PCSK9 inhibitor significantly lowered levels of the toxic metabolite 27-hydroxycholesterol (27-OHC) in plasma (median (IQR), 589(487-644) vs. 396(348-468) ng/ml , P < 0.001). CSF 27-OHC decreased in 12 (71%) patients with a median reduction by 11% from the median 10 ng/ml before treatment to 8.3 ng/ml after treatment (P = 0.012). Most importantly, axonal degeneration, assessed by using neurofilament light (NFL) as a quantitative biomarker, receded at 30 days after single-dose Evolocumab treatment. Additionally, using iPSC-derived motor neurons, this study also showed that PCSK9 inhibitor had anti-apoptosis activity in SPG5 patients. Interpretation: The potential biological activity of cholesterol modulation for SPG5 patients, that is, alleviation of damage to axons from the effects of neurotoxic oxysterol, as well as the absence of adverse effects associated with the use of PCSK9 inhibitor therapy documented here deserves, in fact urges, full evaluation by well-designed long-term clinical trials. Trial Registration: This study is registered with ClinicalTrials.gov, number: NCT01892345. Funding Statement: This work has been supported by grants U1905210 (W.-J.C.), 81771230(W.-J.C.) and 81801130 (X.L.) from the National Natural Science Foundation of China, Joint Funds for the Innovation of Science and Technology of Fujian Province (2017Y9094) (W.-J.C.) and (2018Y9082) (N.W.), the Natural Science Foundation of Fujian Province (2019J02010) (W.-J.C.) and (2019J05076) (X.L.), the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.). Declaration of Interests: All authors report no conflict of interest. Fujian medical university school of public health have received consultant fees as statistician to perform the data analysis. Ethics Approval Statement: The study protocol and informed consent procedures were approved by the institutional review board. Written informed consent was provided by the patients and their health care proxies.