CER-001 (Abyonyx Pharma), a high-density lipoprotein (HDL) mimetic, restored kidney function and vision in a patient with a rare congenital kidney disease, lecithin-cholesterol acyltransferase (LCAT) deficiency, a case report shows. "CER-001 is the first treatment that showed beneficial clinical effect in familial LCAT deficiency," Dr. Stanislas Faguer of INSERM U1297 and Universite Paul Sabatier-Toulouse III told Reuters Health by email. "Kidney failure rapidly progressed (eGFR decline - 20 mL/min/1.73 m2 in eight months) before the start of CER-001, whereas kidney function has been stable (during) follow-up of 11 months." Further, he said, "The patient reported a full reversal of her visual blurring that persists over time, (and) the treatment was well tolerated." The report, published in Annals of Internal Medicine, describes a 37-year-old woman referred for nephrotic syndrome. Blood tests showed regenerative anemia; chronic kidney disease (estimated glomerular filtration rate, 29 mL/min/1.73 m2); and dyslipidemia, characterized by very low HDL-C plasma levels - 0.32 mmol/L and apoA-1 (0.41 g/L) - and by circulating lipoprotein X. Cardiovascular screening results were normal. The patient had splenomegaly, white corneal ring opacities and normal visual acuity; however, she experienced blurred vision, especially at night. Ophthalmologic examination showed hyperreflective corneal opacification. Kidney biopsy revealed mesangial hypertrophy with glomerular lipids and massive mesangial C3 and C5b9 deposits, as well as a thickened glomerular basement membrane. Numerous pseudomyelin lipid deposits within the mesangial and endothelial cells were seen on electronic microscopy, leading to capillary obstruction and pseudomembranous aspects. A glomerular proteome analysis confirmed enrichment of complement pathway components C3, C4, C8, and C9. The patient was identified as compound heterozygous for missense and splice-site LCAT gene variations. CER-001 treatment was started because antihypertensive medications and atorvastatin did not stop kidney function decline. As Dr. Faguer noted, after treatment, her eGFR stabilized over 11 months (five months on treatment and six months of off-treatment follow-up). The urinary protein-creatinine ratio returned to initial values, vision normalized and blurred vision did not recur by the end of follow-up. Splenomegaly remained during treatment and LpX was still detectable. No adverse events were observed. Dr. Faguer said, "Whether an earlier introduction of CER-01 with iterative treatment periods may fully prevent kidney progression should be tested in further studies." The group's next steps will include a prospective international observational study to identify patients who might benefit from CER-001, and to test whether the drug can also prevent disease progression in other rare nephropathies with common underlying molecular defects. Dr. Caleb Bupp, chief of genetics and genomics at Spectrum Health and Helen DeVos Children's Hospital in Grand Rapids, who was part of the team that that recently discovered another rare disorder, Bachmann-Bupp syndrome (OMIM #619075), commented by email. "In rare and ultra-rare disorders, treatment can be challenging, as traditional drug trials are not possible due to the paucity of affected patients," he told Reuters Health. "Combining rarity, best evidence, and the often devastating and irreversible effects of genetic syndromes such as LCAT, the authors' approach represents the new paradigm of precision medicine and 'n of 1' treatment," he said. One question is whether a treatment on a single patient will work for a second patient and ultimately others," he noted. "This can be dependent on the molecular mechanism of disease, such as the difference between gain-of-function or loss-of-function variants in the same gene, which may not cause similar symptoms or be equally amenable to treatment." "Though many drugs and treatments may be readily available," he added, "the ability for clinicians to actually obtain a 'medical grade' of the compound and administer treatment can be limited." "Factors such as cost of the drug, willingness for insurance to cover treatment and the necessary clinical monitoring, and the route by which treatment is provided - i.e., via a 'n of 1' research treatment trial or investigational/compassionate use protocol - can be difficult barriers," he acknowledged. "However, with more successful results such as this study, this process will hopefully become more streamlined and widely available." —Marilynn Larkin Source
