The complicated clinical course in a case of atypical lipodystrophy after development of neutralizing antibody to metreleptin: treatment with setmelanotide

Abstract

Summary: A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Keywords: 2020; Adipose tissue; Adolescent/young adult; Alanine aminotransferase; Amenorrhoea; Anion gap; Antinuclear antibody; Apolipoprotein A-1*; Apolipoprotein B*; Appetite*; BMI; Beta-hydroxybutyrate; C-peptide (blood); Cholesterol:HDL ratio*; Cirrhosis; Complement 4*; DEXA scan; DNA sequencing; Diabetes mellitus type 1; Diabetic ketoacidosis; Diet; Fat loss*; Fatigue; Female; Fenofibrate; Fluid repletion; Food intake*; GADA; Gamma-glutamyl transpeptidase*; Glucose (blood); Haemoglobin A1c; Hand contractures*; Histopathology; Hyperglycaemia; Hyperlipidaemia*; Hypertriglyceridaemia*; Hypoglycaemia; Hypogonadism; Hypoleptinaemia*; Insulin; Insulin resistance; Ketones (plasma); Ketones (urine); Leptin; Leptin*; Lipodystrophy; Liver biopsy; Liver fat*; Liver function; MRI; March; Metformin; Metreleptin*; Mixed meal test*; Nonalcoholic steatohepatitis*; Novel treatment; Obesity; Paediatrics; Pancreatitis; Pioglitazone; Plasmapheresis; Polydipsia; Prednisone; Radioimmunoassay; Scoliosis; Setmelanotide*; Tanner scale; Thiazolidinediones; Triglycerides; United States; Visceral fat*; Vision - blurred; Weight; White.

Figure 1

Patient description and compassionate treatment efforts. (A) Patient pictures showing atypical partial lipodystrophy at her presentation. Briefly, her mother began noticing a change in her body shape with thin arms and legs, and physical examination revealed lack of fat in her extremities with preservation of her trunk, face, and neck at age 11 when she was evaluated by her primary care physician for body changes that had occurred over the last year, enlarged liver and high triglycerides. She also had scoliosis and hand contractures. She had only Tanner stage 2 breast development and pubic hair, but no menstrual cycles. Her gonadal hormones indicated hypogonadotropic hypogonadism. Her morning cortisol, IGF-1, and thyroid functions were within normal limits (Table 1). Glutamic acid decarboxylase (GAD) antibodies were elevated at presentation. She demonstrated slightly low levels of Complement 4 (C4), and her Antinuclear Antibody (ANA) was positive. Family history was significant for atypical form of systemic lupus erythematosus (SLE) in her father and sudden cardiac death in his thirties. Mother had obesity and hypothyroidism. (B) Serial ‘fat shadow’ images obtained from dual-energy X-ray absorptiometry (DXA) scan showing partial lipodystrophy (2). Total fat percentage was reported as 21%, and fat mass ratio (FMR) was 1.99 at presentation. Note the increase in total fat over time, which is due to an increase in truncal fat. Patient underwent corrective surgery for scoliosis between age 14 and 15. It was hard to classify her lipodystrophy using the current classification schema. Although our patient’s fat distribution resembles familial partial lipodystrophy, we opted to classify her as atypical partial lipodystrophy considering the age of onset, a wide range of symptoms in addition to lipodystrophy including hand contractures, scoliosis, and amenorrhea, underlying autoimmunity, and disease progression. Even though our patient was classified as atypical partial lipodystrophy, the cluster of type 1 diabetes and autoimmune hepatitis in association with an acquired form of generalized lipodystrophy is well known, which is associated with low C4 levels. Our patient has substantially more upper body adiposity and subcutaneous abdominal fat compared to those other patients previously described. Therefore, she does not quite fit any of the established patterns in the current classification system of lipodystrophy. (C) The figure shows the complicated course of the disease and investigational treatment efforts. Metreleptin was initially successful to improve nonalcoholic steatohepatitis (NASH) and to keep the patient’s metabolic status stable; however, it was complicated by the development of neutralizing antibodies (Nab-leptin). At month 18, the patient reported fatigue, increased thirst, blurred vision, and polydipsia, and had lost 5 Ibs in a month. Lab results showed significant hyperglycemia and hyperlipidemia with a positive anion gap and positive ketones. The anti-GAD65 level was 5.39 nmol/L (repeat Anti-GAD65: 8.38 nmol/L, 2 months later), and leptin level, drawn 1-h post injection, was undetectable. The presence of Nab-leptin was confirmed by the assay performed by the manufacturer of metreleptin. For her type 1 diabetes, she was started on insulin at high doses plus metformin. Upon tapering and discontinuation of metreleptin, she was treated with fenofibrate for hypertriglyceridemia and pioglitazone for improving severe insulin resistance. Her liver function test results rose to a ten-fold above normal 1 month following the initiation of pioglitazone. Liver biopsy showed patchy portal and periportal inflammation that included plasma cells and interface injury, consistent with autoimmune hepatitis. She responded well to a short course of prednisone with normalization of her liver tests, but her metabolic control worsened. She was started on frequent plasmapheresis as shown, but this did not prevent recurrent episodes of pancreatitis. (D) The effect of setmelanotide on weight and hunger scores. Note that patient had mild reduction in hunger scores while on setmelanotide. Daily Hunger Questionnaire scores were assessed by asking the patient to score her hunger based on a Likert-like scale, where 0 is not hungry at all and 10 is the hungriest possible. These were completed on 3 separate days during screening and everyday thereafter during the setmelanotide treatment period prior to dosing in the morning (fasted). Hunger questionnaire and scales are presented in Table 4. Data shown are from scores on Question 2 (analyses of other questions showed a similar profile with no additional data shown). Also, no change was observed in the Global Hunger Assessment (data not shown). (E) The effect of setmelanotide on triglycerides, HbA1c, and total daily insulin. Because the patient developed hypoglycemia upon initiation of setmelanotide, her insulin dose was reduced to prevent further hypoglycemia. The triglyceride levels were somewhat lower in the earlier part of the therapy, but the effect was not sustained. By the end of pre-specified treatment period, it was necessary to re-initiate plasmapheresis. (F) The effect of setmelanotide on the liver and visceral fat content. Axial magnetic resonance (MR) images are presented as well as quantification. Liver fat reported as proton-density fat fraction and visceral fat were quantified as described previously. There was no real change in liver fat and a slight reduction in visceral fat using this short-term treatment. (G) The effect of setmelanotide on quality-of-life parameters. The summary assessments of Short Form (SF)-36 version 1 (v1) Health Questionnaire at baseline and after setmelanotide therapy are presented, showing no real change with therapy.

Figure 2

(A) Mix meal test before and after metreleptin. (B) Liver biopsy before and 12 months after metreleptin. The liver biopsy prior to metreleptin shows steatohepatitis with bridging fibrosis and cirrhosis by histology in the area that was biopsied. NASH scoring before metreleptin: Fibrosis 4, hepatocellular injury 2, steatosis 2, parenchymal inflammation 1, and total NASH score: 9 and after metreleptin: fibrosis 3, injury 2, steatosis 1, inflammation 1, and total NASH score 7. (C) Liver biopsy showing evidence for autoimmune hepatitis obtained when liver tests results were elevated ten-fold. This acute elevation in liver tests occurred upon discontinuation of metreleptin and sequential addition of fenofibrate and pioglitazone. Both agents were then discontinued and patient was treated with a short course of prednisone. Arrow heads indicate bile ductular reaction with mild chronic inflammation, including plasma cells.