MASH Resolution Index: development and validation of a non-invasive score to detect histological resolution of MASH.

BACKGROUND: Dynamic changes in non-invasive tests, such as changes in alanine aminotransferase (ALT) and MRI proton-density-fat-fraction (MRI-PDFF), may help to detect metabolic dysfunction-associated steatohepatitis (MASH) resolution, but a combination of non-invasive tests may be more accurate than either alone. We developed a novel non-invasive score, the MASH Resolution Index, to detect the histological resolution of MASH. METHODS: This study included a derivation cohort of 95 well-characterised adult participants (67% female) with biopsy-confirmed MASH who underwent contemporaneous laboratory testing, MRI-PDFF and liver biopsy at two time points. The primary objective was to develop a non-invasive score to detect MASH resolution with no worsening of fibrosis. The most predictive logistic regression model was selected based on the highest area under the receiver operating curve (AUC), and the lowest Akaike information criterion and Bayesian information criterion. The model was then externally validated in a distinct cohort of 163 participants with MASH from a clinical trial. RESULTS: The median (IQR) age and body mass index were 55 (45-62) years and 32.0 (30-37) kg/m2, respectively, in the derivation cohort. The most accurate model (MASH Resolution Index) included MRI-PDFF, ALT and aspartate aminotransferase. The index had an AUC of 0.81 (95% CI 0.69 to 0.93) for detecting MASH resolution in the derivation cohort. The score calibrated well and performed robustly in a distinct external validation cohort (AUC 0.83, 95% CI 0.76 to 0.91), and outperformed changes in ALT and MRI-PDFF. CONCLUSION: The MASH Resolution Index may be a useful score to non-invasively identify MASH resolution.

Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.

BACKGROUND: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established. METHODS: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed. RESULTS: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea. CONCLUSIONS: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

BACKGROUND: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. OBJECTIVES: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). METHODS: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. RESULTS: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). CONCLUSIONS: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Therapies for dopaminergic-induced dyskinesias in Parkinson disease.

Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents.

Natriuretic and neurohormonal responses to nesiritide, furosemide, and combined nesiritide and furosemide in patients with stable systolic dysfunction.

BACKGROUND: In patients with heart failure, few data describe the neurohormonal response to nesiritide and furosemide either alone or in combination. This study systematically compared the effects of nesiritide, furosemide, and their combination on natriuresis/diuresis and plasma aldosterone in patients with chronic stable heart failure who were relatively diuretic resistant. HYPOTHESIS: Natriuretic, diuretic, and neurohormonal responses to furosemide and nesiritide will differ when these agents are administered alone vs. in combination. METHODS: Twenty-eight subjects completed a multicenter, open-label, three-arm crossover study. Each subject received the following treatments in random order on alternate days: (1) furosemide, 40 mg intravenous bolus; (2) nesiritide, 2 microg/kg intravenous bolus followed by a 0.01 microg/kg/min infusion for 6 hours; (3) both furosemide and nesiritide, with furosemide given at least 15 minutes after initiation of nesiritide. RESULTS: Plasma aldosterone increased by 2.2 +/- 1.6 ng/dL after furosemide alone, decreased by 3.9 +/- 1.6 ng/dL after nesiritide alone (P = 0.005 vs furosemide alone and P = 0.56 vs furosemide plus nesiritide), and decreased by 2.8 +/- 1.6 ng/dL after furosemide plus nesiritide (P = 0.02 vs furosemide alone). CONCLUSIONS: Furosemide alone produced natriuresis/diuresis and a prompt rise in plasma aldosterone values. Nesiritide alone produced no significant natriuresis/diuresis, but decreased plasma aldosterone values. When furosemide was administered on a background of nesiritide infusion, the observed natriuresis/diuresis was similar to that seen with furosemide alone, without the anticipated increase in plasma aldosterone observed with furosemide alone.

New frontiers in the pharmacological management of Parkinson's disease.

Rasagiline, a selective COMT inhibitor, and rotigotine, a transdermal dopamine (D2) agonist, are two new agents that have been approved in the U.S. and Europe for the treatment of Parkinson's disease. Rasagiline is approved in the U.S. for both monotherapy and as an adjunct to levodopa. Its role in preventing disease progression has yet to be proven, but a large-scale study (ADAGIO) is under way. Rotigotine is approved for early-stage disease in Europe and the U.S. but is only approved in Europe for late-stage disease. It has recently been recalled due to the formation of insoluble crystals that interfere with absorption and may reduce its efficacy. Measures are being taken by the manufacturer to solve this problem. Istradefylline, and adenosine receptor antagonist, showed early promise but efficacy has not been demonstrated consistently, possibly due to higher than expected placebo effect. This has resulted in a nonapprovable letter from the FDA. With regard to perampanel, additional studies are needed to demonstrate safety and efficacy. Sanifamide and pardoprunox are agents that target multiple receptors that may modulate dyskinesia and other nonmotor symptoms in addition to motor symptoms, but phase III data are not yet available. Lusuride is an older dopamine agonist that has been reformulated as a transdermal patch and as a subcutaneous injection and may offer advantages in refractory patients with motor fluctuations. Sphermaine is a novel cell therapy designed to provide a localized source of levodopa directly to the brain. Gene therapies including AAV-GAD, AAV-AADC and AAV2-neurturin are in early stages of development in patients with advanced-stage disease but early safety data are promising.