The Impact of Mavacamten on the Pathophysiology of Hypertrophic Cardiomyopathy: A Narrative Review.

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial.

OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.

Morquio A syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database.

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype-phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.

Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information.

BACKGROUND: The Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment. METHODS: Seven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case-control cohort of 1664 case patients and 1636 control subjects within the Women's Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer-Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%-2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided. RESULTS: The SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 × 10⁻5). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10⁻5). CONCLUSIONS: Combining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk.

Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells.

Classical Hodgkin lymphoma (cHL) is a malignancy of B-cell origin in which the neoplastic cells, known as "Reed-Sternberg" (RS) cells, are characteristically binucleated. Here we describe a family where multiple individuals developing cHL have inherited a reciprocal translocation between chromosomes 2 and 3. The translocation disrupts KLHDC8B, an uncharacterized gene from a region (3p21.31) previously implicated in lymphoma and related malignancies, resulting in its loss of expression. We tested KLHDC8B as a candidate gene for cHL and found that a 5'-UTR polymorphism responsible for decreasing its translational expression is associated with cHL in probands from other families with cHL and segregates with disease in those pedigrees. In one of three informative sporadic cases of cHL, we detected loss of heterozygosity (LOH) for KLHDC8B in RS cells, but not reactive T lymphocytes, purified from a malignant lymph node. KLHDC8B encodes a protein predicted to contain seven kelch repeat domains. KLHDC8B is expressed during mitosis, where it localizes to the midbody structure connecting cells about to separate during cytokinesis, and it is degraded after cell division. Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its reduced expression in the formation of cHL's signature RS cell.

Neutrophil elastase in cyclic and severe congenital neutropenia.

Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic neutropenia and severe congenital neutropenia (SCN). Genetic evaluation of other forms of neutropenia in humans and model organisms has helped to illuminate the role of NE. A canine form of cyclic neutropenia corresponds to human Hermansky-Pudlak syndrome type 2 (HPS2) and results from mutations in AP3B1 encoding a subunit of a complex involved in the subcellular trafficking of vesicular cargo proteins (among which NE appears to be one). Rare cases of SCN are attributable to mutations in the transcriptional repressor Gfi1 (among whose regulatory targets also include ELA2). The ultimate biochemical consequences of the mutations are not yet known, however. Gene targeting of ELA2 has thus far failed to recapitulate neutropenia in mice. The cycling phenomenon and origins of leukemic transformation in SCN remain puzzling. Nevertheless, mutations in all 3 genes are capable of causing the mislocalization of NE and may also induce the unfolded protein response, suggesting that there might a convergent pathogenic mechanism focusing on NE.

Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas.

Although somatic mutations in a number of genes have been associated with development of human tumors, such as lipomas, relatively few examples exist of germline mutations in these genes. Here we describe an 8-year-old boy who has a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3, and a phenotype including extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas. His chromosomal inversion was found to truncate HMGA2, a gene that encodes an architectural factor involved in the etiology of many benign mesenchymal tumors and that maps to the 12q14.3 breakpoint. Similar truncations of murine Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas, features strikingly similar to those observed in the child. This represents the first report of a constitutional rearrangement affecting HMGA2 and demonstrates the role of this gene in human growth and development. Systematic genetic analysis and clinical studies of this child may offer unique insights into the role of HMGA2 in adipogenesis, osteogenesis, and general growth control.