Amifampridine an Effective Treatment for Spinal Muscle Atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. The resulting deficiencies in the SMN protein lead to progressive lower motor neuron degeneration. Clinical severity in this disorder is variable, depending on the presence of the SMN2 gene, which can partially compensate for the SMN protein deficiency. Currently approved treatments for SMA target increasing SMN protein production by SMN2 (nusinersen, risdiplam) or reintroduce the SMN1 gene (gene therapy with onasemnogene abeparvovec).
READ MORE...
SMA-001, a phase 2, randomized, double-blind, placebo-controlled crossover study, explored a new avenue of treatment for SMA. Patients with SMA Type 3 commonly report fatigue and display a significant response on nerve stimulation studies, signs that suggest impaired neuromuscular junction (NMJ) transmission has a role in the disorder. Amifampridine, a voltage-dependent potassium channel blocker approved for treatment of Lambert-Eaton myasthenic syndrome, prolongs depolarization of the presynaptic NMJ terminal, enhancing neuromuscular transmission and muscle function.
From January 2019 to September 2020, SMA-001 enrolled ambulatory patients with SMA Type 3 (able to walk unaided at least 30 meters) who had not received SMN-targeting therapies such as nusinersen. The study included 13 patients, 5 women and 8 men, mean age, 34.5 years. Patients first entered a run-in phase, in which amifampridine was individually titrated up to a maximal effective dose, but no higher than 80 mg/day. Then, those who achieved at least a 3-point improvement in the Hammersmith Functional Motor Score Expanded (HFMSE) were randomly assigned to amifampridine or placebo in a 28-day blinded crossover phase. Patients were assigned to amifampridine/placebo or placebo/amifampridine sequence, which they took for 2 weeks, then switched to the other, with no washout period. The dosage of amifampridine given in this crossover phase was that determined for each individual in the run-in phase. During weekly clinic visits, the HFSME was administered, as were a number of timed tests of motor skills and quality of life assessments.
Statistically significant improvement in HFMSE was observed in patients taking amifampridine compared to placebo (mean difference, 0.792). This effect is small, but the fact that the HFMSE score had already improved by at least 3 points before randomization might explain that. However, no significant differences were observed in results of timed tests. In quality-of-life measures, statistically significant improvement was observed in the fatigue subscale, as well as a significant reduction in the expected treatment subscale, but for all other subscale scores, differences were nonsignificant. No serious adverse events were reported, and treatment adherence was high throughout the study.
Results provided Class II evidence that amifampridine is safe and effective in treating ambulatory SMA Type 3 patients, demonstrating that fostering neuromuscular transmission can improve fatigability in these patients. The study findings were limited by the small sample size and the brevity of the study, since SMA Type 3 doesn’t typically progress rapidly. Larger, well-powered studies may better define the role of amifampridine as adjunctive treatment to SMN-enhancing treatments. (Bonanno, S., et al. (2022). Amifampridine safety and efficacy in spinal muscular atrophy ambulatory patients: A randomized, placebo-controlled, crossover phase 2 trial. J Neurol, 269, 5858–5867. Retrieved November 2022 from https://link.springer.com/article/10.1007/s00415-022-11231-7)
Released: November 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Etrolizumab for Crohn Disease
Results of BERGAMOT, a randomized, double-blind, phase 3 study published in The Lancet Gastroenterology and Hepatology, demonstrated that maintenance treatment with etrolizumab, an antibody against β7 integrin, produced significantly higher rates of clinical remission in patients with moderate to severe Crohn disease. The study, conducted at 326 treatment centers worldwide, compared the safety and efficacy of etrolizumab, in two dosage strengths, with placebo as both induction and maintenance therapy.
READ MORE...
The study, conducted from March 2015 through September 2021, enrolled patients ages 18 to 80 with moderate to severe active Crohn disease, as defined by a Crohn Disease Activity Index (CDAI) score between 220 and 480, mean daily stool frequency score greater than or equal to 6, or daily stool frequency score greater than or equal to 3 and mean daily abdominal pain score greater than or equal to 1, and presence of active inflammation on ileocolonoscopy. The patients also had intolerance to or inadequate or no response to treatment with corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years.
BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort; an active cohort without placebo control; and a placebo-controlled, double-blind pivotal cohort) and a maintenance cohort. This report discusses the findings of cohort 3, in which 385 patients were randomly assigned to placebo (n = 97), 105 mg etrolizumab subcutaneously every 4 weeks (n = 143), or 210 mg etrolizumab subcutaneously every 4 weeks (n = 145). At week 14 of induction therapy, patients from all three cohorts who had a response to etrolizumab as measured by CDAI-70 were rerandomized to receive 105 mg etrolizumab or placebo as maintenance every 4 weeks for 52 weeks. As a result, 434 patients took part in the maintenance phase, 217 in the placebo arm, and 217 in the etrolizumab arm.
The researchers determined the proportion of patients who entered clinical remission, defined as mean daily stool frequency less than or equal to 3 and mean daily abdominal pain less than or equal to 1, with no worsening, and the proportion who demonstrated endoscopic improvement, as shown by greater than or equal to 50% reduction in Simple Endoscopic Score for Crohn’s Disease (SES-CD). At week 14, 48 patients (33%) in the 210-mg induction group versus 28 patients (29%) in the placebo group were in clinical remission (adjusted treatment difference, 3.8%). Endoscopic improvement was seen in 40 patients (27%) in the 210-mg induction group vs. 21 patients (22%) in the placebo group (adjusted treatment difference, 5.8%). At week 66 of maintenance treatment, significantly higher proportions of patients receiving etrolizumab than those receiving placebo were in clinical remission: 76 patients (35%) in the etrolizumab maintenance group versus 52 patients (24%) on placebo (adjusted treatment difference, 11.3%). Significantly higher proportions of patients in the etrolizumab arm showed endoscopic improvement: 51 patients (24%) vs. 26 patients (12%) in the placebo arm (adjusted treatment difference, 11.5%).
These findings demonstrate a significantly higher incidence of clinical remission and endoscopic improvement in patients with moderate to severe Crohn disease during the maintenance phase of treatment with etrolizumab, but not during induction. (Sandborn, W., et al. (2022). Etrolizumab as induction and maintenance therapy in patients with moderately to severe active Crohn’s disease (BERGAMOT): A randomized, placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. Advance online publication. Retrieved November 2022 from https://www.thelancet.com/journals/langas/article/PIIS2468-1253(22)00303-X/fulltext)
Released: November 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Abnormal Menstrual Bleeding Associated with Anticoagulant for Acute VTE
Abnormal uterine bleeding (AUB) is common among women of reproductive age treated with anticoagulants for acute venous thromboembolism (VTE), with a considerable negative impact on quality of life (QOL). The TEAM-VTE study, an international multicenter prospective cohort study in patients of reproductive age (18 to 50) diagnosed with acute VTE, was conducted at 12 hospitals across 8 European countries between August 2018 and September 2021. The study, published in the journal Blood, aimed to quantify the burden of AUB and to identify unmet clinical needs in patients receiving anticoagulant therapy.
READ MORE...
From August 2018 to March 2021, 98 patients with confirmed symptomatic first or recurrent VTE and active menstrual cycles, with a mean age of 34, were enrolled shortly after diagnosis of VTE (before the first day of the next menstrual cycle after VTE diagnosis or within 1 month of diagnosis) and were followed until discontinuation of anticoagulant treatment or 6 months, whichever came first. If AUB was discovered, a diagnostic workup was performed to rule out other causes of the bleeding. The patients were followed using various measures:
· Menstrual blood loss for the last menstrual cycle before VTE and then for each cycle in the 3 to 6 months of follow-up was measured by pictorial blood loss assessment charts (PBAC), a validated self-reporting tool.
· AUB-related QOL was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire (MBQ); these were available for 74 women.
Patients were followed for recurrence of symptomatic VTE, any bleeding event other than AUB, and all-cause mortality, and were managed according to accepted guidelines and local preference. The researchers noted which anticoagulant was administered to treat the VTE in these patients; 78 were treated with oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), 13 with vitamin K antagonists (warfarin) or low-molecular-weight heparins, and 7 with the direct thrombin inhibitor dabigatran.
Overall, AUB as defined by one of three accepted measures (PBAC score greater than 100, PBAC score greater than 150, or self-report) occurred in 66% of patients at any time during the follow-up period; for 90% of them, this occurred within the first 2 months after VTE diagnosis. Among women without AUB before VTE based on retrospective PBAC scores (assessing blood loss during the last menstrual cycle before VTE diagnosis), new-onset AUB occurred in 60% (37% of the overall population of study) in those with retrospective PBAC less than or equal to 100, and in 63% (43% of the overall population) in those with retrospective PBAC less than or equal to 150.
The median PBAC score increased during the first menstrual cycle compared with the retrospective PBAC (median PBAC before VTE was 35 and for first menstrual cycle was 95). After the first menstrual cycle, the amount of blood loss decreased gradually, followed by median PBAC scores that remained stable in the 2nd through 6th cycles at about twice the retrospective PBAC score. The observational design of the study and the low number of patients exposed to the different anticoagulants prevent drawing any definitive conclusions about differences among the oral anticoagulants; however, patients treated with dabigatran showed no increase in blood loss during the first cycle, in contrast to patients treated with either oral direct factor Xa inhibitors, vitamin K antagonists, or low-molecular-weight heparin.
The overall QOL decreased significantly over time, with a mean increase in MBQ score of 5.1 points between baseline and cessation of anticoagulation or 6-month follow-up. On analysis, the decrease in QOL was observed only among those who had new-onset AUB, with mean difference in MBQ score of +9.2 points for those with new-onset AUB versus those without AUB and of +9.3 points for those with new-onset AUB versus those who had experienced AUB before VTE.
These findings support the proposed association of incident AUB with anticoagulation and highlight the critical need to include assessment of AUB in daily practice. It should increase awareness and should lead to development of evidence-based strategies to routinely and adequately prevent and treat incident AUB in this setting. (de Jong, C. M. M., et al. (2022). Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism. Blood, 140(16), 1764–1773. Retrieved November 2022 from https://ashpublications.org/blood/article/140/16/1764/486115/Incidence-and-impact-of-anticoagulation-associated)
Released: November 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer