Novartis (United Kingdom)

Intrathecal onasemnogene abeparvovec (OAV101 IT) may enable a one-time gene transfer therapy, addressing an unmet need across the broader spinal muscular atrophy (SMA) population. STRENGTH ( NCT05386680 ) was a 52-week, phase 3b, single-arm, open-label, multicenter study evaluating OAV101 IT in participants with SMA aged 2 to <18 years who discontinued nusinersen or risdiplam. The primary objective was safety/tolerability. Twenty-seven participants were enrolled (mean (s.d.) age at OAV101 IT, 7.4 (3.35) years; range, 2.4-17.7 years) with prior nusinersen or risdiplam (mean (s.d.) duration of 4.3 (1.07) years; range, 1.86-6.18 years or 3.0 (2.02); range, 0.39-6.28 years). All (n = 27) experienced at least one adverse event (AE), most frequently nasopharyngitis (n = 15, 55.6%), pyrexia (n = 14, 51.9%) and vomiting (n = 13, 48.1%). Thirteen participants (48.1%) experienced treatment-related AEs, most frequently vomiting (n = 6, 22.2%), headache (n = 4, 14.8%) and pyrexia (n = 3, 11.1%). Serious adverse events (SAEs) were reported for four participants (n = 4, 14.8%) (mostly respiratory infection related). No AEs leading to death or study discontinuation were reported. Adverse events of special interest (AESI) reported were in categories of transient thrombocytopenia (n = 8, 29.6%), hepatotoxicity (n = 4, 14.8%) and signs and symptoms that may be suggestive of dorsal root ganglia toxicity (n = 2, 7.4%). The OAV101 IT safety profile was consistent with findings in treatment-naïve patients. Trial registration: ClinicalTrials.gov identifier: NCT05386680 .

6501 Background: ASC, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket, recently received FDA Accelerated Approval for newly diagnosed CML-CP based on major molecular response (MMR) rates in the ASC4FIRST trial (NCT04971226). We present results from ASC4START (NCT05456191), with the primary objective of assessing the tolerability of ASC vs second-generation tyrosine kinase inhibitor NIL in patients (pts) with newly diagnosed CML-CP. Methods: Adults were randomized 1:1 to receive ASC 80 mg once daily or NIL 300 mg twice daily, stratified by ELTS risk category. The primary endpoint is TTDAE. Events included AEs leading to treatment (tx) discontinuation and deaths due to AEs. Secondary endpoints include molecular response and safety. Results: Pts were recruited by 120 participating sites across 24 countries and randomized to ASC (n=284) or NIL (n=284). Two pts who did not receive NIL were excluded from safety analyses. Median follow-up was 9.7 mo. At cutoff (Sep 3, 2024), 10.9% and 17.3% of pts discontinued ASC and NIL, respectively, most commonly due AEs (4.9% vs 11.6%) and unsatisfactory therapeutic effect (2.5% vs 2.8%). The study met its primary endpoint, showing statistically significant difference in TTDAE in favor of ASC with a cause-specific hazard ratio of 0.45 (95% CI, 0.25-0.81; P =.004). Fewer pts discontinued due to AEs with ASC (16/284 [5.6%]) vs NIL (34/282 [12.1%]). There were 3 deaths on study due to AEs (ASC: cardiac arrest and suicide, n=1 each; NIL: cardiac arrest, n=1). Median duration of exposure was 39.1 wk with ASC vs 38.0 wk with NIL. Mean relative dose intensity was 94.8% vs 92.6%, respectively. Any-grade AEs occurred in 80.3% of pts with ASC vs 86.5% with NIL. Grade ≥3 AEs occurred in 25.0% and 31.9% of pts, respectively. AEs leading to dose adjustment/interruption occurred in 24.3% of pts with ASC vs 30.1% with NIL. Most frequent any-grade AEs (≥10%) with ASC vs NIL were thrombocytopenia (15.1% vs 13.8%), headache (10.2% vs 13.1%), myalgia (10.2% vs 8.2%), rash (8.5% vs 16.3%) and increased alanine aminotransferase (3.2% vs 12.4%). AEs of special interest included arterial occlusive events (0.7% vs 2.1%), acute pancreatitis (clinical events; 0.4% vs 2.5%), and hepatotoxicity (including laboratory terms; 8.1% vs 24.8%). BCR::ABL1 IS ≤10% (89.8% vs 82.0%), BCR::ABL1 IS ≤1% (69.0% vs 52.5%), MMR (22.9% vs 10.2%), MR 4 (4.6% vs 1.1%), and MR 4.5 (2.5% vs 0.4%) rates by wk 12 were higher with ASC vs NIL. Conclusions: The study met the primary endpoint with ASC showing significantly superior tolerability vs NIL based on TTDAE. The study is ongoing with additional analyses planned for tolerability and efficacy. The findings further support the potential for ASC to be a preferred therapy for newly diagnosed CML-CP, allowing more pts to meet tx goals without requiring tx switch. Clinical trial information: NCT05456191 .

On May 23–25, 2024, a multidisciplinary expert group met in Bergen, Norway, the site of the first description of Mycobacterium leprae (M. leprae) in 1873, to discuss advancements and remaining knowledge gaps in the transmission of M. leprae at the Global Partnership for Zero Leprosy Zero Transmission Symposium. Research and operational approaches to interruption of transmission were identified; the research approaches from the symposium are described here. Updates since a previous symposium at the National School of Tropical Medicine, Baylor College of Medicine in Houston (USA), in 2014 from these fields of research are presented here: epidemiology; microbiological diagnosis; immunodiagnostics; genotyping; geospatial mapping; leprosy elimination monitoring and transmission under low-endemic circumstances; leprosy post-exposure prophylaxis (PEP); modelling relevant to interruption of transmission of M. leprae; OneHealth; environmental transmission of M. leprae; social determinants; control programmes relevant to interruption of transmission of M. leprae; and organizations of persons affected. Progress and outstanding gaps since 2014 are identified, and recommendations for relevant research in these areas to achieve interruption of transmission are presented. These include research into human reservoirs, including platforms for field-friendly diagnostics; routes of entry/exit of M. leprae; the roles of animals or vectors in transmission; the role of social determinants in transmission; host-pathogen interactions; transmission networks; and enhanced epidemiological data. Fulfilment of these research recommendations and further understanding of which settings require intensified control efforts, will help to advance the aim of achieving complete interruption of transmission of M. leprae and the elimination of leprosy disease.

Visceral leishmaniasis (VL) is a vector-borne disease caused by Leishmania parasites and transmitted by sand fly bites, targeted for elimination in India. VL primarily affects rural, low-income populations with limited health care access. In South Asia, few studies have explored patients' perspectives, diagnoses, and treatment experiences; particularly lacking an understanding about the patients' life experiences outside of clinical research settings. A qualitative study was conducted in Bihar, India, using moderator-facilitated, protocol-defined discussion. Eighteen adult patients and 12 caregivers of children diagnosed with and treated for VL within the last 12 months were identified by self-report. Mean time from symptom onset to diagnosis was 13.8 days. Challenges of the early patient life experience included lack of urgency by health care professionals, delayed diagnosis, and no guarantee of treatment at the location of their VL diagnosis (63% had to switch to a different center for treatment, at times delaying treatment). Key barriers identified in previous studies that were re-confirmed in this study include out-of-pocket financial burden, absence from work/home duties, and long-distance travel to hospitals. Patients and caregivers (n = 29/30) expressed a preference for a potential oral treatment that could be taken close to home. This study reveals new insights about the patient life experience and reconfirms previous research indicating that access to care for patients with VL in the Bihar area remains a challenge. Although most patients with VL seek care early, diagnosis often requires multiple visits to a health care facility. Despite access to therapy in public hospitals, some patients reported a preference for private care. Even if diagnosis takes place in a government-funded public setting, some patients reported needing to move from the location of diagnosis to another center to receive therapy, creating an additional burden for patients. As a potential alternative to current parenteral treatment, adult patients and caregivers of pediatric patients expressed interest in a potential oral therapy because it may reduce barriers to access care.