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Ionis Pharmaceuticals, Inc. Familial chylomicronemia syndrome (FCS) is a rare genetic disorder that markedly increases plasma triglycerides (TG), causing pancreatitis, abdominal pain, and other symptoms that profoundly impact patients' quality of life. In a randomized, placebo-controlled phase 3 study (Balance; NCT04568434), olezarsen significantly reduced TGs among adults with FCS. To further explore the FCS patient experience during olezarsen treatment, including perceptions of meaningful changes in FCS symptoms and impacts. Patients with FCS (US, Canada, Spain, Italy) continuing olezarsen treatment in an open-label extension (OLE) of the Balance study participated in 1-hour semistructured qualitative interviews via telephone. Thematic analysis was conducted. Eighteen of 60 OLE participants completed interviews (10 female; 55.6%); mean age at interview was 43.5 (range, 23-73) years. (See Table 1 for participant characteristics.) When interviewed, participants randomized to active drug in Balance had received olezarsen for 67-113 weeks, whereas participants randomized to placebo had received olezarsen for 16-47 weeks. Seventeen of 18 participants reported a history of pancreatitis, including 14 with pancreatitis events in the 10 years prior to enrollment in the Balance study (13/14 requiring hospitalization). Moreover, all participants reported experiencing at least 1 FCS-related symptom prior to enrollment, such as abdominal pain (n=17; 94.4%), physical fatigue (n=12; 66.7%), diarrhea (n=10; 55.6%), vomiting (n=9; 50.0%), nausea (n=6, 33.3%), and difficulty thinking (n=5, 27.8%). Fifteen participants reported being symptomatic in the absence of pancreatitis, most commonly experiencing abdominal pain (n=12). All participants reported FCS-related impacts, including dietary restrictions (n=18; 100%), mood/emotions (n=17; 94.4%), hospitalizations (n=14; 77.8%), and social activities (n=14; 77.8). Participant feedback on treatment-related improvements was based on their experiences and belief of starting olezarsen, either within Balance or OLE. Fifteen of 18 participants (83.3%) reported improvements, including reductions in FCS-related symptoms (abdominal pain [n=14/17; 82.4%], physical fatigue [n=7/12; 58.3%], diarrhea [n=6/10; 60.0%], vomiting [n=7/8; 87.5%], nausea [n=3/5; 60.0%], difficulty thinking [n=3/5; 60.0%]) and impacts (relationships [n=6/7; 85.7.0%], hospital admittances [n=11/14; 78.6%], finances [n=3/4; 75.0%], mood/emotions [n=12/17; 70.6%]). All 14 participants with pancreatitis events in the past 10 years reported pancreatitis-related improvements, including 11 (78.6%) with no pancreatitis events and 3 (21.4%) with less frequent and/or less severe events since they believed they started olezarsen treatment. Overall, most participants (15/18; 83.3%) reported meaningful improvements and indicated they were satisfied with olezarsen treatment. Results of this qualitative study both underscore the significant burden of FCS and support the efficacy of olezarsen from the patient perspective. [ABSTRACT FROM AUTHOR]

• To date, understanding of how patients with progressive forms of multiple sclerosis (MS) experience fatigue and how it impacts their daily lives has been limited. • Fatigue among individuals with progressive MS is severe, frequent, and one of the most bothersome MS symptoms. • Fatigue has an impact on social, emotional, and cognitive functioning and on activities of daily living. Patient-focused literature on fatigue in progressive forms of multiple sclerosis (MS) is sparse. This study aimed to explore progressive MS patients' experiences of fatigue. Adult patients in the United States with primary progressive MS (n=21) and secondary progressive MS (n=23), recruited from research panels, completed the following PRO measures: Patient Global Impression of Severity (Fatigue) (PGI-F); Fatigue Scale of Motor and Cognitive Functions (FSMC); Modified Fatigue Impact Scale (MFIS); Patient Health Questionnaire, two-item version (PHQ-2); and Patient Determined Disease Steps (PDDS). Patients subsequently participated in a 45-minute semistructured telephone interview and were asked to describe their MS symptoms and to comment on how MS affected their day-to-day lives. More detailed questions followed on the nature of their fatigue, including symptoms, impacts, frequency, and bothersomeness. Patients' mean age was 52.5 years, mean time since diagnosis was 14.7 years, and 81.8% were female. 79.5% of patients were unemployed and/or receiving disability benefits. Of all spontaneously reported MS symptoms, fatigue was the most common (n=38, 86.4%), followed by ambulation problems (n=31, 70.5%) and muscle weakness (n=25, 56.8%). Patients used the words "tired," "exhausted," "wiped out," and having "little or no energy" to describe their fatigue. More patients rated fatigue as their "most troubling symptom" (n=17, 38.6%) compared with other MS-related symptoms. Half of patients reported feeling constantly fatigued, and more than 90% reported experiencing fatigue at least daily. The top three most frequently reported negative impacts of fatigue were social functioning, emotional well-being, and cognitive functioning (all >80%). Patients described themselves as "homebodies," as fatigue limited their social interactions with friends and family and impacted the types of activities they could participate in. Patients attributed their inability to think clearly or focus for long periods of time to their fatigue. Patients also reported experiencing depression and anxiety because of their fatigue, which would often have further negative effects on their relationships with friends and family. On the fatigue PRO measures, mean (standard deviation) scores were 75.2 (14.7) on the FSMC and 55.0 (15.2) on the MFIS. Most participants scored in the "high" fatigue category on the FSMC (84.1%) and above the clinically significant fatigue threshold (86.4%). MFIS and FSMC total scores correlated with PGI-F (polyserial correlations r=0.74 and r=0.62, both p<0.01) and PHQ-2 (r=0.56 and r=0.57, both p<0.01), but not with PDDS (r=0.09 and r=0.02, both p>0.05). Fatigue is a common, troublesome, and disabling symptom which has a profound impact on patients' daily lives, as evidenced by qualitative analyses and high scores on established fatigue measures observed in this sample. These findings provide insights into the burden of fatigue and can inform its measurement in both clinical and research settings. Treatments that improve the symptoms of fatigue or prevent exacerbations are needed for patients with progressive MS. [ABSTRACT FROM AUTHOR]