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Background. Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis.
Methods. In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis.
Results. A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range.
Conclusions. In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).
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Background. Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton's tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis.
Methods. In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.
Results. A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P = 0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P = 0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).
Conclusions. Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.).
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Background. Narcolepsy type 1 is a disorder of hypersomnolence caused by a loss of orexin neurons, which results in low orexin levels in the brain.
Methods. In this phase 2, randomized, placebo-controlled trial, participants with narcolepsy type 1 received once- or twice-daily oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (MWT) (range, 0 to 40 minutes; normal, ≥20). Secondary end points included the change from baseline to week 8 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, ≤10), the weekly cataplexy rate at week 8, and the occurrence of adverse events.
Results. A total of 90 participants received oveporexton (0.5 mg twice daily, 23 participants; 2 mg twice daily, 21 participants; 2 mg followed by 5 mg daily, 23 participants; and 7 mg once daily, 23 participants), and 22 received placebo. The mean changes from baseline to week 8 in average sleep latency on the MWT were 12.5, 23.5, 25.4, 15.0, and -1.2 minutes, respectively (adjusted P≤0.001 for all comparisons vs. placebo). The mean changes in the ESS total score at week 8 were -8.9, -13.8, -12.8, -11.3, and -2.5, respectively (adjusted P≤0.004 for all comparisons vs. placebo). The weekly incidence of cataplexy at week 8 was 4.24, 3.14, 2.48, 5.89, and 8.76, respectively (adjusted P<0.05 for 2 mg twice daily and 2 mg followed by 5 mg daily vs. placebo). The most common adverse events associated with oveporexton were insomnia (in 48% of the participants; most cases resolved within 1 week), urinary urgency (in 33%), and urinary frequency (in 32%), without any hepatotoxic effects.
Conclusions. In this phase 2 trial involving participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks. (Funded by Takeda Development Center Americas; TAK-861-2001 ClinicalTrials.gov number, NCT05687903.).
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Background. Children living with human immunodeficiency virus (HIV) have limited options for second-line antiretroviral therapy (ART).
Methods. In this open-label trial with a 2-by-4 factorial design, we randomly assigned children with HIV who had first-line treatment failure to receive second-line therapy with tenofovir alafenamide fumarate (TAF)-emtricitabine or standard care (abacavir or zidovudine, plus lamivudine) as the backbone and dolutegravir or ritonavir-boosted darunavir, atazanavir, or lopinavir as the anchor drug. The primary outcome was a viral load of less than 400 copies per milliliter at 96 weeks. We hypothesized that TAF-emtricitabine would be noninferior to standard care, that dolutegravir and ritonavir-boosted darunavir would each be superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination, and that ritonavir-boosted atazanavir would be noninferior to ritonavir-boosted lopinavir. Safety was also assessed.
Results. A total of 919 children underwent randomization; 458 were assigned to receive TAF-emtricitabine, and 461 to receive standard care. Assigned anchor drugs were dolutegravir (229 participants), ritonavir-boosted darunavir (232), ritonavir-boosted atazanavir (231), and ritonavir-boosted lopinavir (227). The median age of participants was 10 years, and 497 (54.1%) were male. The median viral load at baseline was 17,573 copies per milliliter. At week 96, TAF-emtricitabine was superior to standard care: the adjusted difference in the percentage of participants with a viral load of less than 400 copies per milliliter was 6.3 percentage points (95% confidence interval [CI], 2.0 to 10.6; P = 0.004). Dolutegravir was superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination (adjusted difference, 9.7 percentage points; 95% CI, 4.8 to 14.5; P<0.001), but ritonavir-boosted darunavir was not (adjusted difference, 5.6 percentage points; 95% CI, 0.3 to 11.0; P = 0.04 [prespecified threshold, P = 0.03]). Ritonavir-boosted atazanavir was noninferior to ritonavir-boosted lopinavir. One child died, and 29 (3.2%) had serious adverse events, with no significant between-group differences.
Conclusions. Second-line ART regimens including TAF-emtricitabine and dolutegravir were effective for children, with no evidence of safety concerns. Ritonavir-boosted darunavir was also effective. (Funded by the European and Developing Countries Clinical Trials Partnership and others; CHAPAS-4 ISRCTN Registry number, ISRCTN22964075.).
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Xenotransplantation offers a potential solution to the organ shortage crisis. A 62-year-old hemodialysis-dependent man with long-standing diabetes, advanced vasculopathy, and marked dialysis-access challenges received a gene-edited porcine kidney with 69 genomic edits, including deletion of three glycan antigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The xenograft functioned immediately. The patient's creatinine levels decreased promptly and progressively, and dialysis was no longer needed. After a T-cell-mediated rejection episode on day 8, intensified immunosuppression reversed rejection. Despite sustained kidney function, the patient died from unexpected, sudden cardiac causes on day 52; autopsy revealed severe coronary artery disease and ventricular scarring without evident xenograft rejection. (Funded by Massachusetts General Hospital and eGenesis.).
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