SUMMARYObjective: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. Methods: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. Results: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (C max ), with all doses demonstrating rapid median time to C max (T max ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. Significance: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.
Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) – the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration – for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.
Background Recurrence of Clostridioides difficile infection (rCDI) is common, prolonging disease morbidity and leading to poor quality of life. We evaluated disease-specific health-related quality of life (HRQL) in patients with rCDI treated with fecal microbiota, live-jslm (RBL) versus placebo. Methods This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific Clostridioides difficile Quality of Life Survey (Cdiff32) was administered at baseline and weeks 1, 4, and 8. Changes in Cdiff32 total and domain (physical, mental, social) scores from baseline to week 8 were compared between RBL and placebo and for responders and non-responders. Results A total of 185 patients (RBL n = 128 [69.2%], placebo n = 57 [30.8%]) with available Cdiff32 data were analyzed. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all p < 0.001); RBL-treated patients showed significantly greater improvements in mental domain compared to placebo. In adjusted analyses, RBL-treated patients were associated with greater improvements than placebo in total score and physical and mental domains (all p < 0.05). Similar improvement in mental domain was observed among responders, while non-responders showed numerical improvements with RBL but not placebo. Conclusions In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements compared with placebo-treated patients. Trial registration ClinicalTrials.gov NCT03244644; https://clinicaltrials.gov/ct2/show/NCT03244644.
Background Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable clinical efficacy data are needed to support regulatory approvals that broaden patient access. Here we provide cumulative data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI recurrence. Methods This analysis included three phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). All participants were ≥18 years old with documented rCDI who completed standard-of-care (SOC) oral antibiotic therapy prior to treatment with RBX2660. Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 or placebo, with Treatment Success (TS) defined as remaining recurrence-free for 8 weeks after treatment. Treatment responders were monitored for additional recurrence through at least 6 months after receiving the last RBX2660 dose. Treatment non-responders were administered SOC antibiotic treatment and/or additional RBX2660 treatment and monitored for recurrence for 8 weeks after the last received RBX2660 treatment. Results Among the 5 trials with a total of 629 participants, RBX2660 consistently reduced the recurrence of rCDI, with TS rates ranging from 50 to 78.9% (Figure 1). Among primary non-responders, additional RBX2660 treatments further reduced recurrence and overall rates of TS ranged from 75.0% to 84.4% (Figure 2). Among CD, CD3, and CD3-OLS, a majority of primary responders remained CDI-free to 6 and up to 24 months with success rates ranging from 74.4% to 92.1%. Conclusion Among 5 trials with consistent investigational product and clinical endpoints, RBX2660 consistently reduced rCDI recurrence, with a majority of treatment responders remaining CDI-free for at least 6 and up to 24 months. Further, initial lack of response to RBX2660 did not preclude clinical benefit of additional RBX2660 treatment. Collectively, these data demonstrate consistency and reliability of the potential benefit of RBX2660 across an entire clinical program. Disclosures Lindy Bancke, PharmD, Rebiotix, a Ferring Company (Employee) Xin Su, MD, Rebiotix/Ferring (Employee)
BackgroundRecurrent Clostridioides difficile infection (rCDI) is an urgent public health threat associated with significant mortality and medical cost. Microbiota therapy is gaining acceptance as a strategy to reduce rCDI recurrence. We present the final 24-month analysis of clinical safety, efficacy, and microbiome restoration from a Phase 2 open-label trial of RBX2660 for prevention of CDI recurrence.MethodsParticipants with multi-recurrent CDI received <2 doses of RBX2660 delivered via enema 7 days apart in this multicenter, open-label Phase 2 study. Efficacy was defined as the absence of CDI recurrence through 56 days after the last dose and was compared with 8-week recurrence-free rates for a historical control cohort that received standard-of-care antibiotic therapy. Fisher exact test compared the proportion of treatment participants who were CDI-free by age and sex. Durability was defined as continued absence of CDI episodes beyond 8 weeks. Safety and durability assessments occurred at 3, 6, 12, and 24 months. Participant stool samples were collected prior to and for up to 720 days after treatment, and microbiome changes were assessed by shallow shotgun sequencing.ResultsThe efficacy of RBX2660 to prevent rCDI at 8 weeks (78.9%; 112/142) was higher than the CDI-free rate in the historical control group (30.7%, 23/75; P < 0.0001). Age and sex did not impact efficacy. Among participants who achieved treatment success at 8 weeks and were evaluable for long-term durability (n = 95), 8 experienced a new CDI episode by the 24-month follow-up for an overall durability of 91.6%. The safety profile was consistent with previous reports for RBX2660. In total, 503 stool samples from 110 treatment responders were analyzed. Within 7 days of treatment, the relative abundance of Bacteroidia and Clostridia remained shifted higher than pre-treatment levels while Gammaproteobacteria and Bacilli declined sharply after treatment, and these changes persisted to at least 24 months.ConclusionRBX2660, a microbiota-based drug, was safe and efficacious for preventing rCDI with clinical durability to 24 months after treatment, independent of age or sex, and RBX2660 durability associated with durable microbiome shifts from pre-treatment to a healthier composition. DisclosuresRobert Orenstein, DO, Rebiotix Inc. (Advisor or Review Panel member), Sarah Mische, PhD, Rebiotix Inc. (Employee), Ken Blount, PhD, Rebiotix Inc. (Employee), Lindy Bancke, PharmD, Rebiotix Inc. (Employee), Xin Su, MD, MSci, Rebiotix Inc. (Employee), Dana Walsh, PhD, Rebiotix Inc. (Employee), Adam Harvey, PhD, Rebiotix Inc. (Employee), Carlos Gonzalez, MS, Rebiotix Inc. (Consultant), Dale N. Gerding, MD, Rebiotix Inc. (Board Member).
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