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Background ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer’s disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. Methods Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [ 1 ] a single ascending dose (SAD) study; [ 2 ] a 14-day multiple ascending dose (MAD) study; and [ 3 ] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. Results ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration ( C max ) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. Conclusions ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Abstract Context Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Objective Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers. Methods This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomly assigned 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary end point was safety and tolerability. Key secondary end points were PK and PD. Results Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomly assigned (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50% to 88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79 to 95 hours for MBX 2109 and 184 to 213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases. Conclusion The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial. The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated. The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA). The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD. https://clinicaltrials.gov/study/NCT04693520 .

Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. Methods: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po ) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po ) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po ). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C max , AUC 0–72 h and AUC 0–∞ were calculated. Tolerance assessments were conducted throughout the study. Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t max of huperzine A was 0.76–0.82 h; the AUC 0–72 h and C max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. Conclusion: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.

Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects. A block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events. Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the Tmax of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration–time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUClast value (29,441–78,062 μg · h/L) and in the Cmax value (2679–6980 μg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%–97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment. Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043.

Abstract Objectives Hydromorphone (HM) is a potent μ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. Design Single-center, randomized, double-blind, crossover study. Setting Clinical research site. Subjects Healthy adult, nondependent recreational opioid users. Methods Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. Results Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on “at-the-moment” (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. Conclusions The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

Background and ObjectiveSacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects.MethodsIn this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study.ResultsFollowing oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (Tmax) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUC0–last), and maximum plasma concentration (Cmax) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects.ConclusionThe pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

This randomized trial involved 160 patients with the acquired immunodeficiency syndrome (AIDS) and newly diagnosed cytomegalovirus retinitis. After four weeks, the response to induction therapy was satisfactory in 72 percent of patients who received oral valganciclovir, as compared with 77 percent of those who received intravenous ganciclovir. The median time to progression of retinitis was 160 days for the valganciclovir group and 125 days for the ganciclovir group. Cytomegalovirus retinitis remains the leading cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). 1 – 3 Induction therapy with intravenous ganciclovir, 4 , 5 foscarnet, 5 , 6 or cidofovir, 7 , 8 followed by maintenance therapy, can effectively make cytomegalovirus retinitis inactive. If recovery of immune function is not possible, indefinite treatment is needed, and an indwelling catheter and daily intravenous medication may be required. The cost, the risk of sepsis, and the adverse effect on the quality of life associated with an indwelling catheter spurred the development of an oral formulation of ganciclovir. 9 When administered orally, ganciclovir requires three doses (up to . . .