Background NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b–3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. Methods We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase–polymerase-chain-reaction–confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. Results Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted — 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest — largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. Conclusions NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802 .)

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.

IMPORTANCE Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. OBJECTIVE To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). INTERVENTIONS Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. MAIN OUTCOMES AND MEASURES Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. RESULTS Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose-and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F 78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. CONCLUSIONS AND RELEVANCE Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).

The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB–001), a humanized monoclonal antibody to amyloid β, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid β was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p< or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.