Rosenstock J, Lingvay I, Ryan D
… +16 more, Jastreboff AM, Kushner R, Acosta A, Blevins TC, Choi M, Holmes FL, Smith T, Connery L, Li Y, Liu MK, Barth A, Butcher J, Civitarese A, Yue H, Coll B, ACCESS Trial Investigators
Aleniglipron is an oral, small-molecule glucagon-like peptide-1 receptor agonist (GLP1-RA) in development for obesity treatment. The ACCESS phase 2b placebo-controlled, double-blind study randomized 230 adults (mean BMI...Aleniglipron is an oral, small-molecule glucagon-like peptide-1 receptor agonist (GLP1-RA) in development for obesity treatment. The ACCESS phase 2b placebo-controlled, double-blind study randomized 230 adults (mean BMI 39.5 kg m, 54% female) with obesity or overweight to examine the effects of once-daily aleniglipron escalated every 4 weeks to 45, 90 or 120 mg. At week 36, the trial met its primary endpoint with a placebo-adjusted LS mean (95% confidence interval) body-weight change from baseline of -8.2% (-11.1 to -5.3%), -9.8% (-12.5 to -7.2%) and -11.3% (-13.9 to -8.6%) for the aleniglipron 45-, 90- and 120-mg arms, respectively (P < 0.0001, all doses versus placebo), with no apparent weight-loss plateau at the end of the double-blind period. Continued weight loss was observed at the interim analysis (median treatment duration of 20 weeks) of the ongoing open-label extension. Gastrointestinal events were generally mild to moderate and decreased in frequency over time, with little to no recurrence of vomiting after reintroduction following permitted dose interruptions. Treatment-related discontinuations were 10.4% across aleniglipron arms, with no events of drug-induced liver injury. Clinically relevant weight reductions of up to 11.3% with a tolerability profile consistent with the GLP-1RA class support further development of aleniglipron for obesity treatment. ClinicalTrials.gov registration: NCT06693843 .
Lu A, Chen WT, Dalby M
… +23 more, Sainz Garcia D, Vanheusden M, de Vries LE, van Lieshout V, Martirosyan A, Craessaerts K, Moonen S, Zielonka M, Chrysidou I, Misbaer A, Wolfs L, Pavie B, Swaab D, Thal DR, Huitinga I, Rozemuller A, Rohde SK, Hulsman M, Holstege H, Balice-Gordon R, Plath N, Fiers M, De Strooper B
Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics an...Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.
Chronic arm and hand hemiparesis is a major cause of disability after stroke. Unfortunately, standard-of-care rehabilitation falls well short of the high doses required to experience improvements. In this feasibility stu...Chronic arm and hand hemiparesis is a major cause of disability after stroke. Unfortunately, standard-of-care rehabilitation falls well short of the high doses required to experience improvements. In this feasibility study, we explored the use of cervical epidural spinal cord stimulation (SCS) to assist motor function and provide meaningful functional improvements without the need of a high-dose rehabilitation program. Here we report the final outcomes of this study testing safety, feasibility and preliminary efficacy of cervical SCS as a neuroprosthetic approach for chronic post-stroke upper limb hemiparesis. We implanted seven participants with profound motor deficits (Fugl-Meyer Assessment (FMA) scores 15-35) using two leads implanted unilaterally in the cervical spinal cord for 4 weeks. No serious adverse events occurred. Under SCS ON, motor function immediately improved regardless of impairment severity (average +32% strength and +5.6 FMA points). Notably, three of seven participants with residual corticospinal connectivity to finger muscles improved hand/finger movement with SCS. Despite performing only 8.6 hours of motor activity (5.5 hours with SCS ON), participants improved by an average of +6.6 FMA points at the end of the study compared to baseline, and spasticity decreased in all participants. Although all benefited, our preliminary analysis indicates that spared sensory function may be a determinant of responsiveness to SCS. These findings provide preliminary evidence of the safety, feasibility and efficacy of cervical SCS for chronic post-stroke hemiparesis, suggesting its potential as a fully implantable neuroprosthetic solution for assisting upper limb function in daily living. ClinicalTrials.gov identifier: NCT04512690 .
Williams AJ, Rhodes CA, Cleare S
… +11 more, Borschmann R, Gross JJ, Petrova K, Posada L, Tench CR, Chapman-Nisar A, Martin L, Hollis C, Townsend E, Slovak P, Digital Youth research team
LGBTQ+ youth commonly have unmet mental health needs and are at elevated risk for self-harm, yet many face persistent institutional barriers to accessing support. One impactful way to reduce risk and promote wellbeing is...LGBTQ+ youth commonly have unmet mental health needs and are at elevated risk for self-harm, yet many face persistent institutional barriers to accessing support. One impactful way to reduce risk and promote wellbeing is by supporting emotion regulation; that is, the process by which individuals can influence which emotions they feel, when they feel them and how they experience or express these emotions. This universal, modifiable process is widely considered a key transdiagnostic target for mental ill-health prevention and intervention efforts. We conducted a randomized controlled trial using Purrble, a socially assistive robot designed to provide in-the-moment emotion regulation support through intuitive tactile interaction. Between 12 January and 1 September 2024, 153 LGBTQ+ youth with self-harm ideation were randomized 1:1 to receive Purrble and safety planning (Purrble + SP) or safety planning alone (SP-Only), stratified by gender identity (50.3% transgender/gender diverse). Data were collected over 13 weeks, with data collection closing on 22 October 2024. The primary outcome was perceived emotion regulation difficulties at follow-up, adjusted for baseline, gender identity and age. Participants allocated to the Purrble intervention reported fewer emotion regulation difficulties at follow-up than those allocated to safety planning alone (adjusted mean difference: -3.04; 95% confidence interval (CI): -4.92 to -1.16; P = 0.002; partial η = 0.07). For secondary outcomes, participants in the Purrble intervention also reported significantly lower symptoms of anxiety and depression, but no significant main effect was observed for self-harm. No serious Purrble-related adverse events were observed. Purrble may offer a scalable intervention to complement existing therapeutic approaches to support LGBTQ+ youth to enhance their emotion regulation. ClinicalTrials.gov: NCT06025942 .
Zheng T, Gao G, Xu C
… +19 more, Li R, Shao J, Wang X, Han X, Li J, Liu P, Xiong Y, Song L, Wang J, Wen S, Zhuo X, Wang G, Jiang L, Qu G, Chen T, She J, Luo Y, Yuan Z, Wu Y
Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal disease characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels and accelerated atherosclerotic cardiovascular disease. Mo...Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal disease characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels and accelerated atherosclerotic cardiovascular disease. More than 80% of patients with HoFH carry low-density lipoprotein receptor (LDLR) mutations. Here we developed an adeno-associated virus gene therapy designed to express LDLR in the liver and evaluated its safety and efficacy in lowering LDL-C levels in experimental animals and in patients with HoFH. NGGT006, a recombinant adeno-associated virus serotype 8-based vector containing a codon-optimized LDLR complementary DNA, lowered LDL-C levels in Ldlr mice and Ldlr hamsters and decreased aortic plaque size in Ldlr mice. In rhesus monkeys, NGGT006 administration led to transient liver enzyme elevations but no severe adverse events. In an open-label, single-arm, dose-escalation trial, three patients with HoFH received doses of NGGT006 of 7.5 × 10, 1.5 × 10 and 3 × 10vg kg. Primary endpoints included safety and LDL-C reduction over a follow-up of 52 weeks. NGGT006 treatment was well tolerated, with no vector-related severe adverse events. All three patients showed elevations of liver enzymes that were resolved after sirolimus and methylprednisolone therapy. The patient who received the highest dose exhibited a sustained reduction in LDL-C from 11 mmol l to <1.8 mmol l starting at 3 weeks after treatment. These results offer initial insights into the safety and therapeutic potential of NGGT006 and warrant future studies of its safety and efficacy. ClinicalTrials.gov: NCT06125847 .
Hussain-Alkhateeb L, He Y, Amatya PB
… +16 more, Diatta SA, Dixit S, Gningue M, Ikilezi G, Lal BK, Masiye F, Moller AB, Moreira I, Musokwa GTKM, Penn-Kekana L, Sarr M, Shrestha N, Thomas JT, Vwalika B, Yarmol-Matusiak EA, Phillips DE
The world has made progress in increasing the number of births attended by skilled health personnel (SHP), but maternal and neonatal mortality have not declined proportionately. This may indicate that quality of care has...The world has made progress in increasing the number of births attended by skilled health personnel (SHP), but maternal and neonatal mortality have not declined proportionately. This may indicate that quality of care has not risen at the same rate as SHP coverage. Several 'Exemplar' countries have been previously recognized for outstanding progress in improving maternal and newborn health, and offer a unique opportunity to understand coverage and quality of care provided by SHP. Here we describe quality of care and how it compares with SHP coverage in three Exemplar countries-Nepal, Senegal and Zambia. We developed a conceptual framework, compiled primary and secondary data, and employed latent variable analysis. We combined quality estimates with coverage estimates to quantify the effective coverage of SHP. Results show that effective SHP coverage ranges between 12% and 43% across subnational regions, compared with crude SHP coverage ranging from 30% to 100%, indicating that mothers and newborns are receiving less lifesaving care than coverage statistics portray. The detection of this quality gap in Exemplar settings, which represent some of the highest-performing health systems among low- and middle-income countries, emphasizes the criticality of quality care to reduce maternal and neonatal mortality worldwide.
Bethlehem L, Bartu L, Marke G
… +13 more, Mar P, Feldman S, Eggers J, Ruprecht C, Britton GJ, Aggarwala V, Bongers G, Li Z, Yang N, Hohmann EL, Mogno I, Faith JJ, Grinspan A
Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LB...Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LBPs) enable both scalability and defined strain composition but with higher manufacturing complexity, resulting in few LBP clinical trials. Here we show how an accessible platform to produce human-grade LBPs could accelerate LBP development. We provide regulatory documentation and manufacturing protocols to facilitate translating microbiome advances to human trials. With this platform, we conducted the first direct comparison of the same bacterial strains from donor-sourced FMT compared to an in vitro manufactured 15-strain LBP drug product, MTC01, for the treatment of rCDI. In a phase 1b randomized controlled trial, 18 of 20 screened patients met eligibility and were randomized equally to one of four arms: low-dose FMT (n = 4), high-dose FMT (n = 5), low-dose MTC01 (n = 4) or high-dose MTC01 (n = 5), with a 5:1 female:male ratio. The primary outcome of safety was met with 10 adverse events across eight patients, evenly spread across MTC01 (five events) and FMT (five events) recipients and no treatment-related adverse events across all four groups. For secondary outcomes of efficacy and engraftment, rCDI was prevented 8 weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients. Strain engraftment was high and durable for both FMT and MTC01 with a dose effect for the LBP. ClinicalTrials.gov: NCT05911997 .
Hager K, Alcusky M, Zhang FF
… +14 more, Sing G, Ash A, Mick E, Terranova J, DiBacco E, Buckler S, Rich A, Bowman J, Folta S, Prendergast K, Frank J, Ball C, Chiang JS, Mozaffarian D
Smaller quasi-experimental studies and short-term controlled trials of medically tailored meals (MTMs) have shown health benefits for several conditions, but MTMs have not been evaluated in large-scale policy initiatives...Smaller quasi-experimental studies and short-term controlled trials of medically tailored meals (MTMs) have shown health benefits for several conditions, but MTMs have not been evaluated in large-scale policy initiatives. Multiple US states are now implementing MTMs in Medicaid, the health insurance program for low-income individuals, yet their impact has not been evaluated. We investigated changes in hospitalizations, emergency department (ED) visits and healthcare costs among 1,866 MTM recipients and 1,372 comparators from 2020 to 2023 across 11 health systems in Massachusetts. Both groups met eligibility criteria for diet-related conditions and food insecurity. We used propensity overlap-weighted generalized estimating equations to compare a 6-month baseline period to the program period. MTM receipt (mean, 6.7 months) was associated with 31% fewer hospitalizations (adjusted incidence rate ratio (aIRR) = 0.69 (95% confidence interval (CI): 0.58-0.82)), 20% fewer ED visits (aIRR = 0.80 (95% CI: 0.72-0.89)) and US$3,433 lower total healthcare costs (95% CI: $-1,215 to -$5,651). Healthcare cost reductions offset 98% of the MTM program costs during the enrollment period. Findings were robust across sensitivity analyses, a negative control test and a secondary comparison group. In stratified analyses, MTM receipt was net cost-saving among participants with cardiovascular disease, chronic kidney disease, depression, diabetes or high comorbidity. This large MTM policy evaluation informs consideration of 'food is medicine' therapies in clinical care.
Glioblastoma (GBM) is an immunologically cold brain tumor with poor outcome, characterized by a myeloid-driven immunosuppressive microenvironment. Here we report an interim analysis of a first-in-human phase 1/2a dose-es...Glioblastoma (GBM) is an immunologically cold brain tumor with poor outcome, characterized by a myeloid-driven immunosuppressive microenvironment. Here we report an interim analysis of a first-in-human phase 1/2a dose-escalation study evaluating Temferon-a genetically engineered autologous stem cell transplant designed to deliver interferon-α2 by means of myeloid progeny recruited to the GBM TME and locally activate antitumor immunity. Twenty-four newly diagnosed patients with GBM and unmethylated MGMT promoter were treated across eight cohorts following surgical resection and radiotherapy, testing Temferon doses ranging from 0.5 × 10 to 4.0 × 10 CD34 cells kg and different conditioning regimens (BCNU or busulfan, with or without thiotepa). The primary endpoint was safety and tolerability within 90 days after infusion. Secondary endpoints included long-term safety, dose and conditioning regimen selection, Temferon engraftment, clinical response, quality of life and survival. No dose-limiting toxicities were observed up to the highest dose level of temferon tested. Busulfan conditioning was selected for further development. Adverse events included laboratory abnormalities, cytopenias and infections consistent with autologous stem cell transplant. Median overall survival and progression-free survival were 16.7 months and 8.1 months from diagnosis, respectively, with most patients maintaining good performance status and quality of life. Genetically engineered cells were detected long term in the bone marrow and the blood, where minimal amounts of interferon-α were measured. Temferon is a safe and tolerable immunotherapeutic strategy in patients with newly diagnosed GBM. ClinicalTrials.gov: NCT03866109 .
Peng Z, Liu T, Wang H
… +40 more, Wang J, Liu H, Ye F, Li E, Zhang J, Liu B, Lin R, Zhou A, Liu Z, Xu H, Wang Q, Niu Z, Yuan Y, Qin Y, Qu X, Bai Y, Liu N, Liu H, Bai C, Pan Y, Wang S, Wu T, Pan Q, Zhong D, Lu H, Wang J, Wang Z, Deng T, Gou H, Huang X, Fu S, Lu P, Yu J, Hong M, Xu Q, Wang L, Ren Y, Fan S, Shen L, Savolitinib in MET-amplified gastric or gastroesophageal junction adenocarcinoma study group
MET proto-oncogene amplification (METamp) is associated with poor prognosis in gastric or gastroesophageal junction (G/GEJ) cancer. Currently, effective targeted therapies for G/GEJ cancer harboring METamp remain unavail...MET proto-oncogene amplification (METamp) is associated with poor prognosis in gastric or gastroesophageal junction (G/GEJ) cancer. Currently, effective targeted therapies for G/GEJ cancer harboring METamp remain unavailable, and clinical evidence supporting the use of MET inhibitors in this disease population is limited. Here we report the results of a phase 2 study of savolitinib, an oral MET inhibitor, in patients with METamp G/GEJ cancer. This open-label, multicenter, phase 2 trial in China comprised an exploratory phase and a pivotal phase. Patients with METamp (gene copy number ≥10 for pivotal phase), locally advanced or metastatic G/GEJ cancer that had progressed following ≥1 (≥2 for pivotal phase) prior lines of systemic therapy received savolitinib orally. The primary endpoint was objective response rate (ORR) by independent review committee in the pivotal phase. In total, 110 patients were enrolled and received savolitinib, including 45 in the exploratory phase and 65 in the pivotal phase. Independent review committee-assessed ORR was 32.3% (95% confidence interval 21.2-45.1%) in the pivotal phase, which met the predefined efficacy threshold (lower limit of 95% confidence interval of ORR ≥15%). Among all patients enrolled (n = 110), grade ≥3 treatment-related adverse events were reported in 38 patients (34.5%); one (0.9%) treatment-related death occurred. Savolitinib monotherapy showed encouraging antitumor activities and a tolerable safety profile in heavily treated, later-line METamp G/GEJ cancers, supporting further investigation in randomized controlled trials. ClinicalTrials.gov identifier: NCT04923932 .
Byers LA, Cho BC, Cooper AJ
… +28 more, Chiang AC, Han JY, Furqan M, Dowlati A, Morgensztern D, Papadopoulos KP, Choudhury NJ, Vieito M, Bar J, Kim JH, Akerley W, Kim TM, Kim YC, Paz-Ares L, Ahn MJ, Yokouchi H, Meiman D, Munasinghe W, Ogunyankin O, Jahchan N, Wang S, Ferlini C, Robinson RR, Kohlhapp FJ, Palenski T, Rivell G, Hingorani P, Chandana S
Seizure-related homolog 6 (SEZ6) is expressed in small cell lung cancer (SCLC) and neuroendocrine neoplasms. In an open label, phase 1 trial, ABBV-706, an antibody-drug conjugate with a SEZ6-directed antibody linked to t...Seizure-related homolog 6 (SEZ6) is expressed in small cell lung cancer (SCLC) and neuroendocrine neoplasms. In an open label, phase 1 trial, ABBV-706, an antibody-drug conjugate with a SEZ6-directed antibody linked to topoisomerase-1 inhibitor (Top1i), was administered intravenously every 3 weeks (Q3W) to 288 patients with advanced solid tumors; 240 received monotherapy, including 124 with relapsed/refractory (R/R) SCLC. Primary objectives of dose escalation (part 1, advanced solid tumors), dose optimization and expansion (part 2, R/R SCLC only) and dose expansion (part 4, central nervous system tumors and high-grade neuroendocrine neoplasms only) were to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and antitumor activity of ABBV-706 monotherapy and, from parts 1 and 2, to determine the recommended phase 2 dose (RP2D) of ABBV-706 in R/R SCLC. In the monotherapy cohort (N = 240), the most common treatment-related adverse events (TRAEs) at any grade were anemia (61%) and fatigue (38%). Grade 3 or higher TRAEs occurred in 61% of patients and were dose dependent (39% at 1.8 mg kg and 70% at 2.5 mg kg). In the R/R SCLC monotherapy cohort (n = 124), any-grade and grade 3 or higher TRAEs occurred in 93% and 61% of patients, respectively. ABBV-706 demonstrated promising preliminary efficacy in patients with R/R SCLC, with an objective response rate (ORR) of 52% (65/124). In patients with R/R SCLC receiving monotherapy in dose optimization and expansion part 2, ORR was similar between 1.8 mg kg and 2.5 mg kg doses (56% (23/41) and 59% (23/39), respectively), with a duration of response that was highest at the 1.8 mg kg dose and with most patients achieving rapid and durable tumor reduction. Although exploratory, long-term efficacy measures were an important consideration in the RP2D determination, and in R/R SCLC monotherapy, overall survival (OS) was highest at the 1.8 mg kg dose, with a median OS of 12.4 months. Based on the totality of available data, including, but not limited to, safety, preliminary efficacy measures and PK, 1.8 mg kg Q3W was confirmed as the optimal RP2D for patients with R/R SCLC. ClinicalTrials.gov: NCT05599984 .
Wermke M, Ochsenreither S, Jaeger D
… +24 more, Becker H, Bleckmann A, Bozorgmehr F, Chatterjee M, Groepper S, Haenel M, Hecker JS, Häring MF, Heudobler D, Hilf N, Hofmann M, Hutt M, Mayer-Mokler A, Missel S, Ruh M, Schuster H, Veremchuk O, Kleemiss M, Knop S, Laban S, Sebastian M, Spoerl S, Britten CM, Reinhardt C
IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorpor...IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401 (0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14% (8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% (8/41) was observed across 15 different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D, namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .