Biogen (United States)

Abstract Protein-protein interactions (PPIs) underpin biological function, yet proteome-scale interaction prediction remains bottlenecked by the quadratic computational complexity of all-vs-all pairwise comparisons. Here, we present FlashPPI, a contrastive learning framework, grounded in residue-level interactions, that enables linear-time prediction of physical protein interfaces across a microbial proteome. By leveraging a genomic language model that captures cross-protein co-evolutionary signals from metagenomic sequences, FlashPPI aligns interacting partners in a shared latent space. We demonstrate a four-fold performance increase over existing sequence-based methods, while reducing proteome-wide screening time from days to minutes. Crucially, FlashPPI achieves comparable screening performance to state-of-the-art structure-folding models at a fraction of the computational cost. Finally, we integrate FlashPPI into seqhub.org , an interactive web platform that combines predicted networks with functional annotations and genomic context, making proteome-wide network analysis rapid and accessible for microbial discovery.

Abstract Introduction: Detecting pathogenic germline variants in BRCA1/2 is crucial for hereditary cancer risk assessment and guiding targeted therapies. While targeted NGS panels are effective for SNVs and indels, they often miss large structural variations (SVs), leading to false negatives. Whole-genome sequencing (WGS) offers a comprehensive solution by providing uniform, genome-wide coverage for robust SV detection. This report presents two clinical cases where WGS identified an identical, complex pathogenic BRCA1 SV missed by conventional panel testing. Methods: DNA was extracted from fresh-frozen tumor tissue and matched normal blood samples from two patients: a 40-year-old premenopausal female with breast and ovarian double primary cancers and a female in her 60s with metastatic pancreatic cancer (history of breast cancer). WGS analysis was performed using the CancerVision™ system. Results: Both patients initially had non-decisive hereditary cancer panel results. WGS revealed an identical, complex pathogenic germline BRCA1 variant in both: a large deletion of exons 12-14 coupled with an adjacent inversion. This BRCA1 deletion was successfully orthogonally confirmed by MLPA. The first patient's breast tumor showed BRCA1 loss of heterozygosity (LOH), a high HRD score (0.93), 40.0% of base substitutions attributed to SBS3 (indicating flawed homologous recombination-based DNA repair), and a high prevalence of SV duplications (45.8%), suggesting a complete BRCA1 defect. The second patient's tumor also showed BRCA1 LOH, 33.7% of base substitutions attributed to SBS3, and high SV duplications (33.7%), collectively suggesting impaired BRCA1 function. This patient achieved and maintained a complete response to platinum-based chemotherapy. Discussion: This study demonstrates WGS's transformative power in resolving clinically important cases missed by conventional genomic approaches. The key finding is the identification of an identical, complex recurrent BRCA1 SV in two unrelated patients, providing definitive molecular diagnoses that significantly impacted clinical management. This recurrence suggests a potential underdiagnosed founder mutation. WGS's unparalleled advantage lies in its uniform, genome-wide coverage, enabling simultaneous detection of diverse genomic variations, including complex SVs, ensuring a comprehensive and unbiased genetic landscape elucidation. WGS provides precise genomic breakpoint locations, allowing unequivocal determination of variant identity across patients and facilitating tracking of origins and population-specific prevalence. These cases underscore WGS's critical role in identifying pathogenic SVs undetectable by standard methods, advocating for its integration into clinical diagnostics for high-risk patients to enhance accuracy and support personalized treatment strategies. Citation Format: B. Oh, S. Choi, S. Seo, H. Park, E. Connolly-Strong, T. Kim, Y. Ju, J. Hwang, Y. Park.. Recurrent, Cryptic BRCA1 Complex Rearrangement by Whole-genome Sequencing in Patients with Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-28.

Abstract GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, the real-world association between discontinuation of GLP-1RA prescriptions and weight change has not been explored. We assessed weight trajectories of 4,182 patients in the six months following their last GLP-1RA prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period post the last known GLP-1RA prescription. In a representative subset of patients with clinician-documented discontinuation near the last prescription (N=300), a similar distribution of weight regain in a minority of patients was observed vs no regain in the majority of patients during the six-month post-GLP-1RA prescription period. To mirror clinical trial-style discontinuation definitions, we also evaluated cohorts with no subsequent GLP-1RA prescription for 1 year after the last prescription (semaglutide N=1,755; tirzepatide N=1,312), observing weight regain in a minority of patients (39.3% semaglutide; 26.6% tirzepatide) and no weight regain in the majority (60.7% semaglutide; 73.4% tirzepatide) in the year following the last known GLP-1RA prescription. Exercise counseling was documented more frequently among patients with durable weight loss post-last GLP1 prescription compared with those with weight regain (26.2% vs. 14.7%; p=0.04). Further studies are warranted to infer the mechanisms underlying these real-world patterns.

Abstract Background The STOMP2 trial sought to determine whether the implantable autologous cell therapy AVB-114 is an effective add-on therapy for patients with persistent Crohn’s perianal fistulas. The trial design incorporated wait-list controlled (WLC) elements, allowing eligible control group subjects who completed the 9 mo primary endpoint visit in Part 1 to request AVB-114 treatment in Part 2 and strengthen the evaluation of AVB-114’s safety and effectiveness. Methods Eligible patients had a single perianal fistula tract and had failed prior treatment or had documented medication intolerance to biologic or conventional Crohn’s disease therapy. Subjects at 14 U.S. sites were randomized 1:1 to either standard of care (SoC; fistula optimization including seton placement) or AVB-114 implantation. The primary endpoint was combined fistula remission at 9 mo, defined as no collections >2cm on MRI, visual closure of the external opening, and no drainage of fluid despite gentle finger compression. A logistic regression time from exposure model through 9 mo utilized complete Part 1 data and all available Part 2 data to estimate combined AVB-114 effectiveness. Results Part 1 combined remission (using Non-Responder Imputation) was 8.3% (2/24) for SoC and 45.8% (11/24) for AVB-114 (38% difference, 95% CI 11 – 60%, post-hoc p-value of 0.0078). Twenty SoC subjects were treated with AVB-114 in Part 2. Four of the 9 Part 2 subjects with 9 mo combined remission data available were in combined fistula remission (44.4%). No subjects failed 9 mo radiological remission (first component of the primary endpoint), thus clinical remission (composite of the latter two components) was equivalent to combined remission. AVB-114 clinical remission in Part 1 and Part 2 to-date were similar, and when combined provided narrower estimates with the same coverage (Figure 1). Mean (SD) 9 mo perianal disease activity index (PDAI) scores for SoC, Part 1 AVB-114, and Part 2 AVB-114 were 5.0 (2.6), 4.1 (2.9), and 3.8 (3.5), respectively. Lower 9 mo scores and decreases from baseline were independently associated with an increased probability of clinical remission. Two serious treatment-emergent adverse events (TEAEs; pseudopolyposis and proctalgia) occurred, with the latter attributed to AVB-114. Non-serious product related TEAE were predominantly related to postoperative perianal pain. Two grade 2 (moderate) AEs of cellulitis and abdominal wall abscess were attributed to adipose tissue collection. Conclusion Both the randomized and combined (all-treated) analyses demonstrated substantial AVB-114 effectiveness through 9 mo in this challenging patient population. AEs were anticipated, and generally mild and infrequent. Conflict of interest: Schwartz, David: 1) Abbvie: consultant 2) Janssen: Consultant 3) Takeda: Consultant 4) Avbios- consultant 5) Olympus- consultant Dozois, Eric: TBD Ehman, Eric: TBD Faubion, William: TBD Hudesman, David: Consultant: Avalo, Abbvie, Abivax, Biocon, BMS, CorEvitas, Eli Lilly, Johnson and Johnson, Pfizer, Prometheus, Sanofi, Takeda, Fresenius Kabi Research Support: Pfizer and Johnson and Johnson Espen, Benjamin: employee of Avobis Bio LLC Pabla, Baldeep: Astellas, J & J - Advisory Board Prometheus - Speaker Eli Lilly - Speaker Papadakis, Konstantinos: TBD

Opicinumab, a human monoclonal antibody against LINGO-1, is hypothesized to promote remyelination by enhancing the differentiation of oligodendrocyte progenitor cells. The objective of the study is to investigate the efficacy and safety of opicinumab as an add-on therapy to anti-inflammatory disease-modifying therapies (DMTs) in participants with relapsing multiple sclerosis (RMS). Participants with RMS aged 18-58 years, with disease duration up to 20 years, were randomized 1:1 to receive intravenous infusions of placebo or opicinumab every 4 weeks for 72 weeks. Primary endpoint was Overall Disability Response Score (ODRS) over 72 weeks. The study enrolled 263 participants. Adjusted mean difference (95% confidence interval (CI)) on ODRS was 0.15 (-0.05 to 0.35; p = 0.148) over 72 weeks, favoring opicinumab versus placebo. Numerically larger differences in favor of opicinumab were observed in participants aged ⩾ 40 years with Expanded Disability Status Scale ⩾ 3.0, with disease duration ⩾ 6 years, and receiving dimethyl fumarate as the background DMT. 85% participants in placebo group and 86% in opicinumab group had adverse events. Although the AFFINITY study did not show significant difference in mean ODRS between opicinumab and placebo groups, data from AFFINITY interpreted with the previous SYNERGY study may inform the design of future remyelination trials. gov identifier:(NCT03222973).

Accurately measuring compound binding affinities is key to driving the pharmaceutical development process. Rigorous physics-based in silico approaches, particularly alchemical free energy methods, have become a gold standard tool for estimating compound affinity changes. Here we present the results of a large-scale pre-competitive collaborative assessment of relative binding free energy (RBFE) calculations generated by 15 pharmaceutical companies. We evaluate an open-source and MIT licensed RBFE Protocol from the Open Free Energy (OpenFE) ecosystem across both public and blinded private datasets, encompassing over 1,700 ligands in total. For the public dataset, the weighted RMSE across the 58 systems was 1.73 [1.53, 1.96] kcal/mol, with 10 of the systems reaching sub-kcal/mol accuracy. For the private dataset, the weighted RMSE across the 37 systems was 2.44 [1.94, 3.06] kcal/mol, with only 2 of the systems reaching sub-kcal/mol accuracy, reflecting the increased complexity of real-world drug discovery. The protocols performance was system-dependent, with no single dominant error source, indicating that accuracy is primarily influenced by input quality and transformation type. Overall, these benchmark results are encouraging and indicate that OpenFE is ready for large-scale industrial applications, with an "out-of-the-box" accuracy that approaches that of commercial solutions. While comparison against published FEP+ results, which were obtained after manual parameter optimization, shows comparable ranking statistics, a gap remains in error statistics, for which we outline possible paths toward improvement. The protocol meets key criteria required for production use in an industrial setting: it shows robust performance, generates reproducible results, and achieves both sufficient throughput and rapid convergence.

BackgroundFabry disease, an X-linked lysosomal storage disorder, is associated with significant multisystem involvement, including small fiber neuropathy. While neuropathic pain is well-documented in females with Fabry disease, the objective confirmation of small fiber dysfunction in pediatric heterozygotes remains underreported. This study highlights the role of quantitative sensory testing (QST) in diagnosing small fiber neuropathy in young female patients.Case reportWe present twin sisters, heterozygous for a pathogenic GLA variant (c.298 A > T), who exhibited symptoms of small fiber neuropathy, including acroparesthesia and gastrointestinal dysfunction. QST revealed altered thermoalgesic and vibratory thresholds in one twin and isolated vibratory hyposensitivity in the other, supporting the diagnosis of small fiber neuropathy.DiscussionThese cases highlight the diagnostic challenge of Fabry disease, as neuropathic symptoms may be overlooked or attributed to other conditions in pediatric patients. The findings emphasize the need for early identification of small fiber dysfunction in heterozygous females, who are increasingly recognized as being clinically affected. The complex alterations in sensory processing reinforce the importance of integrating QST as an objective assessment tool for small fiber function in Fabry disease.ConclusionsSmall fiber neuropathy is an early and clinically relevant manifestation of Fabry disease in pediatric heterozygotes. Early recognition and intervention, including enzyme replacement therapy (ERT), are essential to mitigating disease progression and improving clinical outcomes. These cases underscore the utility of QST in confirming small fiber neuropathy and highlight its potential role in the early diagnosis and monitoring of Fabry-related neuropathy in pediatric patients.

The hallmark neuropathological changes associated with Alzheimer's disease (AD) include extracellular amyloid beta plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Because NFTs are strongly associated with clinical impairment, multiple therapeutic programs focused on reducing tau pathology have been initiated, necessitating the development of biomarkers specific to tau pathology. Current tau blood‐based biomarkers (e.g., phosphorylated tau 181 [p‐tau181] and 217 [p‐tau217]) are more closely associated with amyloid pathology than tau pathology and may not allow specific assessment of the presence of, or therapeutic impact on, neuropathological tau. BIIB080 is a microtubule associated protein tau (MAPT)–targeting antisense oligonucleotide that reduces production of tau protein. Exploratory analysis from the BIIB080 Phase 1b trial (NCT03186989) demonstrated that BIIB080 treatment was associated with a dose‐dependent and sustained reduction in soluble tau protein in cerebrospinal fluid (CSF), and exploratory analysis evaluating the change in soluble p‐tau in plasma is in progress. Moreover, BIIB080 impacted aggregated parenchymal tau pathology, as measured by tau positron emission tomography, demonstrating a reduction of tau pathology from baseline across all brain composites assessed at the end of the long‐term extension. These data were the first to show this magnitude of treatment response on this pathological hallmark of AD. The ongoing Phase 2 CELIA trial (NCT05399888) will further evaluate impacts of BIIB080 on these biomarkers, as well as the safety and efficacy of BIIB080 in a larger and broader AD population. Emerging candidates for tau‐specific biomarkers include p‐tau205 and a portion of the microtubule binding region of tau containing the residue 243 (MTBR‐tau243). Evaluation of the impact of BIIB080 on these measures and other novel biomarkers of tau pathology is ongoing. However, these biomarkers are currently measured in CSF only, and evidence for their use as treatment‐response measures is limited. Based on emerging tau biomarker advances and biomarker results from BIIB080, this presentation will provide future directions on the use and importance of tau biomarkers for development of therapies targeting tau.

Cost-effective and scalable production is critical for advancing the clinical translation of adeno-associated virus (AAV)-mediated gene therapy. The widely used transient transfection method using plasmid DNA (pDNA)-loaded transfection particles for AAV production faces technical challenges due to instability of the particles and the concentration limits for particle preparation, hindering reproducibility and scalability. Here, we report a streamlined and scalable strategy to generate shelf-stable, highly concentrated pDNA/poly(ethylenimine) (PEI) transfection particles. By incorporating trivalent citrate ions in the dilution buffers, we kinetically modulate electrostatic complexation to achieve uniform nanoparticle assembly and prevent aggregation at high concentrations. This enables a tenfold increase in pDNA concentration in stabilized transfection particles from a typical range of 10–20 μg/mL to 200 μg/mL, while reducing the required dosing volume from 5–10% to 0.5% of the cell culture medium. The particle assembly process is robust to changes in mixing scale and timing and is compatible with standard workflows. We demonstrate equivalent AAV production efficiencies to standard methods and consistent performance in various production scales, which confirms the practical utility of this assembly method in developing robust, scalable, and cost-effective AAV manufacturing processes.