lonigutamab (VB421) / Pierre Fabre, ACELYRIN - LARVOL DELTA

Lonigutamab (Anti-IGF-1R Monoclonal Antibody) Induces Efficient Degradation of IGF-1R in Thyroid Eye Disease Orbital Fibroblasts (ENDO 2025) - "To assess the mechanism of lonigutamab-mediated IGF-1R degradation, TED OFs were treated with a proteasome inhibitor (MG132) and/or an autophagy/lysosome inhibitor (bafilomycin) and analyzed by Western blot... Findings from this study demonstrate that lonigutamab, a high-affinity anti-IGF-1R monoclonal antibody, induces efficient internalization and degradation of IGF-1R in TED OFs. Inhibition of the IGF-1/IGF-1R axis through elimination of IGF-1R from the surface of OFs has the potential to provide a meaningful benefit in TED and supports the continued clinical development of lonigutamab."

Breast Cancer • Oncology • Ophthalmology • Solid Tumor • Targeted Protein Degradation • Thyroid Eye Disease • IGF1R

Lonigutamab, a Novel Anti-IGF-1R, Has a Limited Impact on Circulating IGF-1 Levels (ENDO 2025) - "Overall, lonigutamab exhibited limited elevation of serum IGF-1 levels in HVs relative to previously published increases in IGF-1 levels reported with competitive IGF-1R inhibitors. These findings support lonigutamab's unique non-competitive mechanism of action, which may translate to an improved safety profile while maintaining the therapeutic benefit of IGF-1R pathway inhibition, and warrant further investigation of lonigutamab as a therapeutic option in TED."

Diabetes • Ophthalmology • Thyroid Eye Disease • IGF1

Lonigutamab (Anti-IGF-1R Monoclonal Antibody) Reduces IGF-1-Mediated Hyaluronan Production in Thyroid Eye Disease Orbital Fibroblasts (ENDO 2025) - "In this study, we demonstrated that lonigutamab effectively inhibited the IGF-1-driven production of HA in OFs from multiple patients with TED, highlighting its potential to modulate a crucial pathogenic disease process and providing mechanistic insights that support the observed preliminary clinical activity of lonigutamab in TED."

Ophthalmology • Thyroid Eye Disease • IGF1

Anticipated Milestones (GlobeNewswire) - "2025: Planned merger with ACELYRIN: Closing of merger with ACELYRIN (2Q 2025); A-005: Initiation of Phase 2 clinical trial in multiple sclerosis (MS); Lonigutamab: Finalize clinical development plan following the closing of the merger with ACELYRIN (mid-2025); Third pipeline program: Investigational New Drug Application filing for third clinical candidate...2026: ESK-001: Psoriasis Phase 3 topline data (1Q 2026); ESK-001: SLE Phase 2b topline data; A-005: MS Phase 2 topline data."

Clinical data • M&A • New P2 trial • Pipeline update • Multiple Sclerosis • Systemic Lupus Erythematosus • Thyroid Eye Disease

Alumis and ACELYRIN Announce Amended Merger Agreement (GlobeNewswire) - "Merger maximizes the potential value for ACELYRIN stockholders and creates a stronger combined company, best-positioned to realize long-term value of multiple late-stage assets...Alumis Inc...and ACELYRIN, INC...announced an amendment to the existing terms of their previously announced merger agreement...Under the terms of the amended agreement, ACELYRIN stockholders will now receive 0.4814 shares of Alumis common stock for each share of ACELYRIN common stock owned, representing a meaningful increase in the ownership percentage of the combined company over the original definitive merger agreement....'We continue to believe that this combination is the most value-maximizing path forward for ACELYRIN stockholders and that Alumis is the right partner to optimize development of lonigutamab.'"

M&A • Immunology • Multiple Sclerosis • Systemic Lupus Erythematosus • Thyroid Eye Disease

Efficacy and Safety of Lonigutamab in Subjects With Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1/2 | N=54 | Active, not recruiting | Sponsor: ACELYRIN Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Ophthalmology • Thyroid Eye Disease

Alumis and ACELYRIN File Joint Definitive Proxy Statement for Proposed Merger (GlobeNewswire) - "Alumis Inc...and ACELYRIN, INC...have jointly filed a definitive proxy statement/prospectus with the U.S. Securities and Exchange Commission in connection with the proposed merger of the two companies. The joint proxy statement/prospectus are being mailed to all Alumis and ACELYRIN stockholders entitled to vote...Topline data from Phase 2b LUMUS trial in systemic lupus erythematosus on track for readout in 2026; Phase 2 clinical trial initiation for Alumis’ A-005 in MS...Pro forma cash of approximately $737 million as of December 31, 2024, provides runway into 2027, beyond multiple expected clinical readouts....By combining assets, resources and talent, including members of ACELYRIN’s lonigutamab program, the combined company will be well positioned to maximize the value of its pipeline."

M&A • New P2 trial • P2b data • Multiple Sclerosis • Systemic Lupus Erythematosus • Thyroid Eye Disease

Alumis and ACELYRIN Reaffirm Strategic and Financial Rationale of Proposed Merger (GlobeNewswire) - "A combined, differentiated late-stage portfolio of therapies and increased resources enabling the development of life-changing medicines. The combined company will have a diversified portfolio of late-stage clinical assets for validated targets that are set to meaningfully change the treatment paradigm for patients in large, well-established multi-billion dollar markets. These programs, including ESK-001 in moderate-to-severe plaque psoriasis and systemic lupus erythematosus, lonigutamab for thyroid eye disease, and A-005 in multiple sclerosis, offer multiple, high-value catalysts that can be achieved with the financial resources of the combined company...Alumis and ACELYRIN had cash, cash equivalents and marketable securities of approximately $289 million and approximately $448 million, respectively, on a preliminary basis, as of December 31, 2024."

M&A • Multiple Sclerosis • Psoriasis • Systemic Lupus Erythematosus • Thyroid Eye Disease

Alumis and ACELYRIN to Merge Creating a Late-Stage Clinical Biopharma Company Dedicated to Innovating, Developing and Commercializing Transformative Therapies for Immune-mediated Diseases (GlobeNewswire) - "Alumis...and ACELYRIN...announced a definitive merger agreement under which Alumis and ACELYRIN will merge in an all-stock transaction....The combined company will benefit from a differentiated late-stage portfolio of therapies and increased resources enabling the development of life-changing medicines....Under the terms of the agreement, ACELYRIN stockholders will receive 0.4274 shares of Alumis common stock for each share of ACELYRIN common stock owned. Upon the close of the transaction, Alumis stockholders will own approximately 55% of the combined company and ACELYRIN stockholders will own approximately 45% of the combined company, on a fully diluted basis."

M&A • Multiple Sclerosis • Parkinson's Disease • Psoriasis • Systemic Lupus Erythematosus • Thyroid Eye Disease

ACELYRIN, INC. to Host Virtual Investor Event to Share new Phase 2 Data and Phase 3 Program Design for Subcutaneous Lonigutamab (GlobeNewswire) - "ACELYRIN...announced it will host a virtual investor event on Monday, January 6, 2025 at 4:30 PM ET to provide updated Phase 2 data for subcutaneous lonigutamab further supporting its potential for a best-in-class efficacy and safety profile in Thyroid Eye Disease (TED). The event will also feature external clinician perspectives on the continuing unmet needs in TED and disclose the design for the Phase 3 LONGITUDE program, which was developed following a successful End-of-Phase 2 meeting with the FDA to be the most inclusive registrational program to date in TED."

Clinical protocol • P2 data • Thyroid Eye Disease

Preliminary Safety and Efficacy of Subcutaneous Lonigutamab (Anti–IGF-1R) from a Phase 1/2 Proof-of-Concept Study in Patients with Thyroid Eye Disease (TED) (ATA 2024) - P1/2 | "These are the first reported proof-of-concept results of a subcutaneous anti–IGF-1R in patients with TED. Patients achieved early clinical responses that were maintained over time, including at week 12 (off-treatment), supporting the potential for longer dosing intervals. Cohort 1 evidence suggests lonigutamab was well tolerated and displayed clinical efficacy responses, which was further substantiated by cohort 2 data."

Clinical • Late-breaking abstract • P1/2 data • Ophthalmology • Otorhinolaryngology • Thyroid Eye Disease

Efficacy and Safety of Lonigutamab in Subjects with Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1/2 | N=54 | Recruiting | Sponsor: ACELYRIN Inc. | N=38 ➔ 54 | Trial completion date: Oct 2024 ➔ May 2025 | Trial primary completion date: Oct 2024 ➔ May 2025

Enrollment change • Trial completion date • Trial primary completion date • Ophthalmology • Thyroid Eye Disease

A Phase 1/2 Proof of Concept Study of Subcutaneous Lonigutamab (Anti–IGF-1R) in Patients With TED (AAO 2024) - P1/2 | "Patients achieved clinical responses early that were maintained over the time points evaluated, including Week 12 off-treatment, supporting the potential for longer dosing intervals. Evidence from cohort 1 indicates that Loni was well tolerated and displayed clinical efficacy responses, which is further supported by cohort 2 data."

Clinical • P1/2 data • Ocular Inflammation • Ophthalmology

Emerging therapies in the medical management of thyroid eye disease. (PubMed, Front Ophthalmol (Lausanne)) - "Teprotumumab - an anti-IGF-1R monoclonal antibody that has recently emerged as a first-line therapy for active, moderate-to-severe TED - has demonstrated statistically significant improvements in proptosis, diplopia, clinical activity score, and quality of life compared to placebo. Currently under investigation are several other agents, with varying administration modalities, that aim to inhibit IGF-1R: VRDN-001 (intravenous), VRDN-002 or VRDN-003 (subcutaneous), lonigutamab (subcutaneous), and linsitinib (oral). Tocilizumab, a monoclonal antibody of interleukin 6, has played a role in the management of multiple autoimmune and inflammatory conditions and may offer promise in TED...Among the agents under investigation that aim to decrease ocular morbidity associated with TED are agents that IGF-1R, interleukin 6, and the neonatal Fc receptor. The management of TED continues to expand with novel immunologic approaches for disease therapy."

Journal • Review • Endocrine Disorders • Grave’s Disease • Immunology • Inflammation • Ocular Inflammation • Ophthalmology • Thyroid Eye Disease • IL6

Preliminary Safety And Efficacy Of Subcutaneous Lonigutamab (anti-IGF-1R) From A Phase 1/2 Proof Of Concept Study In Patients With Thyroid Eye Disease (ENDO 2024) - P1/2 | "These findings with lonigutamab represent the first proof-of-concept results of a SC anti-IGF-1R in pts with TED (cohort 1). Pts achieved clinical responses across manifestations of disease early and were able to maintain their responses through the time points evaluated, including the wk 12 off-treatment time point, supporting the potential for longer dosing intervals. Data from cohort 2 further substantiate the efficacy seen in cohort 1."

Clinical • Late-breaking abstract • P1/2 data • Immunology • Ocular Inflammation • Ophthalmology • Optic Neuritis • Otorhinolaryngology • Pain • Thyroid Eye Disease

Efficacy and Safety of Lonigutamab in Subjects With Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1/2 | N=38 | Recruiting | Sponsor: ACELYRIN Inc. | Trial completion date: Feb 2024 ➔ Oct 2024 | Trial primary completion date: Feb 2024 ➔ Oct 2024

Trial completion date • Trial primary completion date • Ophthalmology • Thyroid Eye Disease

Efficacy and Safety of Lonigutamab in Subjects With Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1/2 | N=38 | Recruiting | Sponsor: ACELYRIN Inc. | Phase classification: P1b ➔ P1/2

Phase classification • Ophthalmology • Thyroid Eye Disease

Efficacy and Safety of VB421 in Subjects With Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1b | N=36 | Recruiting | Sponsor: ACELYRIN Inc. | Trial primary completion date: Sep 2023 ➔ Jan 2024

Trial primary completion date • Ophthalmology • Thyroid Eye Disease

Efficacy and Safety of VB421 in Subjects With Thyroid Eye Disease (TED) (clinicaltrials.gov) - P1b | N=36 | Recruiting | Sponsor: ValenzaBio, Inc.

New P1 trial • Ophthalmology • Thyroid Eye Disease

ValenzaBio Announces FDA Clearance of Investigational New Drug Application for VB421, an Anti-IGF-1R Monoclonal Antibody for the Treatment of Thyroid Eye Disease (Businesswire) - "Topline results from the Phase 1a expected in Q3 2022....ValenzaBio...today announced that its investigational new drug (IND) application for its lead drug candidate, VB421, for the treatment of thyroid eye disease (TED), has been cleared by the U.S. Food and Drug Administration (FDA) for clinical evaluation....The Company will begin enrollment in a Phase 1a trial of VB421 in the second quarter of 2022...Based on findings from this study, the Company plans to initiate a Phase 1b study to evaluate multiple ascending doses of the low-volume, subcutaneous formulation in patients with TED before year end."

Enrollment status • IND • New P1 trial • P1 data • Ophthalmology • Thyroid Eye Disease