ABBV-154 / AbbVie - LARVOL DELTA

Immune mediated inflammatory disease: T cell engager versus antibody drug conjugate. (PubMed, J Autoimmun) - "In contrast, ADCs deliver immunomodulatory payloads to disease-relevant cells, with agents like ABBV-154 and brentuximab vedotin showing promise in rheumatoid arthritis and systemic sclerosis. However, challenges such as cytokine release syndrome with TCEs and off- and on-target toxicities with ADCs highlight the need for optimal target selection and innovative design. This review provides a comprehensive comparison of the mechanisms, current evidence, and future directions of TCEs and ADCs in IMIDs, highlighting their potential to address unmet needs in disease management."

Journal • Review • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis

Solving scalability: Use of impinging jet in the preparation of the ABBV-154 drug-linker (ACS-Fall 2025) - "A 3D printed jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity."

Efficacy and Safety of ABBV-154 for the Treatment of Active Rheumatoid Arthritis: A Phase 2b, Randomized, Placebo-Controlled Trial. (PubMed, Arthritis Rheumatol) - "ABBV-154 demonstrated superior efficacy over placebo in patients with RA and inadequate response to prior b/tsDMARDs. TEAE rates in all ABBV-154 arms were comparable with placebo. These findings provide useful insights into the design of new ADCs for RA."

Journal • P2b data • Immunology • Infectious Disease • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Efficacy, Safety, Pharmacokinetics, and Immunogenicity of ABBV-154 in Adults With Glucocorticoid-Dependent Polymyalgia Rheumatica: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial. (PubMed, Arthritis Rheumatol) - P2 | "Treatment effects were observed for ABBV-154 cohorts compared with placebo for time to flare. ABBV-154 was generally well tolerated. Due to early study termination, results should be interpreted with caution."

Clinical • Journal • P2 data • PK/PD data • Giant Cell Arteritis • Immunology • Infectious Disease • Musculoskeletal Pain • Novel Coronavirus Disease • Pain • Rheumatology

Development of a scalable route to an immunology ADC drug-linker for ABBV-154 (ACS-Fall 2024) - "A scalable route has been developed to the bromoacetamide glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce antibody-drug conjugate ABBV-154. Notably, the final step involves a global acidic deprotection of three t-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element."

Investigational agents for polymyalgia rheumatica treatment: assessing the critical needs for future development. (PubMed, Expert Opin Investig Drugs) - "Currently, there are 12 ongoing clinical trials exploring potential treatments such as leflunomide, low-dose IL-2, rituximab, abatacept, secukinumab, Janus kinase inhibitors, and selective inhibitors like SPI-62 and ABBV 154...The development of internationally accepted definitions for remission and relapse is urgently needed. Early referral strategies to specialist settings would improve disease stratification and personalized treatment."

Journal • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatoid Arthritis • Rheumatology • IL6R

Minimising the payload solvent exposed hydrophobic surface area optimises the antibody-drug conjugate properties. (PubMed, RSC Med Chem) - "Solving the crystal structure of compound 2, the GRM payload from ABBV-3373 and ABBV-154, in the ligand binding domain of the glucocorticoid receptor (GR) revealed key information to facilitate optimal ADC payload design. Confirmation of the stereochemistry of the acetal in compound 2 as (R) was established. Finally, the importance of minimising the exposed hydrophobic surface area of a payload to reduce the negative impact on the properties of resulting ADCs, like aggregation, was rationalised by comparison of (R)-acetal compound 2 and (S)-acetal compound 3."

Journal • Oncology

Discovery of ABBV-154, an anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody-Drug Conjugate (iADC). (PubMed, J Med Chem) - "Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration."

Journal

AIM-RA: Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Rheumatoid Arthritis (RA) (clinicaltrials.gov) - P2 | N=473 | Terminated | Sponsor: AbbVie | Trial completion date: Feb 2026 ➔ Aug 2023 | Active, not recruiting ➔ Terminated; Business decision

Adverse events • Trial completion date • Trial termination • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

AIM-PMR: A Study to Evaluate the Change in Disease State and Adverse Events in Adult Participants With Polymyalgia Rheumatica (PMR) Dependent on Glucocorticoid Treatment, Receiving Subcutaneous Injections of ABBV-154 (clinicaltrials.gov) - P2 | N=181 | Terminated | Sponsor: AbbVie | Trial completion date: Apr 2024 ➔ Jul 2023 | Active, not recruiting ➔ Terminated; Business Decision

Adverse events • Trial completion date • Trial termination • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

AIM-CD: A Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Intravenous (IV) Infusion and Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Crohn's Disease (clinicaltrials.gov) - P2 | N=176 | Terminated | Sponsor: AbbVie | N=265 ➔ 176 | Trial completion date: Jul 2026 ➔ Jul 2023 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2024 ➔ Jul 2023; Strategic considerations

Adverse events • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

"@abbvie is shutting down development of Humira-steroid antibody-drug congugate (Abbv154) after interim analysis. Very disappointing news for our hopes of novel combo strategies." (@ShomronH)

Study to Assess Adverse Events and Compare How Two Subcutaneous ABBV-154 Injection Formulations Move Through the Body of Adult Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Adverse events • Trial completion

Discovery of ABBV-154, an anti-TNF glucocorticoid receptor modulator immunology antibody drug conjugate (iADC) (ACS-Sp 2023) - "The design considerations for an Immunology Antibody Drug Conjugate (iADC) need to enable self-administration by the patient via subcutaneous injection and support chronic dosing. This talk will discuss aspects of drug-linker design in conjunction with the screening assays that were used for efficacy, safety and ADC property assessment to identify ABBV-154."

Immunology • Oncology

AIM-PMR: A Study to Evaluate the Change in Disease State and Adverse Events in Adult Participants With Polymyalgia Rheumatica (PMR) Dependent on Glucocorticoid Treatment, Receiving Subcutaneous Injections of ABBV-154 (clinicaltrials.gov) - P2 | N=181 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

Study to Assess Adverse Events and Compare How Two Subcutaneous ABBV-154 Injection Formulations Move Through the Body of Adult Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed

AIM-RA: Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Rheumatoid Arthritis (RA) (clinicaltrials.gov) - P2 | N=473 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: May 2024 ➔ Feb 2026 | Trial primary completion date: Nov 2022 ➔ Aug 2022

Adverse events • Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP

ABBV-154: Data from P2 AIM-CD trial (NCT05068284) for Crohn’s disease in 2024 (AbbVie) - Q3 2022 Results

P2 data • Crohn's disease • Immunology • Inflammatory Bowel Disease

Study to Assess Adverse Events and Compare How Two Subcutaneous ABBV-154 Injection Formulations Move Through the Body of Adult Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: AbbVie | Not yet recruiting ➔ Recruiting

Adverse events • Enrollment open

Study to Assess Adverse Events and Compare How Two Subcutaneous ABBV-154 Injection Formulations Move Through the Body of Adult Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: AbbVie

Adverse events • New P1 trial

AIM-CD: A Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Intravenous (IV) Infusion and Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Crohn's Disease (clinicaltrials.gov) - P2 | N=265 | Recruiting | Sponsor: AbbVie | Trial completion date: Feb 2025 ➔ Jul 2026

Adverse events • Trial completion date • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

AIM-CD: A Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Intravenous (IV) Infusion and Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Crohn's Disease (clinicaltrials.gov) - P2 | N=265 | Recruiting | Sponsor: AbbVie | Trial completion date: Jul 2026 ➔ Feb 2025

Adverse events • Trial completion date • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

AIM-PMR: A Study to Evaluate the Change in Disease State and Adverse Events in Adult Participants With Polymyalgia Rheumatica (PMR) Dependent on Glucocorticoid Treatment, Receiving Subcutaneous Injections of ABBV-154 (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: AbbVie | Trial completion date: Sep 2023 ➔ Apr 2024 | Trial primary completion date: Dec 2022 ➔ Jul 2023

Adverse events • Trial completion date • Trial primary completion date • Giant Cell Arteritis • Immunology • Musculoskeletal Pain • Pain • Rheumatology

AIM-CD: A Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Intravenous (IV) Infusion and Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Crohn's Disease (clinicaltrials.gov) - P2 | N=265 | Recruiting | Sponsor: AbbVie | Trial completion date: Apr 2025 ➔ Jul 2026

Adverse events • Trial completion date • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

AIM-RA: Study to Evaluate Adverse Events and Change in Disease Activity in Participants Between 18 to 75 Years of Age Treated With Subcutaneous (SC) Injections of ABBV-154 for Moderately to Severely Active Rheumatoid Arthritis (RA) (clinicaltrials.gov) - P2 | N=473 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CRP