Abstract 929: Characterizing first- & second-generation follow on drugs: Clinical trial & development timelines of Bruton tyrosine kinase (BTK) inhibitors
Authors: Varma Ashwin , Feldman William B. , Kesselheim Aaron S. , Cliff Edward R. 
Published: March 2024

Abstract
Once a promising new cancer therapy emerges, other manufacturers often develop drugs with the same molecular target. Some follow on drugs offer meaningful benefit via improved efficacy or reduced toxicity, but others offer minimal benefit. We hypothesized there are two cohorts of follow on drugs: those developed concurrently before efficacy & safety of the therapy is established (first generation) & those developed as follow ons after that point (second generation). We analyzed BTK inhibitor (BTKi) development to evaluate patterns of concurrent & follow on development.
Methods BTKis from 1996-2023 were identified in Pharmaprojects (Citeline, NY). We collected drug development information including indications pursued, development phase reached, & outcome (ongoing development, discontinued development, or completed development with FDA approval). We constructed timelines including the first publicized report of the drug, Phase 2 initiation & date of development discontinuation or FDA approval.
Results We identified 19 BTKis targeting CLL, of which 6 (32%) were concurrent and 13 (68%) were follow-ons relative to ibrutinib’s 2014 approval. A cluster of new agents began development immediately after ibrutinib approval, suggesting two distinct groups in this case. We identified 10 BTKis for MCL, of which only 2 (20%) were concurrently developed drugs, and 8 (80%) were follow on, based on ibrutinib’s 2013 approval for MCL, with similar clustering to CLL.
Conclusions Among BTKis, market entry progressed in two phases. In a first phase, a smaller group of sponsors attempted to demonstrate safety & efficacy of the novel class. After proof of safety & efficacy, lowering risks for later competitors, a follow on phase of development began in which multiple sponsors sought to enter the market. Knowledge of which drugs belong to which class can aid with evaluation of trial design as part of regulatory approval decisions & with drug price negotiation.
Bruton Tyrosine Kinase inhibitors in Clinical Stage Development in Chronic Lymphocytic Leukemia Drug Sponsor Entry Date Date of approval/discontinuation Outcome Ibrutinib AbbVie/J&J 12/12/2007 02/13/2014 Approved (first in class) Spebrutinib Bristol Myers Squibb 12/12/2008 01/16/2014 Discontinued Vecabrutinib Biogen/Viracta 04/07/2011 03/23/2016 Discontinued Tirabrutinib Gilead/Ono 01/14/2012 09/19/2023 Discontinued Fenebrutinib Roche 11/26/2013 Unknown Discontinued Pirtobrutinib Eli Lilly 12/27/2013 08/08/2023 Approved Acalabrutinib Acerta/AstraZeneca 01/01/2014 06/11/2019 Approved Luxeptinib Apstose Biosciences 08/19/2014 - Ongoing Zanubrutinib BeiGene 08/27/2014 01/14/2022 Approved Nemtabrutinib Merck 05/06/2016 - Ongoing Orelabrutinib Biogen, Beijing Innocare 06/20/2017 - Ongoing AS-1763 Carna Biosciences 11/24/2017 - Ongoing JNJ-624264681 J&J 08/03/2018 - Ongoing HMPL-760 Hutchmed 06/10/2020 - Ongoing
Citation Format: Ashwin Varma, William B. Feldman, Aaron S. Kesselheim, Edward R. Cliff. Characterizing first- & second-generation follow on drugs: Clinical trial & development timelines of Bruton tyrosine kinase (BTK) inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 929.