Risk of Myasthenia Gravis with Tyrosine Kinase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

Friday, August 26, 2022

5:15 PM – 5:20 PM CEST

Location: C1M2

Publication Number: 102

Background:
Myasthenic syndromes are typically characterized by muscle weakness and increased fatigability due to an impaired transmission at the neuromuscular junction (NMJ); most cases are caused by acquired autoimmune conditions such as myasthenia gravis (MG). Different drugs are among the major factors that may complicate pre-existing autoimmune myasthenic conditions by further impairing transmission at the NMJ.

Objectives:
To quantify disproportionate reporting (Disp-Rep) for the risk of drug-associated MG for 41 clinically approved tyrosine kinase inhibitors (TKIs) in 2 groups: 1) Anti-angiogenic (AA) TKIs; 2) Non-anti-angiogenic (NAA) TKIs.

Methods:
We used the AERS and VigiBase databases, with data up to Dec2021 and Mar2022 for analysis respectively. Cases of MG were identified using MedDRA (v24.1) and the preferred-term (PT) ‘myasthenia gravis' (MG). Empirical Bayes Geometric Means (EBGM) with 90%CI were calculated to quantify Disp-Rep. We considered the lower bound of the 90% CI, EB05 > 2 as the threshold for claiming an observation of Disp-Rep. We studied 3 groups of drugs: 1) Positive control group (non-TKIs associated with MG: penicillamine and prednisone) and two groups of TKIs: 2) AA TKIs & 3) NAA TKIs. Drugs were identified by non-proprietary name.

Results:
We retrieved 392 MG cases in AERS and 281 in VigiBase. In AERS, Disp-Rep with EBGM [90%CI, EB05-EB95] was confirmed for the positive control group: prednisone 3.21 [2.92-3.52] and in VigiBase for penicillamine 6.40 [2.48-34.12] and prednisone 5.80 [5.19-6.46].
In AERS, no Disp-Rep was confirmed for any of the 25 NAA TKIs: afatinib, alectinib, avapritinib, bosutinib, brigatinib, ceritinib, crizotinib, dabrafenib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, lapatinib, lorlatinib, nilotinib, osimertinib, pemigatinib, pexidartinib, pralsetinib, tucatinib and zanubrutinib. No Dis-Rep was found for any of the 16 AA TKIs: acalabrutinib, axitinib, cabozantinib, dacomitinib, lenvatinib, neratinib, nintedanib, pazopanib, ponatinib, regorafenib, ripretinib, selpercatinib, sorafenib, sunitinib, tivozanib and vandetanib. The analysis in VigiBase database yielded similar results.

Conclusions:
No Disp-Rep was found for any of the 41 TKIs (25 NAA TKIs and 16 AA TKIs) evaluated and the risk of MG. Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing.

Presenting Author(s)

Luis G. Velez-Nandayapa, MD

PhD Student in Pharmacoepidemiology
University of Basel
University of Basel
Z�rich, Z�rich, Switzerland

Slides

Co-Author(s)

AS

Amit Saxena, MD

Safety Signal Detection & MQM, Novartis, India
MI

Miguel Izquierdo, MD

Clinical Development Oncology, Novartis, Basel, Switzerland, Switzerland
MN

Maria Nicolaides, MD

Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
Pd

Pierre de Zeeuw, MD

Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
AR

Alicia Rossiter, MD

Patient Safety Oncology, Novartis, New Jersey, USA, United States
JE

Johannes Eisinger, MD

Patient Safety Oncology, Novartis, Basel, Switzerland, Switzerland
CM

Christiane Michel, MD, MSc

Safety Signal Detection & MQM, Novartis, Switzerland