04 February 2019 by Patricia Thistlethwaite

DELTA-LIKE 4 inhibitor treatment causes pulmonary arterial hypertension in humans - review of 6 randomized clinical trials

Background:

NOTCH signaling pathways have been implicated in the development of pulmonary arterial hypertension. Expression of NOTCH receptors and NOTCH ligands has been identified in a large number of human malignancies. Results of 6 randomized Phase I clinical trials assessing intravenous infusion of monoclonal antibodies to Delta-like 4 (DLL-4), a NOTCH ligand, for the treatment of advanced cancers have recently been published.

Objective:

To review the current data showing that DLL-4 inhibition in humans is highly associated with the adverse effect of development of pulmonary arterial hypertension.

Methods and Results:

Six Phase Ia or Ib clinical trials have been reported, each using one of four different monoclonal antibodies directed against DLL-4 to treat advanced human malignancies. The four monoclonal antibodies were developed by independent companies to specific DLL-4 epitopes. These trials have reported a 6.5% - 28.6% incidence of pulmonary arterial hypertension developing during treatment. Pulmonary arterial hypertension occurred in patients receiving higher dosing over longer periods of time, for each of the four antibodies given. Pulmonary arterial hypertension was confirmed with right heart catheterization and cardiac echocardiography and was not associated with left heart impairment. In several cases, autopsy demonstrated diffuse small vessel remodeling in the lung consistent with advanced pulmonary arterial hypertension. Severity of pulmonary arterial hypertension as a side effect led to: 1) de-escalation of dosing, 2) termination of continuous dosing strategies, and 3) complete drug cessation. Discontinuation or reduced dosing of the respective DLL-4 antibody treatment resulted in reversal of pulmonary arterial hypertension over a period of 2-14 months.

Conclusion:

Use of DLL-4 drugs is associated with the development of pulmonary arterial hypertension in humans. Deciphering the mechanism of this phenomenon is crucial to understanding the pathobiology of this disease.

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Rapid-Fire presentation

Moises Hernandes presented this abstract on behalf of Patricia Thistlethwaite at the PVRI AWC in Barcelona 2019.

About the author


profile picture of Patricia Thistlethwaite

Patricia Thistlethwaite

University of California, San Diego

United States

Key Contributors

Moises Hernandez M.D., Yu Zhang M.D.-Ph.D., Ataollah Rajabnejad M.D., Patricia A. Thistlethwaite M.D.-Ph.D. : Division of Cardiothoracic Surgery, University of California San Diego


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