Pulmonary Vascular Research Institute Engage PVRI2021 Clinical abstract
The aerosol delivery of tyrosine kinase inhibitors (TKI) may improve risk benefit ratio in PAH but the overall molecular TKI fingerprint is important in determining clinical efficacy and safety
PVRI Engage PVRI2021 Video abstract
PVRI Engage. 2021 Jan 12; Pulmonary Vascular Research Institute PVRI2021 Clinical Abstracts (online).
Authors: Benjamin T. Dake, PhD & Hunter Gillies, MD
Pulmonary vasculopathy in PAH has similar pathogenic mechanisms to cancer (Cool 2020). Growth factors are instrumental in the vascular remodeling process via kinase dependent signaling through PDGFR, EGFR, VEGFR and IGF amongst others that appear to be important in PAH pathogenesis. Targeting these kinases with different small molecule inhibitors has been successful in oncology but use of the same drugs has resulted in discordant outcomes in PAH patients.
Imatinib demonstrated efficacy in the phase 3 IMPRES trial, but was hampered by systemic intolerability (Hoeper 2013). A similar kinase inhibitor nilotinib did not progress beyond phase 2 in PAH (NCT01179737), nintedanib did not show benefit in a small compassionate use trial (Richter 2018) despite positive preclinical data (Rol 2019, Tsutsumi 2019) and dasatinib is known to induce PAH in oncology patients (Shaw 2015). Reproducing the differential clinical effects of these drugs in toxicology studies and rodent models of PAH has been difficult (Pullamsetti 2012, Guignabert 2016, Baumgart 2017).
A novel clinical strategy to overcome the intolerability of TKIs in PAH is to focus the drug more directly where it is needed via aerosol administration. The higher local drug exposure in the diseased tissues could potentially result in reproducing or increasing efficacy from the oral route of administration while reducing systemic adverse effects. Two clinical stage kinase inhibitors pursuing this strategy via dry powder aerosols are AV-101 (dry powder imatinib) and seralutinib. Table I shows the top kinases inhibited by these two drugs using the standard Kinomescan assay (Eurofins).
There are multiple lines of evidence showing the importance of PDGFR signaling in animal models and in human PAH. However, the other targets of these drugs are not as well explored. These kinase inhibitors all target a conserved ATP-binding domain and thus it is well established that each molecule has its own fingerprint of targets and potencies. Figure 1 illustrates that Imatinib is the most selective kinase inhibitor targeting ABL, PDGFR, DDR, KIT and CSF1R at physiologic concentrations while not hitting SRC or VEGFR as dasatinib and nintedanib do respectively.
Conclusion: All of these drugs hit PDGFR but the clinical outcome is very different. Given the wealth of published data on PDGFR in PAH, it is reasonable to suggest that PDGFR inhibition is one component necessary for clinical success in PAH. Ultimately, the balance of inhibition with the other kinases determines the overall efficacy and safety in the clinic.
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