Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFβ pathway inhibition
Jonathan M Maher1, Rui Zhang1, Gopinath Palanisamy2
1Theravance Biopharma US, Inc., South San Francisco, CA, USA.
Abstract:
Systemic therapies targeting transforming growth factor beta (TGFβ) or TGFβR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate that systemic ALK5-associated toxicities can be mitigated through localized lung delivery. Lung-selective (THRX-144644) and systemically bioavailable (galunisertib) ALK5 inhibitors were compared to determine whether lung selectivity is sufficient to maintain local tissue concentrations while mitigating systemic exposure and consequent pathway-related findings. Both molecules demonstrated potent ALK5 activity in rat precision cut lung slices (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib at doses ≥150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause similar systemic findings up to the maximally tolerated doses in rats or dogs (10 and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS IC50 across tolerated doses. At a dose level exceeding tolerability (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were observed when systemic drug concentrations reached pharmacologic levels. In conclusion, the current preclinical work demonstrates that localized pulmonary delivery of an ALK5 inhibitor leads to favorable TGFβ pathway pharmacodynamic inhibition in lung while minimizing key systemic toxicities.
Insights
Localized lung delivery of ALK5 inhibitors, like THRX-144644, effectively inhibits the transforming growth factor beta (TGFβ) pathway in the lungs while significantly reducing systemic toxicities, such as cardiac valvulopathy.
Area of Science:
- Pharmacology and Toxicology
- Drug Delivery Systems
- Molecular Biology
Background:
- Systemic transforming growth factor beta (TGFβ) inhibitors targeting TGFβR1 kinase (ALK5) face significant toxicity challenges, including cardiac valvulopathy and bone dysplasia, hindering clinical development for pulmonary diseases.
- Mitigating these dose-limiting toxicities is crucial for advancing TGFβ pathway inhibitors in treating lung conditions.
Purpose of the Study:
- To evaluate if localized pulmonary delivery of an ALK5 inhibitor can mitigate systemic toxicities associated with TGFβ pathway inhibition.
- To compare a lung-selective ALK5 inhibitor (THRX-144644) with a systemically available one (galunisertib) for efficacy and safety in pulmonary indications.
Main Methods:
- Assessed ALK5 inhibitory activity using p-SMAD3 half-maximal inhibitory concentration (IC50) in rat precision cut lung slices (PCLS).
- Conducted 14-day repeat-dose toxicity studies in rats and dogs using oral galunisertib and inhaled nebulized THRX-144644.
- Measured lung-to-plasma ratios and lung trough concentrations of THRX-144644 to assess drug distribution and local pharmacodynamics.
Main Results:
- Both THRX-144644 and galunisertib showed potent ALK5 inhibition in rat PCLS.
- Oral galunisertib induced dose-related cardiac valvulopathy in rats, while inhaled THRX-144644 did not cause systemic toxicities up to maximally tolerated doses in rats and dogs.
- THRX-144644 achieved high lung-to-plasma ratios (100-1200x) and sustained lung concentrations (3-17x IC50) with minimal cardiac and bone changes, even at supratherapeutic doses.
Conclusions:
- Localized pulmonary delivery of ALK5 inhibitors can effectively achieve therapeutic concentrations in the lung.
- This targeted approach significantly mitigates key systemic toxicities observed with systemically administered TGFβ pathway inhibitors.
- Preclinical data support the potential of inhaled ALK5 inhibitors for treating pulmonary diseases with an improved safety profile.
