The ALPHA phase 1 study: pulmonary ArteriaL hypertension treated with CardiosPHere-Derived allogeneic stem cells.
Progenitor cell therapy
Pulmonary arterial hypertension
Regenerative medicine
Right ventricle
Short- and long-term safety
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
07 Dec 2023
07 Dec 2023
Historique:
received:
26
05
2023
revised:
09
11
2023
accepted:
17
11
2023
medline:
14
12
2023
pubmed:
14
12
2023
entrez:
13
12
2023
Statut:
aheadofprint
Résumé
Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation. The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a double-blind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year. No short-term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6-min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months. Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease-modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm. California Institute for Regenerative Medicine (CIRM). Project Number: CLIN2-09444.
Sections du résumé
BACKGROUND
BACKGROUND
Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodelling and plexiform lesions. Cardiosphere-derived cells (CDCs) are heart-derived progenitor cells exhibiting anti-inflammatory and immunomodulatory effects, are anti -fibrotic, anti-oxidative and anti-apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation.
METHODS
METHODS
The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH-connective tissue disease (CTD) and PAH-human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n = 6). Phase 1b was a double-blind placebo-controlled study (n = 20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year.
FINDINGS
RESULTS
No short-term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 h monitored in hospital. There were no long-term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long-term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favouring CDCs (n = 16) compared to placebo (n = 10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6-min walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favouring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long-term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12-months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long-term follow up through 12 months.
INTERPRETATION
CONCLUSIONS
Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease-modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDC's potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.
FUNDING
BACKGROUND
California Institute for Regenerative Medicine (CIRM). Project Number: CLIN2-09444.
Identifiants
pubmed: 38092579
pii: S2352-3964(23)00466-8
doi: 10.1016/j.ebiom.2023.104900
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104900Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests MIL: PI on CIRM grant that funded this study. No relevant conflicts of interest to report. SS: Site PI for PAH research with the following companies: Medtronic, United therapeutics, Pharmosa, Liquidia, Gossamer, Aerovate, Lung Rx. RJO: Research funding: Actelion/JnJ/Janssen, Acceleron/Merck, Gossamer Bio, Insmed, Liquidia, United Therapeutics. Speaker bureau: Janssen, United Therapeutics. Advisory: Actelion/JnJ/Janssen, Acceleron/Merck, Aerami, Aerovate, Gossamer Bio, Insmed, Liquidia, OptumRx, Respira, United Therapeutics. MN: No relevant conflicts of interest to report. DG: No relevant conflicts of interest to report. YM: Site PI for PAH research with Aerovate Therapeutics, Mallickrodt, Penumbra. AH: Site PI for PAH research with the following companies: Bayer, United therapeutics/Lung Rx LLC, Insmed Incorporated, Acceleron Pharma Inc. Bayer (Advisory board, consulting). VFT: VP medical affairs, Inara Medical Inc. TDH: No relevant conflicts of interest to report. PA: No relevant conflicts of interest to report. RS: Consultant: Aria; Third Pole; United Therapeutics; Janssen; Liquidia; Insmed; Acceleron; Funding for clinical studies: United Therapeutics; Altavant; Aerovate; Acceleron; Bellerophon. JM: No relevant conflicts of interest to report. OK: No relevant conflicts of interest to report. JvE: No relevant conflicts of interest to report. EM: Owns founder's equity in Capricor Therapeutics.