Development of the first oral disease-modifying treatment for chronic obstructive pulmonary disease (COPD)

Project Information

RESPIRE

Grant agreement ID: 190151672

DOI

10.3030/190151672

Project closed

EC signature date 6 October 2022

Start date 1 January 2022

End date 30 June 2024

Funded under

• The European Innovation Council (EIC)

Total cost

€ 3 537 295,00

EU contribution

€ 2 476 106,50

Coordinated by

PALO BIOFARMA SL
Spain

Periodic Reporting for period 2 - RESPIRE (Development of the first oral disease-modifying treatment for chronic obstructive pulmonary disease (COPD))

Reporting period: 2023-01-01 to 2024-06-30

Summary of the context and overall objectives of the project

Palobiofarma is a Spanish clinical stage biotech company focused on discovering and developing innovative treatments that modulate adenosine receptors. Our lead compound, PBF-680, is being developed as a first-in-class, disease-modifying therapy for chronic obstructive pulmonary disease (COPD)—the third leading cause of death worldwide.

Despite over 65 million people suffering from COPD, no approved therapies effectively target disease progression. Current treatments, such as inhalers and oral medications, primarily focus on symptom relief (e.g. bronchodilation) and fail to slow disease progression or reduce mortality. Additionally, these treatments often have severe side effects and are only effective for a limited subset of patients.

COPD patients urgently need a therapy that not only relieves symptoms but also modifies the course of the disease. PBF-680 has the potential to meet this need. It is an oral, selective adenosine receptor 1 (A1R) antagonist, designed to address both airway inflammation and bronchoconstriction—areas where we have pioneered clinical evidence for the role of A1R signaling. PBF-680 stands out for its safety, short response time, and easy, adaptable dosing, which are crucial for patient adherence.

PBF-680 has already demonstrated safety and tolerability in phase 1 trials, and its efficacy was validated in phase 2 trials in mild asthmatics, where it reduced pulmonary symptoms and inflammation. The ongoing development shows promise for significantly lowering healthcare costs related to COPD, including hospitalizations and lost productivity.

The primary goal of this project has been to advance the clinical development of PBF-680 as an oral disease-modifying COPD therapy. In the phase 2 trial founded by this project, PBF-680 successfully met its primary endpoint, significantly reducing circulating eosinophil levels in moderate to severe COPD patients, indicating its potential to reduce exacerbations and inflammation.

Our next step is to secure funding—through investment or an IPO—to initiate a phase 3 trial for either severe asthma or COPD, with a target for regulatory approval and market entry by 2032.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project has been successfully conducted. The main objective was to advance the clinical development of a new drug under study, PBF-680 as a new therapy for the treatment of COPD through:
1) Clinical activities: Phase II clinical trial in moderate to severe COPD patients
2) Preclinical Activities: Regulatory long-term toxicicology studies in rats and dogs and an efficacy study of PBf-680 in a validated animal model of COPD.
To meet the general project objectives, three main activities were proposed for the second year:
1) Complete the pharmaceutical development and manufacturing of the PBF-680 capsules for the clinical trial, ensuring availability of medication throughout the clinical study (drug substance and drug product production).
2) Finish preclinical toxicology study in dogs with PBF-680 and carry out an efficacy study in an animal model of COPD.
3) Complete the Phase II clinical trial in COPD patients.

An extension of 6-months execution period was required to complete all planned activities.

In the case of preclinical work packge activities (WP-4), main task and achievements were as follow:
1) Regulatory Long-term toxicology study in dogs was completed
2) Results of adminsitration of PBF-680 in a validated preclinical model of COPD were available and study report generated.

In the case of clinical trial activities (WP-5), the following planned tasks were performed in order to speed up the patient recruitment and the study completion:
1) Major protocol amendment was filed to ethic committee to include new sites.
2) Protocol amendment to update inclusion/exclusion criterias.
3) 12 sites were finally open, with 10 active sites enrolling patients.
4) Clinical trial finalization, reaching the last patient out the study in April 2024.
5) Site-closing activities and trial master file completion.
6) Statistic analysis and Clinical trial report elaboration.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Current COPD treatments aim to relieve disease symptoms (inhaler bronchodilator), instead of acting disease modifying. COPD patients have to juggle 12-15 different medications with different schedules to manage the various COPD symptoms, such as bronchoconstriction, inflammation, and chronic bronchitis. The key added value of PBF-680 rely in its potential to be the first safe oral disease modifying anti-inflammatory therapy for COPD treatment. PBF-680 might represent a corticoid-like drug, targeting a new mechanism of action and with better safety profile.

The efficacy of PBF-680 reducing blood eosinophils, inflammation biomarkers and improving lung function in severe COPD patients were investigated in the phase 2 clinical trial. Thus, this clinical trial was designed to investigate whether PBF-680 have an effect in reducing blood eosinophil count in COPD patients on top of their standard therapy after 4 weeks of treatment. Moreover, the effect of PBF-680 on inflammatory biomarkers like plasma fibrinogen, IL-5, IL-13, IL-17 and TNFα and on pulmonary function has been evaluated.

The trial demonstrated that a 28-day treatment with PBF-680 significantly reduced blood eosinophil count in patients with moderate to severe COPD on triple therapy (Standard of care) compared to placebo. Given that high blood eosinophil levels in patients correlate with COPD exacerbations, PBF-680 has the potential to become the first oral disease-modifying therapy for COPD patients.

Figure 2. Study design of the clinical trial in COPD patients.

Figure 1. Medication kit of PBF-680 for the clinical trial “Respire”

Figure 3. Initiation visit of Respire clinical trial in Santa Creu i Sant Pau Hospital, Barcelona.

Figure 4. COPD study primary outcome result