• ETD001 is a novel, first in class blocker of the epithelial sodium channel (ENaC) aimed at treating people with cystic fibrosis without current effective therapies
• ETD001 commenced Phase 2 clinical trials in July 2024, expected to complete in 2025

Brighton, UK, 26 September 2024: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of those suffering from respiratory disease, today announced its novel cystic fibrosis (CF) investigational therapy, ETD001, has been granted ‘rare pediatric disease designation’ (RPD) in the US by the Food and Drug Administration (FDA).¹

ETD001 is a low molecular weight compound with first-in-class potential, which targets the sodium channel (ENaC) in the airway epithelium to increase the hydration and clearance of mucus. Enterprise announced dosing of the first person with cystic fibrosis (pwCF) in its Phase 2a trial of ETD001 on 23^rd July 2024². The trial aims to deliver clinical proof-of-concept and to assess the safety and efficacy of ETD001 in the ~10% of pwCF with the highest unmet medical need. The study will assess lung function (FEV1) in pwCF who are either ineligible for or are not receiving CFTR modulator therapy.

The RPD designation was based on the assessment of CF as a serious or life-threatening disease, primarily affecting individuals aged from birth to 18 years.

CF is estimated to affect over 100,000 people worldwide, with an average life expectancy of only 50 years. Failed mucociliary clearance and mucus congestion in the lungs leads to cycles of infection and inflammation and an ongoing decline in lung function. Increasing fluid volume in the lung by inhibiting ENaC with ETD001 will hydrate mucus, improve clearance, reduce mucus congestion, and is expected to drive substantial improvements in lung function. ETD001 has previously demonstrated a well-tolerated profile in healthy subjects in a Phase 1 trial and has been shown to be long-acting in pre-clinical studies³.

Dr John Ford, CEO, Enterprise Therapeutics, said: “We’re delighted with the FDA’s decision and would like to thank the Office of Pediatric Therapeutics and the Office of Orphan Products Development for their consideration. As we progress though our Phase 2a trial of ETD001, this RPD designation will further support our mission to advance this novel approach for treating pwCF with the highest unmet medical need, as rapidly as possible.”

Annabella Amatulli, Head of Regulatory Affairs, commented: “We are thrilled to be granted the RPD designation by the FDA, a regulatory framework intended to encourage and accelerate innovative therapies, in recognition of the significance of our programme in addressing an unmet medical need. The RPD designation will give Enterprise access to valuable incentives and support from the FDA during the development of ETD001, including the eligibility to request a Priority Review Voucher (PRV) at the time of marketing approval.”

1. https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions
2. https://enterprisetherapeutics.com/enterprise-therapeutics-doses-first-person-with-cystic-fibrosis-in-phase-2-trial-for-novel-therapy-etd001/
3. https://enterprisetherapeutics.com/enterprise-therapeutics-publishes-preclinical-profile-of-etd001-a-novel-inhaled-enac-blocker/

• Trial aims to deliver clinical proof-of-concept and assess the safety profile of novel long acting ENaC inhibitor ETD001
• ETD001, a CFTR mutation agnostic approach to CF, is focussed on providing a novel treatment for members of the CF community that do not benefit from currently available mutation-targeted therapies

Brighton, UK, 23 July 2024: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of those suffering from respiratory disease, today announced dosing of the first person with cystic fibrosis (pwCF) in its Phase 2a trial of ETD001.

ETD001, a low molecular weight compound with first-in-class potential, targets the epithelial sodium channel (ENaC) in the airway epithelium to increase the hydration and clearance of mucus. The Phase 2a trial aims to deliver clinical proof-of-concept and to assess the safety profile of ETD001 in the 10% of pwCF with the highest unmet medical need. The study will be performed at sites located in UK, Germany, France and Italy and will assess lung function (FEV1) in pwCF who are either ineligible for or are not receiving CFTR modulators.

CF is estimated to affect over 100,000 people worldwide, with an average life expectancy of only

50 years. Failed mucociliary clearance and mucus congestion in the lungs of pwCF leads to cycles of infection and inflammation and an ongoing decline in lung function. Increasing fluid volume in the lung by inhibiting ENaC with ETD001 will hydrate mucus, improve clearance, reduce mucus congestion, and is expected to drive substantial improvements in lung function. ETD001 has previously demonstrated a strong safety profile in healthy participants in a Phase 1 trial and has been shown to be long-acting in pre-clinical studies.

Dr John Ford, CEO, Enterprise Therapeutics, said: “The dosing of the first person with CF in our Phase 2a trial of ETD001 represents an incredible milestone, testament to Enterprise’s dedication to advancing a novel approach to treating pwCF with the highest unmet medical need. ETD001 has already demonstrated an excellent safety profile in healthy participants, as well as a pharmacokinetic (PK) profile consistent with a long lung residency. We look forward to progressing ETD001 through Phase 2 trials and beyond.”

Paul Russell, Head of Development, Enterprise Therapeutics, commented: “By targeting the underlying mechanisms of mucus congestion in the lungs through ENaC inhibition, ETD001 has the potential to be a transformative respiratory therapeutic. This is not only for the ~10% of pwCF who are not genetically suited to, or do not benefit from CFTR modulators, but also those suffering from other muco-obstructive lung diseases such as COPD and asthma. The commencement of our Phase 2a trial brings us an exciting step closer to realising that potential.”

Dr Renu Gupta, CMO, Enterprise Therapeutics, said: “We are grateful to the pwCF participating in our Phase 2 study of ETD001, and to the clinical investigators for achieving this major milestone. We are hopeful that our steadfast commitment to advancing this innovative ENaC targeting molecule, along with our partnerships with the CF community, will lead to a treatment that will vastly improve the lives of people living with CF.”

• Low doses of ETD001 demonstrate exceptionally long duration of action in sheep model of airway mucus clearance
• Report in Journal of Cystic Fibrosis discloses best-in-class profile of ETD001
• ETD001 scheduled to commence Phase 2 clinical study in people with cystic fibrosis in summer 2024

Brighton, UK, 12 June 2024: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of people with respiratory diseases, today announced the publication of a peer reviewed study in the Journal of Cystic Fibrosis¹. The paper describes low doses of the ENaC blocker ETD001, Enterprise’s lead asset, enhancing airway mucus clearance with an exceptionally long duration of action in a sheep model.

This study indicates that ETD001, at a dose level that was well tolerated in healthy volunteer studies, provides an opportunity to test whether a long-acting ENaC blocker can deliver benefit to people with cystic fibrosis (pwCF). ETD001 is scheduled to commence a Phase 2 clinical study in pwCF in summer 2024, to understand whether 28 days of treatment will improve lung function.

Blocking ENaC in the airways offers a novel approach to improve mucus clearance in pwCF, including in the ≥10% of individuals who are either intolerant of or genetically unsuited to CFTR modulators. Recently, several other ENaC blocking drugs (VX-371, AZD5634, BI 1265162, QBW276) failed to show any benefit in clinical trials. This study provides a potential explanation for these failures as data from the sheep model indicate that each may have been dosed in clinical trials at a dose too low to observe an extended duration of action on mucus clearance.

Dr Henry Danahay, Head of Biology, Enterprise Therapeutics, and lead author of the paper, said: “This data provides strong evidence that ETD001 has a superior profile compared to other inhaled ENaC blockers. Along with the results from the Phase 1 trials where ETD001 was well-tolerated, this study supports our high level of confidence going into the Phase 2 clinical trial. We remain passionate in our drive to discovery novel therapies that have the potential to transform the lives of all people with cystic fibrosis.”

1. https://www.sciencedirect.com/science/article/pii/S156919932400081X

For more information about Enterprise Therapeutics, visit www.enterprisetherapeutics.com

Dr Prasad will lead Enterprise’s development strategy to support the continued advancement of the Company’s respiratory programmes through the clinic

Brighton, UK, 8 February 2022: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of patients suffering from respiratory disease, today announced it has appointed Dr Niyati Prasad as Chief Medical Officer. With her extensive experience in respiratory drug development, Dr Prasad will offer full-time, UK-based support to lead the continued advancement of the Company’s clinical programmes.

Enterprise is developing novel disease-modifying therapies which target the underlying mechanisms of mucus congestion, to enhance the clearance of mucus from the airways, restore lung function, and ultimately to reduce morbidity and mortality in chronic respiratory diseases like cystic fibrosis (CF). ETD001, a novel ENaC inhibitor with chemical properties aimed at delivering best-in-class potential, will be evaluated in a CF Phase 2 clinical trial later this year.

Dr Prasad joins Enterprise with over 20 years’ experience at the forefront of global clinical programmes focusing on immunology, respiratory, and rare diseases, having most recently been Senior Director of Clinical Development at GSK. Prior to this she held various leadership roles at leading biopharmaceutical organisations, including Galapagos, Vertex, Takeda and Novartis, where she oversaw drug development teams and programmes for respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD), successfully progressing several therapeutics through regulatory approvals.

Dr Prasad received her Medical Degree from Gauhati Medical College, India, and her Diploma in Pharmaceutical Medicine from Universite Libre De Bruxelles. She also completed a Masters in Drug Development Science at Kings College London.

Dr John Ford, CEO, Enterprise Therapeutics, said: “Niyati’s long-standing expertise in respiratory drug development and impressive track record in directing clinical programmes will be an invaluable asset to Enterprise. We are confident that Dr Prasad will play a key role in progressing our novel respiratory therapies through the clinic.”

Dr Niyati Prasad, CMO, Enterprise Therapeutics, commented: “Enterprise is a dynamic and exciting company, with its programmes offering huge potential, especially in the treatment of cystic fibrosis regardless of underlying mutations. I look forward to working closely with the team to bring these novel therapies for respiratory disease to patients.”

For further information about Enterprise’s team, please visit: https://enterprisetherapeutics.com/about-us/leadership-team/.

• Enterprise’s novel TMEM16A potentiator portfolio includes ETD002, a first in class compound which is currently in Phase 1
• TMEM16A potentiation is a novel therapeutic approach applicable to all cystic fibrosis patients, independent of CFTR genotype, and may provide benefit in other respiratory diseases
• Enterprise’s shareholders received an upfront payment of £75 million

Brighton, UK, 07 October 2020: Enterprise Therapeutics Ltd (Enterprise), a biopharmaceutical company dedicated to the discovery and development of novel therapies to improve the lives of patients suffering with respiratory disease, today announced its novel TMEM16A potentiator portfolio has been fully acquired by Roche and will be developed by Genentech, a member of the Roche Group. The portfolio includes ETD002 which recently entered Phase 1 trials.

Enterprise’s shareholders received an upfront payment of £75 million and are eligible to receive additional contingent payments, to be made based on the achievement of certain predetermined milestones.

The TMEM16A portfolio is focused toward treating all people with cystic fibrosis (CF), with potential to benefit people with other severe respiratory diseases characterised by excessive mucus congestion.

 Dr John Ford, CEO, Enterprise Therapeutics, said: “Roche and Genentech have a proven track record of bringing new medicines to people with respiratory diseases, and have recognised the opportunity that our TMEM16A potentiator portfolio presents. I am very proud of the team at Enterprise for identifying and developing this innovative approach to treat patients, with ETD002 the first of our compounds to reach clinical stage. TMEM16A potentiation has the potential to significantly increase the quality of life for people living with cystic fibrosis, for many of whom existing therapies are not effective.”

 Dr James Sabry, MD, PhD, Global Head of Pharma Partnering, Roche, commented: “We are excited to add Enterprise’s TMEM16A potentiator program to our existing respiratory portfolio. We have deep capabilities in this area and look forward to a robust program focused on helping cystic fibrosis patients and patients suffering from other muco-obstructive disorders as quickly as possible.”

CF is estimated to affect 75,000 people globally. One of the main causes of difficulty in breathing and increased risk of infection is mucus congestion in the lungs. The ETD002 compound targets the underlying mechanisms of mucus congestion, and is expected to restore lung function, reduce the frequency of lung infections and improve patient quality of life. CF is caused by loss of function mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, that normally produces an anion channel highly expressed by the airway epithelium. Increasing anion conductance via CFTR modulation is a clinically validated approach for treating CF, however it is not currently available or effective for all people with CF.

In pre-clinical models, Enterprise has demonstrated that ETD002 enhances the activity of TMEM16A, an alternative anion channel present in airway epithelial cells, and by doing so increases anion and fluid flow into the airways, thinning the mucus and increasing its clearance. As TMEM16A potentiation is independent of the mutational status of CFTR, this makes the approach potentially applicable to all people with CF, and perhaps patients with non-CF muco-obstructive lung disease.

Moelis acted as financial advisor and Goodwin Procter acted as legal counsel to Enterprise Therapeutics.