Next Generation Therapeutics in COPD

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, causing 3.23 million deaths in 2019, as per WHO. In addition to having high mortality rate, the disease, being progressive in nature, is a cause of concern as it impacts the patient’s ability to perform routine activities, sleep quality, and even causes weight loss. According to the DelveInsight’s epidemiology insights, the United States possessed the largest diagnosed prevalent population of COPD compared to 7MM countries, i.e., the US, EU-5 (Germany, France, Italy, Spain, and the UK) and Japan. DelveInsight estimates that the number of diagnosed prevalent population of COPD in the 7MM was approximately 32,259,000 in the year 2021.

Significant advancement has been made in understanding of its pathophysiology and disease drivers to develop COPD care. However, currently available pharmacological options provide exacerbation prevention and symptom management only, where slowing down of disease progression and reversal of lung damage are objectives yet to be achieved. The conventional therapies, as divided into categories based on their mechanism of action, are – Muscarinic antagonists (SAMA & LAMA), Beta-2 adrenergic agonists (SABA & LABA), Corticosteroids, and Phosphodiesterase-4 inhibitors administered by Oral or Inhalation route. Based on the severity of disease, combination of these therapies may be used to give either symptomatic relief or maintenance support. Some marketed brands are as follows-

Moving beyond the typical target mechanisms, disease modifying drugs are under trial, aiming at mitigating the disease progression and its subsequent reversal through lung regeneration. Astrazeneca, already present in the COPD market with approved drugs- Duaklir Pressair & Daliresp, is working on various novel pathways as follows—

Interleukin 33 Inhibition- Interleukin 33 is newly characterized cytokine, part of inflammatory cascade, released in lungs upon cell damage or stress, causing amplification of both innate and adaptive immune responses. It increases the permeability of the vascular endothelium and further enhances the inflammatory effect. Studies have shown that IL33 may contribute directly to lung tissue damage by inducing alveolar epithelial cells to undergo cortactin-mediated apoptosis. In addition, both the COPD risk factors CSE (cigarette smoke extract) and LPS (lipopolysaccharide) may promote IL33 secretion. High IL33 in patients with stable COPD was associated with a future risk of exacerbation. So, inhibition of this inflammatory pathway could have the potential to deliver disease modification by addressing the IL-33-driven inflammation associated with tissue remodeling in the lung. Through its in-house Genomics Research Center (CGR), AstraZeneca is gaining a better understanding of the potential of IL33 as a biomarker for COPD and other chronic diseases.

Myeloperoxidase Inhibition- Myeloperoxidase (MPO) is recognized as a marker of neutrophil activity and is taken to be the underlying cause of inflammation in COPD. MPO increased level have been reported in COPD patients, considered to be involved in triggering of exacerbations and damaging of lungs in diseased state. Therefore, the development of targeted MPO inhibitors or therapeutic regimens designed to mitigate damage to MPO-related host tissues without compromising pathogen killing by the innate immune system is an important future direction for the treatment of disease.

Forkhead box O4 inhibition- FOXO4 is a transcription factor involved in cell cycle and is considered a tumor suppressor. It is involved in interactions with several proteins, including p53, to regulate apoptosis, cancer and age-related diseases. Fork Headbox O (FOXO) plays important role in cell cycle regulation, metabolism, stress tolerance, and longevity. AstraZeneca identified the function of the FOXO4-p53 interplay in promoting cell senescence inside the lung and is exploring strategies to disrupt this pathway that might provoke cellular demise and elimination of broken cells from the lung.

Clinical developments:

MEDI3506 (Tozorakimab) is an anti-interleukin33 monoclonal antibody that AstraZeneca is developing. The drug is either administered subcutaneously or intravenously. The company evaluated the drug in multiple ascending doses in COPD subjects and a single dose in healthy Japanese subjects in Phase I. The company is also assessing the safety and tolerability of the drug in Phase II in adult participants with moderate to severe COPD and chronic bronchitis. The molecule has also been tested for COVID19, atopic dermatitis, and asthma. AstraZeneca at the American Thoracic Society (ATS) International Conference, 2022, presented proof of the mechanism for anti-interleukin-33 antibody Tozorakimab in a Phase I study in healthy adults and patients with COPD. The target involvement with tozorakimab was shown in serum. Tozorakimab increased serum IL33/tozorakimab complex levels (all cohorts) and nasal mucosal fluid (MAD cohort) and decreased serum IL33/sST2 complex levels. Tozorakimab significantly reduced serum IL5 and IL13 levels compared to placebo. And the results support the proof of the mechanism by target engagement of tozorakimab and identification of PD biomarkers in the first human study. It is well tolerated and no safety concern were raised, the SC and IV doses demonstrated linear and time-independent serum PK profiles and the data of MAD cohorts supported tozorakimab to enter into phase II AND phase III studies. In December 2020, AstraZeneca initiated Phase II, a randomized, double-blind, placebo-controlled, parallel-group, evidence idea examination to assess the efficacy and protection of MEDI3506 in adult individuals with mild to extreme COPD and chronic bronchitis. The anticipated completion of the study is in July 2023 (NCT04631016). With this AstraZeneca, sponsored 2 more trials initiated in first quarter of 2022 that are in Phase III in recruiting status (NCT05158387 and NCT05166889) both are anticipated to complete by June 2025.

Similarly, Sanofi/Regeneron Pharmaceuticals’ Itepekimab (REGN3500), is currently in Phase III recruiting state and expected to be completed by December 2023. REGN3500 is a fully human monoclonal antibody that inhibits interleukin 33 (IL33), a protein thought to play an important role in type 1 and type 2 inflammation. The drug is given subcutaneously. Preclinical studies have shown that REGN3500 blocks multiple markers of both types of inflammation. Study analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. The Phase II clinical trial showed a 40% reduction in the rate of deterioration. If approved, itepekimab will be the first biologic approved in the COPD ex-smoker patient pool and will compete with AstraZeneca MEDI3506 (Tozorakimab).

With advancement in research associated with the disease, there is constant expansion of the treatment paradigm which could help limit the impact of this debilitating and life-threatening indication.

For a more detailed analysis of the COPD market, visit: Chronic Obstructive Pulmonary Disease market