Industry Frontiers

In the vast field of pharmaceutical research and development, the respiratory field is quietly undergoing a profound transformation. In recent years, innovative drugs in the field of respiratory medicine have ushered in a year of transformation, with multiple drugs of transformative significance emerging one after another, among which the breakthrough of drugs for the treatment of idiopathic pulmonary fibrosis (IPF) is particularly noteworthy. With the rapid development of technology, AI technology has gradually integrated into the field of respiratory medicine research and development, bringing unprecedented opportunities and challenges to this field.

Respiratory Medicine: A Potential Field with Frequent Emergence of Major Drugs

In the global medical field, tumor research has attracted a large amount of research and development funding and time, and competition in various sub fields is fierce. However, in terms of the top ten disease categories by number of deaths in the United States, chronic lower respiratory diseases rank fifth. If accidental injuries are excluded and cardiovascular diseases (CVD) and stroke are classified as cardiovascular diseases, their actual ranking should be third, and the harm should not be underestimated. At the same time, this also means that the respiratory field contains huge blue ocean market opportunities.

Most respiratory diseases have chronic characteristics, with a long course of illness, and patients require long-term medication. This characteristic enables broad-spectrum drugs for respiratory diseases to often create extremely high sales peaks. For example, corticosteroids such as budesonide are typical representatives.

According to the Fraser Sullivan analysis, in addition to lower respiratory tract infection, asthma, interstitial lung disease and chronic pulmonary obstruction (COPD) are among the top three incidence rate of chronic respiratory diseases in the incidence rate of major global respiratory diseases, and the global incidence rate is 37.0, 24.2 and 16.2 per million people, respectively.

Asthma, as a chronic respiratory disease that is prone to recurrent attacks, cannot be completely cured at present, and most patients need to take medication for long-term control; The current treatment drugs for COPD can only alleviate symptoms, improve quality of life, and reduce the risk of complications. They also require long-term medication and cannot be cured.

The law of 'big drugs for respiratory diseases' has strong endogenous logic support.

Some of the "old drugs" in the past have fully demonstrated this point, such as Novartis/Genentech's Xolair, as the first global targeted drug for the treatment of moderate to severe asthma, with sales reaching 3.987 billion US dollars in 2023 and cumulative sales exceeding 30 billion US dollars since its launch; AstraZeneca's budesonide/formoterol for treating asthma and COPD has a global sales peak of $2.3 billion in 2023.

And some innovative drugs have further validated this law in terms of market performance and stock price trends. Ensifentrine, owned by Verona Pharmaceuticals, is an inhaled medication with a novel mechanism for treating COPD, filling the gap in COPD patients' intolerance to previous therapies. Since its approval in June 2024, its sales have repeatedly exceeded market expectations, with sales of $5.6 million in Q3 2024 and $36 million in Q4 2024. After going public, new prescriptions and feedback from doctors and patients have shown strong trends.

With the approval of Ensifentrine, the cumulative increase in Verona's stock price has reached 281.49%, and its current market value is $4.808 billion. Insmed's DPP1 inhibitor Brensoacatib is the world's first innovative drug for successful phase III clinical treatment of non cystic fibrosis bronchiectasis, for which there was no specific treatment method prior to this. Since the success of Brensoacatib Phase III in May 2024, the company has seen a cumulative increase of 255.1%, with Insmed's latest market value closing at $13.976 billion.

IPF, as a serious disease in the field of respiratory medicine, is a chronic progressive fibrotic interstitial pneumonia with unknown etiology, endangering life. Patients may experience symptoms of difficulty breathing and gradual deterioration of lung function, causing irreversible damage to the lungs.

Data shows that patients diagnosed with IPF within one year have a 5-year survival rate of approximately 66%, while the median survival time from diagnosis to death for IPF patients is 2-3 years. In terms of therapeutic drugs, for over half a century, the preferred treatment for IPF has still been steroids, but the efficacy is not ideal and there are many adverse reactions.

The FDA has only approved two new oral drugs, Nidanib and Pirfenidone, for the treatment of idiopathic pulmonary fibrosis. In 2020, the combined global sales of these two drugs exceeded $3 billion. However, there is still an unmet need for the treatment of IPF in clinical practice.

The breakthrough of the first IPF innovative drug in many years

Although nintedanib and pirfenidone can delay the decline of lung function in IPF patients, they both have a "hard injury". They not only fail to reverse the progression of the disease, but also cause varying degrees of liver, gastrointestinal, and other side effects. In this context, the Nerandomilast film from Boehringer Ingelheim (BI) brings new hope.

Nerandomilast is a novel PDE4B selective inhibitor. PDE4 regulates the production of pro-inflammatory and anti-inflammatory cytokines by specifically hydrolyzing cAMP, and multiple approved drugs have been applied in various inflammatory diseases. The PDE4 family consists of four subtypes (PDE4A, B, C, and D), with PDE4B subtype being highly expressed in lung tissue and immune cells.

Compared with the pan PDE4 inhibitor roflumilast, Nerandomilast has a selectivity for PDE4B that is about 10 times higher than PDE4D. This design allows it to exert highly anti-inflammatory and anti fibrotic effects on lung tissue while reducing the risk of side effects caused by pan inhibition. For example, in the treatment of COPD with roflunomide, some patients interrupt the treatment due to intolerable side effects such as diarrhea, nausea, headache, insomnia, etc.

The Phase III clinical trial of Nerandomilast includes two trials, namely FIBRONEER-IPF ™ 4 and FIBRONEER - ILD ™， Corresponding to idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). The primary endpoint of both Phase III clinical trials is the absolute change in forced vital capacity (FVC) at week 52. FVC is an important indicator of lung function, referring to the amount of air a patient tries to exhale after maximum inhalation.

Although the complete efficacy and safety data of the two trials will be released in the first half of 2025, the absolute change in FVC from baseline to the primary endpoint, as well as preliminary data readings supporting overall consistent safety and tolerability (with overall adverse events comparable to the placebo group), may provide some answers from the Phase II clinical trial of Nerandomilast.

In May 2022, BI released clinical data of Nerandomilast Phase II for IPF patients at NEJM. A total of 147 patients were enrolled in this clinical study, with the primary endpoint being the change in FVC compared to baseline at 12 weeks, and the secondary endpoint being the proportion of patients experiencing adverse events during treatment.

The research results showed that at week 12, regardless of whether patients received anti fibrotic therapy or not, the lung function of patients in the Nerandomilast treatment group remained stable compared to baseline, while the lung function of patients in the placebo group significantly decreased. In the MMRM and Bayesian analysis methods, the difference in FVC changes between patients with anti fibrotic background treatment at 12 weeks was 80.4mL and 62.4mL, respectively, while the difference in FVC changes between patients without fibrotic background treatment was 101.7mL and 88.4mL, respectively.

From the perspective of secondary endpoint safety, the main adverse event (AE) in the Nerandomilast group was gastrointestinal disease, and the incidence of severe AE was similar to that of the placebo group (the severe AE rate was even lower than that of the placebo group). Approximately 13.4% of patients experienced adverse events that led to treatment interruption, and the overall patient tolerance was good.

Although Nerandomilast cannot reverse the course of the disease and is an anti fibrotic drug, it still provides a new treatment option for IPF patients, and it is also the first innovative mechanism drug to achieve success in IPF global Phase III clinical trials in 10 years.

Challengers at home and abroad and the entry of AI

According to the prospectus of Changfeng Pharmaceutical, the number of IPF patients worldwide is expected to increase from approximately 596600 in 2023 to 700100 by 2033. Although it belongs to the category of "small diseases" or rare diseases, the number of global research and development pipelines is not large, and research targets are also diverse.

In addition to BI's Nerandomilast, the most representative clinical mid to late stage pipelines are BMS's BMS-986278 and Ins018_055 from Insilicon Intelligence. BMS-986278 is the fastest progressing LPAR1 antagonist globally, and research evidence shows that elevated LPA levels and activation of LPA1 are associated with the pathogenesis of pulmonary fibrosis. Antagonising the action of LPA1 may be beneficial for the treatment of lung injury and pulmonary fibrosis.

The latest phase II clinical results showed that compared with the placebo group (regardless of whether basic anti fibrotic therapy was used), the decrease rate of ppFVC was relatively reduced by 62% when using 60mg BMS-986278. At the same time, the incidence of adverse events (AEs) was similar to placebo, with a lower discontinuation rate and good safety.

The IPF field has also attracted the participation of AI Biotech and British Silicon Intelligence. INS018_055 from Insilicon Intelligence is a "global innovation first in class" TNIK inhibitor, which belongs to the embryonic center kinase family. Previous studies on TNIK have mainly focused on its role in lung squamous cell carcinoma, obesity, and other areas, but in IPF, this is a novel target.

It is worth noting that the molecule has significantly shortened the time from preclinical candidate compound to clinical entry through AI assisted target discovery and molecular design optimization. Currently, the molecule has entered the second phase of clinical trials. The first phase of data released by it showed good PK characteristics in healthy subjects, and no significant accumulation was found after 7 days of administration, consistent with the prediction results of previous preclinical models; At the same time, the patient had good tolerance and there were no reports of death or serious adverse events (SAEs) during the study period.

In China, there are also numerous innovative pharmaceutical companies laying out in the IPF field. ZSP1603 from Zhongsheng Pharmaceutical is the first PDGF antibody approved for clinical use in China and is currently in phase II clinical trials; There are still a large number of domestic companies that have not publicly disclosed their research progress or targets.

The application of AI technology in the development of respiratory medicine is gradually demonstrating its unique advantages. In the traditional drug development process, from target discovery, drug molecule design to clinical trials, it often requires a lot of time and money, and the success rate is relatively low.

The integration of AI technology can quickly screen potential drug targets and molecules through methods such as big data analysis and machine learning, accelerating the process of drug development. Taking Ins018_055 from Insilicon Intelligence as an example, the AI assisted research and development process significantly shortens its time to enter clinical practice, which is difficult to achieve under traditional research and development models.

In addition, AI can make more accurate predictions about the safety and efficacy of drugs. By analyzing a large amount of clinical data and biological information, AI can detect potential adverse drug reactions and poor efficacy in advance, thereby optimizing drug design and improving the success rate of research and development. Meanwhile, AI technology can also help researchers better understand the pathogenesis of diseases, providing more ideas and directions for developing new treatment methods.

However, the application of AI technology in the development of respiratory medicine also faces some challenges. The quality and security of data are the primary issues, and drug development involves a large amount of biomedical data, the accuracy, completeness, and privacy protection of which are crucial. In addition, the interpretability of AI models is also a challenge. Currently, most AI models are trained based on complex algorithms and data, and their decision-making process is difficult to understand, which to some extent limits their application and promotion in drug development.

The respiratory field is currently in a golden age of constantly emerging innovative drugs, and breakthroughs in IPF treatment drugs have brought new hope to patients. The entry of AI technology has injected new vitality into this field. With the continuous development and improvement of technology, AI is expected to play a greater role in the research and development of respiratory drugs, promote the birth of more innovative drugs, and bring good news to patients with respiratory diseases worldwide. We look forward to seeing more innovative drugs based on AI technology successfully launched in the future, filling unmet clinical needs and improving patients' quality of life.

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Source: Xianji.com

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