Pulekang Pharma Advances Multiple Ophthalmic Innovative Drug Pipelines; China's First Self-Developed Class I IGF1R Antibody Enters Clinical Trials

With the aggravation of population aging and changes in social lifestyle, the incidence of age-related eye diseases and metabolism-related eye diseases is increasing, showing a trend of younger onset of eye diseases.

According to a report released by VCBeat in 2022, the issue of ophthalmic diseases in China is relatively severe, with 990 million people suffering from non-blinding eye diseases and 252 million people afflicted with blinding eye diseases.

With the increase in the prevalence of ophthalmic diseases both in China and abroad, the market size for ophthalmic drugs has also grown rapidly. According to statistics from Frost & Sullivan,In 2021, the market size of ophthalmic drugs in China approached 26 billion yuan, with a compound growth rate of around 8%.. With the continuous expansion of the population affected by ophthalmic diseases and the increasing penetration rate of ophthalmic drugs,By 2030, the overall market size will exceed 100 billion yuan, with enormous potential.

As a rare "double-high" track with high growth and high barriers, the ophthalmology industry has long been known as the "golden track" in the capital market. In the "14th Five-Year Plan" for national health issued by the State Council in 2022, a separate notice on the national eye health plan was listed, bringing the ophthalmology industry back into the spotlight. According to the 2022 ophthalmology industry report by VCBeat, the growth potential of China's ophthalmic drug market in the next decade is expected to expand to five times its current size, indicating tremendous potential.

China's ophthalmic drug market started relatively late, and the research and development of innovative ophthalmic drugs is at a lower level. Currently, it is mainly dominated by generics and license-in, with few self-developed innovative drugs. Through generics and License-in, the drug R&D cycle can be quickly shortened, drugs can be rapidly brought to market, and the risks of drug development can be reduced. However, this is also the root cause of the homogenization problem in the market.

If we want to pursue a path of independent research and development, there are still many obstacles. Firstly, the understanding of the pathogenesis of many ophthalmic diseases is relatively lagging. Secondly, patients' awareness of seeking medical treatment and medication is relatively weak. The capital market's understanding of innovative ophthalmic drugs also needs time, and the market penetration rate of ophthalmic drugs is relatively low.

It can be said that in the field of ophthalmic innovative drugs, independent research and development is a more challenging path. Pro-heal Pharmaceuticals (hereinafter referred to as Pro-heal) is one such company that has risen to the challenge.

"In the 1990s, when I was still pursuing my Ph.D., my research project focused on the development of macromolecular drugs. This was also the first plasmid gene drug in China to enter clinical trials," said Guo Shuhua. The development of macromolecular drugs began in the 1970s-1980s. Macromolecular drugs can achieve precise humoral immunity, cellular immunity, or cell-mediated immunity in the human body by targeting specific components of the immune system.

After obtaining his Ph.D., Guo Shuhua went to the United States to conduct postdoctoral research. In the laboratory, he and his team discovered a natural protein with anti-tumor activity. After attracting the attention of venture capital institutions and securing over 30 million US dollars in funding, Guo Shuhua devoted himself to the development of this recombinant protein. This marks another significant large-molecule drug development project for Guo Shuhua, following his successful gene drug development in China.

Guo Shuhua, who officially entered the industry, has worked in several multinational pharmaceutical companies, participating early on in the development of mRNA vaccines and the process development and scale-up of various antibody drugs. On the path of large-molecule drug development, Guo Shuhua has been charging ahead at full speed.

In 2011, Guo Shuhua joined Allergan, a leading ophthalmic pharmaceutical company, where he and his team participated in the CMC development of Abicipar, the world's first anchor protein drug, for the treatment of wet age-related macular degeneration (wAMD). It was also here that Guo Shuhua first encountered ophthalmic drug development.

"Even from a global perspective, the level of new drug development for ophthalmic drugs was relatively low in previous years due to the lagging understanding of the pathogenesis of eye diseases. When it comes to China, this level is even further behind."Guo Shuhua said.

Due to the highly specialized and segmented nature of ophthalmic diseases, the pathological mechanisms of many eye conditions remain unclear. Additionally, patients' limited awareness and understanding of these diseases have resulted in low diagnosis and treatment rates in China. This has indirectly led to the early-stage development of ophthalmic drugs in the country. Currently, antibiotics and eye drops still dominate the market, with key medications primarily imported.

After Guo Shuhua returned to China, he founded Ruiyang Bio in 2015. Here, Guo Shuhua carefully analyzed the clinical pain points of the then mainstream anti-VEGF drugs for treating wet age-related macular degeneration (wAMD), such as medication adherence, patient acceptance, safety, cost, and other issues. To address these clinical challenges, he pioneered the development of a small-molecule VEGF inhibitor eye drop for wAMD in China. It was also here that Dr. Ma Lin, who is dedicated to developing precision medicine and conducting clinical trials, joined Guo Shuhua's new drug development team.

Malin earned a Ph.D. in Biochemistry from the University of Minnesota in the United States and has over 10 years of work experience at pharmaceutical giants such as Merck and Pfizer. At Quest Diagnostics, the largest third-party clinical diagnostics company in the U.S., she led a panel for tumor companion diagnostics involving more than 400 genes. In 2018, she returned to China and joined Pro-heal Pharmaceuticals, where she completed and obtained approvals for...The first new drug application in China registered with the CDE using biomarkers (rather than disease types) as the clinical indication.

Ma Lin's reason for wanting to return to China is simple, "To develop drugs based on biomarkers, it’s not easy to realize this idea in large foreign pharmaceutical companies." Thus, with one person aiming to develop biomarker-based drugs and another wanting to delve into ophthalmic drug development, Pro-heal Pharmaceuticals was founded in 2019.

The eye is an organ with a special structure. Its microenvironment lacks a typical lymphatic system and has very few immune cells, which makes the immune microenvironment of the eye possess the characteristic of immune privilege. Due to this feature, some gene therapies have been first applied in ophthalmology.

“Many difficult ophthalmic diseases are closely related to the disorder of the immune environment. We believe that considering this factor in the development of ophthalmic drugs will achieve better therapeutic effects."."Guo Shuhua said. Based on the regulatory mechanism and clinical value of the eye's immune cell microenvironment, Pro-heal Pharmaceuticals has advanced several projects to the preclinical and clinical trial stages.

PHP1003 is a specific drug for the treatment of Thyroid Associated Ophthalmopathy (TAO), which isThe first domestically developed and approved clinical trial in ChinaIGF1R Antibody Drug。

TAO is an organ-specific autoimmune disease., ranking first among adult orbital diseases. Its prevalence rate is 0.3%, with female patients far outnumbering males. There are approximately 4 million patients in China, of which 25-30% are moderate to severe cases. During the active phase of the disease, hormone therapy is generally used, while surgical treatment (which may require multiple surgeries) is adopted during the inactive phase.

Currently, there is only one FDA-approved monoclonal antibody drug for active moderate to severe TAO, and it has not been marketed in China. In preclinical trials, PHP1003 demonstrated good safety and compliance. The innovative formulation developed enables home-based self-administration and long-term storage at room temperature (traditional antibody drugs are generally stored at 2~8°C).

IGF1RAntagonismThe main side effects of the drug in clinical settings are twofold: hyperglycemia and reversible hearing loss, with an incidence rate of around 8-10% for both. The innovative drug development mechanism of PHP1003 effectively prevented elevated blood glucose levels in preclinical animal trials.

Wet age-related macular degeneration (wAMD) is a multifactorial disease,Although anti-VEGF therapy has become the first choice for wAMD treatment, there are still a considerable number of cases where anti-VEGF therapy is ineffective.Anti-VEGF treatment only addresses the symptoms, not the root cause. Long-term use may lead to drug resistance and recurrence, and could also cause macular atrophy or fibrosis, resulting in permanent vision damage.

According to CIC, the number of wAMD patients in China increased from 3.4 million in 2015 to 3.9 million in 2019. Driven by the accelerating aging population, the number of wAMD patients is expected to rise to 5.2 million by 2030. Due to the large patient population and extremely low diagnosis rate, there remains a significant unmet clinical need in China.

A large amount of data demonstrates that chronic intraocular inflammation and disruption of the immune microenvironment caused by factors such as light damage, oxidative stress, hyperglycemia, and aging are closely related to the pathogenesis of wAMD.

Based on this, Pro-heal Pharmaceuticals developed PHP0003 eye drops with an innovative mechanism of action. By modulating immune cells in the eye, it suppresses the expression of wAMD pathogenic factors such as VEGF and TGFβ from upstream, acting on the disease at its early, middle, and late stages. When used in combination with VEGF inhibitors, it can improve response rates and reduce the number of injections. Its favorable safety profile, convenient usage, and low cost suggest that it will carve out a niche in the wAMD drug market. Currently, PHP0003 is in the preclinical research stage.

In addition, based on the characteristics of the eye's immune microenvironment, Pro-heal Pharmaceuticals has developed a pipeline of products with innovative mechanisms of action for dry eye syndrome, uveitis, presbyopia, and certain rare diseases. The formulations include eye drops, subcutaneous injections, and intravenous infusions, covering both large-molecule and small-molecule drugs.

The eye is a highly sensitive organ, and the safety requirements for its therapeutic drugs are extremely stringent.There is no room or opportunity for trial and error with drugs used for the eyes, which also need to provide a good user experience; the eyes cannot tolerate any damage or irritation."Guo Shuhua said when discussing the particularities of eye drug development."

Therefore, the safety of a drug is the primary criterion in drug development and selection. If a drug has safety issues, mild cases may cause tearing, inflammation, and other symptoms during use, making it unbearable for patients, while severe cases can lead to permanent damage or even blindness.

"The eye is an organ that is both complex and delicate. Its complexity lies in the fact that many ophthalmic diseases are closely related to systemic diseases, so treating ophthalmic conditions also requires attention to managing systemic health. Additionally, there is a wide variety of highly specialized ophthalmic diseases— even for the same condition, significant heterogeneity may exist, demanding precise treatment options. The delicacy of the eye means it has extremely high requirements for drug safety and patient experience, and once damage occurs, it is difficult to repair." Guo Shuhua repeatedly emphasized the critical importance of safety in ophthalmic medications.

Currently, the development of ophthalmic drugs is not yet refined, and research on biomarkers remains insufficient. The future development of ophthalmic drugs will advance along several pathways, "First, accelerating the development of improved new drugs and optimizing existing treatment plans; second, pursuing combination therapies; third, advancing precision medicine; fourth, intensifying the research and development of treatments for rare diseases; fifth, strengthening fundamental research and accelerating the application of new technologies in the treatment of ophthalmic diseases," said Guo Shuhua.

In November 2022, Pro-heal's "Development of New Drugs with Novel Mechanisms of Action Related to Immunity" won the first prize in the finals of the Global Challenge for Ophthalmic Innovation and Entrepreneurship at China Eye Valley. "In the future, we will strive to become a leading innovative ophthalmic pharmaceutical enterprise in China," said Guo Shuhua.