Hengrui Therapeutics, Inc.

March 27, 2023. Chengdu Shengdi Pharmaceutical Co., Ltd., a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (“Hengrui Pharma”), recently received the “Notice of Acceptance” from the Chinese National Medical Products Administration (NMPA). The marketing authorization application for SHR8028 (cyclosporine ophthalmic solution) eye drops for the treatment of the signs and symptoms of dry eye disease was accepted by NMPA. The marketing authorization application is based on a multi-center, randomized, vehicle-controlled, double-blind, phase 3 clinical study (study number SHR8028-301). The results showed that SHR8028 eye drops, compared to its vehicle, significantly improved the signs and symptoms of dry eye disease. At the same time, SHR8028 eye drops were safe, reliable, and well tolerated. The incidence of adverse events and local instillation site reactions after taking the drops were comparable between SHR8028 and the vehicle. About the SHR8028-301 Study The SHR8028-301 study is a multi-center, randomized, vehicle-controlled, double-blind, phase 3 clinical study evaluating the efficacy and safety of SHR8028 eye drops for the treatment of dry eye disease. A total of 206 subjects with moderate to severe dry eye disease were randomized 1:1 to receive either SHR8028 eye drops or the vehicle respectively. The results of the study showed that compared to vehicle, SHR8028 eye drops can significantly improve the signs and symptoms of patients with moderate to severe dry eye disease. This effect was maintained during the viewing period. About Dry Eye Disease The International Tear Film & Ocular Surface Society Dry Eye Working Group (TFOS DEWS) defines dry eye disease as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.1 Due to the different definition standards of dry eye disease, the estimated global prevalence of dry eye disease varies greatly between 5.5% to 33.7%.2 Epidemiological survey data from 2010 showed that the prevalence of dry eye disease in Chinese people aged 5-89 years based on signs and symptoms was 13.6% and based on symptoms only 31.4%.3 With the acceleration of China’s population aging process, changes in people’s living environment, lifestyle, and work intensity, as well as the popularization of electronic equipment, it is expected that dry eye disease will occur more frequently.4 In the current treatment of dry eye disease, tear replacement with ocular lubricants (“artificial tears”) is traditionally considered a mainstay of treatment in China. However, these products often only relieve dry eye symptoms but do not target the underlying pathophysiology of dry eye disease which may lead to symptoms to recur. The 2017 consensus of dry eye experts from the International Tear Film and Ocular Surface Association pointed out that key etiologies of tear film instability, hyperosmolarity, and ocular surface inflammation and damage were determined to be important for inclusion in the definition, thus, has become an important link in the comprehensive management of dry eye.5 The Expert Consensus on Dry Eye in China (2020) clearly stated that cyclosporine and other immunosuppressants can be used for moderate to severe dry eye with ocular inflammation, especially for immune-related dry eye.6 About SHR8028 eye drops SHR8028 eye drops (0.1% cyclosporine ophthalmic solution), a topical anti-inflammatory and immunomodulating drug, was introduced by Hengrui Pharma from Novaliq GmbH, Germany. Cyclosporine is a highly potent and selective immunosuppressant used in the treatment of T-cell- mediated ocular surface diseases, such as dry eye. There have been advances in research related to immunomodulatory drugs with anti-inflammatory properties and the ability to reduce inflammatory markers and decrease elevated tear film osmolarity, with promising clinical effects.5 SHR8028 eye drops use EyeSol®, a new water-free drug delivery platform based on semifluorinated alkanes (SFAs). The use of the semifluorinated alkane perfluorobutylpentane (F4H5) as a solvent increases the dissolution of cyclosporine in SHR8028 eye drops, and its physical properties make it an optimal solvent for topical ophthalmic formulations. SHR8028 eye drops are free of oils, surfactants, and preservatives with potential benefits including high topical bioavailability, rapid onset of action, good topical tolerance and reduction of visual impairment related to oil-based eye drops, emulsions, or ointments.7 SHR8028 has completed several clinical trials and Novaliq, a partner of Hengrui, submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in August 2022 and is currently under review for the proposed indication for the treatment of the signs and symptoms of dry eye disease. Note: The text above is a translation into English of the original press release by Hengrui Pharma from March 21, 2023. See 8 for the original version. About Novaliq Novaliq is a biopharmaceutical company focusing on the development and commercialization of first- and best-in-class ocular therapeutics based on EyeSol®, the worldwide first water-free technology. Novaliq offers an industry-leading portfolio addressing today’s unmet medical needs of millions of patients with eye diseases. In 2019, Hengrui Pharma and Novaliq announced a strategic collaboration under which Hengrui Pharma secured exclusive rights to develop, manufacture, and commercialize NOV03 (local drug name SHR8058 eye drops) and CyclASol® (local drug name SHR8028 Eye Drops) in China. Novaliq GmbH is headquartered in Heidelberg, Germany and Novaliq Inc. has an office in Cambridge, MA, USA. The long-term shareholder is dievini Hopp BioTech holding GmbH & Co. KG, an active investor in Life and Health Sciences companies. More on www.novaliq.com. References Craig, J. P. (2017). TFOS DEWS II Definition and Classification Report. the Ocular Surface,15, 276- 283. Fiona Stapleton, MCOptom, Monica Alves, et.al. TFOS DEWS II Epidemiology Report. The Ocular Surface 15 (2017) 334-365. Song P, Xia W, Wang M, et al. Variations of dry eye disease prevalence by age, sex and geographic characteristics in China: a systematic review and meta-analysis. J Glob Health; 2018 Dec;8(2 ):020503. Benitez-del-Castillo J, Labetoulle M, Baudouin C, et al. Visual acuity and quality of life in DED: Proceedings of the OCEAN group meeting. The Ocular Surface 2017; 15: 169-178. Lyndon Jones, Laura E. Downie, Donald Korb, et al. TFOS DEWS II Management and Therapy Report. The Ocular Surface 2017: 575-628 Asian Dry Eye Association China Chapter, Ocular Surface and Tear Diseases Group of the Cross- Strait Medical and Health Exchange Association Ophthalmology Specialty Committee, Ocular Surface and Dry Eye Group of the Chinese Physicians Association Ophthalmologist Branch. Expert Consensus on Dry Eye in China: Treatment (2020). Chinese Journal of Ophthalmology, 2020, 56:907-913 John D Sheppard, David L Wirta, Eugene McLaurin, et al. A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study. Cornea 2021 Oct 1; 40(10):1290-1297. https://www.hengrui.com/media/detail-314.html

February 2, 2023. Chengdu Shengdi Pharmaceutical Co., Ltd., a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (“Hengrui Pharma”), received the “Notice of Acceptance” from the Chinese National Medical Products Administration (NMPA). The marketing authorization application for SHR8058 (perfluorohexyloctance) eye drops was accepted for the treatment of dry eye disease associated with Meibomian gland dysfunction by NMPA. SHR8058 is a Class 1 new drug developed by Hengrui Pharma. The marketing authorization application is based on a multi-center, randomized, saline-controlled, double-blind phase III clinical study (study number SHR8058-301). SHR8058 eye drops showed that it can treat dry eye disease associated with Meibomian gland dysfunction, and to significantly improve the symptoms and signs of dry eye disease. Also, SHR8058 eye drops are safe and reliable, well tolerated, and the incidence of local instillation site reaction after taking the drops was comparable to that of placebo.1 About the SHR8058-301 Study The SHR8058-301 study is a multi-center, randomized, saline-controlled, double-blind phase III clinical study evaluating the efficacy and safety of SHR8058 eye drops for the treatment of dry eye disease associated with Meibomian gland dysfunction. Professor Jieying from Beijing Tongren Hospital affiliated to Capital Medical University (Beijing, China) served as the principal investigator and 17 centers across the People’s Republic of China participated in the study. The primary study endpoints were: 1) change from baseline of total corneal fluorescein staining (tCFS) at the end of the treatment (day 57) and 2) change from baseline of the eye dryness score of the visual analogue scale (VAS) at the end of the treatment (day 57). Secondary study endpoints included the tCFS at different visits, corneal fluorescein staining in each subregion, the VAS score, the ocular surface disease index (OSDI) questionnaire and their respective changes from baseline as well as safety. In this study, a total of 312 subjects with dry eye disease associated with Meibomian gland dysfunction were randomized 1:1 to receive either SHR8058 eye drops or placebo (0.6% saline solution) four times a day for 8 weeks. The results of the study showed that SHR8058 eye drops significantly improved symptoms of dry eye and corneal staining scores starting on day 15 of administration, and the efficacy continued until the end of the 57-day trial. About Dry Eye Disease Dry eye disease is an eye surface injury caused by a variety of factors. Patients not only suffer from uncomfortable symptoms such as dryness, foreign body sensation, pain or itching, but also visual impairment due to tear film instability, which in turn has a negative impact on their quality of life and even their mental health. Epidemiological and clinical evidence suggests that 60%-90% of dry eye disease is due to evaporative dry eye disease caused by Meibomian gland dysfunction2, especially as people’s lifestyles, work intensity, and the prevalence of electronic devices increase each year. The clinical treatment of Meibomian gland dysfunction is currently based on physical therapy supplemented by aqueous artificial tears to relieve patients’ ocular discomfort, but the clinical treatment needs are not being met. About SHR8058 eye drops SHR8058 is a clear, colorless, particle-free, almost odorless, sterile eye drop with a single active ingredient, perfluorohexyloctane. It does not contain any excipients such as oils, surfactants and preservatives. SHR8058 eye drops have a very low surface tension and spread rapidly over the surface of the eye. Interacting with the lipophilic portion of the tear film and covering the surface of the aqueous layer of the tear film, SHR8058 eye drops may form a protective layer at the air interface of the tear film and stabilize the tear film, thus preventing excessive tear evaporation. In addition, SHR8058 eye drops may penetrate and interact with the Meibomian glands, dissolve the mucous secretions in the glands leading to a restoration of the Meibomian gland function to secrete lid esters, thus achieving the treatment of lid gland dysfunction related to excessive evaporation type dry eye disease. Note: The text above is a translation into English of the original press release by Hengrui Pharma from February 2, 2023. See 3 for the original version. About Novaliq Novaliq is a biopharmaceutical company focusing on the development and commercialization of first- and best-in-class ocular therapeutics based on EyeSol®, the worldwide first water-free technology. Novaliq offers an industry-leading portfolio addressing today’s unmet medical needs of millions of patients with eye diseases. In 2019, Hengrui Pharma and Novaliq announced a strategic collaboration under which Hengrui Pharma secured exclusive rights to develop, manufacture, and commercialize NOV03 (local drug name SHR8058 eye drops) and CyclASol® (local drug name SHR8028 Eye Drops) in China. Novaliq GmbH is headquartered in Heidelberg, Germany and Novaliq Inc. has an office in Cambridge, MA, USA. The long-term shareholder is dievini Hopp BioTech holding GmbH & Co. KG, an active investor in Life and Health Sciences companies. More on www.novaliq.com. References http://static.sse.com.cn/disclosure/listedinfo/announcement/c/new/2021-12-01/600276_20211201_2_ZrlSb3Ox.pdf Craig, J. P. (2017). TFOS DEWS II Definition and Classification Report. the Ocular Surface,15, 276-283. https://www.hengrui.com/media/detail-303.html

CStone Pharmaceuticals continues to expand its oncology presence aimed at the Chinese market. On Sunday, the company forged a licensing agreement with Jiangsu Hengrui Pharmaceuticals that grants the company access to a monoclonal antibody aimed at multiple forms of cancer. Currently, the only anti-CTLA-4 monoclonal antibody that has been approved globally is Bristol Myers Squibb's Yervoy, which was first approved by the U.S. Food and Drug Administration in 2011 and has also been approved for use in China. Yervoy generated approximately $1.69 billion in 2020. Based on its developmental data, CStone believes that CS1002 has the potential to carve away Yervoy’s revenue. CStone licensed CS1002, an investigational anti-CTLA-4 monoclonal antibody to Hengrui. Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) is one of the few clinically validated targets for IO combination therapies. Based on previous preclinical and clinical studies, CStone believes that CS1002 has the potential to become a backbone therapeutic for multiple immuno-oncology combinations. And that evidence was strong enough for Hengrui to pay $200 million in upfront payment for the asset. Under terms of the deal, Hengrui gains the exclusive rights for research, development, manufacturing, and commercialization of CS1002 in Greater China. CStone will retain rights to market CS1002 outside of China. Lianshan Zhang, president of global R&D at Hengrui, said that the combination therapy potential of CS1002 will provide synergy with the company’s existing pipeline and bolster its competitiveness across China. “As a leading Chinese biopharmaceutical company, CStone has demonstrated its outstanding research and development capabilities with impressive early-stage clinical data and differentiated dosing schedules of CS1002. We have full confidence in the future development of it to provide more innovative drugs for Chinese patients,” Zhang said in a statement. Frank Jiang, chairman and chief executive officer of CStone, expressed his satisfaction of the agreement reached with Hengrui. “As a leading global China pharmaceutical company with an extensive oncology pipeline and strong integrated capabilities in commercialization, we are very confident that Hengrui will bring the full potentialities of CS1002 into the Greater China market. Through this collaboration, we believe we will join forces to bring forward more high-quality innovative oncology therapies to patients,” Jiang said in a statement. For CStone, the partnership with Hengrui follows a regulatory win in China for anti-PD-1 therapy. In September, China’s National Medical Products Administration approved the company’s checkpoint inhibitor sugemalimab as consolidation therapy in patients with unresectable stage III non-small-cell lung cancer. The company said the approval marks a first as sugemalimab becomes the “world’s first anti-PD-1/PD-L1 monoclonal antibody to significantly improve progression-free survival in patients with stage III non-small cell lung cancer (NSCLC) without disease progression after concurrent or sequential chemoradiotherapy.” In August, CStone saw the fruits of a partnership with Servier Pharmaceuticals after that company won U.S. approval for Tibsovo (ivosidenib tablets) for the treatment of adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation. Tibsovo is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma, a cancer of the bile ducts. CStone is no stranger to working with pharma giants. In 2019, the company partnered with Bayer, and then in 2020, CStone struck a partnership with Pfizer in support of the development of sugemalimab that included the pharma giant taking a $200 million stake in the company.