Ascletis Announces Dosing Of 24 Healthy Subjects Of The First 3 Cohorts In Multiple-Dose Escalation Phase I Clinical Trial Of Oral RdRp Inhibitor ASC10 For COVID-19

• The multiple-dose escalation Phase I clinical trial will enroll 72 healthy subjects including 60 subjects in 6 dose escalation cohorts and 12 subjects in food effect trial. The enrollment is expected to be completed in the fourth quarter of 2022
• ASC10 is an oral double prodrug. After oral administration, both ASC10 and single prodrug molnupiravir are rapidly and completely converted in vivo into the same active metabolite ASC10-A
• ASC10-A has broad spectrum of antiviral activity against Omicron variants including the most spreading variant BA.5 and the emerging variant BA.2.75^[2]

Hangzhou and Shaoxing /PRNewswire/ - Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") today announces dosing of 24 healthy subjects of the first 3 cohorts in multiple-dose escalation Phase I clinical trial of oral RNA-dependent RNA polymerase (RdRp) inhibitor ASC10 for COVID-19 at the National Medical Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University.

The multiple-dose escalation Phase I clinical trial will enroll 72 healthy subjects including 60 subjects in 6 dose escalation cohorts and 12 subjects in food effect trial. The enrollment is expected to be completed in the fourth quarter of 2022. 60 healthy subjects will be randomized into 6 cohorts to receive escalated multiple doses of ASC10 tablets of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg twice daily (BID) or matching placebo for 5.5 days in a double-blind, placebo-controlled manner to evaluate the safety, tolerability, and pharmacokinetics (PK) of ASC10 tablets. Another 12 subjects will be randomized to receive two single 800 mg doses (fed or fasted) to evaluate the food effect on PK of ASC10 tablets in healthy subjects.

Ascletis is China's first biotech company which has obtained Investigational New Drug (IND) approvals of an oral RdRp inhibitor from both the U.S. Food and Drug Administration (FDA) and China National Medical Products Administration (NMPA). On August 3, 2022, Ascletis announced that FDA had approved the IND application for ASC10 to conduct the Phase Ib clinical trial in mild-to-moderate COVID-19 patients (https://www.ascletis.com/news_detail/179/id/726.html). On August 22, 2022, Ascletis announced that China NMPA had approved the IND application of ASC10 to conduct Phase I clinical trial in healthy subjects (https://www.ascletis.com/news_detail/179/id/734.html). Ascletis is actively communicating with regulatory authorities to explore the possibility of further accelerating the clinical development of ASC10.

ASC10 is an oral double prodrug which has a new and differentiated chemical structure from the single prodrug molnupiravir. After oral administration, both ASC10 and molnupiravir are rapidly and completely converted in vivo into the same active metabolite ASC10-A, also known as β-D-N4-hydroxycytidine (NHC). ASC10 was discovered and developed in-house. Ascletis has filed multiple patent applications for ASC10 and its use globally. ASC10 oral tablet formulation for the clinical study was developed with in-house proprietary technology of Ascletis.

By applying a double prodrug strategy, ASC10's permeability in Caco-2 cells (human colorectal adenocarcinoma cells) and active metabolite exposure in monkeys reached 3.2-fold and 2.1-fold of molnupiravir's, respectively. In the SARS-CoV-2 infected mouse models, ASC10 at 240 mg/kg twice daily led to a 4.0 log reduction in viral titer in lungs, equivalent to molnupiravir at 500 mg/kg twice daily^[1]. Studies demonstrated^[2,3] that ASC10-A (also known as EIDD-1931) has potent cellular antiviral activity against Omicron variants (BA.1 EC50=0.3 µM; BA.2 EC50=0.25 µM; BA.5 EC50=0.23 µM; BA.2.75 EC50=0.90 µM), Delta variant (EC50=0.5 µM) and wild-type virus (EC50= 0.7 µM). It also suggested that there were no drug-drug interactions between ASC10 and other common medicines.

"The Omicron strain is still circulating widely around the world. The virus is highly infectious, fast spreading with frequent mutation. The oral inhibitor ASC10 targets the polymerase (RdRp), an essential polymerase during the replication of COVID-19, thus makes ASC10 a drug candidate with broad-spectrum antiviral potential. ASC10 has entered into clinical study at our center. We will accelerate clinical research with high quality so as to make contributions to epidemic prevention and control in China." said Prof. Yunqing Qiu, Vice President of the First Affiliated Hospital, School of Medicine, Zhejiang University and principal investigator of ASC10 Phase I study.

"ASC10-A has broad antiviral activity against Omicron variants including the most spread variant BA.5 and the emerging variant BA.2.75. A recent study^[2] published by The New England Journal of Medicine (NEJM) showed that ASC10-A (also known as EIDD-1931) remains effective against the most spread variant BA.5 and the emerging variant BA.2.75 which has been spread across at least 25 countries and designated by the World Health Organization as a 'variant of concern lineage under monitoring'^[2]. The epidemic rebounded in many cities in mainland China recently once again reminds us that the prevention and control of the epidemic is far from ending. We will continue to accelerate the clinical development of our proprietary COVID-19 pipeline including ASC10 (RdRp inhibitor) and ASC11 (3CLpro inhibitor) to fight against the pandemic." said Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis.

^[1] Wahl, et al., Nature. 2021 March; 591(7850): 451-457.

^[2] Takashita E, Yamayoshi S, Fukushi S, et al. Efficacy of Antiviral Agents against the Omicron Subvariant BA.2.75. N Engl J Med. 2022;387(13):1236-1238.

^[3] In-house studies.

About Ascletis
Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to manufacturing and commercialization. Led by a management team with deep expertise and a proven track record, Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has three marketed products, i.e. ritonavir tablets, GANOVO® and ASCLEVIR®, and 20 drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (HBV functional cure), ASC10 and ASC11(oral small molecules for COVID-19 treatment), ASC40 (recurrent glioblastoma), ASC42 (PBC, primary biliary cholangitis), and ASC40 (acne).

For more information, please visit www.ascletis.com.