Ascletis focus on breakthrough therapies for HBV functional cure with subcutaneously injected PD-L1 antibody - ASC22.
HBV Functional Cure: ASC22 mechanism
Prolonged activation of T cells leads to high expression of PD-1. By blocking the connection between PD-1 and PDL-1 through PD-1 antibodies or PD-L1 antibodies, T-cells can remain activated and exert immune functions, ultimately leading to clinical cure.
In the area of chronic hepatitis C, Ascletis has twoall-oral regimen, among which ASCLEVIR®/GANOVO®regimen has been approved for marketing for marketing in China by National Medical Products Administration (NMPA).
The human immunodeficiency virus (HIV) is an infectious virus that is primarily transmitted through certain body fluids and attacks the immune system. Patients with HIV have a weakened immune system that is more susceptible to other infections and diseases.
In 2017, 1.1 million people are living with HIV in China, with approximately 100,000 new infections in the same year. Without any cure for HIV and due to the inaccessibility to HIV medication, sharing unsterilized needles and social stigma surrounding HIV, HIV patient population in China is expected to grow to 1.73 million in 2025.
ASC09F is a fixed dose combination (FDC) of ASC09 and Ritonavir. ASC09 is a potential best-in-class protease inhibitor to treat HIV type-1 infections. ASC09 has an unprecedented genetic barrier to resistance and has completed phase I and phase IIa clinical trials, which have shown that ASC09 has potent anti-viral activity, and is safe and well-tolerated. After two weeks of treatment of mono-therapy, ASC09 demonstrated up to a 1.79 log viral load decrease (62-fold reduction of viral load in blood samples of patients). ASC09 has unprecedented genetic barrier to resistance. Studies have shown that ASC09 requires more than seven mutations before HIV develops resistance to ASC09, indicating that ASC09 has a high genetic barrier to resistance compared to other approved protease inhibitors. The high genetic barrier to resistance makes ASC09 a promising candidate for HIV-therapy for both treatment-naïve and treatment-experienced patients.
Current Therapies and Limitations
Currently, there is no cure for HIV/AIDS. Current HIV treatments need to be taken for a lifetime. The currently available primary HIV therapy in China is a combination therapy of nucleos(t)ide reverse transcriptase inhibitors (“NRTIs”) and non-nucleos(t)ide reverse transcriptase inhibitors (“NNRTIs”). Although such combination therapy is available in China, patients taking such therapy, such as Lopinavir, may develop drug resistance. As a result, HIV patients generally will turn to a combination therapy of protease inhibitors and NRTIs.
We believe only one HIV protease inhibitor, Lopinavir, was approved and marketed in China. Limitations of this drug primarily include:
• Resistance. During life-long treatments, many HIV patients have or may develop viral resistance mutations that lower the effectiveness of the treatment. Resistance to protease inhibitor drugs remains a critical factor in the failure of antiretroviral therapy. Patients in China failing approved protease inhibitors due to the emergence of resistant viruses face limited therapeutic options.
• Tolerability. Because current HIV treatments are life-long treatments, prolonged use of protease inhibitors has side effects, including dyslipidemia, insulin-resistance, lipodystrophy and cardiovascular and cerebrovascular diseases. Thus, there is a strong need for safer HIV treatments.
Advantages of ASC09F
We believe that, based on clinical trials and pre-clinical studies, ASC09F has the potential to be a best-in-class HIV protease inhibitor and address the limitations of current HIV therapy in the following aspects:
• Anti-viral activity. A phase IIa clinical trial has shown that ASC09 displayed similar high anti-viral potency for patients with three or more protease inhibitor resistance-associated mutations as well as for patients with less than three protease inhibitor resistance-associated mutations at baseline. After two weeks of mono-therapy, ASC09 demonstrated up to a 1.79 log viral load decrease (62-fold reduction of viral load in blood samples of patients).
• Safety and tolerability. The phase IIa clinical trial has indicated that short-term treatment with ASC09 boosted by ritonavir was generally safe and well tolerated. We believe ASC09F has strong potential to be a more tolerable alternative to current therapies for HIV.
• Unprecedented genetic barrier to resistance. During the lifetime treatment, almost all patients will develop resistance to protease inhibitors. Therefore, HIV protease inhibitors with high genetic barrier to resistance have a significant therapeutic advantage over those protease inhibitors with low genetic barrier to resistance. Studies have shown that ASC09 requires more than seven mutations before HIV develop resistance to ASC09, indicating ASC09 has high genetic barrier to resistance compared to other approved protease inhibitors. The high genetic barrier to resistance makes ASC09 a promising candidate for HIV-therapy for both treatment-naïve and treatment-experienced patients. ASC09 is more active than any of the approved protease inhibitors against multi-protease inhibitors resistant clinical isolates.
• High anti-viral activity against DRV-resistant viral strains. Darunavir (DRV) is considered to be a best-in-class protease inhibitor among approved protease inhibitors globally. Virological studies suggest that ASC09 is a promising candidate for 72% clinical isolates resistant to DRV, indicating ASC09 has the potential to be the best-in-class protease inhibitor.
|Anti-PD-L1 antibody ASC22 in combination with chidamide potentiates HIV latency reversal and immune function from ART-suppressed individuals: a single center,single-arm,phase Ⅱ study||The 12th International AIDS Society (IAS) Conference (IAS 2023)||Poster||7/2023|
|A phase 2 study of ASC42, a novel farnesoid X receptor (FXR) agonist, in combination with PEGylated interferon (PEG-IFN) and entecavir (ETV) in chronic hepatitis B patients with 12-week treatment||The International Liver Congress™ 2023 of the European Association for the Study of the Liver (EASL)||Poster||6/2023|
|The 33rd European Congress of Clinical Microbiology & Infectious Diseases(ECCMID) 2023||Poster||4/2023|
|Effects of Subcutaneous PD-L1 Antibody ASC22 (Envafolimab) Plus nucleos(t)ide analogs on HBsAg reduction in patients with chronic hepatitis B infection are correlated with pre-treatment HBsAg level||The 2023 Annual Meeting of the Asian Pacific Association for the Study of the Liver (APASL)||Oral||2/2023|
|ALT flares were linked to HBsAg reduction, seroclearance and seroconversion: interim results from a Phase IIb study in chronic hepatitis B patients with 24-week treatment of subcutaneous PD-L1 antibody ASC22 (Envafolimab) plus nucleos(t)ide analogs||The International Liver Congress™ 2022 of the European Association for the Study of the Liver (EASL)||Oral||6/2022|
|Significant in vitro and in vivo inhibition of HBsAg and HBV pgRNA with ASC42, a novel non-steroidal FXR agonist||The International Liver Congress™ 2021 of the European Association for the Study of the Liver (EASL)||Poster|