Pipeline
Drawing upon our extensive experience in developing therapeutics for chronic liver diseases and viral infections, we are building a pipeline of potentially best-in-class drug candidates. These drug candidates target multiple clinically validated mechanisms of action and are designed to become transformative treatment options MASH and viral diseases.
Chronic Hepatitis B
Chronic hepatitis B (CHB) is the most common chronic viral infection in the world and an area of substantial unmet medical need.4 There were over 290 million chronic carriers worldwide as of July 2020 and approximately 30 million individuals become newly infected every year despite the availability of a prophylactic vaccine. In 2015, there were more than 90 million cases of CHB in China alone, while the EU, United States and Japan accounted for nearly 8 million cases. Complications from CHB include cirrhosis, end-stage liver disease, and hepatocellular carcinoma, which collectively resulted in approximately 900,000 deaths in 2015, according to the World Health Organization. CHB is the primary cause of liver cancer worldwide, and the mortality associated with HBV-related liver cancer continues to increase.
We are developing a portfolio of wholly owned drug candidates with distinct mechanisms of action that are designed to disrupt the life cycle and associated immunosuppressed state of CHB: capsid assembly modulators (CAMs), small interfering RNAs (siRNA) and orally delivered inhibitors of the programmed death ligand-1 receptor (PD-L1). These drug candidates are designed to disrupt hepatitis B cccDNA levels and derived transcripts (CAM, siRNA) by reducing expression of viral markers such as surface antigen (HBsAg), DNA, and RNA or boosting the host immune response to HBV-infected hepatocytes (oral PD-L1 inhibitor). We believe a combination of these drug candidates with their distinct mechanisms of action, possibly in combination with existing treatment regimens such as nucleos(t)ide analogs and interferons, or other exploratory agents, can result in enhanced rates of functional cure in CHB. Our CAM (ALG-000184) and siRNA (ALG-125755) drug candidates are currently being evaluated in Phase 1 studies in CHB subjects, while our PD-L1 inhibitor program is currently in the Discovery phase.
Chronic Hepatitis B
Chronic hepatitis B (CHB) is the most common chronic viral infection in the world and an area of substantial unmet medical need.4 There were over 290 million chronic carriers worldwide as of July 2020 and approximately 30 million individuals become newly infected every year despite the availability of a prophylactic vaccine. In 2015, there were more than 90 million cases of CHB in China alone, while the EU, United States and Japan accounted for nearly 8 million cases. Complications from CHB include cirrhosis, end-stage liver disease, and hepatocellular carcinoma, which collectively resulted in approximately 900,000 deaths in 2015, according to the World Health Organization. CHB is the primary cause of liver cancer worldwide, and the mortality associated with HBV-related liver cancer continues to increase.
We are developing a portfolio of wholly owned drug candidates with distinct mechanisms of action that are designed to disrupt the life cycle and associated immunosuppressed state of CHB: capsid assembly modulators (CAMs), small interfering RNAs (siRNA) and orally delivered inhibitors of the programmed death ligand-1 receptor (PD-L1). These drug candidates are designed to disrupt hepatitis B cccDNA levels and derived transcripts (CAM, siRNA) by reducing expression of viral markers such as surface antigen (HBsAg), DNA, and RNA or boosting the host immune response to HBV-infected hepatocytes (oral PD-L1 inhibitor). We believe a combination of these drug candidates with their distinct mechanisms of action, possibly in combination with existing treatment regimens such as nucleos(t)ide analogs and interferons, or other exploratory agents, can result in enhanced rates of functional cure in CHB. Our CAM (ALG-000184) and siRNA (ALG-125755) drug candidates are currently being evaluated in Phase 1 studies in CHB subjects, while our PD-L1 inhibitor program is currently in the Discovery phase.
Chronic Hepatitis B
Chronic hepatitis B (CHB) is the most common chronic viral infection in the world and an area of substantial unmet medical need.4 There were over 290 million chronic carriers worldwide as of July 2020 and approximately 30 million individuals become newly infected every year despite the availability of a prophylactic vaccine. In 2015, there were more than 90 million cases of CHB in China alone, while the EU, United States and Japan accounted for nearly 8 million cases. Complications from CHB include cirrhosis, end-stage liver disease, and hepatocellular carcinoma, which collectively resulted in approximately 900,000 deaths in 2015, according to the World Health Organization. CHB is the primary cause of liver cancer worldwide, and the mortality associated with HBV-related liver cancer continues to increase.
We are developing a portfolio of wholly owned drug candidates with distinct mechanisms of action that are designed to disrupt the life cycle and associated immunosuppressed state of CHB: capsid assembly modulators (CAMs), small interfering RNAs (siRNA) and orally delivered inhibitors of the programmed death ligand-1 receptor (PD-L1). These drug candidates are designed to disrupt hepatitis B cccDNA levels and derived transcripts (CAM, siRNA) by reducing expression of viral markers such as surface antigen (HBsAg), DNA, and RNA or boosting the host immune response to HBV-infected hepatocytes (oral PD-L1 inhibitor). We believe a combination of these drug candidates with their distinct mechanisms of action, possibly in combination with existing treatment regimens such as nucleos(t)ide analogs and interferons, or other exploratory agents, can result in enhanced rates of functional cure in CHB. Our CAM (ALG-000184) and siRNA (ALG-125755) drug candidates are currently being evaluated in Phase 1 studies in CHB subjects, while our PD-L1 inhibitor program is currently in the Discovery phase.
NASH (NonAlcoholic Steatohepatitis)
One of the effects of improper diet and insufficient exercise is the accumulation of fatty deposits in the liver, referred to as nonalcoholic fatty liver disease (“NAFLD”), which was estimated to occur in approximately 25% of the worldwide population as of 2015.¹ At that time, an estimated 1.5% to 6.5% of the global population was believed to have an ongoing inflammatory response to these excess fat deposits, which is referred to as nonalcoholic steatohepatitis (NASH). In the United States alone, the prevalence of NASH is projected to increase from approximately 16.5 million in 2015 to 27.0 million in 2030.²
In the absence of changes in diet and exercise, the inflammation inherent in NASH persists and may result in progressive fibrosis of the liver, which may result in cirrhosis. These fibrotic changes are associated with numerous morbidities including recurrent hospitalization for complications of cirrhosis, hepatocellular carcinoma, need for liver transplant, and death.
The only widely accepted treatment for NASH is weight loss through behavioral modifications such as diet and exercise, which is difficult to achieve at the broad population level. As there are currently no approved drugs to treat NASH, many development programs are underway to identify drugs to address this growing epidemic. One of the most promising MOAs in the NASH space appears to be drugs which preferentially target the beta subtype of the thyroid hormone receptor (THR-β). Multiple drug candidates in this class have shown improvements in liver fat deposits in Phase 2 studies and one of these drugs has recently been shown to reduce liver inflammation and fibrosis in a large Phase 3 study.3 Our lead THR-β drug candidate, ALG-055009, will be evaluated in a Phase 2a study in NASH subjects in 2024 with top line data expected at the end of 2024.
NASH (NonAlcoholic SteatoHepatitis)
One of the effects of improper diet and insufficient exercise is the accumulation of fatty deposits in the liver, referred to as nonalcoholic fatty liver disease (“NAFLD”), which was estimated to occur in approximately 25% of the worldwide population as of 2015.¹ At that time, an estimated 1.5% to 6.5% of the global population was believed to have an ongoing inflammatory response to these excess fat deposits, which is referred to as nonalcoholic steatohepatitis (NASH). In the United States alone, the prevalence of NASH is projected to increase from approximately 16.5 million in 2015 to 27.0 million in 2030.²
In the absence of changes in diet and exercise, the inflammation inherent in NASH persists and may result in progressive fibrosis of the liver, which may result in cirrhosis. These fibrotic changes are associated with numerous morbidities including recurrent hospitalization for complications of cirrhosis, hepatocellular carcinoma, need for liver transplant, and death.
The only widely accepted treatment for NASH is weight loss through behavioral modifications such as diet and exercise, which is difficult to achieve at the broad population level. As there are currently no approved drugs to treat NASH, many development programs are underway to identify drugs to address this growing epidemic. One of the most promising MOAs in the NASH space appears to be drugs which preferentially target the beta subtype of the thyroid hormone receptor (THR-β). Multiple drug candidates in this class have shown improvements in liver fat deposits in Phase 2 studies and one of these drugs has recently been shown to reduce liver inflammation and fibrosis in a large Phase 3 study.3 Our lead THR-β drug candidate, ALG-055009, will be evaluated in a Phase 2a study in NASH subjects in 2024 with top line data expected at the end of 2024.
Coronavirus
SARS-CoV-2, the coronavirus responsible for the ongoing COVID-19 pandemic, has caused widespread morbidity and mortality throughout the world since 2019. Early in the pandemic, we initiated a program to identify purpose-built drug candidates with pan-coronavirus activity, including against SAR-CoV-2. Through a collaboration with Prof. Johan Neyts and CD3 at the Rega Institute, we have identified multiple promising pan-coronavirus protease inhibitors (PI) which are more potent than other known PIs in development and do not require ritonavir boosting. Our lead drug candidate, ALG-097558, is currently being evaluated in a Phase 1 study in healthy volunteers.
Coronavirus
SARS-CoV-2, the coronavirus responsible for the ongoing COVID-19 pandemic, has caused widespread morbidity and mortality throughout the world since 2019. Early in the pandemic, we initiated a program to identify purpose-built drug candidates with pan-coronavirus activity, including against SAR-CoV-2. Through a collaboration with Prof. Johan Neyts and CD3 at the Rega Institute, we have identified multiple promising pan-coronavirus protease inhibitors (PI) which are more potent than other known PIs in development and do not require ritonavir boosting. Our lead drug candidate, ALG-097558, is currently being evaluated in a Phase 1 study in healthy volunteers.
MOA (Mechanism of Action)
Chronic Hepatitis B
CHB is the most common viral infection in the world and an area of substantial unmet medical need.1 There were over 290 million chronic carriers worldwide as of July 2020 and approximately 30 million individuals become newly infected every year despite the availability of a prophylactic vaccine. In 2015, there were more than 90 million cases of CHB in China alone, while the EU, United States and Japan accounted for nearly 8 million cases. Complications from CHB include cirrhosis, end-stage liver disease, and hepatocellular carcinoma, which collectively resulted in approximately 900,000 deaths in 2015, according to the World Health Organization. CHB is the primary cause of liver cancer worldwide, and the mortality associated with HBV-related liver cancer continues to increase.
We are developing a portfolio of wholly owned drug candidates targeting four distinct mechanisms of action: STOPS™, ASO, siRNA and CAM, each of which has been clinically validated in CHB patients. These drug candidates are designed to reduce S-antigen (HBsAg) and/or HBV DNA/RNA, which may lead to higher rates of functional cure in a significant percentage of CHB patients, relative to existing standard of care treatment options.
CAMs (Capsid Assembly Modulators)
Suppressing HBV replication: CAMs are small molecules that interfere with HBV capsid (dis)assembly and viral replication. In clinical trials, CAMs have demonstrated significant reductions in HBV DNA and RNA in patients with CHB.2,3 We have optimized a proprietary class II CAM series (those that result in the formation of non-infectious empty viral particles) that demonstrate substantially higher potency in preclinical studies compared to other CAM molecules currently in clinical development.4 Our lead molecule ALG-000184 will enter the clinic in the second half of 2020.
siRNA (Small interfering ribonucleic acids)
Suppressing HBsAg: siRNAs are a selective means of inhibiting HBV mRNA transcripts that encode HBsAg. siRNAs in clinical development have been shown to substantially reduce HBsAg levels.10 We have selected ALG-125097, a potentially best-in-class siRNA for advancement into clinical development.
NASH
One of the effects of improper diet and insufficient exercise is the accumulation of fatty deposits in the liver, referred to as nonalcoholic fatty liver disease (“NAFLD”), which was estimated to occur in approximately 25% of the worldwide population as of 2015. At that time, an estimated 1.5% to 6.5% of the global population was estimated to have an ongoing inflammatory response to these excess fat deposits, which is referred to as nonalcoholic steatohepatitis (NASH).11 In the United States alone, the prevalence of NASH is projected to increase from approximately 16.5 million in 2015 to 27.0 million in 2030.12
In the absence of changes in diet and exercise, the inflammation inherent in NASH persists and may result in progressive fibrosis of the liver, which may result in cirrhosis. These fibrotic changes are associated with numerous morbidities including recurrent hospitalization for complications of cirrhosis, hepatocellular carcinoma, need for liver transplant, and death.
The only widely accepted treatment for NASH is weight loss through behavioral modifications such as diet and exercise, which is difficult to achieve at the broad population level. As there are currently no approved drugs to treat NASH, many development programs are underway to identify drugs to address this epidemic. One of the promising MOAs in the NASH space appears to be drugs which preferentially target the beta subtype of the THR receptor (THR-β).
THR-β (Thyroid hormone receptor beta) agonists
Several THR-β agonists are currently in the clinic and have demonstrated favorable effects on plasma lipid levels, liver fat burden, as well as liver histology in NASH patients.13,14 Our lead THR-β agonist,
ALG-055009, appears to have best-in-class properties compared to other compounds currently in the clinic.15
Coronavirus
SARS-CoV-2, the coronavirus responsible for the ongoing COVID-19 pandemic, has caused widespread morbidity and mortality throughout the world. We have initiated multiple discovery programs to identify purpose-built drug candidates with pan-coronavirus activity, including against SAR-CoV-2. Protease inhibitors have proved highly effective in the treatment of other viral infections such as HIV and HCV and we have initiated a collaboration with Prof. Johan Neyts and CD3 at the Rega Institute to develop a protease inhibitor. We have also initiated efforts to identify oligonucleotide drug candidates.
References:
- Younossi et al., Hepatology, 2016; 64(1): 73-84
- Estes et al., Hepatology, 2018; 67(1): 123-133
- Harrison et al., EASL (GS-001), 2023
- Global Hepatitis Report (2017, World Health Organization) and hepb.org