ARO-AAT (Alpha-1 Liver Disease)Alpha-1 Liver DiseasePartnered with Takeda
ARO-HSD (Liver Disease)Liver Disease
ARO-C3 (Complement Mediated Disease)Complement Mediated Disease
ARO-ENaC (Cystic Fibrosis)Cystic Fibrosis
ARO-COV (COVID-19 )COVID-19
ARO-HIF2 (Renal Cell Carcinoma)Renal Cell Carcinoma
ARO-XDH (Gout)GoutPartnered with Horizon
JNJ-3989 (Hepatitis B)Hepatitis BLicensed to Janssen
AMG 890 (Cardiovascular Disease)Cardiovascular DiseaseLicensed to Amgen
JNJ-75220795 (NASH)NASHLicensed to Janssen
ARO-JNJ2 (Undisclosed)UndisclosedPartnered with Janssen
ARO-JNJ3 (Undisclosed)UndisclosedPartnered with Janssen
Pipeline Development Strategy
Arrowhead is focused on developing innovative drugs for diseases with a genetic basis, characterized by the overproduction of one or more proteins. The depth and versatility of our RNAi technologies enable us to address conditions in virtually any therapeutic area and pursue disease targets that are not otherwise druggable by small molecules and biologics.
ARO-AAT is being developed to treat the liver disease associated with alpha-1 antitrypsin deficiency (AATD), a rare genetic disorder that severely damages the liver and lungs of affected individuals.
ARO-AAT is designed to knock down the hepatic production of the mutant alpha-1 antitrypsin (Z-AAT) protein, the cause of progressive liver disease in AATD patients. Reducing production of the inflammatory Z-AAT protein is expected to halt the progression of liver disease and potentially allow it to regenerate and repair.
AATD is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AAT is primarily synthesized and secreted by liver hepatocytes. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, the Z mutant, has a single amino acid substitution that results in improper folding of the protein. The mutant protein cannot be effectively secreted and accumulates in globules inside the hepatocytes. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.
Individuals with the homozygous PiZZ genotype have severe deficiency of functional AAT leading to pulmonary disease and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant, with its attendant morbidity and mortality, is currently the only available cure.
Study Name: Study of ARO-AAT in Normal Adult Volunteers
A Phase 1 Single and Multiple Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Effect of ARO-AAT on Serum Alpha-1 Antitrypsin Levels in Normal Adult VolunteersClinicalTrials.gov Identifier: NCT03362242
Study Name: Assessment of Changes in a Novel Histological Activity Scale in Response to ARO-AAT
A Pilot Open Label, Multi-dose, Phase 2 Study to Assess Changes in a Novel Histological Activity Scale in Response to ARO-AAT in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)ClinicalTrials.gov Identifier: NCT03946449
Study Name: Safety, Tolerability and Effect on Liver Histologic Parameters of ARO-AAT (SEQUOIA)
SEQUOIA – A Placebo-Controlled, Multi-dose, Phase 2/3 Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters in Response to ARO-AAT in Patients With Alpha-1 Antitrypsin Deficiency (AATD)ClinicalTrials.gov Identifier: NCT03945292
ARO-APOC3 is designed to reduce production of Apolipoprotein C-III (apoC-III), a component of triglyceride rich lipoproteins (TRLs) including VLDL and chylomicrons and is a key regulator of triglyceride metabolism. The company believes that knocking down the hepatic production of apoC-III may result in reduced VLDL synthesis and assembly, enhanced breakdown of TRLs, and better clearance of VLDL and chylomicron remnants.
Elevated triglyceride levels are an independent risk factor for cardiovascular disease. Severely elevated triglycerides (often over 2,000 mg/dL) in patients with familial chylomicronemia syndrome (FCS), a rare genetic disorder, can result in potentially fatal, acute pancreatitis.
Study Name: Study of ARO-APOC3 in Healthy Volunteers, Hypertriglyceridemic Patients and Patients With Familial Chylomicronemia Syndrome (FCS)
A Phase 1 Single and Multiple Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of ARO-APOC3 in Adult Healthy Volunteers as Well as in Severely Hypertriglyceridemic Patients and Patients With Familial Chylomicronemia SyndromeClinicalTrials.gov Identifier: NCT03783377
ARO-ANG3 is designed to reduce production of angiopoietin-like protein 3 (ANGPTL3), a liver synthesized inhibitor of lipoprotein lipase and endothelial lipase. ANGPTL3 inhibition has been shown to lower serum LDL, serum and liver triglyceride and has genetic validation as a novel target for cardiovascular disease.
Hyperlipidemia and hypertriglyceridemia are risk factors for atherosclerotic coronary heart disease and cardiovascular events.
Study Name: Study of ARO-ANG3 in Healthy Volunteers and in Dyslipidemic Patients
A Phase 1 Single and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of ARO-ANG3 in Adult Healthy Volunteers and in Dyslipidemic PatientsClinicalTrials.gov Identifier: NCT03747224
ARO-HSD is designed to reduce production of HSD17B13, a hydroxysteroid dehydrogenase involved in the metabolism of hormones, fatty acids and bile acids. Human genetic studies indicate that loss-of-function mutations in HSD17B13 provide risk-reduction for development of both alcohol related and non-alcohol related liver disease.
Study Name: Study of ARO-HSD in Healthy Volunteers and Patients With Non-Alcoholic Steatohepatitis (NASH) or Suspected NASH
A Phase 1 Single and Multiple Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of ARO-HSD in Normal Healthy Volunteers as Well as in Patients With NASH or Suspected NASHClinicalTrials.gov Identifier: NCT04202354
ARO-C3 is designed to reduce production of complement component 3 as a potential treatment for various complement mediated diseases.
ARO-ENaC is designed to reduce production of the epithelial sodium channel alpha subunit (αENaC) in the airways of the lung. In cystic fibrosis patients, increased ENaC activity contributes to airway dehydration and reduced mucociliary transport.
Cystic fibrosis (CF) is a rare disease caused by a genetic mutation that leads to mucus buildup in the lungs and pancreas. In CF lung disease, patients can have difficulty breathing and experience frequent and persistent lung infections.
Study Name: Study of ARO-ENaC in Healthy Volunteers and in Patients With Cystic Fibrosis
A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic Effects of ARO-ENaC in Normal Healthy Volunteers and Safety, Tolerability and Efficacy in Patients With Cystic FibrosisClinicalTrials.gov Identifier: NCT04375514
ARO-Lung2 is being developed against an undisclosed target as a potential treatment for chronic obstructive pulmonary disorder (COPD).
ARO-COV is being developed to address the current novel coronavirus that causes COVID-19 and other possible future pulmonary-borne pathogens.
ARO-HIF2 is being developed as a promising new drug candidate for the treatment of clear cell renal cell carcinoma (ccRCC). ARO-HIF2 is designed to inhibit the production of HIF-2α, which has been linked to tumor progression and metastasis in ccRCC. Arrowhead believes it is an attractive target for intervention because over 90% of ccRCC tumors express a mutant form of the Von Hippel-Landau protein that is unable to degrade HIF-2α, leading to its accumulation during tumor hypoxia and promoting tumor growth.
ARO-HIF2 is Arrowhead’s first therapeutic candidate delivered using a new extra-hepatic delivery vehicle.
Renal cell carcinoma is a type of kidney cancer that originates in the cells that line the small tubes that filter waste material from the blood. RCC is the most common type of kidney cancer accounting for more than 90% of cases with approximately 50,000 diagnoses in the U.S. each year.
Unfortunately, patients with advanced stages of RCC have a 5-year survival rate of only 12-25%. Surgical resection is the mainstay of current treatment while chemotherapy and radiation have not been successful at prolonging survival. The treatment options for patients with metastatic disease are extremely limited.
Study Name: Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma
A Phase 1b Adaptive Dose-Finding Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell CarcinomaClinicalTrials.gov Identifier: NCT04169711
ARO-DUX4 is designed to target the gene that encodes human double homeobox 4 (DUX4) protein as a potential treatment for patients with facioscapulohumeral muscular dystrophy (FSHD). FSHD is an autosomal dominant disease associated with the failure to maintain complete epigenetic suppression of DUX4 expression in differentiated skeletal muscle, leading to overexpression of DUX4, which is myotoxic and can lead to muscle degeneration.
ARO-XDH is an investigational RNAi therapeutic being developed under a collaboration and license agreement with Horizon Therapeutics targeting xanthine dehydrogenase as a potential treatment for people with uncontrolled gout.
JNJ-3989, formerly ARO-HBV, is being developed in collaboration with Janssen Pharmaceuticals, Inc. to be a potentially curative therapy for patients with chronic hepatitis B infection, when used in combination with other direct antivirals. JNJ-3989 is a sub-cutaneous, ribonucleic acid interference (RNAi) therapy candidate which is designed to silence all HBV gene products and intervenes upstream of the reverse transcription process where current standard-of-care nucleotide and nucleoside analogues act. The company believes this may allow the body’s natural immune defenses to clear the virus and potentially lead to a functional cure.
Chronic hepatitis B viral infection, caused by HBV, is a potentially fatal liver disease Current drugs suppress viral replication but rarely lead to a functional cure and therefore must be taken indefinitely. Developing curative therapy is a priority.
There are approximately 300 million people worldwide. In the immune tolerant phase of chronic infection, which can last for many years, the infected person typically produces very high levels of viral DNA and viral antigens. However, the infection is not cytotoxic and the carrier may have no symptoms of illness. Over time, the ongoing production of viral antigens causes inflammation and necrosis, leading to cirrhosis and liver cancer (HCC). Hepatitis B is responsible for 80% of primary liver cancers.
The current standard of care for treatment of chronic HBV infection is a daily oral dose of nucleotide/nucleoside analogs (NUCs) or a regimen of interferon injections for approximately one year. NUCs are generally well tolerated, but patients may need lifetime treatment because viral replication often rebounds upon cessation of treatment. Treatment with pegylated interferon for up to 2 years can lead to functional cure in up to 10% of treated patients, however this regime is poorly tolerated and not widely used.
Study Name: Study of ARO-HBV in Normal Adult Volunteers and Patients With Hepatitis B Virus (HBV)
A Phase 1/2a Single Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic Effects of ARO-HBV in Normal Adult Volunteers and Multiple Escalating Doses Evaluating Safety, Tolerability and Pharmacodynamic Effects in HBV PatientsClinicalTrials.gov Identifier: NCT03365947
Study Name: A Study of JNJ-73763989 in Healthy Japanese Adult Participants
A Double-blind, Placebo-controlled, Randomized, Parallel, Single Dose Study to Investigate Pharmacokinetics, Safety, and Tolerability of JNJ-73763989 in Healthy Japanese Adult ParticipantsClinicalTrials.gov Identifier: NCT04002752
Study Name: A Study of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection (REEF-1)
A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to Investigate the Efficacy and Safety of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus InfectionClinicalTrials.gov Identifier: NCT03982186
Study Name: A Study of JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection
A Randomized, Double Blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, Pharmacokinetics, and Safety of 48-week Study Intervention With JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus InfectionClinicalTrials.gov Identifier: NCT04129554
AMG 890 (formerly ARO-LPA) is designed to reduce production of apolipoprotein A, a key component of lipoprotein(a), which has been genetically linked with increased risk of cardiovascular diseases, independent of cholesterol and LDL levels. Amgen acquired a worldwide, exclusive license in September 2016, to develop and commercialize AMG 890.
Elevated lipoprotein(a), or Lp(a), is widely viewed as a key risk factor for cardiovascular diseases, including coronary artery disease, atherosclerosis, thrombosis and stroke.
JNJ-75220795 is an investigational siRNA therapeutic developed using Arrowhead’s proprietary TRIMTM platform and designed to reduce expression in the liver of patatin like phospholipase domain containing 3 (PNPLA3) as a potential treatment for patients with non-alcoholic steatohepatitis (NASH). PNPLA3 has strong genetic and preclinical validation as a driver of fat accumulation and damage in the livers of patients who carry the common I148M mutation.
Arrowhead entered into a research collaboration and option agreement with Janssen in October 2018, which resulted in collaboration on JNJ-75220795
ARO-JNJ2 is being developed against an undisclosed liver-expressed target as part of a research collaboration and option agreement with Janssen Pharmaceuticals, Inc.
ARO-JNJ3 is being developed against an undisclosed liver-expressed target as part of a research collaboration and option agreement with Janssen Pharmaceuticals, Inc.