Pipeline

Novel Drugs to
Treat Intractable Diseases

Drug(indication)
Indication
Pre-clinical
Phase 1
Phase 2
Phase 3
Launch
  • ARC-520 (Hepatitis B)
    Hepatitis B
  • ARC-521 (Hepatitis B)
    Hepatitis B
  • ARC-AAT (Alpha-1 Antitrypsin Deficiency)
    Alpha-1 Antitrypsin Deficiency
  • ARC-F12 (Thrombosis and Angioedema)
    Thrombosis and Angioedema
  • ARC-LPA (Cardiovascular Disease)
    Cardiovascular Disease
  • ARC-HIF2 (Clear Cell, Renal Cell Carcinoma)
    Clear Cell, Renal Cell Carcinoma

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. Our clinical programs address diseases of the liver and our expanding preclinical pipeline of RNAi therapeutics includes both intravenous and subcutaneously administered, liver-targeted and extra-hepatic candidates.

ARC-520

Arrowhead’s ARC-520 and ARC-521 are designed to be potentially curative therapies for patients with chronic hepatitis B infection. ARC-520 and ARC-521 silence all HBV gene products and intervene upstream of the reverse transcription process where current standard-of-care nucleotide and nucleoside analogues act. The company believes this will allow the body’s natural immune defenses to clear the virus and lead to a functional cure.

Disease

Chronic hepatitis B infection is the most common serious liver infection. Current drugs suppress viral replication but rarely lead to a cure and therefore must be taken indefinitely. Developing curative therapy is a priority.

There are 16 million people with chronic hepatitis B in the U.S. and Western Europe and 400 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. Interferon therapeutics can result in a functional cure in around 10% of some patient types, but treatment is often associated with significant side effects, including severe flu-like symptoms, bone marrow suppression, and autoimmune disorders.

Clinical Trials

Study Name: Heparc-1001

Stage: Phase 1 Status: Enrollment Complete Description:

Single dose escalation study in healthy volunteers to evaluate safety and tolerability of ARC-520

ClinicalTrials.gov Identifier: NCT01872065

Study Name: Heparc-1002

Stage: Phase 1 Status: Enrolling Description:

Single dose study to evaluate tolerability of increasing infusion rates of ARC-520

ClinicalTrials.gov Identifier: NCT02535416

Study Name: Heparc-2001

Stage: Phase 2a Status: Enrollment Complete Description:

Single dose escalation study in HBV patients to evaluate reduction in viral antigens in response to ARC-520

ClinicalTrials.gov Identifier: NCT02065336

Study Name: Heparc-2001 OLE

Stage: Phase 2a Status: Enrolling Description:

Open label multi-dose extension study in patients completing Heparc-2001

ClinicalTrials.gov Identifier: NCT02065336

Study Name: Heparc-2002

Stage: Phase 2b Status: Enrolling Description:

Multi-dose study to determine the depth of HBsAg reduction in response to ARC-520 in combination with entecavir or tenofovir in HBeAg negative patients

ClinicalTrials.gov Identifier: NCT02604199

Study Name: Heparc-2003

Stage: Phase 2b Status: Enrolling Description:

Multi-dose study to determine the depth of HBsAg reduction in response to ARC-520 in combination with entecavir or tenofovir in HBeAg positive patients

ClinicalTrials.gov Identifier: NCT02604212

Study Name: Heparc-2004

Stage: Phase 2b Status: Enrolling Description:

Multi-dose study to determine the depth of HBsAg reduction in response to ARC-520 in combination with entecavir or tenofovir in HBeAg positive patients

ClinicalTrials.gov Identifier: NCT02452528

Study Name: Heparc-2007

Stage: Phase 2b Status: Enrolling Description:

Open label multi-dose extension study for patients completing Heparc-2002 and Heparc-2003

ClinicalTrials.gov Identifier: NCT02738008

Study Name: Heparc-2008 (MONARCH)

Stage: Phase 2b Status: Enrolling Description:

Open label multi-dose study to evaluate ARC-520 alone and in combination with other therapeutics in patients with chronic HBV

ClinicalTrials.gov Identifier: NCT02577029
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ARC-521

Arrowhead’s ARC-520 and ARC-521 are designed to be potentially curative therapies for patients with chronic hepatitis B infection. ARC-520 and ARC-521 silence all HBV gene products and intervene upstream of the reverse transcription process where current standard-of-care nucleotide and nucleoside analogues act. The company believes this will allow the body’s natural immune defenses to clear the virus and lead to a functional cure.

Disease

Chronic hepatitis B infection is the most common serious liver infection. Current drugs suppress viral replication but rarely lead to a cure and therefore must be taken indefinitely. Developing curative therapy is a priority.

There are 16 million people with chronic hepatitis B in the U.S. and Western Europe and 400 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. Interferon therapeutics can result in a functional cure in around 10% of some patient types, but treatment is often associated with significant side effects, including severe flu-like symptoms, bone marrow suppression, and autoimmune disorders.

Clinical Trials

Study Name: ARC521-1001

Stage: Phase 1/2 Status: Enrolling Description:

Single and multiple dose escalation study to evaluate safety and tolerability and antiviral activity of ARC-521 in healthy volunteers and HBV patients

ClinicalTrials.gov Identifier: NCT02797522
Read More »

ARC-AAT

ARC-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. ARC-AAT has been granted Orphan Drug Designation in both the U.S. and the E.U.

ARC-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.

Disease

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.

Clinical Trials

Study Name: ARCAAT-1001

Stage: Phase 1a/1b Status: Enrolling Description:

Single dose escalation study to determine the safety, tolerability and effect on circulating alpha-1 antitrypsin levels of ARC-AAT in healthy volunteers and patients

ClinicalTrials.gov Identifier: NCT02363946
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ARC-F12

ARC-F12 is in preclinical development as a potential treatment for factor 12 (F12) mediated diseases such as hereditary angioedema (HAE) and thromboembolic disorders. Factor 12 initiates the intrinsic coagulation pathway and reducing its production using Arrowhead’s RNAi technology may present opportunities in both disease areas.

Disease

Thrombosis is the formation of blood clots that can obstruct blood flow. Broadly speaking, thrombosis can occur in veins or arteries and may cause serious repercussions if not treated. HAE is a rare genetic disorder with a prevalence of approximately 1/5,000-1/10,000. Patients with HAE can experience recurrent and dangerous acute inflammatory attacks in multiple tissues, with attacks of laryngeal edema being particularly serious and potentially fatal.

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ARC-LPA

ARC-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. ARC-LPA is Arrowhead’s first drug candidate to use a subcutaneously administered delivery construct.

Disease

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.

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ARC-HIF2

ARC-HIF2 is being developed as a promising new drug candidate for the treatment of clear cell renal cell carcinoma (ccRCC). ARC-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.

ARC-HIF2 is Arrowhead’s first therapeutic candidate delivered using its new Dynamic Polyconjugate™ designed to target tissues outside of the liver.

Disease

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.

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