GSK Acquires Innovative Hepatitis B Therapies from Ionis, Paving the Way Toward Functional Cure

Today, Ionis Pharmaceuticals, a company focused on developing antisense oligonucleotide (ASO) drugs targeting RNA, announced that GSK will exercise its option to acquire the development and commercialization rights for two investigational therapies, IONIS-HBVRx and IONIS-HBV-LRx, based on positive results from Phase 2 clinical trials in patients with chronic hepatitis B (CHB). In recent years, innovative therapies targeting hepatitis B virus gene expression have demonstrated promising efficacy in clinical trials. Could they herald the dawn of a “functional cure” for hepatitis B?

Chronic hepatitis B virus (HBV) infection is the most common serious liver infection worldwide and is highly contagious, affecting over 200 million people globally. The virus is transmitted through contact with the blood and body fluids of infected individuals, with a transmissibility 50 to 100 times higher than that of HIV. Although many patients with chronic hepatitis B exhibit no obvious symptoms, they still maintain high levels of viral DNA and antigens. Persistent long-term antigen expression leads to inflammation and hepatocellular necrosis, thereby contributing to the development of liver cirrhosis and hepatocellular carcinoma.

The current standard of care for chronic hepatitis B is oral nucleotide/nucleoside analogs (NUCs) or interferon injections. Although NUCs are well tolerated, viral replication rapidly rebounds upon discontinuation of therapy, necessitating lifelong medication for patients. Therefore, the development of innovative therapies that address the root cause of the disease remains a shared expectation and goal for both patients and researchers.

▲Diagram of Ionis antisense therapy (Image source: Ionis official website)

IONIS-HBVRx and IONIS-HBV-LRx, antisense oligonucleotide drugs developed by Ionis Pharmaceuticals, utilize Ligand-Conjugated Antisense (LICA) technology. This technology enhances drug delivery to specific tissues by attaching specific chemical structures or molecules to the antisense drugs, thereby efficiently and specifically inhibiting HBV replication and expression. These two drugs are designed to reduce viral proteins associated with hepatitis B virus infection and replication, including hepatitis B surface antigen (HBsAg), which is expressed in both acute and chronic hepatitis B.

Under the agreement, GSK will be responsible for all subsequent research and development, regulatory, and commercialization activities for the two drugs. Ionis Pharmaceuticals will receive milestone payments of up to $262 million and corresponding sales royalties.

“Our antisense technology targets the root cause of hepatitis B, potentially providing a revolutionary drug for patients with chronic hepatitis B,” said Brett P. Monia, Chief Operating Officer of Ionis Pharmaceuticals. “We believe GSK’s expertise in the development and commercialization of infectious disease therapies can make a significant contribution to addressing this high unmet need.”

Innovative Therapeutic Approaches Targeting Hepatitis B Virus Gene Expression

Currently, multiple companies are employing RNA interference (RNAi) or antisense oligonucleotide therapies to target the gene expression process of hepatitis B virus (HBV). One of the primary reasons for the difficulty in curing HBV is that the virus forms covalently closed circular DNA (cccDNA) upon entering host cells, where it persists long-term. Existing therapies are unable to effectively eliminate cccDNA.

RNA interference (RNAi) or antisense oligonucleotide therapies can target mRNA produced by covalently closed circular DNA (cccDNA), thereby degrading viral mRNA and reducing the potential for viral replication. Advances in manufacturing processes in recent years have made the synthesis and targeted delivery of these therapies more feasible. The advantages of these therapies lie in their high specificity for hepatitis B virus (HBV) and their ability to significantly reduce serum levels of hepatitis B surface antigen (HBsAg), an effect currently unattainable with polymerase inhibitors.

More importantly, studies have shown that such therapies may lead to a significant reduction in viral cccDNA levels. This unexpected outcome may be an indirect effect resulting from decreased HBsAg levels, which impairs the ability of these proteins to maintain immune suppression, thereby prompting the immune system to attack cells harboring HBV cccDNA.

In April last year, clinical trial results presented by Arrowhead Pharmaceuticals at the 2018 International Liver Congress demonstrated that ARC-520, an RNAi therapy developed by the company, significantly reduced HBsAg levels in patients during Phase 1/2 clinical trials and elicited a durable host immune response. Sustaining a long-term immune response against HBV is key to achieving a “functional cure” for HBV infection.

Currently, multiple innovative therapies targeting HBV gene expression have entered Phase 2 clinical development. We anticipate that these novel therapeutic approaches will bring humanity closer to achieving a “functional cure” for hepatitis B.

References:

[1] Ionis licenses hepatitis B program to GSK, Retrieved August 27, 2019, from https://www.prnewswire.com/news-releases/ionis-licenses-hepatitis-b-program-to-gsk-300907423.html

[2] GSK licenses Ionis' experimental hep B treatments in up to $262M deal， Retrieved August 27, 2019, from https://endpts.com/gsk-licenses-ionis-experimental-hep-b-treatments-in-up-to-262m-deal/

[3] Soriano, (2019). Hot News: Hepatitis B Gene Therapy Coming to Age. AIDS Reviews, Retrieved August 27, 2019, from http://www.aidsreviews.com/resumen.php?id=1431&indice=2018202&u=unp

Headline: Flash | A Potential “Functional Cure” for Hepatitis B? GSK Secures Innovative Hepatitis B Therapy

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