Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) partner GSK announced that the U.S. Food and Drug Administration (FDA) has approved Hibsago (bepirovirsen) for the treatment of chronic hepatitis B (CHB) virus infection in combination with nucleos(t)ide analogue reverse transcriptase inhibitor (NrtI) therapy in adult patients without cirrhosis, receiving NrtI therapy for at least 6 months, who have suppressed HBV deoxyribonucleic acid (DNA), and with hepatitis B virus (HBV) surface antigen (HBsAg) levels ≤3000 IU/ml, as determined by an FDA-authorized test. GSK licensed bepirovirsen from Ionis and collaborated with them on its development.

Bepirovirsen is a first in class RNA-targeted medicine that offers unprecedented functional cure rates compared to current standard of care. The approval was granted under FDA priority review and Breakthrough Therapy Designation, recognizing significant improvement of bepirovirsen and nucleos(t)ide analogue therapy over existing standard of care.

“About 1.7 million people in the U.S are living with chronic hepatitis B, and yet treatment options have been historically limited and the vast majority of people living with the chronic infection require lifetime care without achieving meaningful functional cure,” said Brett P. Monia, Ph.D., chief executive officer, Ionis. “We are pleased to see the FDA approval of Hibsago, which adds to a growing portfolio of transformative medicines discovered and developed by Ionis that address serious diseases, including many that previously had limited or no available treatment options. We believe Hibsago will bring new hope to people living with chronic hepatitis B, offering the potential to achieve unprecedented functional cure rates after a six-month treatment course.”

The approval was supported by results from the Phase 3 B-Well trials showing functional cure rates of 19% in adults with ≤3000 IU/ml HBsAg, compared to current standard of care alone, which typically achieves less than 1% functional cure rate after one year of treatment. Functional cure occurs when HBV DNA and HBsAg are undetectable for at least 24 weeks after stopping all treatment, indicating the disease is controlled by the immune system without medication.

“This is the start of a new era in treating people living with CHB,” said Norah Terrault, MD, MPH, FAASLD, Chief of Gastroenterology & Hepatology, USC Keck Medical Centre. “Bepirovirsen offers patients the potential to achieve functional cure after a short period of treatment, a long-standing goal for patients and physicians alike."

“CHB is a major public health challenge, affecting millions of people in the U.S. and accounting for approximately 56% of all global liver cancer cases,” said Chari Cohen, DrPH, MPH, president, Hepatitis B Foundation. “Today marks significant progress towards our aim of transforming the way CHB is managed with improvements in screening, diagnosis, and the availability of innovative treatment options for our community.”

Quantitative surface antigen testing will support the diagnosis and identification of patients suitable for treatment with bepirovirsen who have baseline HBsAg levels ≤3000 IU/ml. Several tests are available, including a recently authorized FDA test.

GSK continues to advance regulatory submissions for bepirovirsen across multiple geographies with key regulatory decisions anticipated in the coming months.

GSK licensed bepirovirsen from Ionis in 2019 under a collaborative development and licensing agreement. Under the terms of the agreement, Ionis has received an upfront payment, license fee and development and regulatory milestone payments and is eligible to receive additional regulatory and sales milestone payments as well as tiered royalties of 10-12% on net sales of bepirovirsen.

Results from the Phase 3 B-Well trials

Pooled data from the Phase 3 B-Well trials showed that six-month treatment with bepirovirsen achieved a clinically meaningful 19% functional cure response rate (233 of 1,220 vs. 0 of 614 in the placebo group). B-Well 1 and B-Well 2 each met the primary endpoint, demonstrating a statistically significant improvement in functional cure versus placebo in the overall study population (adults with ≤3000 IU/ml HBsAg level). In a key secondary endpoint, a functional cure rate of 26% (200 of 768 vs. 0 of 393 in the placebo group) was achieved in participants with ≤1000 IU/ml HBsAg level, a group that represents approximately 45% of diagnosed CHB cases globally.

Exploratory analyses also showed bepirovirsen reduced HBsAg to ≤100 IU/ml in 49% of participants (598 of 1220) in the overall study population, and in 62% of bepirovirsen recipients in the ≤1000 IU/ml (476 of 768) sub-group as of the week 72 visit. Medical literature has linked this low level of surface antigen with increased immune control and improved patient outcomes.

The trials showed an acceptable safety and tolerability profile consistent with other studies of bepirovirsen. The three most frequently observed adverse events were injection site erythema, local pain and temporary rise in the blood level of a liver enzyme.