Hillevax's Challenges and Expansion Strategies in the Norovirus Vaccine Market

As of July 8, 2024, Hillevax's market capitalization has declined to $1,000,000, primarily due to the company's disclosure that its bivalent norovirus vaccine (HIL-218) failed to meet the primary endpoint for preventing acute gastroenteritis in the NEST-IN1 Phase 2b infant trial. This news has led to market uncertainty about Hillevax's research and development capabilities. Notably, Hillevax is seeking to address this challenge by expanding its pipeline in China.

In January 2024, HilleVax signed an exclusive licensing agreement with Chengdu Kanhua Bio, granting HilleVax the global rights (excluding China, Hong Kong, Macau, and Taiwan) to develop, manufacture, and commercialize Kanhua Bio's recombinant hexavalent norovirus vaccine (HIL-216) and its derivatives. In the deal, Kanhua Bio received a $15,000,000 upfront payment and is eligible for up to $255,500,000 in milestone payments upon achieving specific development and sales milestones. Additionally, Kanhua Bio is entitled to receive a single-digit percentage royalty on net sales in the aforementioned territories.

HIL-216 is a hexavalent norovirus vaccine developed by Kanhua Bio using genetic engineering technology. It is based on virus-like particles (VLPs) and covers the six major circulating norovirus genotypes - GI.1, GII.2, GII.3, GII.4, GII.6, and GII.17 - theoretically preventing more than 90% of norovirus infections and acute gastroenteritis. HIL-216 has received clinical trial authorization in Australia and the United States in February and September 2023, respectively, but has not yet obtained clinical trial approval in mainland China. As the world's first and only hexavalent norovirus vaccine to receive clinical authorization, HIL-216 has been used in recent clinical trials, and the company plans to initiate a Phase 1 clinical trial in 2024.

In addition to the collaboration with Kanhua Bio, HilleVax's pipeline includes the bivalent norovirus vaccine HIL-214 (formerly Takeda's TAK-214), which has been under development for decades. Upon its establishment, HilleVax was granted the exclusive global (excluding Japan) development and commercialization rights for HIL-214, while Takeda retained the commercialization rights in Japan.

HIL-214 is a VLP-based bivalent vaccine covering the GI.1 and GII.4 strains, which are the two major causes of human gastroenteritis. Currently, this vaccine is under development to prevent moderate to severe acute gastroenteritis (AGE) caused by norovirus infections. Norovirus has seven known genogroups, but genogroups I and II are the source of most human cases, with a small number of cases associated with norovirus GIV. Although both genogroups I and II are clinically relevant, the specific GII.4 strains of norovirus are the primary drivers of most human outbreaks and often cause more severe illness with higher mortality rates.

In May 2022, HilleVax initiated a Phase 2b clinical trial (NEST-IN1), a randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and efficacy of HIL-214 in approximately 5-month-old infants. In December 2022, HilleVax reported interim immunogenicity data from the first 203 participants in the NEST-IN1 trial, showing that HIL-214 elicited robust immune responses 28 days after the second dose, with geometric mean titers (GMTs) of pan-Ig antibodies reaching 11,102.0 IU/mL and 2,185.5 IU/mL for GI.1 and GII.4, respectively, compared to 59.6 IU/mL and 73.5 IU/mL in the placebo group. These results represent a greater than 18-fold increase in geometric mean fold rise (GMFR) from baseline. Additionally, HIL-214 demonstrated serum antibody response rates (SRRs) of 99.0% and 86.9% for GI.1 and GII.4, respectively, compared to 4.1% and 3.1% in the placebo group. In April 2023, HilleVax announced the completion of enrollment of over 3,000 participants in the NEST-IN1 trial, with top-line data expected in mid-2024.

While advancing the pediatric registration for HIL-214, HilleVax is also planning to seek approvals for the vaccine in other age groups. In the third quarter of 2023, HilleVax initiated three additional clinical trials to support the progress of HIL-214, including: (1) NOR-109: a Phase 1 trial of HIL-214 in Japanese infants; (2) NOR-206: a Phase 2 trial evaluating the co-administration of HIL-214 with other standard infant vaccines; and (3) NOR-212: a Phase 2 trial assessing the safety and immunogenicity of HIL-214 in older adults.