REC603-Recombinant HPV 9-valent vaccine

REC603, our Core Product, is designed to provide protection against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58.

Summary of Clinical Trial: We jointly applied, and obtained the umbrella IND approval for REC603 in July 2018. The umbrella IND approval covers all three phases (phase I, II and III) of clinical trials. In March 2019, we commenced the phase I clinical trial of REC603 in China. We completed phase I clinical trial of REC603 in China in July 2020. Based on communications with the CDE of the NMPA, the NMPA has no objection for us to proceed with phase III clinical trial in China directly. Accordingly, we did not conduct any phase II clinical trial for REC603.

The CDE of the NMPA issued the “Technical Guidelines for the Clinical Trials of Human Papillomavirus Vaccines (for Trial Implementation)” (the “Guidelines”) in July 2023, which clearly points out that the randomized, double-blind and placebo-controlled design is still the best strategy to confirm the immunogenicity profile of the first-generation of vaccine for the time being. We are in the process of conducting phase III clinical trial in China. The phase III clinical trial in China consists of three parts, i.e., the primary efficacy trial, the immuno-bridging trial in younger-age groups, and the immunogenicity comparative trial with Gardasil®9, with a multicenter, randomized, blinded and parallel controlled design and with a total size of 16,050 subjects. At the same time, follow-up on the subjects of REC603’s primary efficacy trial is being conducted in accordance with the clinical protocol. We have completed the visit of the 24th month and are in the process of conducting the visit and observation of the 30th month. We will carry out an interim analysis by taking pathological endpoints and plan to submit a BLA application to the NMPA in 2025 when conditions are satisfied. Since obtaining the IND approval in China, no material unexpected accidents or adverse changes in relation to REC603 have occurred.

Advantages of REC603

Favorable immunogenicity profile

REC603 demonstrates a positive immunogenicity profile in its phase I clinical trial. In general, we observed a significant increase in terms of NAb GMT level against all of the target HPV types.

High-yield and stable production of HPV VLPs

REC603 adopts H. polymorpha expression system. In general, the VLPs expressed from different expression systems are all highly similar to natural HPV capsid in structure and epitope in order to trigger immune response after vaccination, including those being produced by H. polymorpha expression system. H. polymorpha, a methylotrophic yeast species, is able to grow to very high cell density rapidly on simple media and has relatively high optimum growth temperature. Owing to its strong and tunable promoters derived from the methanol utilization pathway, high secretion capacity, and lower hyperglycosylation activity compared to S. cerevisiae, H. polymorpha is suitable for production of recombinant proteins for medical use. With high copies of expression cassettes integrated stably in the genome of H. polymorpha, high-yield and stable expression of HPV VLPs is achieved, making our vaccine candidate more suitable for commercial production.

Favorable safety profile

REC603 was safe and well-tolerated as shown in the phase I clinical trial for REC603. There were no statistical differences in terms of incidences of AEs between the vaccine group and the placebo group. Although there is currently no available paper reporting a head-to-head clinical trial comparing domestic HPV vaccines and foreign HPV vaccines, in the clinical trial conducted by Merck Sharp & Dohme for Gardasil 9 in 2009, the rate of adverse event was 86.6% among subjects enrolled in the vaccine cohort, as compared to 53.75% as observed in the phase I clinical trial of REC603. The main adverse reactions were expected fever and inject site pain, mostly were transient and mild.

Scalable manufacturing potential

Our patented technology in HPV VLPs in combination with optimized fermentation strategy and purification process enable us to achieve high and stable yield in bulk production. With well-defined critical process parameters^[1], manufacturing of REC603 can be easily scaled-up to meet the market demand domestically and globally.

Opportunities and potentials

Superiority of HPV 9-valent vaccines

In general, HPV 9-valent vaccines can provide protection against 90% of cervical cancer and 90% of the anal and genital warts^[2] and therefore are the most recommended vaccines for HPV protection. However, to the best knowledge and information of the Company with reference to independent market research, currently there is only one HPV 9-valent vaccine approved in China, and it is expected HPV 9-valent vaccines will account for a larger market share in China after more HPV 9-valent vaccines are approved in China.

Domestic Substitute

In recent years, the Chinese government has also promulgated policies in favor of domestic HPV vaccine developers. For example, in 2019, the National Health Commission of the People’s Republic of China released the “Healthy China Action–Cancer Prevention and Control Implementation Plan (2019-2022)”, stating to accelerate the review and approval process of domestic HPV vaccines and improve the accessibility of HPV vaccines. As one of the few domestic vaccine companies to have phase III stage HPV 9-valent vaccine candidate, we believe we will benefit from such favorable government policies in the future.

Same age coverage as imported vaccines

On August 30, 2022, HPV 9-valent vaccine available in the market in China has been expanded for females aged 9 to 45. Our Core Product, REC603, has also initiated phase III clinical trial for females aged 9 to 45 in 2021, indicating a potential broader coverage in terms of age as compared to the current approved vaccines.

Next-generation HPV vaccines under development

We are also developing next generation quadrivalent and 9-valent HPV vaccine candidates with novel adjuvants, which are designed to adopt a two-shot regimen without compromising the efficacy/safety profile of vaccine candidates, and are potentially superior as compared to the commercialized products as they are all adopting three-shot regimen.

[1]Related patents
·Method for producing HPV18 L1 protein using Hansen's yeast expression system, patent/application number: CN103215302B
·Method for producing HPV6 L1 protein using Hansen's yeast expression system, patent/application number: CN103361377B
·Method for producing HPV11 L1 protein using Hansen's yeast expression system, patent/application number: CN103361280B
·Method for producing HPV58 L1 protein using Hansen's yeast expression system, patent/application number: CN104120088B
·Method for producing HPV52 L1 protein using Hansen's yeast expression system, patent/application number: CN104120089B
·Method for producing HPV33 L1 protein using Hansen's yeast expression system, patent/application number: CN104164446B
·Method for producing HPV68 L1 protein using Hansen's yeast expression system, application/patent number: CN104164373B
·Method for producing HPV31 L1 protein using Hansen's yeast expression system, patent/application number: CN104164374B
·Method for producing HPV45 L1 protein using Hansen's yeast expression system, patent/application number: CN104164447B
·Method for producing HPV33 L1 protein using Hansen's yeast expression system, patent/application number: CN110305807B
·Method for producing HPV52 L1 protein using Hansen's yeast expression system, patent/application number: CN110484554B

[2]National Medical Products Administration.HPV vaccine and cervical cancer prevention.Index number: XZXK-2020-1263.

[3]The above information was derived from multiple clinical trials conducted for different vaccines without the support of controlled, head-to-head clinical studies, and a number of factors (including the different subject enrollment standards adopted in different trials, different population characteristics of subjects, physicians’inoculation skills and experiences, and lifestyle of the subjects) could affect the relevant clinical results and could render cross-trial comparison results less meaningful.