Established in 2011, we are a biopharmaceutical company specializing in the discovery, development and commercialization of multifunctional, multi-targeted therapies for the treatment of metabolic and digestive diseases. We have developed a product pipeline of one Core Product and other four product candidates in-house. Our Core Product, HTD1801 (berberine ursodeoxycholate), a new molecular entity, is a gut-liver anti-inflammatory metabolic modulator which targets multiple pathways pivotal to metabolic regulation, including those associated with metabolic and digestive diseases.
WE MAY NOT BE ABLE TO SUCCESSFULLY DEVELOP AND/OR MARKET OUR CORE PRODUCT.
Our Pipeline
As of the Latest Practicable Date, we have researched and developed in-house a pipeline with five proprietary drug candidates covering nine indications, including five indications that are at clinical stage. The following chart summarizes the development status of our drug candidates as of the Latest Practicable Date.
Core Product
HTD1801 is a salt with an ionic bond formed between two active moieties (the molecule or ion responsible for the physiological or pharmacological action of the drug substance), berberine (“BBR”) and ursodeoxycholic acid (“UDCA”). The two active moieties BBR and UDCA have a long history of medicinal applications as treatments for gut and liver diseases in traditional Chinese medicine. In HTD1801, BBR and UDCA work in tandem in the salt form with unique microstructure to produce distinct and improved properties as demonstrated in our studies. The improved properties are not observed with either of the individual active moieties or their physical mixture. Our clinical results show that HTD1801 delivers a therapeutic effect for patients including metabolic improvement, liver protection, anti-inflammation and antioxidative stress. However, therapeutic effect of the Core Product is based on preliminary clinical data only which is yet to be validated in later clinical trials, and the Core Product may fail to meet the primary and secondary endpoints at the late-stage clinical trials due to higher clinical development risks. For details, see “Risk Factors — Risks relating to development, clinical trials and regulatory approval of our drug candidates — the Core Product may fail to meet the primary and secondary endpoints at the late-stage clinical trials due to higher clinical development risks resulted from HTD1801 being a new molecular entity and potential rejection from competent authorities” in this Document. HTD1801 is currently being developed by us for indications across metabolic dysfunction-associated steatohepatitis (“MASH”, formerly known as nonalcoholic steatohepatitis or NASH), type 2 diabetes mellitus (“T2DM”), severe hypertriglyceridemia (“SHTG”), primary sclerosing cholangitis (“PSC”) and primary biliary cholangitis (“PBC”) globally, with a focus on comorbidities and a potential for indication expansion. However, we may face uncertainties in clinical trial development which are subject to a variety of factors, including satisfactory safety and efficacy results from clinical trials, successful enrollment of patients, performance of CROs and other parties involved in clinical trial development and others. For more details, please see “Risk Factors — Risks relating to development, clinical trials and regulatory approval of our drug candidates — Clinical drug development involves a lengthy and expensive process with uncertain outcomes, and we may be unable to commercialize our drug candidates at all.”
In the United States, we have received fast track designation (“FTD”) from the Food and Drug Administration (“FDA”) for MASH and PSC indications, as well as orphan drug designation (“ODD”) for the PSC indication. Under the Orphan Drug Act, the FDA granted the ODD to HTD1801 for PSC on the condition that HTD1801 is intended to treat a rare disease of PSC affecting fewer than 200,000 individuals in the United States. For more details, please see “Regulatory Overview — Laws and Regulations in the United States and EU — Orphan Drugs.” According to CIC, HTD1801 is the first PSC drug candidate to receive FTD from the FDA. The FTD is based on available preclinical and clinical data that demonstrate the potential to address an unmet medical need and is intended to facilitate an expedited regulatory review process. In China, we received government support from “Major National Science and Technology Projects for New Drug Development” under the “National 13th Five-Year Plan”, which may further accelerate the domestic market approval for HTD1801. According to the current development progress and timeline, we expect to submit the first New Drug Application (“NDA”) for HTD1801 for T2DM in 2025 in China.
As of the Latest Practicable Date, we held 58 patents and patent applications in relation to our Core Product, representing four types of patents that have been applied in different jurisdictions, including a new molecular entity (a “composition-of-matter” patent), the process used to manufacture the drug, the way the drug is used and new formulations of the drug to protect our assets. The reasons for applying these patents in various jurisdictions are to provide extensive patent protections and maintain our Core Product’s exclusivity in these jurisdictions. We have successfully obtained composition of matter patent for HTD1801 in many countries and regions, including the United States, China, the European Union and Japan, as well as crystalline form patent in United States and China.
Considering the market size and addressable patient population of MASH and T2DM, we have and will continue to prioritize our resources for the clinical development of the MASH and T2DM indications of HTD1801. We are currently conducting the Phase IIb clinical trial for the MASH indication of our self-developed HTD1801, and may seek joint development opportunities for its Phase III clinical trials. For T2DM, we completed two Phase I clinical trials, one Phase Ib clinical trial, and one Phase II clinical trial in China, which are all required by the NMPA. In November 2023, we initiated the two Phase III clinical trials (i.e. one with HTD1801 as a standalone treatment and one with HTD1801 as an add-on therapy with metformin) for the T2DM indication of our self-developed HTD1801 in China. We expect to complete those two Phase III studies in 2025. In addition, we have no immediate plans to conduct clinical trials for and commercialise T2DM outside of China. Since the completion of Phase II clinical trials for PSC in August 2020 and for PBC in May 2022, no clinical development progress has been made for the PSC and PBC indications of HTD1801. We have no immediate development plans and will not allocate any net proceeds of the Global Offering to these two indications, and we are seeking collaboration opportunities with global partners for future clinical development and commercialisation of HTD1801 for PSC and PBC indications. Despite the rebound in liver biochemistry during the follow-up period in the Phase II trial for PBC and a long period of clinical development suspension for the PBC and PSC indications, we have not encountered any difficulties in identifying collaboration opportunities with global partners for future clinical development and commercialisation of HTD1801 for PBC and PSC. In addition to Hepalink obtaining a license to commercialize HTD1801 in Europe for the MASH and PSC indications, we are in negotiations with global partners for the future development of HTD1801 for such orphan diseases of cholestasis (the category of diseases which PSC and PBC fall within); however, due to the time required to negotiate the commercial terms, as of the Latest Practicable Date, no collaboration agreements had been entered into. The follow-up periods in the Phase II clinical trial for PBC, during which HTD1801 treatment was withdrawn, showed a worsening in liver biochemistry compared with baseline, also suggesting the efficacy of HTD1801. Therefore, we believe that it has no impact on our clinical development.
We designed the MRCTs for HTD1801 for MASH and PSC indications. The use of MRCT for MASH and PSC was determined in 2017. The Phase IIb clinical trial for MASH and Phase II clinical trial for PSC were conducted in the form of MRCT, and MRCT would also be the approach for the clinical trials going forward for MASH and PSC. We believe MRCTs can expedite global clinical development and facilitate registration in multiple regions across the globe. We use the same study protocol for IND approval of clinical trials and conducting clinical trials in different phases after obtaining IND approvals in each of MRCT’s jurisdictions. The clinical results of the MRCT in various jurisdictions can be used to support registration approval by the competent authorities in those jurisdictions. There are no differences in primary endpoints, extent or type of clinical trials to be conducted across various jurisdictions but might be slight differences in materials to be submitted among the different regulatory bodies.
For Phase IIb MRCT of HTD1801 for MASH indication in the United States, Hong Kong, Mexico and Mainland China, the details of communications with competent authorities have been set forth in the section “Business — Clinical-Stage Candidates — Core Product HTD1801 — Material Communications with Competent Authorities”. In April 2023, we submitted the Phase IIb study protocol to the FDA and we did not receive any comments or rejections from the FDA within the 30-day clearance period. We also obtained the IND approvals in Hong Kong and Mainland China in August and September 2023, respectively, and filed an IND application in Mexico in July 2023.
For Phase II MRCT of HTD1801 for PSC in the United States, Mainland China and Canada, the details of communications with competent authorities have been set forth in the section “Business — Clinical-Stage Candidates — Core Product HTD1801 — Material Communications with Competent Authorities”. We obtained IND approvals from the FDA in 2017, and from the NMPA and the Health Canada in 2019.
Other Product Candidates
Building on our expertise in the development of HTD1801, we have also invested in and developed our pipeline to cover alcoholic hepatitis (“AH”), obesity, inflammatory bowel disease (“IBD”) and other metabolic diseases to address large unmet medical needs. For AH, we are advancing the early clinical development of HTD4010. AH is one of the manifestations from alcohol-associated liver disease (“ALD”) characterized by acute liver inflammation. There are currently no approved drug treatments specifically targeting AH. The current standard of care, corticosteroids, often used in patients with severe AH, has not shown a meaningful long-term survival benefit and usually carries serious side effects. HTD4010 is a Toll-like receptor 4 (“TLR4”) inhibitor potentially capable of modulating the innate immune response and the resulting liver inflammation, a major contributor to AH pathogenesis. In animal studies, HTD4010 demonstrated potent beneficial effects for AH, alleviating signs of severe liver injury and reducing systemic inflammation. Our completed Phase I clinical trial demonstrated its favorable safety profile in healthy humans.
We are also evaluating HTD1804 for the treatment of obesity, which is a growing global health risk associated with a wide range of comorbidities, most notably cardiovascular diseases (“CVDs”) and T2DM. Preclinical studies show that HTD1804 may be an important modulator of energy metabolism as well as cardiovascular protection. HTD1805, another drug candidate in our pipeline, is a multifunctional small molecule drug for the treatment of metabolic diseases. HTD2802 is a preclinical-stage, multifunctional drug for the treatment of IBD. In preclinical studies, HTD2802 has shown positive effects on stool formation and the occurrence of fecal occult blood, as well as reducing inflammatory cytokine levels and preventing pathological injury.
Source: HighTide-B (02511) Prospectus (IPO Date : 2023/12/14) |