Major product upgrade, leading the new chapter of BTK inhibitors with an innovative technology platform

The US FDA divides the new drug approval process into two categories: 505(b)(1) and 505(b)(2). 505(b)(1) refers to new drugs with novel active pharmaceutical ingredients, while 505(b)(2) refers to improved versions of drugs that have already been approved by the FDA, or molecules that were not developed into drugs before but used data not authorized by others. According to public information from the FDA, in 2021, a total of 104 new drugs were approved, including 54 under 505(b)(1) and 50 under 505(b)(2). China, based on the 'Chemical Drug Registration Classification Reform Work Plan' issued by the NMPA in 2016, classifies new drug applications into Class 1 new drugs and Class 2 improved new drugs. In 2022, according to the registration classification, the NMPA approved 18 Class 1 new drugs and 23 Class 2 improved new drugs (excluding Class 2.4), with the number of approved Class 2 new drugs exceeding that of Class 1, becoming an important route for new drug approval. Class 2 improved new drugs have their own unique advantages:

1) In terms of clinical treatment, improved new drugs have significant clinical advantages such as enhancing efficacy, reducing side effects, and improving patients' medication compliance.

Data source: Analysis by Frost & Sullivan

2) In terms of drug research and development, improved new drugs have significant advantages such as low cost, high returns, and a long lifespan. The traditional new drug research and development model involves screening from numerous alternative compounds to obtain target active compounds, followed by preclinical studies such as pharmacokinetics and toxicology, and finally conducting clinical trials. According to data from the Biotechnology Innovation Organization, the development of new molecular entities typically takes about 10 to 15 years, with development costs reaching up to $5 to $1 billion, facing challenges such as long research cycles, high costs, and low success rates. In contrast, the development time for improved new drugs is about 5 to 10 years, with development costs far lower than those of new molecular entities, and the success rate is also 2.3 times that of new molecular entities.

Source: Biotechnology Innovation Organization, Informa Pharma Intelligence, QLS Advisors, Frost & Sullivan analysis

Compared to traditional R&D models, Shanghai Guizhiyan Pharmaceutical Technology Co., Ltd. (hereinafter referred to as 'Guizhiyan') explores new ideas in new drug R&D. Utilizing an independently established innovative drug R&D platform, it modifies the pre-formulation structure of marketed drugs while screening and matching the delivery systems. It studies the efficacy, pharmacokinetics, drug absorption, and distribution within the same system, ultimately achieving better therapeutic effects and lower adverse reactions. Unlike traditional new drug R&D models, Guizhiyan's R&D platform collaborates on drug design with areas such as pharmacokinetics and formulation, ensuring the effectiveness and safety of the drugs while making the R&D process efficient, economical, and more targeted.

The innovative drug R&D platform of your company mainly includes the 'AI Chemical Drug Screening System' and the 'NDSIP Delivery to Drug System'. Among them, the 'AI Chemical Drug Screening System' can screen out chemical drugs that have more advantages in terms of cell affinity, metabolic stability, in vivo transport, solubility, and permeability; the 'NDSIP Delivery to Drug System' can enhance the structural characteristics of APIs, formulation composition, and preparation technology. The new drug innovation platform integrates the advantages of both systems, enabling targeted modifications to existing clinical therapeutic small molecule drugs, drug structure and formulation transformation, thereby improving the drug's targeting in clinical use, reducing adverse reactions, enhancing patient compliance, and lowering patient costs.

Data source: Company data, Frost & Sullivan analysis

Non-Hodgkin lymphoma (NHL) is a group of malignant tumors originating from lymph nodes and other lymphoid tissues and is one of the major types of lymphomas. According to data from the International Agency for Research on Cancer (IARC), new cases of NHL globally increased from 498,000 in 2017 to 556,000 in 2021, with a compound annual growth rate of 2.8%. It is estimated that by 2025 and 2030, the number will reach 606,000 and 670,000 respectively. According to data from the Chinese Cancer Registry (NCCR), the number of new NHL cases in China increased from 86,000 in 2017 to 95,000 in 2021, with a compound annual growth rate of 2.6%. It is estimated that by 2025 and 2030, the number of new cases in China will reach 105,000 and 117,000 respectively.

Source: IARC, NCCR, Frost & Sullivan analysis

According to the 'Chinese Guidelines for the Diagnosis and Treatment of Lymphoma (2022 Edition)', the first-line treatment for diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL) typically involves rituximab or obinutuzumab combined with CHOP, DHAP, CVP, bendamustine, lenalidomide, and other drugs. At the same time, treatment methods such as transplantation, radiotherapy, chemotherapy, and surgery should be considered based on the specific conditions of the patient. For chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), the guidelines recommend the use of BTK inhibitors alone or in combination with obinutuzumab for initial or relapsed patients. The guidelines also point out that most NHL subtypes can achieve remission after treatment, but relapse is also relatively common. For relapsed or refractory DLBCL, MCL, and MZL, the guidelines all recommend the use of BTK inhibitors for treatment.

BTK inhibitors refer to Bruton's tyrosine kinase (BTK) inhibitors. BTK is a cytoplasmic non-receptor tyrosine kinase that belongs to the Tec kinase family (a family of tyrosine kinases expressed in liver cancer cells). It plays a central role in signal transduction through various cell surface receptors (mainly including the B-cell antigen receptor, BCR). BTK inhibitors work by acting on the BCR signaling pathway, binding to BTK, inhibiting its own phosphorylation, preventing BTK activation, further blocking cell signaling, and inducing apoptosis, thereby suppressing the growth of malignant tumors and achieving control over the development of B-cell tumors.

Currently, BTK inhibitors in the market can be divided into two generations. Imbrutinib, as the first approved BTK inhibitor, is known as the first-generation BTK inhibitor. Subsequently, other BTK inhibitors such as axitinib, zanubrutinib, and obitinib that were approved are referred to as second-generation BTK inhibitors.

BTK inhibitors exert their antitumor effect by inhibiting BTK, which is required for tumor cell replication and metastasis. The Chinese 'Lymphoma Diagnosis and Treatment Guidelines (2022 Edition)' recommend BTK inhibitors for the treatment of newly diagnosed or relapsed CLL/SLL patients, or for the treatment of relapsed or refractory DLBCL, MCL, and MZL patients. In addition, the approved indications for ibrutinib also include first-line treatment for Waldenström macroglobulinemia (WM) and second-line treatment for chronic graft-versus-host disease (cGVHD).

Approved BTK inhibitor products have advantages such as strong binding activity to the target, and their efficacy is not dependent on pharmacokinetics. However, there are some clinical pain points with current BTK inhibitor products: they may cause unnecessary off-target effects at high concentrations, leading to side effects; if mutations occur in the target, drug resistance can arise. Therefore, the market's demand for BTK inhibitor products with higher safety and better resistance is growing day by day.

As of January 2023, there are six BTK inhibitors listed globally, namely ibrutinib jointly developed by AbbVie and Johnson & Johnson, acalabrutinib developed by AstraZeneca, zanubrutinib from BeiGene, Velexbru (Tirabrutinib) from Ono Pharmaceutical/Gilead, orelabrutinib from Novartis and Jaypirca (Pirtobrutinib) from Eli Lilly. In China, three BTK inhibitors have been approved by the National Medical Products Administration (NMPA), namely ibrutinib, zanubrutinib and orelabrutinib. The indications for currently marketed BTK inhibitors cover diseases such as CLL/SLL, MCL, WM, MZL, cGVHD, LPL (lymphoplasmacytic lymphoma), and PCNSL (primary central nervous system lymphoma).

Source: Public information, Frost & Sullivan segmentanalyze

After the global first BTK inhibitor ibrutinib was approved for marketing in 2013, it quickly occupied the main markets for BTK inhibitors worldwide. According to the annual reports of AbbVie and Johnson & Johnson, in 2021, ibrutinib sales reached $6.94 billion, accounting for 82.9% of the total BTK inhibitor product sales for that year, making it one of the top 20 best-selling drugs globally.

Data source: Annual report of the company, analysis by Frost & Sullivan

According to incomplete statistics, as of January 31, 2023, there were approximately 46 BTK inhibitor drugs in development globally. The indications for these BTK inhibitors cover chronic lymphocytic leukemia, small lymphocytic lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, pemphigus, and other diseases.

According to CDE data, there are 30 BTK inhibitors under research in China, and several large multinational companies are also actively promoting the development of BTK inhibitor products in China. Eli Lilly's BTK inhibitor LOXO-305 has started Phase III clinical trials in China, with indications including mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma; Sanofi's SAR442168 has started Phase III clinical trials in China, with indications for relapsing multiple sclerosis, non-relapsing secondary progressive multiple sclerosis, and primary progressive multiple sclerosis (PPMS). BTK inhibitors are expected to be applied in more disease areas in the future.

Since the global first BTK inhibitor, ibrutinib, was introduced in 2013, the market size of BTK inhibitors has expanded rapidly worldwide. From 2017 to 2021, the global market size for BTK inhibitors grew from $3.2 billion to $8.38 billion, with a compound annual growth rate of 27.2%. It is estimated that by 2025, the global market will grow at a compound annual rate of 14.1% to reach $141.8 billion, and by 2030, the global market is expected to reach $199.2 billion.

The Chinese BTK inhibitor market grew from 2018's RMB 200 million to RMB 1.81 billion in 2021, and is expected to grow at a compound annual growth rate of 38.8% to reach RMB 67.0 billion by 2025. By 2030, it is projected to grow at a compound annual growth rate of 17.5% to reach RMB 150.1 billion.

Data source: Analysis by Frost & Sullivan

Currently, the global BTK inhibitor market is mainly dominated by ibrutinib. However, during the approximately 10 years of clinical use, ibrutinib has gradually revealed some clinical pain points: it can cause a variety of grade ≥3 adverse reactions such as infections, hypertension, atrial fibrillation, massive hemorrhage, etc., with an oral bleeding risk as high as 66%, and a small number of patients (1-8%) have a serious bleeding risk; there are also issues such as significant first-pass metabolism, large dosages required but low bioavailability.

Aiming at the current clinical pain points of imatinib, Guizhiyan is fully committed to advancing the research and development of its BTK inhibitor product GY-1068. GY-1068 is a prodrug formulation of the already marketed drug imatinib. Preliminary animal experiment results show that GY-1068 has significantly improved drug absorption and resistance compared to imatinib, and an IND application is currently underway. Guizhiyan's new drug innovation platform uses a drug structure screening system to design prodrug molecules (new chemical entity molecules) that meet pharmacokinetic requirements, and combined with micro-nano formulation technology, a new delivery system can be obtained. The innovative delivery system changes the absorption and distribution characteristics of the drug, showing an advantage of enriched active drugs at the lesion site while peripheral drug concentrations are relatively lower.

The preclinical study results of a new generation BTK inhibitor developed by the New Drug Innovation Platform, valued for its insights, indicate that the product has a strong competitive advantage.

Data source: Analysis by Frost & Sullivan

Shanghai Guizhiyan Pharmaceutical Technology Co., Ltd. is a biopharmaceutical technology R&D company with innovative formulation and new target small molecule chemical drugs as its core competitiveness. The company is oriented towards clinical needs and conducts R&D around malignant tumors and their adjuvant treatment and pain management. The company has independently created a new drug design platform that integrates the 'AI chemical drug screening system' and the 'NDSIP delivery system', focusing on new drug research and development in three major disease areas: tumors, autoimmune diseases, and anti-infection. Multiple products under development will gradually enter the clinical trial stage.

Currently, there are four drugs under development at your company, namely BTK inhibitors, TNF inhibitors, DNA alkylating agents, and TYK2 inhibitors. The company has exclusively adopted an innovative system that combines structural design with delivery systems, designing a product that integrates prodrug technology with micro-nano formulation technology: NDSIP Oral. While enhancing bioavailability, NDSIP Oral changes the absorption and distribution characteristics of the drug, improving both efficacy and reducing side effects. Among them, the under-development BTK inhibitor is about to file for IND. Animal experiments conducted using ibutilimab as a control found that the bioavailability of NDSIP Oral is several times higher than that of the ibutilimab prototype, with significant drug enrichment in lesion tissues.

DLBCL is a major subtype of non-Hodgkin lymphoma, accounting for about 37.1% of all NHL patients. However, currently, there are no BTK inhibitor products approved for this indication globally. Your company's research has found that GY-1068, an investigational BTK inhibitor product, also has a good therapeutic effect on DLBCL and other indications and is expected to be confirmed in future clinical studies. GY-1068 has the potential to expand its indications while improving the clinical pain points of ibrutinib, with many advantages that make it a strong competitor in the BTK inhibitor market in the future.

New drug research and development is an important driving force for the survival and development of pharmaceutical companies. Your words have injected strong momentum into the company's new drug research and development efforts with the establishment of a new drug innovation platform, and several new drug R&D projects are advancing steadily. Looking ahead, we look forward to better new drug products benefiting the vast number of patients.

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