Guojin Securities: Targeted protein degradation is expected to make up for inhibitor-resistant and drug-resistant targets that do not meet demand

The Zhitong Finance App learned that Guojin Securities published a research report saying that protein degraders adopt a unique “event-driven” model that can directly induce target protein degradation, and the degradants can then be continuously recycled. The unique mechanism of action makes degradants have a series of advantages. Compared with inhibitors, degraders can theoretically act on a wider range of proteins, and due to different mechanisms, degradants are expected to become optional treatment options for clinically inhibitor resistant patients. Guojin Securities believes that the two core application scenarios of proteolytics in the future are those resistant to existing small molecule inhibitors + targets that are difficult to target with existing small molecule inhibitors. At the same time, in the field of cancer treatment, proteolytics are also expected to enter 1L treatment through combination with other drugs. PROTAC Pharmaceuticals reached a critical milestone in the second half of the year. Catalyzed by this, it is expected that multinational pharmaceutical companies may increase their will to reach relevant cooperation with domestic companies with relevant pipeline layouts.

Protein-degrading agents are expected to make up for traditional small molecule shortages. Traditional small molecule inhibitors mainly use a “position-driven” mode of action, resulting in: 1. It is difficult to target proteins that lack hydrophobic pockets; 2. They cannot damage the function of scaffolding proteins; 3. Long-term use is prone to drug resistance. In contrast, protein degraders adopt a unique “event-driven” mode, which can directly induce the degradation of the target protein, and the degradant can then be continuously recycled without maintaining long-term binding to a target protein. The unique mechanism of action makes degradants have a series of advantages. Compared with inhibitors, degraders can theoretically act on a wider range of proteins, and due to different mechanisms, degradants are expected to become optional treatment options for clinically inhibitor resistant patients. In summary, Guojin Securities believes that the two core application scenarios for proteolytics in the future are people resistant to existing small molecule inhibitors + targeting targets that are difficult to target with existing small molecule inhibitors. At the same time, in the field of tumor treatment, proteolytics are also expected to enter 1L treatment through combination with other drugs.

The quick-progressing technology routes for proteolytic agents are PROTAC (targeted proteolytic chimera) and molecular glue. Among them, PROTAC is more hopeful to become the next universal drug development technology platform, and molecular glue has an advantage in pharmacokinetics. Thalomid (Thalomid), which has been approved by the FDA, and its analogue lenalidomide (Revlimid) are molecular glues. Compared with PROTAC, molecular glue has a small molecular weight, so it often has better bioavailability, but it is more difficult to design molecular glue from scratch, so currently the target of molecular glue drugs is concentrated on IKZF1/3 (IKAROS family zinc index transcription factor 1/3). However, PROTAC is structurally similar to ADC drugs. It includes three parts: ligands targeting target proteins, ligands, and functional modules targeting E3 enzymes. Theoretically, PROTAC for different targets can be obtained by simply replacing different ligand molecules. It is a highly modular technology platform.

PROTAC Pharmaceuticals reached a critical milestone in the second half of the year. Catalyzed by this, it is expected that multinational pharmaceutical companies may increase their will to reach relevant cooperation with domestic companies with relevant pipeline layouts.

(1) The field of protein degradation will soon usher in an important catalyst: ARV-471 is PROTAC targeting ER (estrogen receptor) developed by Arvinas, and is undergoing phase III clinical trials for 2L ER+ breast cancer patients. This is the world's first phase III clinical involving PROTAC drugs. PROTAC, a versatile technology platform, is expected to complete conceptual verification. Meanwhile, the world's first proTAC targeting irak4 developed by Kymera is carrying out phase II clinical trials to treat atopic dermatitis and suppurative hidradenitis. It is expected that phase II top-line data will be read in the first half of 2025. If the data is positive, it is expected that the indication layout of proteolytics will be further broadened.

(2) In recent years, many multinational MNCs have introduced protease related drugs through acquisitions and cooperative licensing (BD). For example, Pfizer introduced ARV-471 from Arvinas with a down payment of US$650 million plus equity investment of up to US$1.4 billion, Sanofi introduced KT-474 with an advance payment of up to US$150 million plus milestone payments of up to US$2 billion plus royalty fees from Kymera. Lilly introduced KT-474 from Kymera with a potential milestone payment of up to US$1.6 billion A relevant cooperation was reached with Lycia, a company focusing on the development of proteolytic drugs, for a price share of sales in digits. Multinational pharmaceutical companies such as Novartis, BMS, and AstraZeneca have also deployed in the field of proteolytics through acquisitions or cooperative licensing (BD).

(3) A number of domestic companies have entered the clinical stage with related products. Among them, BeiGene has deployed BTK PROTAC and is currently developing phase II clinical trials for relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia. The ORR for treating patients with treated B-cell lymphoma (median number of treatment lines is 4) is 57%, of which the CLL/SLL subgroup has an ORR of 72%, and the drug is still effective for patients resistant to BTK inhibitors, showing good application potential. Hengrui Pharmaceutical also has a layout in the field of protein degradation. The company mainly adopts a fast-follow strategy. The overall layout is similar to ProTAC leader Arvinas, which mainly includes PROATC drugs for ER and AR. Hisco, on the other hand, chose a differentiated layout of targets such as AR V7 and EGFR, which have a relatively mild competitive pattern for proteolytics. Nuochengjianhua further enriched the company's product layout in the field of hematoma through the layout of ICP-490, a molecular glue targeting IKZF1/3.

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