The PD-1/L1 track is inward, can small molecule drugs become the key to breaking the game?

For nearly a decade, immunotherapy has become the subject of scientific discussion and experimentation as a new pillar of tumor therapy
.
Among them, the PD-1/L1 pathway is known as the most successful target in the field of tumor immunotherapy so far, and its application and commercialization are expanding rapidly, covering almost all tumor indications
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Since the first PD-1, Opdivo monoclonal antibody, was approved by the FDA in 2014, up to now, 8 PD-1 inhibitors and 4 PD-L1 inhibitors have been launched in China
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PD-1/L1 antibodies can be said to be the "overheated" track in the current development of cancer-targeted drugs
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Since the PD-1/L1 inhibitors approved at this stage are all macromolecular antibody drugs, monoclonal antibodies have many inherent disadvantages, including poor oral bioavailability, prolonged tissue retention time and half-life, poor membrane permeability, transport The disadvantages of storage and other aspects, in addition, the high cost of antibody drugs is also a problem that cannot be ignored
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Therefore, more and more researchers are exploring small-molecule chemicals as PD-1/L1 inhibitors to circumvent the shortcomings of therapeutic antibodies
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In the past few years, many new small-molecule inhibitors targeting PD-1/L1 have been reported at home and abroad, and these small-molecule inhibitors are currently in different stages of preclinical or clinical research
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Ascletis - ASC61 On January 10, 2022, Ascletis Pharma announced that ASC61, an oral PD-L1 small molecule inhibitor developed by itself, has been submitted for a US clinical trial application (IND) for the treatment of advanced solid tumors
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ASC61 is a potent and highly selective oral PD-L1 small molecule inhibitor that blocks the PD-1/L1 interaction by inducing the formation and endocytosis of PD-L1 dimers
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ASC61 single drug showed significant anti-tumor efficacy in humanized mouse model and other animal models
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Preclinical studies show favorable safety and pharmacokinetic profiles of ASC61 in animal models
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The ASC61 oral tablet for clinical trials was developed using the company's proprietary formulation technology
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Compared with PD-1/L1 antibody injections, oral PD-L1 inhibitor ASC61 has the following advantages: (1) It is convenient to administer, and there is no need to go to the hospital for injection drugs; (2) It is combined with other oral antitumor drugs to form a complete Oral treatment plan; (3) The dosage can be adjusted in time to better manage immune-related adverse events
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Betta - BPI-371153 On November 12, 2021, the State Food and Drug Administration (CDE) undertook the clinical application of Betta Pharmaceuticals' Class 1 new drug BPI-371153 capsules
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BPI-371153 is a new molecular entity compound independently developed by Betta Pharmaceuticals.
It is a novel potent and highly selective oral PD-L1 small molecule inhibitor
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Intended for the treatment of patients with locally advanced or metastatic solid tumors or relapsed/refractory lymphoma
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Preclinical data show that BPI-371153 potently induces and stabilizes the formation and endocytosis of PD-L1 dimers, thereby potently blocking the PD-L1/PD-1 interaction
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Excellent in vitro and in vivo activity, good safety and pharmacokinetic properties have been demonstrated in preclinical studies
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Arnold Biopharmaceuticals - AN4005 On October 11, 2021, the Drug Evaluation Center undertook the clinical application of Hangzhou Arnold Biopharmaceutical Class 1 chemical drug AN4005 tablets
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AN4005 tablet is a new oral small molecule PD-L1 inhibitor developed by Arnold & Son.
On May 20 last year, Arnold & Son announced that it had submitted a clinical trial application for AN4005 to the FDA, and will start the drug safety and pharmacokinetics in the United States.
Clinically evaluated Phase I trial
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Preclinical studies have shown that AN4005 has excellent in vitro activity and potent antitumor activity, and can effectively induce and stabilize the formation and dimerization of PD-L1 dimers, thereby potently disrupting the PD-1/L1 protein interaction
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Meanwhile, AN4005 also showed good druggability and safety
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Incyte - INCB086550 At the 2021 SITC (Society for Cancer Immunotherapy Annual Meeting), Incyte reported the first clinical data for its small molecule PD-L1 inhibitor INCB86550
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Preliminary results from a phase I study showed that in 68 evaluable patients with advanced cancer who did not receive immune checkpoints, INCB86550 had an overall response rate of 11.
8%, including 1 complete response and 7 partial responses
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Meanwhile, 5 patients had stable disease, and the disease control rate was 19.
1%
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Zaiji Medicine - MAX-10181 On February 1, 2021, the CDE official website showed that Zaiji Medicine's class 1 new drug MAX-10181 tablet was approved for clinical use in China for the first time for advanced solid tumors
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MAX-10181 is an oral PD-L1 inhibitor that has previously initiated Phase I clinical trials in Australia
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At the 2019 Annual Meeting of the American Association for Cancer Research (AACR), Zaiji Pharma announced head-to-head comparison data of MAX-10181 with AstraZeneca's PD-L1 durvalumab in a humanized tumor model
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In both trials, MAX-10181 and durvalumab exhibited the same MC38 tumor suppressor activity, while MAX-10181 exhibited a higher CD8+/Treg ratio (p<0.
01)
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Red Sun Pharmaceuticals - Emdiphen The clinical trial notice issued by the Supervision Bureau agreed to conduct clinical trials.
This is the first oral PD-L1 small molecule inhibitor approved for clinical trials in China
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The study plans to enroll 96 patients with malignant solid tumors to evaluate the safety and tolerability of 60, 120, 240, and 360 mg of emdiphene in the treatment of malignant solid tumors, and to determine the maximum tolerated dose and phase II recommendations of emdiphene dose, while evaluating the pharmacokinetic effect of food in patients with advanced solid tumors
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In addition, Nanjing Shenghe and Sunshine Pharmaceutical are also developing small molecule inhibitors of PD-L1
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For PD-1/L1 antibodies, in addition to the difficulty in reducing the cost, the main method of administration is intravenous administration, once every 2 to 3 weeks, with an average administration time of 1-2 hours and requiring hospitalization
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Under such circumstances, subcutaneous injection formulations came into being.
Last year, as the world's first PD-L1 subcutaneous injection formulation, nvolimumab was launched.
Compared with the marketed PD-1/L1 injection, its patient compliance , security has been improved
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However, the forefoot of nvolimab has just been launched, and oral small-molecule PD-L1 drugs are already on the way
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Compared with subcutaneous injection preparations, the convenience of oral small-molecule drugs is further, and patients only need to take drugs at home, which makes it easier to achieve chronic cancer management
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In addition, the cost of oral small molecule drugs is lower, and compared with intravenous and subcutaneous injection preparations, the price can be said to have an absolute advantage
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In addition, compared with PD-1/L1 antibody injections, oral small-molecule drugs can easily penetrate into tissues and thus can target extracellular and intracellular targets to promote antitumor immunity and achieve modulation of the tumor microenvironment , and is even expected to turn "cold" tumors into "hot" tumors
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And they usually have a short half-life, reducing the chance of adverse effects
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Based on these characteristics, the research on the combination of small molecule targeted drugs and antibodies is in full swing.
The current challenge is how to rationally select chemoimmunotherapy combinations based on the known molecular mechanisms
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In addition, the focus should be on optimizing the dose and timing of these combination therapies to maximize their synergistic effects
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From the perspective of making up for the shortcomings of macromolecular antibody drugs and the advantages of oral administration, the market potential of oral small molecule PD-L1 is still great
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Once the development is successful, the commercial strategy will be very flexible.
You can choose to combine with antibody drugs to solve existing problems, or you can go further and directly challenge the status of antibody drugs to replace them
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Scarcity will help oral small molecule PD-L1 gain pricing power in the early stage, and low cost will help it compete for the market of macromolecule drugs in the later stage
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Although oral PD-L1 small molecule inhibitors have the advantages of better penetration and production cost in theory, the druggability still needs further clinical verification
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Previously, Gilead terminated the development of PD-L1 small molecule inhibitors, and the track still has some uncertainties.
.
.
References: 1.
CDE official website; 2.
Wu, Q.
, Jiang, L.
, Li, Sc .
et al.
Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway.
Acta Pharmacol Sin 42, 1–9 (2021).
3.
Qian Wang.
Patent research on PD-1/PD-L1 small molecule inhibitors Review of progress[J].
Shanghai Pharmaceuticals, 2019, 40(17):5.
4.
Lu, CH.
, Chung, WM.
, Tsai, CH.
et al.
In vitro characterization of a small molecule PD-1 inhibitor that targets the PD-l/PD-L1 interaction.
Sci Rep 12, 303 (2022).
The columnist has a background in photobiochemistry and molecular biology.
He has worked on the molecular typing of esophageal squamous cell carcinoma, and is familiar with the pathogenesis and medication of various solid tumors.
Program
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Now I take the discovery and dissemination of knowledge as a means of making a living, and I have no end to learn.
I hope that I will always maintain a humble attitude and plasticity, and welcome the golden age of the medical field with my colleagues
.