Recently, Incyte of the United States reported the Phase I clinical data of oral small molecule PD-L1 inhibitor INCB086550 in Journal for ImmunoTherapy of Cancer. It is understood that this is the first human trial data of oral small molecule PD-1/PD-L1 inhibitor. 

First human trial data of oral small molecule PD-1/PD-L1 inhibitor in the world 

It is known that adult patients (≥18 years) with advanced solid tumors were enrolled into this open-label study (NCT03762447). Patients had disease progression after standard available therapy or were intolerant of or ineligible for standard treatment.  At first, the improved 3+3 dose-escalation plan was adopted, followed by the dose expansions. The main clinical endpoints of the study include: the safety and tolerability of INCB086550, identification of a pharmacologically active dose and/or MTD, and the recommended dose in Phase II clinical research. The secondary endpoints include PK, pharmacodynamics, and objective response rate (ORR) and disease control rate (DCR) determined by the researchers. 

128 subjects were originally planned to be recruited in the clinical trial. As of April 9, 2021, 79 patients have received the treatment of INCB086550. 57.0% of them were female, 62.0% had ≥2 prior lines of therapy, and 16% received IO (tumor immunity) treatment. The results showed that among the 68 efficacy-evaluable patients, ORR was 11.8% and DCR was 19.1%. 

In terms of safety, 46 patients (58.2%) had treatment-related adverse events; 10 patients (12.7%) had grade ≥3 treatment-related TEAEs, 10 patients (12.7%) had TEAEs of peripheral neuropathy, and 5 patients (6.3%) died of TEAEs. All the TEAEs mentioned above were considered unrelated to study drug.  

Comparative advantage of oral small molecule PD-1/PD-L1 inhibitors 

At present, there are 10 PD-1/PD-L1 monoclonal antibodies approved for listing in China, including 8 (6 domestic and 2 imported) PD-1 monoclonal antibodies and 2 (all imported) PD-L1 monoclonal antibodies. In addition, many PD-1/PD-L1 monoclonal antibodies are in the stage of submitting listing application.

Compared with other approved monoclonal antibodies for injection at the same target, some shortcomings of monoclonal antibodies are overcome in oral small molecule PD-1/PD-L1 inhibitors, and it is oral and eligible for patients. It can enter brain tissue and be used for the treatment of brain diseases. The production process is relatively simple and the cost is low. It can also avoid the adverse reactions caused by macromolecular drugs. There is a perfect market prospect, being an attractive and important direction in the field of PD-1/PD-L1 inhibitors. 

Two domestic oral PD-L1 small molecule inhibitors 

On April 13, 2020, Chase Sun Pharmaceutical registered for the start of the Phase I clinical trial of its small molecule oral PD-L1 inhibitor IMMH-010 in the treatment of advanced malignant solid tumors on ClinicalTrials.gov. In this trial, 96 patients with malignant solid tumors were intended to be recruited. The main purpose was to evaluate the safety and tolerance of IMMH-010 in the treatment of malignant solid tumors at doses of 60, 120, 240 and 360mg respectively, to determine the MTD and Phase II recommended dose (PR2D) of IMMH-010, and to evaluate the effects of food on the pharmacokinetic profiles after IMMH-010 in patients with advanced solid tumors.       

IMMH-010 is an oral small molecule PD-L1 inhibitors developed by Chase Sun Pharmaceutical, and is the first oral small molecule PD-L1 inhibitors approved by clinical trials in China. If you are looking for medical supplies suppliers of this kind of inhibitor, then Pharmasources would be your best choice.

In addition to IMMH-010 of Chase Sun Pharmaceutical, MAX-10181, an oral small molecule PD-L1 inhibitor, is under the research of Maxinovel Pharmaceuticals. Its application for clinical trial in China was submitted in November last year, and Phase I clinical trial to treat advanced solid tumors was conducted in Australia at the same time. 

In September this year, Maxinovel Pharmaceuticals started the recruitment of MAX-10181 for Phase I clinical trial in China, which is intended to be used for advanced or metastatic solid tumors. It is reported that MAX-10181 can promote PD-L1 protein on the surface of tumor cells to form dimer, block the combination of PD-L1 and PD-1 on T cells, and finally prevent the immune escape of tumor cells and awaken the anti-tumor effect of patients themselves. 

At the AACR in 2019, Maxinovel Pharmaceuticals published the head-to-head comparison data between its oral PD-L1 inhibitor and AstraZeneca's PD-L1 antibody drug Durvalumab in a humanized tumor model, and they showed the same MC38 tumor inhibitory activity. As a small molecule compound, MAX-10181 also has good ability to penetrate the blood-brain barrier. 

At present, the competition in the domestic PD-1/PD-L1 inhibitor market segment is very fierce. In terms of monoclonal antibody products, a large number of pharmaceutical companies are ready for submitting the listing application and laying out new indications. In light of the fierce competition, these companies could be creative on creating novel oral small molecule PD-1/PD-L1 inhibitors, which is expected to be attractive by virtue of comparative advantages. 

About  the Author:    

Xiaoyaowan, a pharmaceutical industry practitioner, a word carrier in the We-media era focusing on changes of the pharma industry.