IDO is just like a spicy chicken! If you don't know this target, would you like to chat with others?

- Jul 17, 2018-

The 2017 American Association for Cancer Research Annual Meeting (AACR2017) was held in Washington, DC from April 1st to 5th. During the conference, in addition to the PD-1/PD-L1 still dominated the screen, there is still a new target suddenly blushing, that is IDO, you can feel the news hot first:


    On March 31, Merck/Incyte revealed seven clinical collaborative development plans for epacadostat (IDO inhibitors) in combination with Keytruda (PD-1 inhibitor), in addition to an ongoing melanoma phase III study. A phase III study of two first-line treatments for NSCLC was performed in patients with high PD-L1 expression and patients without PD-L1 expression; two first-line or second-line treatments for bladder cancer; one first-line treatment for kidney Phase III study of cell carcinoma, a phase III study of first-line treatment of head and neck squamous cell carcinoma.


    On April 2, BMS/Incyte announced that it will advance the clinical study of epacadostat + Opdivo first-line treatment of NSCLC (regardless of PD-L1 expression level) and head and neck cancer to phase III. The two sides also decided to expand the ECHO-204 I/II research collaboration reached in 2014 to conduct a phase III registration study in patients with relapsed/refractory melanoma.


    On April 4th, the AACR2017 conference published a phase II clinical data of an indoximod (IDO inhibitor) combined with Keytruda second-line treatment of advanced melanoma, showing that the combination of the two uses Keytruda alone to increase the ORR from 33% to 52%. .


    Opdivo and Keytruda, the two most popular tumor immunotherapeutics at the moment, are pleading with epacadostat for a three-phase clinical trial. In addition, AstraZeneca's PD-L1 monoclonal antibody has an early clinical collaboration with epacadostat. Epacadostat, an IDO inhibitor, seems to have suddenly become a star-studded drug. Why can it attract the competition of tumor immunotherapy giants?


    IDO's full name, indoleamine 2, 3-dioxygenase (IDO), is the rate-limiting enzyme in the metabolism of tryptophan in humans. Like PD-1, it is also a key immune regulator for regulating tumor immune response. Inhibition of enzymes. Tumor cells usually overexpress IDO, induce immune tolerance to the human immune system, thus escaping the surveillance and killing of the human immune system. Currently in prostate cancer, pancreatic cancer, breast cancer, gastric cancer and other tumor cells Overexpression of IDO was found inside.


    In fact, IDO is not a new target. The pharmaceutical industry's previous focus on IDO mainly stayed in the field of Alzheimer's disease and neurological disorders, but the tumor immunotherapy that accompanied the rise of PD-1 made everyone to IDO. The focus has changed, and BMS and Merck's support for epacadostat have allowed IDO to stand in the spotlight.


    PD-1 wars warm up, IDO rides the wind


    PD-1/PD-L1 drugs are now a topic that must not be bypassed. The performance of several drugs after the market is also very amazing.


O-K-T global quarterly sales data (100 million US dollars)

    Note: Tecentriq sales unit is CHF 100 million


    However, the PD-1/PD-L1 type of immunological checkpoint inhibitor alone has a response rate of about 20% for some advanced tumors, and there is still much room for improvement. In order to exploit the therapeutic potential, PD-1/PD-L1 has become the main route in combination with various other mechanisms of action, such as chemotherapy drugs, various targeted drugs (PARP, EGFR), immunotherapy drugs (CTLA-4), and intervention. The therapy is taking turns. The combination of PD-1+ IDO is also believed to synergistically exert a stronger de-immunosuppressive effect.

    Lung cancer is the early indication of PD-1/PD-L1, and it is also the largest tumor indication in the market. The degree of competition can be imagined. The original Opdivo, Keytruda, and Tecentriq seats in the field of lung cancer have been scheduled (see: PD-1 lung cancer market has been determined, what are the other indications?), but some news released during AACR2017 let everyone smell the smell of gunpowder.


    Merck just said that it is necessary to carry out the Phase III study of Keytrud combined with epacadostat in the first-line treatment of NSCLC as soon as possible. BMS immediately started the Phase III study of the first-line treatment of NSCLC with Opdivo and epacadostat. It seems that the combination of BMS to PD-1+ IDO is better than PD- 1 (Opdivo) + CTLA-4 (Yervoy) is more confident.


    The cooperation between several major tumor immunotherapy giants and Incyte is not just beginning, but Merck and BMS are so happy, Incyte is still very happy, not only finds the door to the cooperation, but also actively declares that with the fourth listed PD -1/PD-1L drug Bavencio (avelumab) is open to cooperation.


    After PD-1 and PARP were hot, IDO became the most sought-after target. After that, if the pharmaceutical company did not have an IDO, would it be embarrassing to say hello?


    When is the mystery of IDO unveiled?


    The current IDO inhibitors are mainly Newlink's indoximod, NLG2103, and Incyte's epacadostat. The three drugs differ in their mechanism of action. Indoximod acts directly on immune cells and reverses the immunosuppression mediated by the IDO signaling pathway. NLG2103 and epacadostat act on the IDO enzyme itself, preventing IDO from degrading tryptophan and activating T cells from immunosuppressive states.


    Despite the IDO heat wave, the current clinical data is very limited, mainly in the field of melanoma. The late melanoma response rate data published at ESMO2016 showed that the objective response rate of Opdivo + epacadostat was close to that of Opdivo + Yervoy (53% vs 58%), but the adverse reactions were smaller. ASCO University, which was held in June this year, is expected to focus on some PD-1+ IDO data in head and neck cancer, non-small cell lung cancer, and kidney cancer.

Source: EvaluatePharma


    In terms of partnership, Incyte's partners include BMS, Merck, AstraZeneca, and Newlink's partners include Merck and Roche. Although BMS itself has an IDO inhibitor BMS-986205 to stage I/II, it seems to be more interested in Incyte's IDO.


    Looking at the domestic market, in March 2016, Professor Yang Qing, a research group of the School of Life Sciences of Fudan University, authorized IDO inhibitors with independent intellectual property rights developed over 10 years to be awarded to US HUYA in the form of milestone payments totaling no more than US$65 million. . This news is like the fact that in 2015, Hengrui's self-developed PD-1 monoclonal antibody was authorized to Incyte with a total amount of nearly 800 million US dollars, which caused a great sensation in China and was a milestone in the transformation of domestic innovation achievements.

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