Domestic v.s. imports, PD-1 inhibitors coming head-to-head

12 of 2018On March 17, the State Drug Administration (NMPA) formally approved the launch of Junshi Bio's self-developed PD-1 inhibitor, Treplimab (trade name Tuoyi), for unresectable or metastatic melanoma after previous systemic treatment failure. With the approval of a number of PD-1 inhibitors, drug prices are expected to be further reduced, is bound to benefit more cancer patients.

First Approved Indications-Melanoma

 Melanoma, the first indication approved this time, does not have a high incidence in the Asian population,About 1.1~1.4/100000 people (East Asia), and the incidence rate in Australia, America and other countries can be as high as 229.2/100000 people. However, melanoma has shown a rapid growth trend in recent years in my country, and it is one of the malignant tumors with the fastest growth in incidence. There are about 20000 new cases each year, and the mortality rate is also increasing rapidly year by year. It has become one of the diseases that seriously endanger the health of our people.

Melanoma has 4The subtypes are Acral (acral melanoma), Mucosal (mucosal melanoma), Chronic Sun Exposure (chronic sun-damaged melanoma), and Non- Chronic Sun Exposure (non-chronic sun-damaged melanoma). In China, the subtypes of acral melanoma and mucosal melanoma are 50% and 23%, respectively, accounting for the majority of melanoma patients. Melanoma is a skin tumor with a high degree of deterioration. It progresses rapidly and is easy to metastasize, which seriously threatens the life and health of patients. Nearly 40% of patients are in stage III or IV when they are first diagnosed.

For a long time, it has been difficult to make a breakthrough in the treatment of advanced melanoma in our country. Chemotherapy is the main treatment method but the effective rate is low. The most important thing is that after the failure of systemic treatment such as chemotherapy and targeted therapy, the PD-1Before the emergence of monoclonal antibody, there was no effective means to significantly prolong the life of patients in China, and the approval of Treprimel injection provided these patients with a new choice of tumor immunotherapy at the international forefront, that is to say, after the failure of systemic treatment in patients with advanced melanoma, Treprimel injection can still bring clinical benefits to patients. Clinical trial results show that, treating patients with unresectable or metastatic melanoma who had previously failed systemic therapy resulted in an objective response rate of 17.3 percent, a disease control rate of 57.5 percent, and a 1-year survival rate of 69.3 percent.

The potential significance of treprozumab also lies in the expansion of other tumor indications,For example, Opdivo and Keytruda have been approved for 12 and 10 indications respectively, including lung cancer, gastric cancer and other cancers with high incidence in China. At present, a number of clinical trials of treprozumab are being carried out. Among them, the first-line treatment of melanoma and nasopharyngeal carcinoma indications have entered clinical phase III, gastric cancer, esophageal cancer, urothelial cancer and non-small cell lung cancer have entered clinical phase II, and four indications are in clinical phase I. It is expected that multiple indications will be approved in the future.

 

Mechanism of action of Treprozumab

Programmed Death Factor 1(Programmed Death-1,PD-1) and the discovery of its mechanism of action is a milestone event in the history of human anti-cancer. Unlike traditional chemotherapy and targeted therapy, it mainly kills tumors by overcoming the immune suppression in the patient's body and reactivating the patient's own immune cells. It is a brand-new anti-tumor treatment concept. This year's Nobel Prize in Physiology or Medicine has been awarded to this research field, based on the development of PD-1 monoclonal antibody, changed the treatment of tumor disease. PD-1 monoclonal antibody activates the body's own immune system to fight tumor cells-blocking the pathway through which tumor cells induce the "dormancy" of human immune cells, thus partially restoring the function of T cells to kill tumor cells, achieving the effect of long-term control or elimination of tumors, and bringing dawn to the cure of cancer. at the same time, it is also suitable for the treatment of a variety of tumors, former US President Carter, who suffered from advanced melanoma and spread to the liver and brain, it is through PD-1 monoclonal antibody treatment that the cancer cells completely "disappear" (magnetic resonance imaging shows no cancer cells).

The approved Treplimab is an anti-PD-1 antibody developed by Suzhou Zhonghe Biopharmaceutical Co.A novel recombinant humanized (97%) monoclonal antibody to the receptor (human IgG4/Kappa subtype) with a novel CDR sequence and a unique FG loop binding site can potently inhibit tumors through a dual mechanism of action.

Mechanism one: can be closed by TThe PD-1 of lymphocytes, blocking its binding to the surface PD-L1 of tumor cells, lifting the immune suppression of tumor cells on immune cells, so that immune cells can re-play the role of anti-tumor cell immunity and kill tumor cells;

Mechanism two: through the endocytic effect to reduce PD-1Membrane surface expression, restore the activation function of T cells.

 

Patent information for Treplimab

Treplimab has completely independent intellectual property rights, and its patent "anti-PD-1 antibody and its application" in China has been authorized and has also been laid out in other countries. Detailed patent information is compiled in the following table:

Open No.	Patent Name	Application Date	Legal status
BR112015031883A2	ANTI-PD-1 ANTIBODY AND THE USE OF IT	2014-02-26	Real Trial
CN104250302B	Anti-PD-1 antibody and application thereof	2013-06-26	Authorization
EP3026062A4	ANTI-PD-1 ANTIBODY AND USE THEREOF	2014-02-26	Real Trial
HK1225392A	Anti-PD-1 Antibody and Its Application	2016-11-25	Public
ID201704380A	ANTI-PD-1 ANTIBODY AND USE THEREOF	2014-02-26	No data
IN11958DELNP2015A	ANTI-PD-1 ANTIBODY AND USE THEREOF	2015-12-31	No data
JP2016523265A	Anti-PD-1 antibodies and their applications	2014-02-26	Rejected
PH12015502819A1	ANTI-PD-1 ANTIBODY AND USE THEREOF	2015-12-18	No data
RU2663795C2	ANTI-PD-1 ANTIBODY AND USE THEREOF	2014-02-26	Authorization
TH180337A	Antibodies-PD-1 antibodies and its use.	2015-12-23	No data
US10066013	Anti-PD-1 antibody and use thereof	2014-02-26	Authorization
VN47074A	PD-1 antibody, quantum acid electrolysis, Hemocyte and primary cell to express antibody, antibody production method, dietary Supplement and antibody drug	2016-01-22	No data
WO2014206107A1	ANTI-PD-1 ANTIBODY AND USE THEREOF	2014-02-26	---

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Listed PD-1inhibitors

So far, there are 5.PD-1 inhibitors are listed in dozens of countries such as Europe and the United States, including two PD-1 antibodies and three PD-L1 antibodies, respectively:

1.  Nivolumab （BMS), trade name Opdivo, abbreviated as O drug, FDA approval time 2014/12/22;

2. Pembrolizumab, referred to as drug k, FDA approval time 2014/9/4;

3. Atezolizumab (Roche), trade name Tecentriq, referred to as T drug, FDA approval time 2016/5/18;

4. avelumab (Merck/Pfizer), trade name Bavencio, abbreviated as drug B, FDA approval time 2017/5/9;

5. Durvalu Lab (April), trade name Info, referred to as drug I, FDA approval time 2017/5/1.

Nivolumab of themAnd keytruda (Chinese name pembrolizumab) has submitted a listing application to the China Food and Drug Administration, and it was listed in June and July 2018. The pricing of the two imported products is much lower than that of the United States and Hong Kong. With a drug donation plan, conscience pricing has brought tremendous pressure to domestic varieties.

In addition, domestic PD-1/PD-L1The competition for the development of class drugs is also very fierce. At present, more than 20 varieties have submitted registration applications to CDE one after another, waiting in line for listing.

So far, the PD-1 currently listed in ChinaThere are three inhibitors: Merck's Drug K, BMS's Drug O and Junshi Bio's Treprolizumab. Since the indication is the same as Melanoma as Drug K, Treprolizumab will directly confront Drug K on the track of Melanoma PD-1. As a leader in domestic PD-1, how will Junshi Bio deal with it? Let's wait and see.