What can save PD-1 is not only the price war but also the CTLA-4 target

Image source @ Visual China

Text | Amino Finance

The PD-1 track is getting lively. On March 24, Henlius' PD-1 monoclonal antibody Slullimonumab was approved for listing, and the Chinese pharmaceutical market ushered in the 7th domestic PD-1 monoclonal antibody.

Nowadays, PD-1 monoclonal antibody has become the most mature product in the world, and relevant statistics show that the total number of clinical trials of PD-1 target drugs in the world has exceeded 3400, of which 675 are registered in China (CDE), accounting for about 20% of the global total, covering almost all cancer indications.

After the listing of Slullimonab, the competition in the domestic PD-1 market will be more involuted, coupled with the impact of overseas products, the time left for the remaining innovative players in the PD-1 market is running out.

Benefiting from the popularity of PD-1, immunotherapy has become the most concerned therapy in the field of tumors.

However, in stark contrast to the popularity of PD-1, the ctLA-4 inhibitor, which is also immunotherapy, has rarely been approved, and only one product of Bristol-Myers Squibb (BMS) ipicumab (Y drug) is still on the market.

You know, CTLA-4 inhibitors are the world's first approved immune checkpoint inhibitors.

As early as 2011, Y-drug was approved in Japan, opening the first immunotherapy, three years before the first PD-1 product was approved. "Father of CTLA-4" James W. Bush P. Allison also won the Nobel Prize in Medicine in 2018 for discovering the CTLA-4 protein.

So what exactly is hindering the development of the CTLA-4 target? Looking to the future, what is the development trend of CTLA-4 targets?

01 The "miracle drug" that was almost abandoned

Although CTLA-4 inhibitors pioneered immunotherapy, they were not very popular when they were first introduced.

At the beginning of the marketing of Y drug, although it has outstanding efficacy in the treatment of malignant melanoma and can effectively prolong the survival of patients, it is helpless to have too high a chance of side effects, which greatly limits its use scenarios.

According to clinical trial data, the median overall survival of patients in the Y drug trial group was 10 months, compared with only 6 months in the control group; the one-year survival rate of patients in the Y drug group was 46% and the control group was only 25%,; the two-year survival rate of the patients in the Y drug group was 24%, and the control group was only 14%.

Although the data has almost doubled, it is exchanged for a very high probability of side effects. As an immunosuppressant, Y medicine is very easy to over-activate the immune system, more than 70% of patients will have diarrhea, rashes and other side effects, and even more due to overactivation of the immune system and death.

In this context, the aura of the first immunotherapy on the head of CTLA-4 inhibitors has become more and more dim, coupled with the strong rise of PD-1 inhibitors later, resulting in a large number of subsequent pharmaceutical companies "abandoning" the research and development of CTLA-4 inhibitors and focusing on PD-1 inhibitors.

In retrospect, the value of PD-1 inhibitors is unquestionable, but CTLA-4 inhibitors are not without merit. While CTLA-4 inhibitors can cause serious side effects, and the overall data for patients is not as eye-catching, there are a number of "super lucky" in patients with Y drugs.

In the return visit of Y drug, the 3-year survival rate was about 25%, which was a doubling improvement over chemotherapy, but the probability was still very low. However, when we continue to stretch the timeline to 10 years, we will find that the 10-year survival rate of Y drugs is also more than 20%.

The meaning behind the data is that Y drug is not ineffective, but the conditions of use are too harsh, and it is very easy to have side effects. And once it is used on the right patient, then such a magical situation that is almost "cured" will occur.

In this way, Y drug is not a perfect product, there is still a lot of room for improvement in it, if the product can be further improved, then CTLA-4 inhibitors or will be promising.

02 CTLA-4 Target Mechanism Controversy

Although CTLA-4 inhibitors are recognized as first-generation immunosuppressants, the mechanism of action of this target remains controversial until now.

Initially, the mechanism of CTLA-4 inhibitors was identified as lifting the "obstruction" of the initial T cells and allowing them to be activated in the lymph nodes and then migrate to the tumor site to kill the tumor cells.

CTLA-4 is a protein with high homology to CD28 on T cells, and they can all bind to B7 molecules (CD80 and CD86). Although the homology of these two cells is as high as 70%, the functions are completely opposite.

CD28 belongs to the co-stimulatory immune checkpoint, which is responsible for transmitting activation signals to T cells after binding to T cells, promoting T cell differentiation and proliferation into effector cells, while CTLA-4 belongs to the co-inhibitory immune checkpoint, which is responsible for transmitting inhibitory signals to T cells after binding to B7 molecules and inhibiting the activity of T cells.

Activation of T cells requires a total of two steps: first the T cells need to complete antigen recognition, that is, the antigen information presented by the MHC binds to the TCR of the T cells; then the synergistic co-stimulating molecule, that is, the B7 protein, binds to the CD28 receptor protein to initiate the immune response.

Since CTLA-4 has a higher affinity with B7 molecules, it will compete and block the activation of CD28 on T cells, thus creating a "block" on the initial T cells, inhibiting the proliferation and activation of T cells. CTLA-4 inhibitors are precisely by blocking CTLA-4, thereby reactivating T cell differentiation and proliferating into effector cells.

However, as people become more familiar with the CTLA-4 target, another speculation about the mechanism of the CTLA-4 target has begun to appear in the industry, which has also become an important breakthrough direction for CTLA-4 inhibitors.

This view is that CTLA-4 inhibitors do not exert anti-tumor effect by blocking the action between CTLA-4 and B7, but through the ADCC effect mediated by antibody Fc receptors, effectively remove tumor local regulatory T cells (Treg) with high expression of CTLA-4, thereby relieving the immunosuppressive effect of Treg and achieving anti-tumor effect.

Treg cells are cells that suppress immune function, and when the war between T cells and infection is over, Treg cells will signal the stop of attack, thereby inhibiting the immune effect.

At present, there is still a lot of controversy about whether the mechanism of the CTLA-4 target is immune checkpoint blockade, or Treg clearance, or both.

For pharmaceutical companies, whether CTLA-4 inhibitors are made into a type of target blocking, or a type with strong ADCC effect mediated by Fc segments, is still a difficult choice.

Although there are still many uncertainties, but the new generation of CTLA-4 inhibitors has become a new direction of research and development in the industry, the first thing to do is to reduce toxic side effects, a CTLA-4 inhibitor attenuation and upgrading war has begun.

03 Attenuation and upgrading of CTLA-4 inhibitors

Looking at the global CTLA-4 inhibitor market, innovation is the mainstream direction of development, based on technical differences, CTLA-4 inhibitors have formed multiple branches.

In terms of traditional CTLA-4 inhibitors, the only Y drug on the market, AstraZeneca's Tremelimumab, is considered most likely to be the next CTLA-4 product on the market.

In 2020, Tremelimumab, in combination with the PD-L1 inhibitor Durvalumab, was granted fda qualifications for first-line treatment of orphan drugs for hepatocellular carcinoma. At present, Tremelimumab has completed the phase III clinical trial.

In terms of innovation, BMS, which launched the first CTLA-4 inhibitor, is still at the forefront of the industry.

After the debate over the new mechanism of the CTLA-4 target appeared, BMS began to make major changes to the CTLA-4 inhibitor, designing the product BMS-986218, which entered the clinic in 2017. This innovative product is the application of a new Fc modification to enhance the ADCC function of the theory, through the elimination of Treg to achieve the effect, is expected to significantly reduce toxic side effects.

Also aimed at Fc modifications to achieve results are another product of BMS, BMS-986218, and products such as Agen1181 of Agenus.

In addition to the modification of Fc, BMS also added masking peptides to the Y drug, thus forming a new product BMS-986249. This product can use specific highly expressed proteases in the tumor microenvironment to selectively activate Y drugs and reduce toxic side effects of peripheral tissues.

Basically, all of the current new CTLA-4 inhibitor routes are iterative on BMS's two methods, and whether these designs can work still depends on the subsequent clinical data results.

In terms of domestic enterprises, CTLA-4 inhibitors designed by Tianyan Pharmaceutical, Innovent Biologics, Hebo Pharmaceutical, and Yuhe Pharmaceutical are all new generation of CTLA-4 inhibitors. In addition to independent research and development, Hengrui Pharmaceutical just spent 1.185 billion yuan to acquire CStone Pharmaceuticals CTLA-4 monoclonal antibody CS1002 in Greater China in November last year.

For an established company like Hengrui Pharmaceutical, why spend so much money to acquire an unproven and early clinical CTLA-4 inhibitor?

04 Break the vanguard of the PD-1 inner roll

Hengrui Pharmaceutical layout CTLA-4 inhibitors, in addition to focusing on the pipeline itself, is also a layout for the future.

With the continuous intensification of the PD-1 industry's internal volume, in order to obtain differentiated competitive advantages, PD-1 combination drugs have become the breakthrough direction of most pharmaceutical companies.

At first, pharmaceutical companies targeted PD-1 combination on chemotherapy and radiation therapy. It was not until 2015 that BMS's dual immunotherapy of Y drug combined with O drug was approved by the FDA for melanoma indications, and the combination of immunotherapy program was gradually accepted by the industry.

According to the mainstream view, CTLA-4 inhibitors and PD-1 inhibitors synergize with each other. CTLA-4 inhibition can not only promote the production of more immune cells, but also remove the Treg cells around the tumor that act as a reaction, playing an immune enhancement role; while PD-1 is to block the camouflage of tumor cells, let the T cells fire up, and further amplify the efficacy of immunotherapy.

On March 18 this year, BMS's LAG-3 antibody Relilimab combined with PD-1 therapy was approved for the treatment of metastatic melanoma, making LAG-3 the third approved immune checkpoint inhibitor in the world after CTLA-4 and PD-1.

In addition to CTLA-4 and LAG-3, TIGIT is also a target that is relatively close to the current drug, but unfortunately, roche subsidiary Genentech's TIGIT monoclonal antibody Tiragolumab and PD-L1 combination scheme ended in failure on March 30, and it was temporarily not approved for listing.

In the past two years, almost all targets have undergone joint trials with PD-1. However, among all the combined targets, CTLA-4 is the target with the most joint trials conducted by pharmaceutical companies in addition to chemotherapy, which makes CTLA-4 inhibitors shoulder the burden of breaking the internal volume of PD-1.

At the annual meeting of the European Society of Medical Oncology in 2019, BMS announced the 5-year results of the Y-drug combined O drug melanoma phase III clinical study CheckMate-067. The 5-year overall survival rate of the OY treatment group was 52%, the 5-year overall survival rate of the O drug monotherapy group was 44%, and the 5-year total survival rate of the Y drug monotherapy group was 26%, and the combination drug effect was remarkable.

It is also relying on the combination scheme with O drugs that the revenue of Y drugs has continued to grow in the past three years, with an annualized compound growth rate of 16.6%. This is sufficient to illustrate the explosive potential of CTLA-4 inhibitors in combination with PD-1 from the side.

Especially at the moment when domestic PD-1 products are becoming more and more involuted, BMS is worth learning from domestic companies, and Hengrui Pharmaceutical has spent huge sums of money to acquire CTLA-4 inhibitors, or also to pave the way for its own PD-1 products.

After all, CTLA-4 inhibitors have become a key link in combination immunotherapy regimens and an important target for popular dual antibody products. Kangfang Bio's PD-1 and CTLA-4 dual antibody products have applied for listing in 9 years last year, and are expected to become the first PD-1 bispecific antibody listed in China; Corning Jereh's PD-1 and CTLA-4 dual antibody products have just completed Phase III clinical trials.

After the Chinese pharmaceutical companies have concentrated on the PD-1 track, it is obvious that there is excess capacity, and how to find a differentiated development path will be the next problem they need to consider, and the CTLA-4 target may be one of the answers to differentiation.

By combining with ctLA-4 targets or making a dual antibody, it can effectively make its own PD-1 products go out of the Red Sea and gain differentiated market competitiveness.

With the approval of more CTLA-4 target-based products, immunotherapy options may gradually become mainstream, and it is expected to further promote the scale growth of PD-1 products.