FDA persuades Agenus to withdraw, PD-1 is getting more and more difficult to market in the United States

A butterfly flapping its wings in the Brazilian jungle can cause a tornado in Texas, the United States
.

The FDA, which holds the "power of life and death" of innovative drugs in the United States, can affect Biotech's life and death every move, and even affect the hearts of domestic pharmaceutical companies, especially on the red-eye PD-1 track
.

Everyone has long been familiar with the congestion of the domestic PD-1 track, in fact, the same is true abroad
.

No, the FDA has already begun to persuade the PD-1/PD-L1 players who flocked to it

On October 22, Agenus announced that it "voluntarily" withdrew its PD-1 monoclonal antibody balstilimab for use in patients with recurrent or metastatic cervical cancer after chemotherapy
.

The reason is that the K drug has been approved for this indication first, and the two have similar effects and are recommended to be withdrawn by the FDA

Prior to this, the Incyte PD-1 monoclonal antibody application for anal cancer indications was rejected by the FDA due to the low objective remission rate
.

You know, small indications are the best way for PD-1 latecomers to counterattack, but at the moment, it is becoming increasingly difficult for PD-1, which is increasingly competitive, to be marketed in the United States
.

For the little-known Biotech like Agenus, now they can only find a way to conquer the FDA with phase III clinical data or combination therapy data
.

So, what does this mean for the domestically produced PD-1s that are aiming to go overseas?

- 01 - K preemptive medicine, FDA discouraging Agenus

- 01 - K preemptive medicine, FDA discouraging Agenus

On October 22, because the ORR of Balstilimab for the treatment of cervical cancer was 20%, the FDA considered it inappropriate to review its accelerated approval and recommended that Agenus withdraw the application for biological product license (BLA)
.

After the complaint was unsuccessful, Agenus "voluntarily" withdrew its PD-1 monoclonal antibody balstilimab for use in patients with recurrent or metastatic cervical cancer who had progressed after chemotherapy
.

On June 17, the drug had just been accepted by the FDA and obtained priority review qualifications at the same time
.

Why did the FDA suddenly change its face in the past 4 months, and the former Xiao Tiantian became Mrs.

This is inseparable from the approval of drug K for the treatment of cervical cancer indications
.

As early as 2018, Drug K received the FDA’s accelerated drug review for cervical cancer indications and became the first anti-PD-1 therapy approved for advanced cervical cancer patients who progressed after chemotherapy
.

The so-called accelerated drug approval is to provide new drugs to patients who have no cure
.

For diseases that seriously endanger the lives of patients and currently lack effective treatments, the FDA can approve drugs or new indications based on the positive results of the initial test endpoints of the drugs under study

However, it should be noted that obtaining accelerated approval does not mean that drug clinical research can be stopped
.

After the accelerated approval is passed, the drug still needs to be tested

Drug K and balstilimab monoclonal antibody have the same indications.
They are both indications for advanced cervical cancer that have progressed after chemotherapy.
Therefore, balstilimab monoclonal antibody can also apply for accelerated approval
.

What caught Agenus by surprise was that the FDA was originally scheduled to make an accelerated approval on December 16, but the K drug was approved 4 months in advance for the second-line full approval, which indirectly led to the closure of the accelerated approval window for balstilimab
.

In other words, due to the early approval of the K drug, patients with advanced cervical cancer who were originally incurable have treatment drugs, and balstilimab monoclonal antibody for 20% ORR (objective response rate) is not better than K drug 14% ORR is too high
.

Therefore, the accelerated approval qualification that was about to be obtained is lost, and balstilimab can only apply for the market with more complete Phase III clinical data in the later period
.

- 02 - listed on the PD-1 small indications more and more difficult to go

- 02 - listed on the PD-1 small indications more and more difficult to go

Retifanlimab monoclonal antibody is also similar to balstilimab monoclonal antibody
.

Incyte's Retifanlimab monoclonal antibody is aimed at patients with locally advanced or metastatic anal squamous cell carcinoma (SCAC)
.

This small indication has not yet been approved for drugs, so Incyte submitted a BLA application with confidence in January this year and obtained priority review qualifications

But the ideal is full, the reality is very skinny
.

Because the objective response rate (ORR) of Retifanlimab Phase II single-arm trial is only 14%, which is much lower than the originally expected 25%; and because the number of patients included in the clinical trial is small, the FDA believes that the potential efficacy of the drug cannot be determined at this time.

Therefore, the FDA rejected Retifanlimab's Biologics Licensing Application (BLA), requiring Incyte to continue to complete Phase 3 clinical studies, and submit a marketing application after the validity of Retifanlimab is proven
.

You should know that small indications are a routine way for latecomers to speed up the market
.

This is true for both Incyte and Agenus

It is not difficult to understand that there are currently 7 PD-1 models approved by the FDA for marketing, covering a wide range of indications
.
For example, K drug, in the United States, has covered 18 cancer types and more than 30 types of medications, ranging from small cancer types such as melanoma and kidney cancer to large cancer types such as non-small cell lung cancer and liver cancer.
PD-1 drugs are available Almost full coverage has been achieved
.

In this case, it is obviously impossible for the new Biotech to compete with Big Pharma through large indications
.
Therefore, starting from the initial indications, the curve to save the country has become the choice of many Biotech
.

However, this is not easy, because BigPharma is also deploying to small indications
.
By then, Biotech will have no chance to counterattack with the disparity in strength between the two sides
.

Take balstilimab and K drugs for cervical cancer indications.
Even if balstilimab gets the rapid approval, in the future competition with K drugs, the commercialization capabilities of the two will be very different, and it is difficult to get balstilimab from K.
The medicine has a slice in the hand
.

Although the FDA has not spoken bluntly, we can also feel that its review of PD-1 is becoming more and more stringent
.
In fact, it is not surprising that the FDA made such a decision
.
Because it is not only the domestic PD-1/PD-L1 track that is rolling, the competition of foreign PD-1/PD-L1 is also intensifying
.

As of February this year, there are currently 154 PD-1 projects under research worldwide.
Behind the craze for PD-1/PD-L research and development is the clustering of targets and lack of innovation, and this homogeneous research undoubtedly creates clinical resources Waste
.

It can be seen that not only Biotech, but also BigParma was rejected for PD-1 indications, and even Yaowang K and O drugs were not spared
.

Previously, drugs O and drug K have announced voluntary withdrawals for the treatment of metastatic small cell lung cancer indications that have received platinum-based chemotherapy or at least one other treatment line after the disease has progressed
.
Earlier, drugs O and K have passed accelerated drug approval for the treatment of metastatic small cell lung cancer, but due to poor efficacy data in the past two years, they were dismissed by the FDA
.

In addition, on February 22, after consultation with the FDA, AstraZeneca voluntarily withdrew its PD-L1 monoclonal antibody duvalizumab for indications for previously treated locally advanced or metastatic bladder cancer adults;

On March 8, Roche announced that it would voluntarily withdraw the PD-L1 monoclonal antibody T drug in the United States for the indications of previously platinum-treated metastatic urothelial cancer
.
The precious experiences of AstraZeneca, Roche, Merck and Besmesch are the same.
They all passed the accelerated drug approval first, but were dismissed due to poor efficacy
.

The FDA is adopting actions to cool PD-1/PD-L1
.
For latecomers, if the curative effect is limited or other big players preempt, there is a high probability that there is no chance
.

- 03 - Domestic PD-1 go to sea?

- 03 - Domestic PD-1 go to sea?

The FDA, which holds the "power of life and death" of innovative drugs in the United States, can affect Biotech's life and death every move, and even affect the hearts of domestic pharmaceutical companies, especially on the red-eye PD-1 track
.

According to data from Southwest Securities, 85 of the 154 PD-1 products under research in the world are developed or co-developed by Chinese companies, accounting for 55%
.

In the near future, we may also see that CDE's approval of PD-1 will also become stricter
.
At that time, it will be very difficult to get through the market with a single-arm test based on only small indications
.

It is precisely because of this that many players have begun to take precautions and regard going to sea as the best way to resolve domestic PD-1 involution
.
Players including Hengrui Medicine, Cinda Bio, BeiGene and other players have embarked on the road to sea
.

Cinda Bio will pin its hopes on North America, Europe and other regions
.
On May 18, the listing application of Sintilimab was accepted by the FDA, and the indication was first-line non-squamous non-small cell lung cancer
.
Sintilimab thus became the first domestically-made innovative biological drug whose complete marketing application was accepted by European and American regulatory agencies and entered the formal review stage
.

BeiGene has partnered with Novartis, who has acquired the development, production and commercialization rights of tislelizumab in multiple countries for US$2.
2 billion
.

However, with the tightening of FDA approval, the journey of domestic PD-1 to sea is destined to be difficult to continue smoothly
.

In the final analysis, no matter whether you are looking for a way out of PD-1 at home or abroad, you need to have a hard enough waist for the drug companies to have tangible clinical benefits
.