The $4.9 billion bet is zero, and Gilead is out behind CD47

Text | Amino observations

The excellent early clinical data of a new drug can often stimulate the enthusiasm of big pharmaceutical companies for mergers and acquisitions, which becomes an important catalyst for BD transactions.

In the field of innovative drugs, there are many cases of pharmaceutical companies being acquired by big pharma companies immediately after announcing brilliant data at important conferences. However, this does not mean that the balance of victory will be tilted in favor of Big Pharma. After all, the research and development of innovative drugs is full of variables, and uncertainty is the greatest certainty.

Recently, Gilead completely "conceded defeat" in a $4.9 billion BD gamble.

In March 2020, Gilead Sciences invested $4.9 billion in the acquisition of ForthSeven, a company specializing in immunotherapies targeting CD47.

A few days ago, at the same time as announcing the first quarter financial report, Gilead updated the pipeline progress, in which all 6 solid tumor clinical trials on the CD47 monoclonal antibody magrolimab were eliminated.

Considering that in February this year, the clinical trial of magrolimab for hematologic tumors has been completely terminated. This also means that Gilead has completely "conceded defeat".

As the fastest player in the development of CD47 antibodies, Magrolimab's exit is undoubtedly embarrassing. Of course, the development of CD47 targets continues.

01 Gilead the Dream Chaser

PD-1, a rare target in this decade, has made Merck and attracted countless latecomers who want to counterattack. In the era of immunotherapy, everyone wants to find the next gold-absorbing target, and CD47 is seen as such an opportunity.

As a "safety guard" that kills tumor cells, the activity of macrophages is controlled by "eating" and "not eating" signals. The surface of tumor cells may express "eating" signals (e.g., calreticulin) that allow macrophages to recognize and destroy them.

To counteract this visibility, cunning tumor cells, which tend to express high levels of the CD47 protein, can transmit the "don't eat me" signal by binding to the signaling regulator SIRPa on the surface of macrophages.

In order to cope with this situation, major pharmaceutical companies have begun to focus on the research of drugs targeting CD47, hoping to block the signal exchange between phagocytic cells and cancer cells, so that phagocytic cells can work normally and kill cancer cells.

Due to overexpression of the CD47 protein, it is common in all types of tumors, including non-Hodgkin lymphoma, colorectal or gastric cancer, lung cancer, etc. Studies have shown that this is associated with more aggressive disease and poorer survival.

For this reason, the CD47 target is considered a promising target. Forty Seven's Phase Ib clinical data for the first-line treatment of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) updated by Forty Seven at the 2020 ASCO Annual Meeting showed that the ORR reached 64% and 91%, respectively, which ignited this track and attracted a number of pharmaceutical companies such as Gilead to enter the game.

In everyone's vision, the development direction of CD47 antibody drugs should be "to explore the potential of solid tumors with hematological malignancies as the cornerstone". Initially realize the field of hematological malignancies (such as AML/MDS) of POC, which has urgent clinical needs, and further expand CD47-related drugs as the cornerstone of combination therapy to other hematological malignc indications such as MM.

After that, it is combined with the existing SoC to treat solid tumor patients who are not sensitive to immunotherapy, or combined with PD-1/PD-L1 antibodies, SHP2 inhibitors, etc. to rescue patients who have failed conventional immunotherapy.

This is also the direction chosen by ForthSeven. However, at the moment, Gilead's bet was not successful.

02 Behind the Pioneers Become Martyrs

It is not easy to drug any target, and this is especially true for CD47.

The CD47 protein is widely expressed in our normal cells and is not limited to cancer cells.

Although blocking the CD47-SIRPα interaction alone is not enough to trigger phagocytosis, it also needs the assistance of "eat me" signals such as calreticulin. However, in tumor cells, senescent erythrocytes, and platelets, blocking the CD47-SIRPα interaction directly triggers phagocytosis.

The main reason why CD47 targets are difficult to drug is that the affinity of red blood cells to drugs is much higher than that of tumor cells, resulting in unavoidable blood toxicity. How to kill tumor cells while avoiding accidental injury to red blood cells has become a thorny problem.

Gilead's magrolimab takes a very primitive route: "can't be provoked, can hide", and only the IgG4 antibody removes the Fc terminal ADCC effect.

As you know, the true face of antibodies is IgG (immunoglobulin). Because the number and position of disulfide bonds vary, there are four isoforms of immunoglobulins: IgG1, IgG2, IgG3, and IgG4.

These different subtypes of antibodies, in different amounts in plasma, have different functions and different killing effects on red blood cells. Overall, IgG4 antibodies appear to be a subtype that minimizes red blood cell toxicity.

However, at present, this modification does not seem to be enough to solve the problem of blood toxicity of CD47 antibodies.

Magrolimab relies on strenuous "pre-excitation" regimens to reduce toxicity issues. Judging from past clinical data, although magrolimab has reduced anemia to a certain extent, its hemotoxicity is still worrying.

At the same time, the "antigen sinking effect" caused by the binding properties of Magrolimab to red blood cells indirectly affects its clinical efficacy.

The unsuccessful modification of the antibody may have been the core reason why Gilead stopped the development of Magrolimab.

On February 7 of this year, Gilead announced that it had terminated the Phase III ENHANCE-3 study of magrolimab for the treatment of AML, and the FDA placed all studies of magrolimab in MDS and AML, including related expansion studies, on full clinical hold.

This is due to the fact that the latest data from the IDMC evaluation found that magrolimab + azacitidine + venetoclax had no therapeutic effect and increased risk of mortality (mainly due to infection and respiratory failure).

03 The exploration continues

As a pioneer, the exit of magrolimab is embarrassing, and once made the market worry about the drug of CD47, but the exploration of CD47 targets will not end because of this.

In the face of the challenge of CD47 targets, pharmaceutical companies at home and abroad have shown an indomitable spirit of innovation and proposed a series of innovative solutions.

These include, but are not limited to, reducing the binding of CD47 drugs to red blood cells to reduce potential side effects, giving up the direct killing effect of CD47 antibodies in favor of new mechanisms of action, developing bispecific antibodies, and exploring combination strategies.

Different R&D ideas have given rise to a diverse range of drug molecules, each with its own unique biological characteristics, clinical safety, and efficacy.

Therefore, the early clinical performance of a single drug molecule cannot be used as the ultimate criterion for judging the value of the entire target.

From this perspective, pharmaceutical companies that learn from the failures of earlier CD47 molecules and build on them to develop a new generation of CD47 molecules still have a chance to succeed in this race.

Of course, Gilead's experience has also sounded the alarm bell for the market, reminding latecomers that success is not easy on the road to R&D of innovative drugs, and pharmaceutical companies should be prepared for possible failures in the R&D process while pursuing innovation, and respond to various challenges in the R&D process with a scientific attitude and prudent strategies.