After about two years of downturn, the once popular innovative drug target CD47 has received bad news again.
On February 7th, multinational pharmaceutical company (MNC) Gilead announced that it had stopped the phase 3 ENHANCE-3 study of magnolimab for the treatment of acute myeloid leukemia (AML). In addition, the US Food and Drug Administration (FDA) has placed all studies on the treatment of myelodysplastic syndrome (MDS) and AML with magnolimab (including related extended access projects) on comprehensive clinical hold.
Gilead stated that these decisions followed the recommendations of the Independent Data Monitoring Committee. The latter reviewed the OS (overall survival) top line data of ENHANCE-3 in the mid-term analysis and found that the treatment of magnolimab+azacitidine+vinacrine was ineffective and increased the risk of death, mainly caused by infection and respiratory failure.
Previously, Geely had terminated the ENHANCE study of magrolimab for high-risk MDS and the ENHANCE-2 study for TP53 mutant AML. The data also indicates that the magnolimab treatment group is not beneficial and increases the risk of death.
Therefore, Gilead also disclosed in this press release that it has decided not to further develop magrolimab for the treatment of hematomas. In addition, the company is reviewing the safety of magnolimab in all ongoing solid tumor trials and has stated that it will provide the latest information on this assessment as soon as possible.
In fact, Gilead is currently a pioneer in the CD47 target. From the pipeline layout and progress of magrolimab, it can also be seen that Gilead has expectations and challenges for the drug.
Image source: Dingxiangyuan Insight database
The CD47 targeted by Magrolimab is not considered an emerging target, but so far no drug has been successfully developed or approved for marketing. In other words, its first in class position is vacant. In 2009, Professor Irving L. Weissman's team in the field of cancer stem cells at Stanford University School of Medicine revealed the role of CD47 on cell surfaces. Simply understood, CD47 can interact with SIRP on the surface of macrophages α Combined, it releases a "don't eat me" signal to protect healthy cells from being "eaten" by macrophages.
Meanwhile, CD47 protein is also overexpressed on the surface of tumor cells, leading macrophages to mistakenly believe that the former is also a healthy cell. Thus, the idea of developing anti-tumor drugs for CD47 was formed, which is to block CD47-SIRP α Signal pathways promote adaptive immune response and enhance macrophage phagocytosis of tumor cells.
Moreover, CD47 is widely expressed in different tumors, making it possible to become a broad-spectrum anti-cancer drug and also considered the "next PD-1". DXY insight database shows that there are as many as 18 pipelines for magrolimab to enter the clinical stage. In addition to the aforementioned hematomas, it also includes colorectal cancer, triple negative breast cancer, head and neck squamous cell cancer, pancreatic cancer and other solid tumors.
But a major issue with this target is safety. The reason is that CD47 is also expressed on normal cells, especially on the surface of red blood cells, and the function of this mechanism itself is to maintain the balance of red blood cells in the body. Therefore, CD47 drugs often "accidentally damage" red blood cells, causing adverse blood reactions. In the early days, products from companies such as Arch Oncology, Xinji, and Surface Oncology all failed here.
Therefore, the development of CD47 drugs often needs to strike a balance between safety and their own therapeutic effects, such as sacrificing the killing ability of some drugs on tumor cells to reduce their impact on red blood cells and platelets. Combination therapy is also used for its development.
The turning point also appeared on Professor Weissman. It founded a company in 2015 to develop CD47 anti-cancer drugs, named Forty Seven, with its core product being magnolimab.
In 2019, the Phase 1b trial data released by Forty Seven showed that among 62 patients, the ORR (objective response rate) of magrolimab combined with azacitidine first-line treatment for MDS and AML were 92% and 64%, respectively. The proportion of patients who stopped treatment due to treatment-related adverse events was only 1.6%. The following year, Geely acquired Forty Seven for $4.9 billion to further develop the magic imab.
This has also attracted a group of MNC and biotech companies to follow up. In 2020, Abbey and Tianjing Biotechnology reached an agreement to acquire the rights of CD47 monoclonal antibody Lemzoparimab outside of Greater China for a maximum cooperation amount of $2.9 billion. This became one of the largest authorized foreign collaborations announced by domestic biotech at that time. In August 2021, Pfizer also acquired Trillium Therapeutics for $2.26 billion. Behind Arch Oncology, there is support from Roche.
However, from then on, it will be difficult to see good news in this field. The first person to apply the brake is Abbey. It terminated a clinical trial of lemzoparimab for the treatment of multiple myeloma (MM) in adults in July 2022, and also terminated a phase 1 study of the drug for MDS/AML one month later. In the same month, Zaiding Pharmaceutical also cancelled the phase 2 trial of its CD47 monoclonal antibody ZL-1201.
In 2023, more bad news will come one after another. In January, Arch Oncology announced the termination of its research and development of CD47, and most of its employees resigned. In July and September, Geely's aforementioned ENHANCE and ENHANCE-2 studies were terminated successively. In August, ALX Oncology also announced the termination of clinical research on the core pipeline CD47 fusion protein Everpacept for the treatment of MDS and AML.
However, ALX Oncology also brought the only good news. In October 2023, Everpacept achieved positive results in the mid-term analysis of the ASPEN-06 trial phase 2 for the treatment of HER2 positive gastric cancer. The company stated that it will enter Phase 3 trials in the second half of 2024.
During this period, domestic biotech also explored CD47 targets, many of which adopted a dual antibody development strategy. According to the Dingxiangyuan Insight database, Maiwei Biotech's 6MW3211 (CD47 × PD-L1) and Hansi Biotech's HX-009 (PD-1 × CD47) are both in the clinical stage 2. In addition, Ligufalimab from Kangfang Biotechnology and timdarpacept from Yiming'anke are also in phase 2.
Among them, Yiming Encore, which was listed on the Hong Kong Stock Exchange in September 2023, can be said to be a biotech supported by CD47. Its core products include Imm-01 (CD47 fusion protein), main products IMM0306 (CD47 × CD20), IMM2902 (CD47 × HER2), and IMM2520 (CD47 × PD-L1) all revolve around the CD47 target.