Investment in the innovative drug track is full of uncertainties. Up to now, in my personal opinion, the post-PD-1 era has yet to see innovative targets or products that can reshape the landscape of cancer treatment. Even the currently popular Claudin18.2 target, which has been mentioned in previous articles, carries hidden concerns. The CD47 target, once highly anticipated, has faced many obstacles.
——CD47 Track Express——
Gilead Sciences |Magrolimab (CD47 monoclonal antibody)
On February 15, 2024, Gilead Sciences announced the suspension of patient enrollment in the Magrilimab CD47 antibody study for solid tumors.
On February 7, 2024, Gilead Sciences announced the termination of the Phase III clinical trial for the CD47 antibody in the treatment of acute myeloid leukemia (AML).ENHANCE-3 StudyThis means that the FDA has requested a clinical hold on all clinical studies of Magrolimab for the treatment of AML and MDS.
On July 21, 2023, Gilead Sciences will halt Phase IIIENHANCE StudyThe study explored the efficacy of Magrolimab (CD47 antibody) in combination with Azacitidine in treating high-risk myelodysplastic syndromes (MDS). The ENHANCE study has been terminated based on the planned analysis results due to ineffective outcomes. The safety data from the study is consistent with the known characteristics of Magrolimab and typical adverse events observed in this patient population. Gilead Sciences recommends discontinuing Magrolimab treatment for MDS patients.
On September 26, 2023, Gilead Sciences announced the discontinuation of the ENHANCE-2 study of the CD47 antibody magrolimab for TP53-mutated acute myeloid leukemia (AML). Based on a special analysis and after review by an independent data monitoring committee, Gilead determined that magrolimab was unlikely to demonstrate a survival benefit in TP53-mutated AML patients compared to standard treatment. No new safety signals were identified in the study, and the safety profiles across treatment groups were comparable.
As early as January 25, 2022, Gilead Sciences announced a partial suspension of all clinical trials investigating the combination therapy of CD47 antibody and azacitidine.The reason for stopping the combination therapy was that researchers discovered a significant imbalance in the investigator-reported Suspected Unexpected Serious Adverse Reactions (SUSARs) across different trial groups in the Magrolimab + azacitidine combination therapy clinical studies, leading to the FDA requesting a partial clinical hold on this combination therapy.In summary,As All Three Phase III Trials Fail Due to Lack of Benefit and Increased Risk of Death, Gilead Completely Abandons Exploration of CD47 Antibody in Hematologic Malignancies.After Gilead acquired Forty Seven's core asset Magrolimab for $4.9 billion in cash,Magrolimab has faced repeated setbacks in clinical development, while another pioneer in the CD47 target—ALX Oncology Shifts Focus to Solid TumorsALX Oncology丨ALX148 (SIRPα V1D1-Fc Fusion Protein)On October 3, 2023, ALX Oncology announced preliminary efficacy in the interim data from the Phase II clinical trial ASPEN-06 of ALX148 (SIRPα V1D1-Fc fusion protein). ASPEN-06 is a randomized, double-blind, multi-center clinical study primarily aimed at evaluating the efficacy of ALX Oncology in combination with trastuzumab + CYRAMZA + paclitaxel for the treatment of HER2-positive gastric/gastroesophageal junction (GEJ) cancer.On October 3, 2023, ALX Oncology (NASDAQ: ALXO), the pioneer in the CD47 field, announced positive interim results from Phase II of its ASPEN-06 clinical trial. This trial is a randomized, multicenter, international study evaluating ALX Oncology'sCD47 blocker evorpacept (ALX148，SIRPα V1D1-Fc Fusion Protein）+Trastuzumab + CYRAMZA® (Ramucirumab) + PaclitaxelCombined Use for TreatmentHER2-positive gastric/gastroesophageal junction ("GEJ") cancer patients. This pre-specified interim analysis includes results from 54 patients with second- and third-line gastric/gastroesophageal junction cancer, including a certain number of patients previously treated with ENHERTU® (trastuzumab) and immune checkpoint inhibitors. Patients received 30mg/kg of evorpacept every two weeks, aligned with the treatment cycles of trastuzumab, CYRAMZA, and paclitaxel.
- Compared with the control group of trastuzumab + CYRAMZA + paclitaxel, the evorpacept combined with trastuzumab + CYRAMZA + paclitaxel group showed an overall efficacy response rate (ORR) of 52%, while the ORR of the control group was 22%.
- The median duration of response (mDOR) in the evorpacept combination therapy group has not yet been reached, compared to 7.4 months in the control group.
- Evorpacept's safety was consistent with previous clinical trials and was well tolerated.
- These interim results compare favorably to the efficacy reported in the RAINBOW study for CYRAMZA plus paclitaxel (ORR of 28%, mDOR of 4.4 months), which is the standard of care for second-line gastric/gastroesophageal junction cancer.
Sophia Randolph, M.D., Chief Medical Officer of ALX Oncology, said: "The ASPEN-06 clinical trial validatedEvorpacept in Combination with Anti-Tumor Antibody TherapyIn the treatment of solid tumorsThe potential of these data highlights the drug's potential as a first-class foundational immunotherapy." "Moreover, ASPEN-06 is the first global randomized study in HER2-positive tumors, with previousKEYTRUDA® (pembrolizumab) and ENHERTU are regulatory approved.We look forward to reporting the final analysis of the ongoing ASPEN-06 Phase II study in the second quarter of 2024 and plan to initiate the Phase III study of ASPEN-06 by the end of 2024."Suddenly remembered the Keynote811 study. In the field of gastric cancer, K drug, which has been consistently defeated by O drug, took a new path bypassing Her2- gastric cancer and chose combination therapy to explore Her2+ gastric cancer, achieving success. In an era where the winner takes all, no one cares about what kind of multidrug combinations are used.The above isALX Oncology's pipeline. The CD47 track has also gradually found its focus after experiencing numerous challenges.On the CD47 track, many companies in China are still expanding in the field of hematological tumors, with varying fortunes.Immunotech丨IMM01（SIRPαFc Fusion Protein）
On November 8, 2023, Immune-Onc Therapeutics announced that the FDA has granted Orphan Drug Designation for IMM01, a SIRPαFc fusion protein targeting CD47, in combination with azacitidine for the treatment of chronic myelomonocytic leukemia (CMML).IMM01, as the first STRPa-Fc fusion protein in China to enter the clinical stage, is being developed for the treatment of various blood cancers and solid tumors in combination with other drugs.In June 2022, Imming Angke officially launched the Phase II cohort expansion trial of IMM01 in combination with azacitidine. Based on the preliminary data from Phase I and Phase II clinical trials, IMM01 is highly likely to become a combination partner for azacitidine due to its dual control and favorable safety profile, exerting synergistic tumor-killing effects without exacerbating hematological toxicity. Public information indicates that Imming Angke plans to conduct pivotal clinical trials in China in the first quarter of 2024.There are three bispecific molecules based on CD47: IMM0306 (CD47×CD20), IMM2902 (CD47×HER2), and IMM2520 (CD47×PD-L1). The first two are globally first-in-class bispecific molecules that have entered clinical trials for their respective targets.
I-Mab Biopharma丨Lemzoparlimab（CD47 Antibody）
On September 22, 2023, I-Mab announced that AbbVie had terminated the collaboration agreement for the CD47 antibody. This decision was made by AbbVie based on previous project terminations and strategic adjustments. The termination of the agreement will take effect on November 20, and I-Mab will regain global rights to the CD47 antibody. The termination does not affect the upfront payment of $200 million plus milestone payments already received by I-Mab. Lemzoparlimab is currently in Phase III clinical trials, in combination with azacitidine as a first-line treatment for high-risk MDS.On February 7, 2024, I-Mab Biopharma (Hangzhou) Co., Ltd. reached an agreement with Nasdaq-listed I-Mab to integrate and restructure all of I-Mab's China operations, teams, and pipeline with the company’s existing pipeline and assets. Meanwhile, I-Mab Biopharma (Hangzhou) Co., Ltd. also announced the completion of a C1 round of financing exceeding 500 million RMB. This round of financing was jointly invested by Tylon Investment, Hedda Healthcare Fund, I-Mab, Hangzhou Qiantang City Development Technology Service Co., Ltd., Bruggemoon Limited, and Ningbo KaiTou Hanrun Capital.In summary, investment in innovative drugs must have a certain professional background, and blind investment is the biggest risk. We still need to review the mechanism of action and drug development defects of CD47 itself to seek appropriate product iteration and upgrades.The star target CD47 has experienced a bumpy development process and remains a highly controversial target due to the significant gap between theory and practice. After Celgene paused related trials, it cast a shadow over CD47. However, attention gradually increased as the leading company, Forty Seven, was acquired by Gilead Sciences for $4.9 billion.Following the entry of major pharmaceutical companies such as Gilead Sciences, AbbVie, and Boehringer Ingelheim into this target area, the track has gradually become active again.
| The English name：Cluster of Differentiation 47 | Number of Marketed Drugs：0 |
| The English name: Differentiation Cluster 47 | Number of Clinical Drugs：20 |
| Target Alias：Protein MER6，Integrin-associated protein，Antigenic surface determinant protein OA3，Leukocyte surface antigen CD47，CD47，MER6，CD_antigen: CD47 | Highest R&D Stage: Phase III Clinical Trial |
Source: Forty Seven public dataCD47, which is highly expressed on tumor cells, can transmit a “don’t eat me” signal to macrophages (by binding to SIRPα on the macrophage surface) and override the “eat me” signals expressed on tumor cells (such as calreticulin), thereby shielding the phagocytic function of macrophages. Thus, if monoclonal antibodies or other agents are used to block the CD47/SIRPα signaling pathway, the phagocytosis of tumor cells by macrophages could be restored, which is, of course, an ideal scenario. But once feasible, it could possess broad-spectrum anti-cancer capabilities. Therefore, this field is highly attractive.The Role of CD47 in Tumor Development and Maintenance of Red Blood Cell BalanceBut the most unavoidable issue with the CD47 target in drug development is the safety concern, as CD47 is also involved in maintaining the balance of red blood cells in the body:CD47 is also expressed on the surface of red blood cells in the body. On the surface of aging red blood cells, the expression of CD47 is downregulated or undergoes conformational changes, reducing the "don't eat me" signal, while the expression of "eat me" signals such as phosphatidylserine increases, promoting the phagocytosis of aging red blood cells by macrophages.CD47 therapeutic agents kill tumor cells while inevitably harming red blood cells.——Defects in the Theory of Patent Medicines——The results of several terminated trials also confirm this point. Anemia and thrombocytopenia have become stumbling blocks for some CD47 candidates under research.Therefore, the core of CD47 drug development is how to maximize the killing of tumor cells while protecting red blood cells, which is also why I have doubts about the so-called tri-specific and tetra-specific antibody products currently available. The human immune system is a highly sophisticated system; the fewer targets triggered, the lower the side effects caused, and the more likely it is to become a viable drug.Four Anti-Tumor Mechanisms of CD47-Targeted DrugsThe mechanism of action mainly includes the four aspects shown in the figure above. Among them, the two most core mechanisms of action are: blocking the macrophage phagocytosis induced by the CD47/SIRPα "don't eat me" signal, or the traditional effector functions caused by the Fc region of monoclonal antibodies, such as ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity).These two mechanisms are also a double-edged sword. Among these two effects, if the Fc end induces overly strong ADCC and CDC effects, it will inevitably lead to massive destruction of red blood cells, causing severe toxicity issues. However, on the contrary, if the effects mediated by the Fc end are completely abandoned and only the biological functions of the CD47/SIRPα signaling pathway itself are relied upon, it is insufficient to activate significant anti-tumor responses. This dilemma has caused the development of CD47 drugs to fall into a deadlock from the very beginning.The mainstream approach, represented by Celgene, Forty Seven, Arch Oncology, and Surface Oncology, is to develop CD47 antibodies with an IgG4-type Fc region, rather than IgG1-type antibodies that can trigger strong ADCC and CDC effects. This strategy will reduce the impact on red blood cells and platelets, but a large amount of data has already proven that replacing IgG1 with IgG4 significantly weakens the tumor cell-killing ability of CD47 monoclonal antibodies.While safety has improved, the reduction in efficacy is also a foreseeable fact. Therefore, in the formulation of clinical trial strategies, the combination of CD47 monoclonal antibody with other drugs has become the mainstream approach.Especially when used in combination, it relies on the phagocytic action of macrophages and natural killer cells and depends on the ADCC effect to exert anti-tumor effects.Targeted drugs. Or PD-1/PD-L1 inhibitors that can modulate the immune system. Naturally, we would consider that bispecific antibodies based on CD47 are another potential direction for research and development.
The second solution is to reduce the binding ability of CD47 drugs to red blood cells, thereby avoidingTrillium adopts this strategy for red blood cell depletion. Trillium's product TTI-621 is a fusion protein composed of the SIRP protein and the antibody Fc region, which has only weak binding ability to red blood cells (possibly related to conformational changes of CD47 on the red blood cell membrane). Therefore, it can utilize the more potent cytotoxic IgG1-type Fc region. However, TTI-621 can still bind to human platelets and white blood cells, thus potentially causing thrombocytopenia or leukopenia.In addition, the method to enhance safety is through the dosing regimen of "low-dose induction + effective dose maintenance," which has proven to be somewhat effective in reducing anemia-related side effects.In China, quite a few companies have laid out plans for CD47, including I-Mab, Innovent Biologics, Immune-Onc Therapeutics, and Akeso Biopharma.
Based on my own tracking of Akeso BiopharmaHumanized monoclonal antibody against CD47 (AK117,IgG4 Subtype）For example, let's look at the specific engineering transformation technologies and corresponding safety data for this target in Chinese Biotech companies.
At the 35th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2020), Akeso Biopharma (9926.HK) presented a poster showcasing the progress of the first-in-human clinical study of its self-developed next-generation humanized monoclonal antibody targeting CD47 (AK117). The title of the presentation was "A Phase I Clinical Study to Evaluate the Safety, Pharmacokinetics, and Antitumor Activity of a Next-Generation Anti-CD47 Monoclonal Antibody (AK117) in Patients with Relapsed/Refractory Advanced or Metastatic Solid Tumors or Lymphoma."AK117 is currently conducting a dose-escalation clinical trial in patients with advanced solid tumors and lymphoma in Australia. The dosing for subjects in the 20mg/kg QW cohort is being prepared. Research on AK117 shows:- In subjects who have completed the 0.3mg/kg, 1mg/kg, and 3mg/kg doses, as well as those in the ongoing 10mg/kg QW cohort, no drug-related anemia symptoms have occurred, and there have been no treatment-related adverse events of grade 3 or higher; therefore, no priming dose is required.
- Subjects in each cohort tolerated the drug well, with no dose-limiting toxicity (DLT) events occurring;
- The receptor occupancy of CD47 on peripheral blood T cells in subjects reached and was maintained at 100% in the 3 mg/kg QW cohort.
In preclinical studies, AK117 demonstrated differentiated characteristics compared to other anti-CD47 antibody drugs while maintaining robust antigen-binding activity, phagocytosis-promoting activity, and antitumor pharmacological activity:- AK117 does not cause red blood cell aggregation;
- AK117-mediated macrophage phagocytosis of red blood cells is significantly weaker than that of tumor cells;
- Compared with the significant anemia symptoms exhibited by other CD47 antibodies, AK117 only showed slight changes in red blood cells in cynomolgus monkeys, and no toxic effects on platelets were observed.
In July 2021, AK117 completed the Phase I dose-escalation trial in Australia. AK117 was evaluated in subjects across all dose-escalation cohorts (0.3mg/kg - 45mg/kg QW).None occurredDLT(Dose-limiting toxicity) and no clinically significant anemia were observed. Subjects in each cohort tolerated the drug well without the need for low-dose priming.Approved by the National Medical Products Administration (NMPA) to conduct a Phase Ib/II clinical study of combination therapy with azacitidine for the treatment of acute myeloid leukemia (AML).From theory to practice, there is indeed a long way to go, with a tortuous and winding process in between. The quasi-drug target CD47 requires more sophisticated design exploration. There is particular anticipation for the CD47 target to achieve druggability by addressing toxic side effects, even if it means compromising efficacy somewhat—this could potentially be realized through combination therapies and technological iterations like bispecific antibodies.
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