Recently, the high-profile HER3 ADC has suffered a series of setbacks: first, the Phase I clinical trial of YL202/BNT326 of Yilian/BioNTech was suspended by the FDA, and then Merck/Daiichi Sankyo's HER3-DXd (U3-1402) was delayed by the FDA due to third-party manufacturing facility problems.
However, the FDA has not disputed the efficacy and safety of HER3-DXd, which means that HER3-DXd is still expected to become the world's first HER3 ADC drug after correcting the manufacturing problems.
Although new ADC drugs have suffered setbacks from time to time in clinical trials, the broad-spectrum anti-cancer targets represented by HER3 still have huge market potential.
01
Double-edged sword properties of HER3 targets
HER3 belongs to the same family as HER2, of which HER2 is a well-known broad-spectrum anti-cancer target, and a number of blockbuster drugs have been born, including trastuzumab targeting HER2 and Daiichi Sankyo's HER2 ADC drug Enhertu (DS-8201).
However, due to the fierce competition in the HER2 ADC market, global pharmaceutical companies are seeking other broad-spectrum anti-cancer targets, preferably similar to or functionally similar to star targets. HER3 is naturally a popular layout direction.
However, HER3 targets have double-edged sword properties.
HER3 is a potential broad-spectrum anti-cancer target, which is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, and colorectal cancer, and is closely related to disease progression, poor prognosis, and resistance to EGFR and HER2-targeted therapies.
As a result, HER3 ADCs frequently have major BD transactions: in October 2023, BioNTech spent more than $1 billion to cooperate with Yilian Biotech to develop a new generation of HER3 ADC drugs, and Merck and Daiichi Sankyo reached a global cooperation of $22 billion to jointly develop three new ADC drugs including HER3-DXd. In December of the same year, Baili Tianheng reached a cooperation with BMS for BL-B01D1, an EGFR/HER3 bispecific antibody ADC drug, with a maximum of US$8.4 billion, and set a new record for overseas authorization of domestic innovative drugs.
However, behind the popularity of BD is the difficulty of developing HER3-targeted therapies. In the past 30 years, neither monoclonal antibodies nor bispecific antibodies targeting HER3 have been able to become drugs.
例如，第一三共的Patritumab、KTN3379、Elgemtumab和Lumretuzumab等HER3单抗，皆因疗效不佳或安全性问题被终止研究；EGFR/HER3双抗Duligotuzumab、HER2/HER3双抗MM-111的临床开发也未能成功。
The reason for this is that HER3 has almost no intracellular tyrosine kinase activity, and the kinase activity is very weak, which limits the efficacy of monoclonal or bispecific antibodies directly targeting HER3. In addition, the relatively low binding power of HER3 to ligands increases the difficulty of drug design, resulting in a high failure rate in clinical trials.
However, the history of HER3 being undruggable may be rewritten by ADC drugs with unique mechanisms of action.
ADC drugs are composed of antibodies, linkers, and cytotoxins, and their uniqueness lies in the fact that they specifically bind to HER3 through their antibodies, but do not rely entirely on the kinase activity of HER3 to work, and the release of payloads (toxins) and cytotoxicity do not need to rely on HER3 to exert effective anti-tumor effects and trigger bystander effects.
In addition, HER3 has a faster internalization rate than HER2 and HER1 (EGFR), which is more conducive to ADC drugs to exert efficacy in tumor cells and improve the therapeutic effect.
02
The challenges of HER3 ADCs
With the confirmed therapeutic potential of HER3 ADC drugs in solid tumors, many pharmaceutical companies have made layouts.
According to the research report of China Securities Construction Investment, as of March 14 this year, there are 17 HER3-targeted ADC drugs in China, of which 5 have entered the clinical stage, including Hengrui Pharmaceutical SHR-A2009, Innovent IBI133 and Baili Tianheng BL-B01D1 (EGFR/HER3 bispecific antibody ADC).
全球进度最快的是第一三共/默沙东的Patritumab deruxtecan（HER3-DXd，U3-1402），尽管因生产问题被FDA延迟批准上市，仍有望拿下全球首款HER3 ADC药物。
As Daiichi Sankyo's third potential blockbuster drug after DS-8201 and Dato-DXd (DS-1062), the therapeutic potential of HER3-DXd has attracted much attention.
The antibody portion of HER3-DXd is PATRITUMAB, a HER3 monoclonal antibody with the same payload as DS-8201, which is a topoisomerase I inhibitor (deruxtecan) and consists of a classical maleimide-GGFG linker with a DAR value of 8.
The NDA for HER3-DXd was based on the results of the pivotal Phase II trial HERTHENA-Lung01, which demonstrated an ORR of 29.8%, a median PFS of 5.5 months, and a median OS of 11.9 months in 225 patients with EGFR-mutated locally advanced or metastatic NSCLC who had progressed on EGFR-TKI and platinum-based chemotherapy treated with HER3-DXd (5.6 mg/kg).
In addition, HER3-DXd also had similar clinical outcomes for patients resistant to third-generation EGFR-TKIs: ORR was 29.2%, median PFS was 5.5 months, and median OS was 11.9 months. The third-generation EGFR-TKI osimertinib has a broad market for drug resistance and is a big gold mine for MNC giants, which is also an important reason for Merck to bet heavily.
In terms of safety, the incidence of TEAEs above grade 4 was 28.9%, mainly blood-related adverse events, and a very small number of patients developed interstitial lung disease (ILD), and the overall safety was controllable, with only 7.1% of treatment-emergent adverse events resulting in TEAEs leading to discontinuation of treatment.
HER3-DXd关键性II期研究HERTHENA-Lung01结果
(Source: Biotech Preview)
However, although the FDA has not disputed the efficacy and safety of HER3-DXd, the safety needs to be improved. This is also a challenge for the development of HER3 ADC drugs.
The main reason why the FDA asked BioNTech/Yilian Biotech to suspend the Phase I trial of YL202/BNT326 was that at higher doses, human subjects could be exposed to unreasonable and significant risk of disease or injury.
According to the phase I clinical data announced by Yilian Biotech at the 2024 ASCO meeting, as of April 16 this year, a total of 55 people (40 with non-small cell lung cancer and 15 with breast cancer) have been enrolled, and the results show that a total of 51 evaluable cases were recorded at all doses, with an ORR of 42.3%, a DCR of 94.2%, an mPFS of 6 months, and an mDOR of 5.8 months, of which the ORR of the 3.0mg/kg dose group was 60% and the DCR was 100%.
Although YL202 is expected to show the potential of BIC, in terms of safety, there was one DLT event (tertiary granule deficiency with fever) in the 5.5 mg/kg dose group, two cases (neutrophil and cytopenias) and one death (interstitial pneumonia after COVID-19 infection) in the 4.0 mg/kg and 5.5 mg/kg dose groups, respectively.
Based on this data, BioNTech/Yilian Biotech may focus on developing clinical trials with doses below 4.0mg/kg in the future.
03
Novel ADC Drugs: Opportunities and Risks
Although HER3 ADC drugs still need to be improved, breakthroughs have been made compared to monoclonal and bispecific antibodies that are frequently defeated.
At present, domestic ADC drugs around HER3 targets are gearing up, including Hengrui Biologics SHR-A2009, Innovent Biologics IBI133, Yingen Biologics DB-1310, as well as bispecific antibody drugs involving HER3 targets, including Baili Tianheng BL-B01D1 (EGFR/HER3 bispecific antibody ADC) and Alphamab Oncology JSKN016 (HER3/TROP2 bispecific antibody ADC).
Among them, there are already a number of drugs that have published positive clinical data. According to the results of the phase I study, SHR-A2009 had an ORR of 30%, a DCR of 76.7%, and a median DoR of 7 months in NSCLC patients (94.4% EGFR mutation; 80.6% of patients were resistant to third-generation EGFR-TKIs); BL-B01D1 showed an ORR of 63.2% and a DCR of 89.5% in 38 patients with EGFR mutation-positive NSCLC who had undergone multiple treatments, 34 of whom had received third-generation EGFR-TKIs.
除HER3 ADC外，还有不少新型ADC药物展现出巨大的商业价值，涉及TROP2、Claudin18.2、Nctin-4、B7-H3/B7-H4、FRα等靶点。
For example, in 2020, Gilead spent $21 billion to acquire Immunomedics and won the world's first TROP2 ADC drug, Trodelvy; In 2023, Pfizer will spend $43 billion to acquire Seagen, and the latter's approved ADC drugs Adcetris, Padcev, and Tivdak target CD30, Nectin-4, and TF respectively, all of which are identical, and AbbVie also acquired ImmunoGen for $10.1 billion in the same year, obtaining the world's first FRα ADC drug Elahere.
As a broad-spectrum anticancer target, Claudin18.2 is highly expressed in multiple solid tumors such as gastric cancer, pancreatic cancer and breast cancer, and is also a must for contention.
According to statistics, there are currently 5 domestic Claudin18.2 ADCs that have achieved BD transactions, including LaNova LM-302, Columbotai SKB315, CSPC Pharmaceutical SYSA1801, Kangnuoya/Lepu Biopharma CMG901, and Hengrui Pharmaceutical SHR-A1904, with a total potential transaction value of more than US$5 billion. Among them, Innovent Biologics, Keynaoya and LaNova Therapeutics' Claudin18.2 ADC has entered Phase III clinical trials.
此外，B7-H3和B7-H4靶点也受到MNC巨头的青睐。
In October 2023, Merck spent $22 billion to reach a new ADC drug collaboration with Daiichi Sankyo, including ADC drugs targeting B7-H3 and CDH6 in addition to HER3 targets; In October and December of the same year, Hansoh Pharma awarded the B7-H4 ADC drug HS-20089 and the B7-H3 ADC drug HS-20093 to GlaxoSmithKline (GSK), respectively, with a total potential transaction value of more than US$3 billion.
Of course, new ADC drugs have taken the road that no one has taken before, and they will inevitably encounter R&D risks.
For example, Gilead's TROP2 ADC drug Trodelvy has failed in non-small cell lung cancer, urothelial carcinoma and bladder cancer indications this year, while rival Columbotech/Merck's SKB264/MK2870 is expected to show BIC potential, and Merck has initiated nine global Phase III clinical trials to gain an edge over the competition.
In addition, MacroGenics' new B7H3 ADC drug, Vobramitamab duocarmazine, saw five patient deaths in the phase II TAMARACK study in prostate cancer patients, causing the stock price to plummet nearly 80%.
Epilogue:
In the final analysis, the development of new drugs is a blessing and a curse, and opportunities and risks coexist.
However, even if the news of clinical failure of new ADC drugs breaks out from time to time, it will still not stop global pharmaceutical companies from continuing to explore, especially for broad-spectrum anti-cancer targets such as HER3 and TROP2, which are "gold mines" that must be won.