Image source: @VisualChina
Text | Amino Observation, author | Fang Taozhi
DS-8201, since it was approved by the FDA in 2019, everyone knows it as: a rewriter of ADC fate, a terminator of HER2 targets, and a catfish wearing gold armor to disrupt the situation.
The appearance of this catfish once excited everyone. Head-to-head defeated the second-generation HER2 ADC drug T-DM1, won the "holy grail" of HER2 low-expression breast cancer, and the ADC ceiling has been repeatedly raised.
ADC has almost become the hottest track of biotechnology, and there is no one.
Next, the ideal story direction should be the catfish effect that we are happy to see, where everyone rolls the story, rolls the quality, and finally jointly raises the overall water level of the ADC.
The reality is that under the dependence of the fast follow path, the Me Too story of domestic pharmaceutical companies cannot be told. Before DS-8201 entered China, most domestic pharmaceutical companies were still following the "old antique" T-DM1 more than a decade ago for research and development.
New drugs need to be created, and the ADC ecosystem and hosting platform need to be updated, which requires both the joint efforts of the whole industry and the drive of the catfish DS-8201.
Under the wheel of history, domestic pharmaceutical companies have been forced to open the road of ADC generational change. Today, anyone who is still developing second-generation ADC drugs is almost a dead end.
But being a follower behind the DS-8201 is also not easy, they do not have many options, either better results or stronger security.
Everyone can only panic and move forward.
01 Me too还是me better
As the strongest ADC drug on the surface to date, DS-8201 has no shortage of followers. Only in China, from Bio-Thera to Lepu Biotech to Hengrui Pharmaceutical, DS-8201 has countless followers.
Among the many followers, Hengrui Pharmaceutical's HER2 ADC drug SHR-A1811 has basically the fastest progress, and in June 2022, SHR-A1811 has entered phase III clinical trials.
Structurally, SHR-A1811 has almost identical linkers and toxic drugs to DS-8201. The difference between the two is that DS-820 has a drug-antibody ratio (DAR) of 8, while SHR-A1811 has a lower DAR of 5.7.
According to Zhang Lianshan, deputy general manager of Hengrui Pharmaceutical, the original intention of SHR-A1811 research and development is to make a drug with a similar effect to DS-8201, but more controllable in terms of safety, and lower DAR helps to achieve this goal.
In preclinical studies, SHR-A1811 was comparable in vitro to ADCI synthesized according to the structure of DS-8201, and the antitumor activity of SHRA1811 was significantly stronger than ADC1 at the same dose.
Of course, there is still a gap between preclinical research and the results of actual clinical trials in humans. Because no clinical data has been disclosed before, SHR-A1811 has also been questioned whether it can follow a similar efficacy of DS-8201.
In other words, SHR-A1811 needs real clinical research data to prove itself. At the recent 2023 AACR conference, Hengrui Pharmaceutical announced the phase I clinical trial of SHR-A1811.
The results showed that the objective response rate (ORR) was 61.6% for all patients, including 81.5% RR for HER2-positive breast cancer patients and 55.8% ORR for HER2-low expression breast cancer patients.
How should this data be evaluated? We can see it by comparing it with the clinical data of DS-8201.
In a phase III clinical trial called DESTINY-Breast 03, DS-8201 had an ORR of 79% for HER2-positive breast cancer patients; In the DESTINY-Breast 04 trial, DS-8201 targeted subgroups of breast cancer patients with HER2 low expression with ORR2 with ORRs ranging from 50 to 60 percent.
In this way, the clinical performance of SHR-A1811 is not inferior, and it seems to be comparable to DS-8201.
However, SHR-A1811 and DS-8201 are not head-to-head clinical trials, and SHR-A1811 has enrolled fewer patients in clinical trials and is still in the early clinical stage.
Therefore, it is not possible to make a conclusive conclusion on SHR-A1811 at present, and we still have to wait for the results of the phase III clinical trial before we can make a complete evaluation of the efficacy of SHR-A1811.
02 Schrödinger's safety
Of course, the dimension of evaluating a drug, in addition to effectiveness but also safety indicators.
You know, although the clinical data of breast cancer of DS-8201 has repeatedly shocked the four times, it also has its own "Achilles heel" - interstitial pneumonia.
Although interstitial pneumonia is treatable in most cases, because the symptoms of interstitial pneumonia are non-specific, it is easy to overlook, resulting in treatment delays, which is why DS-8201 is black-boxed by the FDA.
Making better improvements in safety has always been regarded as the key to survival for domestic DS-8201 followers.
So, did DS-8201 followers really do this? We still look at the SHR-A1811's performance.
According to the clinical data disclosed by Hengrui Pharmaceutical at the AACR conference, among the 250 patients with metastatic breast cancer who had previously received median 3-line therapy, 1 patient experienced DLT (dose-limiting toxicity). Among them, the incidence of treatment-related adverse reactions (TRAEs) was 97.2%, the incidence of TRAE in grade 3 ≥ was 52.4%, and the incidence of severe TRAE was 12.4%.
In terms of TRAE, SHR-A1811 is comparable to DS-8201. In three clinical trials DESTINY-Breast01/02/03, the incidence of TRAE in DS-8201 ranged from 95% to 99% and tertiary TRAE ranged from 52% to 57%.
However, in terms of the incidence of interstitial pneumonia, SHR-A1811 appears to perform better than DS-8201. In its clinical trials, only 3.2% of patients reported interstitial pneumonia.
In contrast, in the phase I clinical study of DS-8201-A-J101 in 2019, 16.9% of patients developed drug-related interstitial pneumonia, and 2 cases of treatment-related pneumonia died.
Similarly, in the DESTINY-Breast01 study, 13.6% of patients developed treatment-related interstitial pneumonia, and 4 patients died of treatment-related pneumonia.
However, some people in the industry have questioned that the safety of SHR-A1811 is better, because SHR-A1811 is facing a different situation today than DS-8201.
It is not difficult to understand that DS-8201 has just entered the clinical trial stage, and there are not many cases of interstitial pneumonia caused by ADC drugs, and the incidence of interstitial pneumonia in the use of T-DM1 drugs is only 0.5%. Therefore, early First Sankyo/AstraZeneca did not predict in advance and responded to interstitial pneumonia.
However, today, researchers have a clear understanding of the interstitial pneumonia events caused by the third generation of ADC, and can reduce the occurrence and development of interstitial pneumonia through earlier patient education, more standardized toxicity treatment and response.
Still taking DS-8201, although the incidence of interstitial pneumonia was as high as 15% previously, in the recent DESTINY-Breast03 clinical trial, the incidence of interstitial pneumonia was reduced to 5%, and no interstitial pneumonia events judged to be DS-8201 related to grade 4/5 were observed. If you compare this data, the safety advantages of SHR-A1811 are not obvious.
As for whether SHR-A1811 has been pretreated to patients to reduce the occurrence of interstitial pneumonia, Hengrui Pharmaceutical has not disclosed it. Therefore, we are not yet sure whether the safety improvement of SHR-A1811 is due to drug or human reasons.
All in all, we cannot conclude the efficacy and safety of SHR-A1811 until final clinical data are available.
However, it is undeniable that the clinical data currently shown by SHR-A1811 is still worth looking forward to. This is also definitely good news for the many followers of the DS-8201, which proves that there is still a way to go under the weight of the DS-8201.
03 Can grass grow under a big tree?
Once upon a time, as DS-8201 continued to hand over crushing clinical data, pessimists were once worried about the fate of domestic DS-8201 followers, believing that the followers' survival place would no longer exist.
However, as more and more followers, including Hengrui Pharmaceutical, disclose clinical data, it is not difficult to find that things seem to be moving in a good direction.
For example, Ambrx's HER2 ADC drug ARX788.
At the 2022 SABCS conference, ARX788 presented preliminary data from a Phase II clinical trial called ACE-Breast-03. The results showed that in patients with T-DM1-resistant or refractory HER2-positive breast cancer, the overall response rate after ARX788 was still 57.1%, and the disease control rate was 100%.
Notably, preliminary clinical data suggest that ARX788 remains 25% effective in patients who are resistant to DS-8201 within 12 months. Based on this, the CEO of Ambrx said that ARX788 may become the first choice for DS-8201-resistant patients.
Another example is the HEER2 ADC drug DB-1303 of Yingen Biologics. It is composed of a monoclonal antibody targeting HER2 and a novel topoisomerase inhibitor-1 inhibitor (P1003).
Preclinical data suggest that P1003 has bystander effect and rapid clearance properties that may help increase the medication safety of DB-1303, and no DS-8201-manifested interstitial pneumonia was observed in monkeys during dosing and convalescence. DB-1303 has also been recognized by overseas biotech, and on April 3, Yingen Biotech's DB-1303 and DB-1311 were licensed to BioNTech for a total price of up to $1.67 billion.
From these followers of DS-8201, it is not difficult to find that by showing better safety, developing suitable indications and other differentiated plays, it is still possible to grow grass under the big tree of DS-8201.
Sure enough, it's still a catfish Dafa. Although the future outlook for DS-8201 followers remains uncertain, at least the trend is improving.
Opportunities are often the most precious.