In the field of solid tumors, ADCs are menacing. But in the field of hematologic tumors, ADCs seem to be a bit strained.
On November 7, 2022, GlaxoSmithKline announced that Blenrep, a BCMA ADC drug, is used as a single agent for the treatment of phase 3 clinical failure of *** or refractory multiple myeloma who have received at least four lines of prior treatment.
In this trial, the median overall survival was 21 in the Blenrep and control groups, respectively2 and 21For one month, Blenrep alone did not show a stronger effect.
Shortly after the failure of the Phase 3 clinical trial, Blenrep reached the end of his life. On November 22, GlaxoSmithKline announced that it had initiated the withdrawal of Blenrep's marketing authorization in accordance with the requirements of the US FDA.
From the earliest landing to the failure of the first-mover advantage to the delisting, Blenrep fully expounded the uncertainty of innovative drug research and development.
However, it may not be appropriate to assert that Blenrep has failed. In the field of innovative drugs, reversal, reversal and reversal are also the norm.
At the beginning of February 2024, the clinical data of Blenrep Triple ** was announced, indicating that it has the potential to change its life.
01 Unpromising ADCs
After the delisting, GlaxoSmithKline has not given up struggling, and Blenrep still has multiple Phase 3 clinical trials in progress. However, the market's expectations for Blenrep have fallen to the bottom.
The core reason is that the current emerging ** for hematological tumors, such as CAR-T ** and bispecific antibody**, directly caused a "dimensionality reduction" blow to ADC.
Blenrep is most typically found in the field of multiple myeloma.
According to the results of the phase II clinical trial, the patients who received 2After 13 months of 5 mg kg of Blenrep monotherapy**, 32% of patients achieved objective response.
Let's look at the performance of the targeted BCMA car-t**carvykti. In the Phase 2 clinical trial, Carvykti achieved an objective response rate of 98%, and 78% of patients achieved a strict complete response. This means that Carvykti works for almost all patients.
There is no harm without contrast, and in terms of efficacy, ADC is simply abused by CAR-T.
Although the efficacy of bispecific antibodies is not as good as that of CAR-T, they still have advantages over ADCs. In the case of Tecvayli, a BCMA CD3 bispecific antibody, the objective response rate was 61 in patients who had received too many prior lines**8%，28.2% of patients enjoyed a complete response or better.
For this reason, although as early as November last year, GlaxoSmithKline announced that the Phase 3 DREAMM-7 trial had met the primary endpoint of progression-free survival ahead of schedule, and emphasized that the data showed a "strong and clinically significant" trend, the market was not cold.
In the eyes of the market, even if Blenrep is a new clinical success, more detailed data may be needed to assess its value.
02 Surprising victory
Now it seems that Blenrep may be attracting the attention of the market again.
The newly published interim analysis data from the DREAMM-7 trial suggest that BlenREP can significantly improve progression-free survival in patients with ** or refractory multiple myeloma when used in a three-drug regimen, and is expected to become a new second-line** option.
Specifically, in the DREAMM-7 study, Blenrep was used in combination with Takeda's Velcade (bortezomib) and dexamethasone (Bordex) and compared to Johnson & Johnson's CD38 monoclonal antibodies, DARAZOLEX and Bordex in combination**.
The results showed that the Blenrep protocol reduced the risk of disease progression or death by 59% compared to the Darzalex-based combination, which was highly statistically significant.
Median follow-up was 28At 2 months, the progression-free survival (PFS) in the Blenrep group was 366 months, almost 13Triple the 4-month PFS.
Although compared to Carvykti, Blenrep still seems to have a disadvantage. In Cartitude-4, Carvykti reduced the risk of disease progression or death by 74% in patients who had previously tried the first to third line** compared to the standard ** combination, with a much greater improvement than Blenrep's 59%.
However, there were some differences between the two trials. Patients in the DREAMM-7 control group received the DARAZALEX-VD combination, while patients in the control group of Cartitude-4 received DARAZALEX-PD or PVD. This difference was reflected in the median progression-free survival of patients in the control group.
Specifically, the median progression-free survival of patients in the Cartitude-4 experimental control group was 118 months, while the median PFS in the control group in DREAMM-7 was 134 months.
Therefore, more data is needed to prove whether Blenrep is necessarily inferior. In fact, based on preliminary OS improvement data, Blenrep may have an advantage. Of course, since it is not head-to-head, this data only has a certain reference significance, and does not prove that its expectations can be completely reversed.
And, in terms of safety, Blenrep also has significant drawbacks. Blenrep is known to increase the risk of ocular toxicity. In DREAMM-7, 34% of patients who received Blenrep** had grade 3 or higher ocular adverse events, and eye-related*** resulted in 9% of patients** discontinuation. This will also be an uncertain factor affecting its subsequent direction.
But in general, the publication of the data on the DreamM-7 experiment is still a good sign.
03 Behind the change of life against the sky
The reversal of Blenrep's plot fully illustrates one point: in research & development, R and D are inseparable.
Research is to design a better molecule, and development is how to develop differentiated development strategies through drug mechanism research, and take the lead in expanding more valuable indications, so as to rewrite or even define the order of a disease and become a solution to unmet clinical needs.
If a pharmaceutical company wants to gain a global foothold, it needs to do better not only at the R level, but also stronger at the D level. If Blenrep can change his life against the sky, he must benefit from "D".
After all, although its performance in monotherapy clinical trials is not satisfactory, it has the possibility of leaping to the forefront through the exploration of combination. And this "exploration" will continue in the future.
For example, Blenrep's DREAMM-8 clinical trial is a combination of pomalidomide and dexamethasone, and a head-to-head combination of pomalidomide and bortezomib and dexamethasone**. If this clinical success is successful, it means that it has the potential to become the choice of more patients in the field of multiple myeloma.
In addition, in terms of improving safety, GlaxoSmithKline is also exploring corresponding improvement measures. GlaxoSmithKline said there is currently a clear strategy to mitigate and reverse Blenrep***
If efficacy data are reliable and safety concerns are addressed, it is not impossible for BLENREP to become the first-line myeloma**. Of course, all of this is still in the "fantasy stage", and the final prospect will require more clinical data to answer.
But in any case, because of the design and route selection of clinical development, the delisted Blenrep has more possibilities.