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On November 23, Arvinas, a star company of PROTAC, announced the preliminary results
of the Phase II expansion trial (NCT04072952, code VERITAC) of its core pipeline ARV-471 for the treatment of severe HR+/HER2-breast cancer a few weeks before SABCS.
As soon as the summary of the meeting came out in the first two days (although it seemed that there was a bug in the letter disclosure process, causing the company to rush to hold a telephone call before the meeting to release the full data), at first glance, it seemed that there was no surprise or shock
.
However, Arvinas, along with several other PROTAC companies, fell sharply that day, so it was necessary to take a good look at the data
.
Keeping up with current affairs hot spots, this clinical result is like hearing a whistle on the PROTAC stadium, and it is a little unclear for a while whether it is a penalty or a fake fall, so we will open VAR to review this moment
in detail.
https://ir.
arvinas.
com/static-files/5b5f4b88-4039-4526-b294-c32f4092dd9e
1.
Results of the VERITAC test published this time
Results of the VERITAC test published this time
The trial included two groups of 200/500mg QD, and the conditions for enrollment required ≥ 1 rounds of endocrine therapy, ≥ 1 rounds of CDK4/6, and ≤1 rounds of chemotherapy
.
The baseline included 57.
7% of ESR1 mutations, and they had previously received a median 4-line of various therapies and 3-line metastatic therapy, of which CDK4/6, AI, fulvestrant, and chemotherapy accounted for 100%, 90%, 79%, and 73%, respectively (of which 45% were metastatic chemotherapy).
The primary clinical endpoint CBR (CR+PR+SD≥24w) was 38%, with little difference between the two dose groups, while CBR was as high as 51%
in the ESR1 mutation subgroup.
Not to mention the comparison with other drugs, the trend of ARV-471's own CBR number is very lost, and the number released by SABCS in the three years of 20/21/22 is from 42%, 40%, 38%, of course, it must be said to be "consistent", but even psychological hints are difficult to make people not associate
negatively.
Similar to the previous phase data, SD is still the vast majority of responding patients, and there are only 2 cases of PR (which is to see that there are other public accounts that write "ORR only 3%" as a source of horror), one in the high and low dose groups, and one
in the wild ESR1 mutation.
Among the secondary endpoint PFS, PFS was 3.
7 months in the whole population, with little difference between the high and low dose groups, and the PFS in the ESR1 mutant population was 5.
7 months, which was significantly
beneficial compared with the wild population.
7 months for the whole population, and 5.
7 months for the population with ESR1 mutations
The degradation amplitude of ER was basically the same as that of the previous phase I clinic, with a median of 69% and an average of 71%.
The safety profile was basically good, with 26% and 17% of grade 3/4 TEAE in the high and low dose groups, 1 death was considered to be unrelated to the drug, and the discontinuation caused by TEAE was 3% and 6%, respectively, including QT prolongation, ECG T wave abnormality and back pain
.
2.
ARV-471 versus other SERD drugs Although ARV-471 and individual SERD levels vary greatly from patient baseline, some comparable angles
can be found 。 The CBR of ARV-471 in the whole population
38%, ORR 2.
8%, PFS 3.
7mo, compared to Amcenestrant (PFS 3.
6mo) and Giredestrant (PFS), which were previously known to have poor results
5.
6mo) is not a clear advantage, of course, consider that both baselines are relatively light; However, Camistrant enrolled patients with relatively heavy baseline (after 2 lines of 3ET, 1 line of chemotherapy, 53% fulvestrant) in the phase I clinical trial, and the proportion of ESR1 mutations was basically around 50%, giving CBR
42.
3%、ORR 16.
3%、PFS
5.
5mo result
.
This shows that the effectiveness data of ARV-471 in the whole population and SERD do not open the gap
.
ARV-471 versus other SERD drugs: ARV-471 population-wide efficacy data and SERD do not widen the gap
After all, 500 mg of fulvestrant would also have about 2.
0-3.
5 mo of PFS in patients with a similar 3L+ baseline for VERITAC, thus like ARV-471
200 mg of PFS of 3.
5 mo for the whole population is likely to be insufficient in head-to-head trials
.
5 mo for the whole population is likely to be insufficient in head-to-head trials
Therefore, the effectiveness of ARV-471 must be pulled by the ESR1 mutation population, which has a CBR of 47.
4% and 54.
5% in the 200/500mg two groups, and a PFS of 5.
5mo, so the difference between the large ESR1 mutation and the wild population is rare in other drug clinical trials, in any case, the effectiveness of ARV-471 in the ESR1 mutation population is in the forefront, but it is only ahead and can not be crushed
.
In terms of safety, the ARV-471 200mg group (also the selected dose for phase III) is basically the same as that of SERD drugs, but it is still necessary to pay attention to cardiac adverse reactions
.
3.
The next development plan of ARV-471 has been said for a long time after reading our feelings, and the next move of real money voting is the most indicative of the company's own attitude, which is what I find most interesting in
the whole material.
ARV-471 is dominated by 3L+ baseline throughout phase 1/2 clinical trials, but in phase 3 VERITAC-2 clinical trials, it is clear that it is a big step to the 2/3L design, requiring patients not to receive fulvestrant and metastatic chemotherapy, which are as high as 79% and 45%
in phase 2 VERITEC clinical trials.
ARV-471 Next Development Program ARV-471 is dominated by 3L+ baselines throughout Phase 1/2 clinical trials, but in Phase 3 VERITAC-2 clinical trials, it is clear that it is a big step to a 2/3L design
This design is closer to fulvestrant (VERONICA clinical) or Elacestrant (EMERALD clinical), which greatly deviates from the support
of previous clinical results.
Forgive the isolation under the down, it is relatively rare to see this kind of sudden jump, registration clinical challenge than early clinical design higher line design
.
Take the liberty to speculate with common sense, the psychology behind such an operation, is it more reasonable to explain the following two explanations: 1) The early clinical results exploded out of the circle, there is no need to mix in the last line, how fast you can save and run into the high line, think about this clinical result is this painting style; 2) In the last line, you can't mix up a big name anyway, fight to change a bicycle into a motorcycle, simply throw off these previous rules, to the high line, even if the early data support is relatively small, see if you can kill a world?
.
Take the liberty to speculate with common sense, the psychology behind such an operation, is it more reasonable to explain the following two explanations: 1) The early clinical results exploded out of the circle, there is no need to mix in the last line, how fast you can save and run into the high line, think about this clinical result is this painting style; 2) In the last line, you can't mix up a big name anyway, fight to change a bicycle into a motorcycle, simply throw off these previous rules, to the high line, even if the early data support is relatively small, see if you can kill a world?
The fate of ARV-471 not only affects Pfizer's $650 million real money upfront, not only Arvinas' current $2 billion poor acid market value, but also the entire PROTAC and targeted protein degradation field vane.
