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The development of antitumor drugs has always been very popular, according to Nature Reviews Drug
According to the statistics of the discovery journal, in 2022, the FDA approved a total of 37 new molecular entities/new biological products, of which anti-tumor drugs still dominate, with a total of 12, accounting for 32.
4%.
This year, many exciting clinical breakthroughs have been made in the field of anti-tumor, and tumor patients have ushered in new hopes and treatment options
.
On the other hand, the development of new anti-tumor drugs is also a lifetime of death, and some pioneers of exploration have also suffered major clinical failures
.
The DS8201 overshadows many ADCs
The DS8201 overshadows the ADCsDS8201DS8201 deserves to be the brightest star in the field of anti-tumor in 2022, not only revolutionizing the entire HER-2 breast cancer treatment pattern, but also shining in the field of other HER-2 solid tumors such as gastric cancer and lung cancer
.
On June 5, 2022, Daiichi Sankyo / AstraZeneca announced that its royal explosive HER2-ADC drug DS8201 has reached the primary and secondary endpoints
in the phase III.
clinical DESTINY-Breast04 in patients with advanced breast cancer with low expression of HER2.
The trial showed statistically significant and clinically significant benefits
in progression-free survival and overall survival compared to standard care.
Clinical significance: DESTINY-Breast04 is the world's first phase III study
to obtain positive results in the treatment of HER2-low breast cancer in patients with advanced breast cancer with HER2 low expression.
In August 2022, the indication was approved by the FDA ahead of schedule
.
BTK inhibitors compete for the crown of Baekje
BTK inhibitors compete for the crown of BaekjeIn the BTK inhibitor market, AbbVie's ibrutinib has been dominant in the market with its first-mover advantage, with global sales of $9.
683 billion in 2021 that make it difficult for other BTK inhibitors to match
.
And with the potential Best
With the arrival of challengers, the market for BTK inhibitors will see a new competitive landscape
.
On October 12, 2022, BeiGene announced the clinical success
of its zebratinib versus ibrutinib phase III head-to-head ALPINE.
An independent review committee (IRC) and investigators assessed zebratinib as having a superior progression-free survival (PFS) result
over ibrutinib.
Zebratinib was generally well tolerated and safety results were consistent
with previous reports.
Clinical significance: Zebratinib is currently the first BTK inhibitor with head-to-head PK ibrutinib in PFS in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and has become the first locally developed new anti-cancer drug
in China to carry out head-to-head phase III clinical studies with multinational giant drugs and obtain efficacy trial results.
The success of zebratinib also means that ibrutinib's market position that has been maintained for decades will be shaken
.
Solid tumors meet new nemesis
Solid tumors meet new nemesisFor a long time, various targeted drugs developed for extracellular antigens have developed into important pillars
of the pharmaceutical industry.
Many intracellular antigens are the crux of the disease, and traditional antibody drugs are difficult to enter the cell to bind
to them.
The successful approval of TCR therapy Kimmtrak as a targeted therapy has opened up a larger imagination for the development of intracellular antigen target drugs
.
On January 26, 2022, Immunocore's TCR therapy, Tebentafusp (trade name Kimmtrak), received early FDA approval for the treatment of adult patients
with HLA-A*02:01 positive metastatic uveal melanoma (mUM).
In terms of efficacy, Kimmtrak is also the first TCR therapy
to be successfully clinically successful in stage III.
solid tumors.
According to the clinical data submitted for marketing applications, compared with other treatment groups (82% pembrolizumab; 12% ipilimumab; 6% dacarbazine), Kimmtrak achieved a significant improvement in overall survival in patients with metastatic uveal melanoma, with a median overall survival of 21.
7 months in the Kimmtrak group and 16.
0 months in the control group, reducing the risk of death by 49%.
And in terms of safety, it is good and does not have more than grade 4 toxic side effects
.
Clinical significance: Kimmtrak's approval has achieved two important milestones, the first of which is the approval of TCR therapy as the first breakthrough in solid tumors
.
Second, as the first new treatment for metastatic uveal melanoma, which has ushered in after 40 years, is of great
significance.
Claudin 18.
2 druggability was verified
2 druggability was verified
Claudin18.
2, currently a hot target for tumor-targeted therapy, became hot when it appeared as a dark horse at the ASCO conference seven years ago
.
Around this target, the development
of monoclonal antibody, bispecific antibody, ADC and CAR-T and other technical routes targeted drugs has been carried out.
After 5 years of clinical promotion, the development of this target finally delivered a satisfactory answer
.
On November 23, 2022, Astellas, the leading player in this target, announced that its Claudin18.
2 antibody Zolbetuximab reached its PFS and OS clinical endpoints as a first-line clinical trial of Claudin18.
2-positive gastric cancer/gastroesophageal junction adenocarcinoma, successfully verifying the druggability of this target, which is also the first Claudin to be successful in phase III clinical trials
18.
2 Targeted drugs
.
Then, on December 16, 2022, Astellas announced the success of its second phase III clinical trial, GLOW, which met the primary endpoint of progression-free survival (PFS) and the key secondary endpoint
of overall survival (OS).
Clinical significance: The success of these two phase III clinical trials of Zolbetuximab has verified the druggability of this target, and Claudin 18.
2 ushered in the first marketable product in sight
.
Apoptosis welcomes a new breakthrough
Apoptosis welcomes a new breakthroughApoptosis is a relatively niche field with a high threshold
for development.
To date, only AbbVie/Genentech Venetoclax has been successfully marketed in this field
.
With APG-2575 making significant clinical progress, the field is finally expected to usher in a second marketable drug
.
At the American Society of Hematology (ASH) Annual Meeting in December 2022, Ascentage orally presented global Phase II clinical data
for the monotherapy or combination treatment of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with its Bcl-2 selective inhibitor APG-2575 。 The first reported clinical data for combination therapy are impressive, with an ORR of 98.
6% (72/73) in the combination group of APG-2575 + Acalabrutinib and up to 88%
in patients refractory or intolerant to previous BTK.
Clinical significance: APG-2575 is the second Bcl-2 selective inhibitor in the world to enter the clinical stage after AbbVie's Venetoclax, and the release of this clinical data further demonstrates that APG-2575 has the potential to compete with Venetoclax and is expected to become the second Bcl-2 inhibitor
marketed in the world.
The road to IL-2 conversion is long and obstacles
The road to IL-2 conversion is long and obstaclesIL-2 has always been a hot topic in cytokine drug development, and NKTR-214, the most leading player in this field, has previously been highly anticipated
by the industry.
Early clinical data previously presented at the 2017 SITC meeting not only led to a $3.
6 billion collaboration between Nektar and BMS, but also drove Nektar's stock price to rise
multiple.
On March 14, 2022, Bristol-Myers Squibb/Nektar, a leading player in the IL-2 field, announced the Phase III clinical trial (PIVOT) of IL-2 receptor agonist therapy Bempegaldesleukin (NKTR-214) in combination with Opdivo for the treatment of metastatic melanoma (PIVOT
IO-001) failed, and the trial did not meet the primary endpoints
of PFS and ORR.
NKTR-214+Opdivo combination therapy was analysed with no additional clinical benefit compared with Opdivo monotherapy, did not meet the primary clinical endpoints such as PFS and ORR in the trial, and did not differ statistically in overall survival time OS
.
The failure of this clinical trial also directly led to the termination
of all IL-2+ Opdivo clinical trials.
Incident Impact: This clinical failure not only cast a shadow over the entire development of IL-2, but also led to the rupture of Nektar's partnership with BMS, and further led to Nektar's great operating pressure
.
A month after the news was announced, Nektar
Therapeutics announced a 70 percent layoff, the company's chief medical officer, Dimitry Nuyten, M.
D.
, and John, chief commercial officer
Northcott also stepped down
.
In addition, the company has significantly reduced its product pipeline to shift its focus to two additional clinical-stage assets
.
The PDC drug Pepaxto was short-lived
The PDC drug Pepaxto was short-livedThe approval of PDC drug Pepaxto has triggered a wave of attention to PDC, and everyone has placed expectations on the successor of the next generation of ADC, and more than ten companies have participated in the development
.
But less than half a year after it was approved, Pepaxto's confirmatory clinical trial OCEAN reported disappointing results
.
Not only did the trial fail to meet the overall survival (OS) endpoint, but the Pepaxto-treated group had a higher number of deaths than the control group (overall survival risk ratio 1.
104), an adverse survival risk that led to the
FDA's immediate enrollment in this and other ongoing clinical trials.
The failure to validate the clinic has raised questions among U.
S
.
regulators about the risk of Oncopeptides benefiting Pepaxto.
After Oncopeptide announced its voluntary delisting and then quickly backtracked, the FDA reconvened its ODAC meeting, and Pepaxto received overwhelming (14 against 2) approval
.
On December 7, 2022, FDA followed the advice of the members of the Expert Council and officially announced the withdrawal of accelerated approval of Pepaxto, prohibiting its continued market
.
Impact of the incident: Pepaxto's real effective sales time was less than half a year, and the road to commercialization came to an abrupt end
.
Combined with the overall research and development progress of PDC drugs, as a new drug type, the safety and efficacy of PDC drugs need to be tested over more time
.
The TIGIT target is in doubt
The TIGIT target is in doubtTIGIT has been widely noted
since the ASCO conference in 2020.
Roche/Genentech's TIGIT monoclonal antibody tiragodlumab's stunning appearance at this conference has made this target chased by many companies, and everyone has high hopes
for its TIGIT.
Roche/Genentech, the leader of this target, announced on March 30, 2022 that the phase III clinical SKYSCRAPER-02 of the combination regimen of tiragolumab + T drug + chemotherapy failed (first-line treatment for extensive-stage small cell lung cancer), and did not meet its common primary endpoint
of progression-free survival 。 Two months later (May 11, 2022), Roche announced the second phase III clinical failure, and the stage III SKYSCRAPER-01 of tiragolumab combined with T drug for the treatment of PD-L1 high-expression locally advanced or metastatic non-small cell lung cancer (NSCLC) did not meet its common primary endpoint of progression-free survival (PFS), and the overall survival (os) data of the other primary endpoint were not yet mature
.
At that time, the two III clinical failures did not completely lose Roche's confidence at that time, and said that the next decision
would be made based on the overall survival (OS) data.
BUT ACCORDING TO SKYSCRAPER-02 REPORTED AT THE 2022 ASCO ANNUAL MEETING
Phase III clinical data showed that the combination regimen of tiragolumab + T drug + chemotherapy did not improve the survival rate
of patients compared with the control group.
Event impact: Tiragolumab, as the world's most leading and promising TIGIT targeted drug, is an important indicator for other layouts
.
Roche announced the failure of two phase III clinical trials of Tiragolumab within two months, which undoubtedly cast a shadow
on the development of TIGIT.
After the announcement of the clinical news, companies with related product line layouts have also been hit
by the stock market.
Oral SE­ RD meat grinder
Oral SE­ RD meat grinderFu­ l­ v­ e­ s­ t­ r­ a­ nt's single-handedly made SE­ The RD mechanism is among the ER+ breast cancer endocrine therapies, and its injection dosage form, poor PK properties, and insufficient efficacy for ESR1 mutation patients have made its oral drugs the focus of development by many giants
.
However, oral SE­ In addition to AZ and Novartis, which tasted early clinical trials in the early years, Sanofi and Roche, two leading players in this field last year
.
In March 2022, Sanofi orally launched SE­ RD inhibitor Am­ c­ e­ n­ e­ s­ t­ r­ a­ Phase II AM&SHY in the second-line treatment of ER+/HER2-breast cancer patients with nt; E­ E­ RA-3 failed
.
Then in mid-August, Sanofi announced again; c­ e­ n­ e­ s­ t­ r­ a­ nt, combined with Pa­ l­ b­o­ c­ i­ c­ l­ Phase III clinical AM­ for the treatment of first-line ER+/HER2-breast cancer patients with ib; E­ E­ The RA-5 interim analysis found that clinical endpoints
could not be met.
To this end, Sanofi has stopped Am­ c­ e­ n­ e­ s­ t­ r­ a­ NT's global clinical development program
.
In addition to Sanofi, Roche oral SERD inhibitors have also suffered setbacks
.
In April 2022, Roche announced that its phase II clinical trial acelERA, of its oral SERD inhibitor giredestrant, in advanced breast cancer did not meet the primary endpoint
of improved PFS.
Impact: At present, no oral SERD inhibitor has been approved for marketing in the world, Sa­ n­o­ fi should have been expected to be the first oral SE­ to punch the line; RD inhibitors, but the first to fold arms
.
For any pharmaceutical company, the loss of a phase III clinical candidate is a big blow
.
Am­ c­ e­ n­ e­ s­ t­ r­ a­ After NT stopped development, Sanofi had only one ADC drug, tusamitamab, left in its phase III clinical-stage tumor pipeline
ravtansine
。
