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Text | Amino Finance
New drug research and development, nine deaths. Drug discovery failures are common, but ideal drug-ready targets are uncommon.
Therefore, in the pharmaceutical industry will always see such a phenomenon, even after the drug research and development of one pharmaceutical company fails, there will be other pharmaceutical companies to continue research and development at the same target, trying to change their lives against the sky.
FRα (folate receptor α) is such a target that pharmaceutical companies are going to follow.
Since its discovery in the 1990s, no new drugs targeting the FRα target have been approved for marketing. Moreover, the giants of the previous layout have folded their swords. The relevant small molecule conjugated drugs and monoclonal antibodies developed by top pharmaceutical companies such as Merck and Eisai have declared clinical failures and terminated research and development.
Successive failures cast a shadow over the FRα target, but its potential cannot be ignored.
Theoretically, FRα is an ideal drug-ready target. Because it is less expressed in normal tissues, it is overexpressed in a variety of solid tumors such as non-small cell lung cancer, mesothelioma, endometrial carcinoma, etc. Similar to PD-L1, once successful in one indication, it can be concocted and expanded.
It is precisely for this reason that there are still latecomers who work this target. As ADC technology matured, ADCs began to challenge the FRα. The fastest-growing FRα ADC drug, IMGN853, is just one step away from being marketed.
Last year, Bristol-Myers Squibb and Eisai reached a $3.1 billion collaboration on the FRα ADC drug MORAb-202, bringing the FRα target back in the spotlight.
Domestic pharmaceutical companies are not far behind. In the past two years, East China Medicine and Tasly have successively laid out THE FRα ADC in the form of license in; on March 9, THE SELF-DEVELOPED FRΑ ADC drug was clinically approved.
Unlike the OVERcrowding of the HER2 ADC track, there are only three FRα ADCs in the world. Therefore, choosing FRα target differentiation to enter the ADC track can be regarded as a wise way to play.
What makes new drug development fascinating is its unpredictability. This time, can ADC change the fate of the FRα target?
01 FRα Target: Giant Meat Grinder
Folic acid is one of the essential vitamins in the human body, and many processes, including DNA synthesis repair and cell division, require folic acid. However, folic acid does not exist in the human body, and the folic acid needed by the human body needs to be ingested from the outside world.
External ingestion of folic acid is mediated by folate receptors, which transport folic acid into the cytoplasm through endocytosis. Members of the folic acid receptor family include FRα, FRβ, FRγ, and FRδ, of which FRα is the most promising receptor to be a drug target.
The reason is that in addition to being able to transport folic acid, FRα is also an "accomplice" of tumor cells.
After the folate is fed into the cell, FRα is transferred to the nucleus and acts as a transcription factor, binding to a cis regulatory element responsible for regulating part of the key DNA of gene transcription, directly regulating the expression of key developmental genes in cancer cells.
In addition, in the process of cancer cell proliferation and metastasis, FRα also plays a role in fueling the waves.
On the one hand, when FRα is bound to folic acid, it activates the intracellular regulatory signaling network and regulates phosphorylation of the non-receptor tyrosine kinase PEAK1 to promote the activation of ERK and STAT3, both of which are signals that regulate the growth, development and division of tumor cells.
On the other hand, the folic acid receptor metastasizes cancer cells by down-regulating the intercellular adhesion molecule E-cadherin.
If the tumor is to continue to metastasize, reducing the adhesion of tumor cells and increasing the ability to move is the key, and the less E-cadherin, the more the tumor's ability to move will increase. Therefore, theoretically, by inhibiting the FRα, the metastasis and invasion of tumors can be controlled.
What's more, like other popular targets, FRα is less expressed in normal tissues and overexpressed in tumor tissues.
According to a literature in Oncotarget, the proportion of FRα overexpressed in non-small cell lung cancer, mesothelioma, endometrial cancer, and epithelial ovarian cancer is about 14 to 74%, 72 to 100%, 20 to 50%, and 76 to 89%, respectively.
It is this differential expression in cancer cells and normal cells that makes the drug focus only on cancer cells to attack, without harming the innocent.
Factors add up to make FRα show potential as an ideal target. But the ideal is very full, and the reality is very bone.
Since its discovery in the 1990s, FRα has experienced many setbacks and has not yet been drugged, and the research and development of monoclonal antibodies and small molecule conjugated drugs has been folded.
In 2013, Eisai developed farletuzumab, a humanized monoclonal antibody that targets FRα, but in a phase III trial in patients with epithelial ovarian cancer, farletuzumab failed to achieve the primary endpoint compared to chemotherapy.
Then, in another clinical trial for lung cancer patients, farletuzumab also failed.
In 2014, the small molecule conjugated drug Vintafolide again failed again.
Vintafolide is a small molecule conjugated drug developed by Endocyte that targets FRα, which increases tumor drug concentrations to treat ovarian cancer by internalizing folic acid after binding to the receptor.
Merck had high hopes for Vintafolide, buying the rights to Vintafolide from Endocyte with an advance payment of $120 million and a milestone of up to $880 million.
Vintafolide was also conditionally approved by the European Medicines Agency, but ultimately failed because it did not reach the primary endpoint without progression.
The successive failures of the giants have undoubtedly cast a haze on the future of the FRα.
However, the development of new drugs is a lifelong one, and the ideal drug target can be encountered but not sought, so even after many failures, the FRα target has not been abandoned.
02 ADC: Savior of the FRα target
After the failure of monoclonal antibodies and small molecule conjugated drugs, ADC drugs began to challenge the FRα target.
As we all know, ADC drugs are composed of antibodies + toxins + connectors, in which the antibody warhead plays a navigation role, bringing the ADC to the tumor cells at a fixed point, and the toxin is responsible for killing the tumor cells.
The high expression of FRα in tumors and the low expression of normal cells make it suitable for ADC warheads.
Since the pharmaceutical companies represented by the first three communists have made a breakthrough in the third generation of ADC drugs in 2018, ADC drugs have triggered competition in the global pharmaceutical circle, and some new changes have occurred in the entire market. For example, there are more and more targets, in addition to HER2, Trop2 and other heavy targets, FRα has also joined the research and development process of ADC drugs.
Perhaps because of the potential of ADC drugs, Eisai did not abandon farletuzumab, but developed it into a warhead of the ADC drug MORAb-202, and the toxin was connected by ezemacin, which was connected by a lysable linker.
In June 2021, Bristol-Myers Squibb reached a partnership with Eisai on the development and commercialization of MORAb-202 with a usable down payment of US$650 million and a milestone of US$2.45 billion.
Prior to this, at the annual meeting of the American Association for Cancer Research, Eisai published phase I clinical data on morAb-202 in the treatment of FRα-positive advanced solid tumor patients, and its ORR (objective response rate) for patients with advanced solid tumor was as high as 45.5%, of which 1 patient achieved complete remission.
Although no head-to-head trials were conducted, the data was initially better than that of ImmunoGen's IMGN853, which had an ORR of 22% in phase III clinical trials.
IMGN853, the fastest-growing and closest-to-market FRα ADC drug, is expected to submit a biologics licensing application to FDA in the first quarter of 2022.
However, IMGN853 can come to this day is also nine deaths.
On March 1, 2019, IMGN853 failed to meet the primary endpoint in a phase III clinical trial as monotherapy for platinum-resistant ovarian cancer, and IMGN853 failed to statistically improve progression-free survival in patients with ovarian cancer compared to chemotherapy.
But fortunately, ImmunoGen found that in patients expressing moderate or high levels of FRα, patients in the IMGN853 group showed a higher ORR (24% vs 10%) compared to chemotherapy.
In addition, the current platinum resistance, bevacizumab treatment after ovarian cancer patients urgently need new treatment methods, which has become a breakthrough in IMGN853.
After communicating with the FDA, ImmunoGen chose to turn around and conduct clinical trials in patients with FRα hyperexpression.
In a one-arm clinical trial called SOAYA, IMGN853 monotherapy for FRα highly expressed platinum-resistant ovarian cancer reached the primary study endpoint with a confirmed ORR of 32.4% and a median duration of remission of 5.9 months, of which 5 patients had a complete response. IMGN853 survived.
Not surprisingly, the IMGN853 will be the first FRαADC to be successfully approved for marketing.
03 The differentiated playing style of domestic pharmaceutical companies cuts into the ADC track
As IMGN853 is getting closer and closer to listing, the medicinal properties of FRα ADC have also been confirmed, and more and more players in China have joined the track.
In October 2020, Huadong Pharmaceutical acquired the Chinese interest of IMGN853 with an advance payment of US$40 million + milestone payment of US$265 million, as well as a certain proportion of the sales share.
On December 24, 2021, Tasly acquired a Chinese interest in the FRα ADC drug STRO-002 developed by Sutro in the United States with a down payment of $40 million and a milestone payment of potentially up to $345 million, as well as a percentage of the sales commission.
BIOTEC, which had previously lost successive defeats in the HER2 and TROP2 ADC fields, once again returned to the ADC field. On March 9, BIOTEC announced the clinical approval of its FRα ADC drug BAT8006 for the treatment of patients with advanced solid tumors.
For latecomers, in the face of the extremely crowded HER2 target and the strong strength of the DS-8201, it is almost impossible to cut into the ADC track through HER2, TROP2 and other targets. According to insight data, there are currently only three FRα ADCs in the clinical stage worldwide. The game has just begun, and anyone can be the winner.
So can THE FRΑ ADC meet the imagination of domestic pharmaceutical companies? In fact, while the IMGN853 is about to be approved, the challenges for the FRα ADC remain daunting.
No, Tianlishi, who had just entered the game, retreated.
On February 28, Sutro disclosed in its annual report that Tasly indicated in February that it would re-discuss cooperation with Sutro on the new drug STRO-002 for FRα ADC, and the two would hold hands for only three months.
Although the annual report did not disclose the specific reasons for Tasly's decision to break up, it is speculated that it may be related to the security problems of STRO-002.
According to the latest clinical data released by Sutro, the adverse reactions of STRO-002 grade III and above are as high as 78%, especially the problem of neutropenia cannot be ignored.
In the 5.2 mg/kg dose group, there was an adverse reaction of more than 5 grades, that is, the patient died of febrile (FN) due to neutrophil deficiency.
FN is a trickier complication in the treatment of malignant tumors. To this end, Sutro adjusted the experimental protocol to take the necessary dose reduction measures in the event of a grade 4 neutropenia.
In fact, the hematological toxicity of ADC drugs has always been criticized, and it seems that FRα ADCs are no exception. This requires latecomers to develop FRα ADCs to ensure that the drug can play an effective role and control adverse reactions.
On this point, not to mention the unpopular target of FRα, even for the well-known target of HER2, some pharmaceutical companies are still unable to do so. This is also a big challenge for FRα ADC players.
However, high risk often also means high reward, and if it can be passed at the FRα ADC, then the latecomers can successfully cut into the ADC track through differentiated play. As for the FRα ADC competition, can domestic players grab a place? It's up to time to test.