While you are still looking at the ADC in the mainstream coupling method of such macromolecules, there is a small molecule coupling method that is about to rewrite the underlying logic of small molecule drugs.
In foreign countries, the fastest pipeline of this therapy has been advanced to phase III clinical practice, which is also one of the largest markets in cancer —— breast cancer market. In China, the innovative drug 1 has also shown its preference for the therapy, and its related pipeline BGB-16673 has recently been granted FDA fast track certification.
PROTAC Therapy is showing a blow to the traditional small molecule drugs, and has great potential to subvert the market logic of the traditional small molecule drugs in the future.
01、PROTAC—— small molecule therapy
The biological underlying logic of PROTAC therapy is to use the cellular ubiquitin-proteasome protein degradation mechanism to achieve the degradation of the target protein.
Ubiquitin (Ub) is a body for labeling protein small protein (only 76 amino acids), through its labeled protein will pass E1, E2, E3 three ubiquitin enzymes, complete ubiquitin activation, transport, finally connected to E3 enzyme (the enzyme is the specific recognition of target protein), through E3 enzyme, ubiquitin and target protein, form of ubiquitin-protein complex. Upon completion of ubiquitination of the protein, the 26S proteasome can specifically recognize this substrate protein with a ubiquitin tag, which in turn will degrade it.
This process can complete the degradation of most of the short-lived proteins in the cell. Thus, PROTAC therapies were developed to degrade specific proteins.
The PROTAC full called proteolytic targeted chimera, its structure is composed of three parts: protein binding ligand, E3 ubiquitin ligase binding ligand and linker, the underlying logic is the target protein by PROTAC molecule and E3 ubiquitin enzyme connection, makes the target protein is marked with ubiquitin, and then will according to the ubiquitin degradation process form ubiquitin-protein complex, and then into the 26S proteasome to complete degradation.
(Photo source: Joint GMP)
In this process, PROTAC molecules can be recycled to rapidly enter the degradation process of another target protein after completing the catalytic degradation of one target protein. Therefore, PROTAC molecules can only exist as a catalyst.
For traditional small molecule drugs, small molecule drugs must first find the active site on the target protein, the affinity is high, and in order to maintain the active concentration, it must be administered at a high frequency. The PROTAC molecules as a catalyst do not have this concern, and its coupled target protein targets do not need to consider the activity, as long as it can be connected.
From this logic, PROTAC molecule can be regarded as a very successful iteration for traditional small molecule drugs, and its advantages over traditional small molecule drugs are as follows:
1. Small molecule drugs need to continuously stimulate the active target of target proteins with high concentrations, but the problem of drug resistance will occur over time. As a catalyst, PROTAC does not need traditional small molecules to stimulate active targets, which makes it more difficult to produce drug resistance.
2. Since PROTAC does not have to decouple the active site in target proteins, it theoretically will greatly broaden the selection of protein targets in the future, and many undruggable targets may be used on PROTAC molecules in the future.
In addition, it is worth mentioning that PROTAC is not the only therapy developed using the ubiquitin-proteasome protein degradation mechanism. Another more advanced therapy is molecular glue. Although both act through E3 enzymes, there is considerable variability.
In terms of advantages, the molecular weight of molecular glue is smaller than that of PROTAC, and it is more convenient to change the structure and optimize the physical and chemical properties. However, due to its relatively large molecular weight, PROTAC may have no pharmacokinetic properties as good as molecular glue from the traditional drug perspective.
In addition, molecular glue can well avoid an important problem of PROTAC: the hook effect (hook effect). For PROTAC, when the concentration of PROTAC as a mediator is too high, it prefers to form a binary complex with E3 or one of the target proteins, rather than the expected ternary complex, which does not form and the expected degradation cannot occur. This effect imposes some limitation on the therapeutic concentration of PROTAC.
Molecular glue is very good, it avoids many problems of PROTAC, but it is too cutting-edge, for its many mechanism research is not very clear, and the screening mechanism of the corresponding molecular glue is not particularly clear, at present, the screened and commercial molecular glue is basically found by chance.
(Photo source: Dong, G., 2021. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery.Journal of Medicinal Chemistry 64.）
From this perspective, the closest thing to the ubiquitin-proteasome degradation pathway therapy is still PROTAC.
02、PROTAC pioneers who are about to open the door to commercialization
Among the biotech with PROTAC therapy, the closest to commercialization is Arvinas, which has been deep for more than a decade.
In fact, it can be seen from the pipeline layout of Arvinas that pioneers will choose to make breakthroughs in breast cancer and prostate cancer, because these two cancers are closely related to sex hormones, so they can degrade the receptor of sex hormones through PROTAC therapy to achieve the purpose of cancer treatment.
Arvinas The fastest progressing pipeline in the cancer field is ARV-471 for breast cancer indications, and in breast cancer, it mainly targets subtyping ER + / HER 2-. The market size of breast cancer is obvious. According to the latest prospectus, the number of breast cancer worldwide reached 2.408 million in 2023 and 3.196 million in 2032. HER 2- / ER + classification accounts for 45-50% of all breast cancers. According to Arvinas itself, the market for breast cancer reached $17 billion.
The ER is the estrogen receptor, and for estrogen receptor-positive breast cancer patients, estrogen antagonism is the most common treatment for small-molecule drugs. In this, first-line therapies can be treated with AI (aromatase inhibitors) and front-line CDK 4 / 6 inhibitors such as early approved CDK 4 / 6i, while second-line therapies with fulvestrant and novel CDK 4 / 6 inhibitors such as rebosinil (Ribociclib); however, for small-molecule drugs (e. g. CDK 4 / 6 inhibitors), resistance remains a major problem, related to the underlying logic of small-molecule drugs described above.
For the ARV-471 pipeline, its early clinical trial design was mainly designed for afterline therapy for small molecule drug resistance. This year's ESMO breast cancer annual conference, its clinical phase Ib results are more fully demonstrated.
At baseline, 87% of the patients had been treated with CDK 4 / 6 inhibitors, 45.7% had received chemotherapy, and 80% had been treated with the estrogen inhibitor fulvestrant, demonstrating impressive efficacy in 31 patients. When combined with drug K, the assessed ORR reached 41.9%, which exceeds the current CDK 4 / 6 inhibitors.
In the published clinical data, the ORR of Ribociclib and ET chemotherapy regimen was 20% (n=35, close clinical sample size), and the baseline was similar to deal with the resistance of CDK 4 / 6 inhibitors. All the patients received CDK 4 / 6 inhibitors, but the proportion of patients receiving chemotherapy and fluvestrant was far less than the early clinical stage of AV-471: the proportion of chemotherapy was 6.7% and 16.8%.
In the large difference of patients' baseline, ARV-471 still reached more than twice the ORR, truly realizing the dimensionality reduction blow of traditional small molecule therapy. For other important indicators such as mPFS, the gap was also more than doubled, and the mPFS of ARV-471 reached 11.2 months, compared with 5.3 months in the previous study of Ribociclib. 3 months.
Other therapies, such as ET chemotherapy, are not comparable in efficacy.
(Photo source: Arvinas official website)
From the expectations of the current Arvinas, although the early drug is specifically for after line treatment to develop clinical, but it also has started early on line treatment layout: at present, the drug with pabosine line treatment of ER + / HER 2-local advanced breast cancer phase III clinical trial has been in progress, after line treatment is the highlight, including monotherapy, also included with small molecule targeted drug everolimus, combined with a new generation of CDK 4 / 6 inhibitor PF-07220060 (Atirmociclib), etc.
As a breast cancer drug with a completely different mechanism from CDK 4 / 6 inhibitors, it stands out in the homogeneity of CDK 4 / 6 inhibitors, and has a very high ceiling in the long term; in the near term, it has key data reading from the end of the year to early next year, which is a key catalytic opportunity for the stock price.
Another blockbuster tumor pipeline is the ARV-766 pipeline for prostate cancer. This drug is iterated from the PROTAC drug ARV-110, ARV-110 can be regarded as a trial and error product, due to the limitations, the pipeline progress has been suspended.
ARV-766 was improved on its basis. Structurally, the comparative critical improvement is the replacement of fluorine-substituted thalidomide with fluorine-substituted benzamide, and this structural improvement enhances the selectivity of the molecule as well as the stability in plasma.
The structural improvements broaden the range of indications for the drug: ARV-110 cannot cope with the AR L702H mutation, while ARV-766 successfully breaks through this dilemma and increases the number of druggable people. According to the phase 1 / 2 clinical trial data released in August 2023, the three patients with androgen receptor (AR) H875 / T878 / L702H mutation had prostate-specific antigen (PSA) levels by more than 50%, achieving a breakthrough in the efficacy of patients with mutations.
Of course, ARV-766 currently needs to be clinically verified with a larger sample size. But it's worth noting that MNC Novartis is bullish on the pipeline. In April, Novartis paid $150 million in advance and $1.01 billion in milestone to capture the global development and commercialization of ARV-766 and another preclinical prostate cancer drug.
In addition to the pioneer Arvinas, early biotech as well as Kymara.
Nurix PROTAC mainly targets BTK for a wide variety of B cell hemotumors, and its pipeline is at a very early stage, and the fastest progressing NX-5948 and NX-2127 are currently in clinical stage 1b. NX-5948 has made great progress this year, with June released its positive early clinical data for CLL (chronic lymphocytic leukemia).
In phase Ia trials, patients received a median of 4 lines, including covalent BTK inhibitors (96.8%), BCL-2 inhibitors (90.3%), and non-covalent BTK inhibitors (25.8%). In evaluable CLL patients (n=26), the ORR reached 69.2% in patients treated at all dose levels of NX-5948, and is also a very promising treatment of CLL.
(Source: Nurix Open PPT)
Kymera The fastest progressing pipeline, KT-474, has progressed to clinical phase II, which is mainly for voluntary indications. The two indications are pyradenitis (HS) and atopic dermatitis (AD). It launched a comprehensive partnership with the KT-474 and Sanofi as early as 2020, with potential payments of as high as $2 billion.
On July 8 this year, Kymera announced that after the IDRC review data, its partner Sanofi decided to expand two phase II clinical trials of KT-474 to treat pyogenic hidradenitis and atopic dermatitis, in order to move it to critical clinical practice faster. The next week later, the stock price saw a sharp surge, from $30 on July 8 to $45 on July 16.
PROTAC Imagination space, in the United States stock price embodiment is very full.
03、Domestic breakthrough progress
Domestic aspects, the current pharmaceutical companies are also working hard to catch up.
BGB-16673 announced not long ago is undoubtedly a huge breakthrough in the PROTAC field in China. Paikche itself is an old player of BTK small molecule inhibitor for more than ten years. Based on its existing technology platform to develop PROTAC targeting BTK, it is relatively firm on the basis.
At R & D Day in 2021, Paikche unveiled its PROTAC platform, the —— CDAC platform. According to Begene, the differential advantage of the platform compared with other PROTAC platforms is that its ability to use a wider range of E3 ligase to reduce DLT (dose-dependent toxicity), further improve drug resistance, and further expand the range of potential targets.
(Photo: 2021 PPT)
BGB-16673 is the first PROTAC pipeline developed by Bekje using this platform, mainly aiming to target the afterline treatment problem of BTK small molecule inhibitor resistance.
Because its targets and indications are similar to NX-5948, some non-head-to-head comparison can be made. According to preliminary data from the clinical phase I dose escalation trial of BGB-16673, it performed very well for CLL / SLL indications, with an ORR of 70% in patient (n=10) baseline BTK inhibitor resistance, which was comparable to the above NX-5948 efficacy.
In the subsequent large sample of clinical practice, the two pipelines will be more intense competition.
The other Biotech is Haichuang Pharmaceutical, which has been deeply engaged in PROTAC technology for many years. It established its own PROTAC technology platform in 2016, and the main indication for deep cultivation is prostate cancer.
The core pipeline of PROTAC of Haichuang Pharmaceutical is HP518, which is also the first PROTAC drug for AR to enter the clinical stage in China. It was approved by the NMPA in November 2023, and the pipeline is currently approved for clinical trials in China, the United States and Australia.
In addition to oral AR PROTAC drugs, there are also pharmaceutical companies that have developed topical AR PROTAC therapy.
The GT20029 is used to treat androgenic alopecia and acne, and to treat hair loss by degrading androgen receptor proteins. GT20029 Is also the first topical PROTAC compound to enter the clinic.
In April, the line reached the phase II endpoint for alopecia, with the 1.0% optimal dose, TAHC (indicator of regional hair count) was 11.94 hair / cm² more from baseline, 7.36 hair / cm² more than placebo.
However, whether non-oral local administration preparations can go through is a questionable topic at present. From the clinical phase II trial design, the primary endpoint in the clinical design is the number of non-vellus hair in the 12-week target area, which is too short. What is needed is the verification of longer cycle follow-up in phase III clinic, and the time when the observation period reaches a plateau.
It has to be said that this is an excellent application of PROTAC technology in an unexpected field, and truly differentiated competition in AR degraders.
Conclusion: The significance of PROTAC therapy mainly lies in opening a new door to the current dilemma of small molecule homogenization, bringing a new imagination of posterior line treatment. In addition, the therapy is not currently limited to tumors, its imagination space is very huge, even external use for hair loss can reach stage III clinical. Now, the exploration of indications is only the tip of the iceberg. In the future, with the great increase of AIDD target screening speed, the indication field of PROTAC therapy will continue to expand to a considerable extent.
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