The world's first PROTAC drug ARV-110 latest developments and pipeline layout.

protein degradation target clycosa (proteolystargeting chimeras, PROTAC) is a very hot drug development technology, the industry is considered to be a small molecule drug research and development of the big killer. One end of these two-function small molecules is a ligand that targets the target protein, and the other end is a ligand binding E3 ubiquitin joining enzyme, which is then connected by a certain length of linker. This allows the target protein and E3 ubiquitin joinulatose close, so that the target protein is labeled by ubiquitin, and then degraded by the ubiquitin-protease pathway.
its main advantages are as follows: 1, targeted degradation "non-medicinal targets" such as KRAS, STAT3, etc.;
the technology has been in the process for 20 years, and in 1999 researchers at Proteinix filed a patent application for the use of ubiquitin mechanisms to degrade specific proteins using small molecular compounds. Two years later, Craig Crews and Dr. Raymond Deshaies designed a series of two-function small molecule-induced metapinase 2 (MetAP-2) degradation based on peptide compounds and formally introduced the PROTAC concept. But the first generation of PROTACs failed because these compounds, which act together based on large, bulky peptides, were difficult to enter the cells. Until 2008, the Crews team designed a second-generation PROTACs based on E3's ubiquitin-linked enzyme MDM2 that can be used to degrade androgen receptors (AR). In 2015, the Crews team designed a new generation of PROTACs that reduced levels of multiple proteins by more than 90% based on the new E3 ubiquitin connectivee VHL and CRBN ligands. It was also the same year that James Bradner, Novartis's head of research and development, set off a new generation of thalidomide-based PROTAC molecules in Science, setting off the entire field. In 2013, Crews established Arvinas, the world's first drug research and development company with PROTAC technology.
is optimistic about this technology, the company developed the world's first PROTAC drug ARV-110, intended to be used for the treatment of dedegeneration resistance prostate cancer, has entered the clinical Phase I phase of the study phase, clinical I initial data show that ARV-110 has good oral utilization and good safety and tolerance.Figure 1: Protein degradation targets the mechanism of the mechanism of the chimeric. From Reference 1
ARV-110 is a global first oral bioavailable PRAOTC small molecule drug in the field of protein degradation-targeted chima, selectively targeted to degrade androgen receptors (AR). In May 2019, ARV-110 was approved by the FDA fast track, primarily for the treatment of metastatic trend-resistant prostate cancer (mCRPC).
in developed Europe and the United States, mCRPC is the second highest incidence of malignant tumors in men, but also has been the field of prostate cancer treatment difficulties and clinical research hot spots. Currently targeted at male hormone receptor targets (AR) of first-line treatments are abitron and enmesyamine. In addition, the Trend towards using abitron in first-line treatment has a better therapeutic effect on patients with mCRPC who carry DNA damage repair mutations (DDM) in first-line treatment, as discussed at the American Society of Clinical Oncology's Society's Society of Urology Cancer (ASCO-GU2020) in March 2020. Targeting androgen receptor -targeted (ARAT) drugs (abitron or enmesylua) for first-line treatment in mCRPC patients will benefit patients more from survival, especially in patients with the prostate catheter cancer (IDC-P) subtype. However, for patients with AR gene or gene enhancer amplification or AR-point mutations, the current first-line therapeutic drug is less effective, 15-25% of patients do not respond to second-generation hormone therapy such as abitron and enmelyume, and most reactive patients end up with severe drug resistance, leading to poor prognosis. The PRAOTC molecule ARV-110, which targets degradation of androgen receptors, currently shows excellent activity in clinical models of AR mutation and overexpression.Figure 1: Introduction to ARV-110. From Reference 2
In order to overcome these challenges and improve current treatment options, ARV-110 distinguishes from traditional inhibitors by using the ubiquitin-protease system to degrade AR proteins that play a key role in the development of prostate cancer, without having to "occupy" receptors to inhibit their function. In addition, the PROTAC drug can also work repeatedly to degrade the newly transcribed target protein, thus overcoming the increase in target protein expression and mutations in the target protein. The exact molecular structure has not yet been announced.
in preclinical studies, ARV-110 has shown promising activity as a targeted degradation agent for AR. In the sensitive model of enmyleamine, ARV-110 showed a decrease in prostate-specific antigens (PSA) similar to enmesyamines, and a lower dose of the drug. In the enthroamine resistance model, ARV-110 can significantly inhibit tumor growth.Figure 2: Preclinical data for ARV-110. Source 2
On May 29, 2019, FDA approved a phased, open-label, dose-increasing clinical Phase I trial to evaluate the safety, tolerance, pharmacokinetics, and pharmacodynamics of ARV-110 in patients with metastatic derebelating prostate cancer who have previously received at least two systemic therapies. The trial estimated that 36 patients, aged 18 years and older, had received at least two approved CRPC systemic therapy (at least one of which must be abitron or enmesy. Patients with sexual mCRPC must undergo ADT (treatment for prostate cancer androgen deprivation) or testicular excision with gonadotropin-releasing hormone analogues or inhibitors.
May 13, 2020, the latest safety data and early efficacy data for Phase I Clinical Trials (NCT03888612) were published in a summary of the American Clinical Oncology School (ASCO). To determine the maximum tolerable dose (MTD) and the recommended dose of Stage 2 (RP2D), ARV-110 is taken orally once daily for mCRPC patients who have previously received at least 2 treatment options, including enmyleamine and/or abitron. Endpoints include dose-limiting toxicity (DLT), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g. AR mutation analysis), RECIST (solid tumor efficacy evaluation criteria) and PSA (prostate-specific antigen) reactions. As of January 2020, 18 patients participated in the trial, with four doses divided into 4 groups: 35 mg (3 cases), 70 mg (4 cases), 140 mg (8 cases), and 280 mg (3 cases). Of these, 12 patients had previously been treated with ethluamine and abitron at the same time, while 14 had previously undergone chemotherapy treatment. In 1 in 18 patients, a level 4 (Gr) dose-limiting toxicity (DLT, 280 mg) occurred when taking the cholesterol drug Rosuvastatin, and an increase in hepatic transaminase AST/ALT followed by acute renal failure. The second patient developed a level 3 (Gr) dose limiting toxicity while taking the cholesterol drug reschuvastatin and an increase in hepatometase AST/ALT, and the aRV-110 treatment could continue after discontinuing use of rishuavastatin. In both patients, the use of reshvastatin and ARV-110 was prohibited in view of the significant increase in the plasma concentration of rishuavastatin at the same time as AST/ALT. In addition, no other related level 3/4 adverse events (AE) have been reported. Fifteen patients received a PSA response assessment (excluding 1 patient who stopped treatment due to disease progression and 2 patients who had just started treatment). Eight of the patients initially took a dose of 140 mg. Two patients in the 140 mg dose group, who had previously received ethluamine and abitron, chemotherapy, bicaruamine and radon 223, as well as other treatment options, were shown to have a decrease of psA by more than 50%. In one of these cases, two AR mutations known to cause enhelyulamine resistance were present. Another patient also received an unconfirmed partial RECIST response (confirmation trial pending). At the time of the data cut-off, patients receiving longer cycles (8 weeks and more) of treatment trials are still ongoing.
the latest clinical trial data available now show that the ARV-110 is acceptable lying safe. The maximum tolerable dose (MTD) has not yet been established and the determination of the recommended dose (RP2D) in stage 2 continues in the trial. In addition, ARV-110 has shown antitumor activity in patients treated with encoryluamine/abitron, with PSA responses confirmed in 2 patients, one of which is associated with a decrease in tumors.
Arvinas is a clinical biopharmaceutical company dedicated to improving the lives of patients with debilitating and life-threatening diseases by identifying, developing and commercializing thetherapies that degrade pathogenic proteins. Arvinas uses its proprietary technology platform to design a project for chimines or PROTAC-targeted protein degradation agents designed to effectively degrade and remove disease-causing proteins using the body's own natural protein treatment system.Figure 3: Arvinas Company Concept. From Reference 2
arvinas currently has two clinical trials in the field of oncology: ARV-110 for the treatment of metastatic derebelcted prostate cancer patients and ARV-471 for the treatment of patients with ER - HER2- local advanced or metastatic breast cancer.
in addition, the company's next generation of androgen receptors and estrogen receptor degradation agents are being developed. Of course, they chose the field of neuroscience outside oncology as their second-largest focus, and there are currently two targets in the field: tau protein (treatment for Alzheimer's disease) and alpha-synaptic nuclein (treatment of Parkinson's). They have also shown that PROTAC drugs, which are slightly larger than traditional small molecule drugs, are more likely to penetrate the blood-brain barrier.
Arvinas spent $45.2 million on research and development in 2018, increased its annual research and development cost to $67.2 million in 2019, and $21.7 million in the first quarter of 2020, primarily for the clinical development of the androgen receptor (AR) degradation agent ARV-110 and estrogen receptor (ER) degradation agent ARV-827.Figure 4: Arvinas develops the pipeline. Source 2
from 2013 to April 2018, Arvinas completed a total of more than $100 million in financing, supported by a number of pharmaceutical investors. On September 29, 2018, Arvinas went public on NASDAQ, raising $120 million. In addition, Merck's $430 million, Genentech's 650 million, Pfizer's $8.3 billion and Bayer's $110 million- and big-money-selling Arvinas have also been a major effort to develop protein degradation therapies. For other PROTAC start-ups (Kymera Therapeutics Kymera, C4 Therapeutics, Vividion, Nurix, etc.), domestic Sequoia Capital, Minand Capital, Hongyu Capital, Tong and TongCheng also participate.Figure 5: Arvinas' financing history. From the reference 6
the domestic layout proTAC's first echelon company is mainly Lingke Pharmaceuticals, Tidi Technology, Suzhou Pioneering Pharmaceuticals and five-yuan biology.
Lingke Pharmaceuticals
Lingke Pharmaceuticals is founded by Dr. Wan Zhaokui, former head of research and development chemistry and related sciences in The Pacific region of Johnson and Johnson, Wang Jun, former vice president of biology of an internationally renowned biopharmaceutical company, Michael Vazquez, former director of pharmaceutical chemistry of an internationally renowned pharmaceutical company, and Chen Wei, former investment partner of Changjiang Capital Biopharmaceutical Fund. The company focuses on cancer, immunity, inflammation and other disease areas. On April 17, 2020, Lingke Pharmaceuticals received tens of millions of yuan in Round A financing. On November 15, 2018, Lingke Pharmaceuticals (Hangzhou) won the first prize for its "non-drugable" protein target project at the 7th China Innovation and Entrepreneurship Competition's Biopharmaceutical Industry Finals challenge "Non-Drug" Protein Target Project. The company's PROTAC research and development pipeline is still in the drug discovery stage and has not yet been declared.
Chengdu Di Technology
Chengdu Di Technology is mainly committed to the field of protein degradation new drug development, founded in 2014, located in Chengdu, China. At present, Tidi Technology has established a proprietary protein degradation new drug development platform, the development of a unique PRODED (Protein Degradation Drug) technology. The new PROTAC drug, which is targeted to degrade Smad3 protein, and the use of PRODED platform to develop anti-coronary virus seed compounds based on protein degradation mechanism, mainly in cooperation with Sun Yat-sen University Affiliated Oncology Hospital, have not been announced. In addition, proTAC drugs, which have not yet been clinically declared, are in the early screening stage.
Suzhou Development Pharmaceutical s
Suzhou Development Pharmaceutical Co., Ltd. was founded in 2009 by Dr. Tong You, a former vice president of Angion Pharmaceutical Research Co., Ltd. of the United States. The main layout includes a diversified product pipeline of small molecule innovative drugs, bio-innovative drugs, and combination therapies, including 5 new drug project sandhormone receptors (AR) antagonists, ALK-1 monotagines, mTOR kinase target inhibitors and Hedgehog/SMO inhibitors, as well as AR-Degrader, c-Myc inhibitors and IDO inhibitors that are conducting preclinical studies.
five-yuan biological
five-yuan biology was established in 2015, is located in Nanchang City high-tech industrial development zone ZTE Science and Technology Park. Its main research and development directions include anti-tumor new drug research and development, the establishment and operation of the big data sample library of artificial intelligence organs, precision medicine and bionic medicine, intellectual property trading and capital operation in the biopharmaceutical industry. At present, the PROTAC platform with independent intellectual property rights is constructed, which is mainly used in the research and development of new drugs for anti-non-small cell lung cancer in a new generation, and the effectiveness and safety evaluation of PROTAC molecules are provided with organ-like technology. <