Oncolytic virus** can specifically replicate in tumor cells and cause tumor cell lysis without affecting normal cells, with the characteristics of high replication efficiency, excellent killing effect and low toxicity, etc., which was once regarded as a "milestone" of cancer**, but clinical trials for many years have not been smooth.
Recently, the positive clinical results of a small phase 3 trial have given the field of oncolytic viruses another wave of hope. In early December, CG Oncology announced that the FDA had granted Fast Track Designation and Breakthrough Designation to its oncolytic virus, CG0070, an intravesical oncolytic virus, with interim analysis results from the Phase 3 clinical trial showing that 755% of patients with evaluable efficacy achieved complete remission at any time.
The industry commented that it "may shake up the world of oncolytic viruses", and even said that "it may become the second oncolytic virus approved in the United States**".
For example, the US FDA approved two more innovative, new chimeric virus-based oncolytic viruses** into the IND, which can independently optimize the combination and express cytokines or signaling molecules that play a key role in anti-tumor immunityA number of domestic companies have also obtained approvals, and the number of oncolytic virus studies entering the clinical stage has increased significantly, including many Sino-US dual-reporting projects.
In some oncolytic virus conferences in China this year, we can clearly feel the increase in enthusiasm for participating in the conference from the crowded scene. A practitioner said: "In the past few years, everyone's understanding of oncolytic viruses has deepened, the safety and acceptance have been greatly improved compared with before, and PI has a more positive attitude." New mechanisms and new targets are constantly emerging, domestic source innovation is sufficient, and national policy support is also strong, which can be said to be full of hope. ”
Oncolytic viruses have a history of 100 years, but the only oncolytic virus that is widely recognized worldwide and approved by the FDA is Amgen's IMLYGIC. Since the FDA approved Imlygic in 2015, it has not approved an oncolytic virus product. The other four drugs marketed in different countries and regions are Sebeno's Imamasei, Latina's Ri**IR, Sunway's Acre, and Daiichi Sankyo's Delytact.
According to Sullivan data, the global oncolytic virus market size is expected to reach 67 in 2025$900 million, with a CAGR of 171 from 2020 to 20252%；In 2025, the market size of oncolytic virus in China will reach 10$400 million, with a CAGR of 213 from 2020 to 20254%。
Is 2023 the dawn for oncolytic viruses?
For the field of oncolytic viruses, one of the big bad news this year is the fall of Oncorus, a star company of oncolytic viruses in the United States. Oncorus was born in 2015, when the FDA approved the oncolytic virus, and its stock price once exceeded $35 shares, and the company's market value was close to $1 billion. Oncorus has also collaborated with Merck to evaluate the combination of its core pipeline ONCR-177 with K in patients with advanced and/or **sexual, subcutaneous or metastatic lymph node solid tumors.
However, the R&D progress of Oncorus was slow, and the Phase 1 clinical results of the combination of OnCR-177 and K drug were unsatisfactory, and then this pipeline was cut, and the remaining three R&D pipelines did not enter Phase 1 clinical trials until the company announced its dissolution in June this year.
The technical route of ONCORUS is more complex, aiming to use LNP to deliver RNA (VRNA) that can encode viruses to tumor cells, and replicate and amplify in tumor cells to kill tumor cells. It is both an oncolytic virus and an RNA drug, and is known as an intravenously administered self-amplifying RNA drug.
In 2023, when the general environment is not good, it is inevitable that such a company with an unclear future and unconvincing products will go bankrupt.
At the same time, China on the other side of the ocean is blooming in the field of oncolytic viruses, with nearly 50 domestic enterprises and a lot of harvest this year.
The pipeline model of domestic oncolytic virus enterprises is divided into license-in and independent research and development. For example, the oncolytic virus candidate products jointly developed by Lepu Biotech, Hengyi Biotech, and Arno Pharmaceutical with foreign companies have all entered the phase 3 clinical trial stage. Among them, Lepu Biotech has introduced CG0070 from CG Oncology mentioned above.
The self-developed oncolytic virus products are also advancing rapidly, and the company is represented by Binhui Biotechnology, Funuojian, Yinuowei, Kangwanda, etc. The common feature of these companies is that the founders of the companies have done scientific research on herpes viruses and adenoviruses for many years. Among them, the BS001 trial for melanoma has entered Phase 3 clinical trial in China.
This year, we can see that nearly 15 domestic self-developed oncolytic virus products have been newly approved for clinical trials, with a variety of virus types, including potential "first-in-class" innovative drugs with target innovation to break through the existing bottleneck.
What is more noteworthy is that in June this year, VG161, an oncolytic virus product developed by Innovajian Biotech for advanced hepatocellular carcinoma, and BS001, developed by Binhui Biopharma, for unresectable stage or stage IV melanoma that is resistant or progressed after anti-PD-1 monoclonal antibody, were successively granted fast-track status by the FDA. This means that the two companies will have more opportunities to communicate with the FDA during the subsequent development and review of oncolytic virus drugsIt is also possible to submit new drug study data to the FDA on a rolling basis at the time of submission to the NDA or BLA.
Subsequently, Binhui Biotech officially launched the A-share listing counseling in early August. The progress of a series of oncolytic virus companies in R&D or commercialization indicates that the field of oncolytic viruses in China may enter a new boom period.
Oncolytic virus is a ready-to-use method, and there is no personalized difference in the preparation for specific cancer types, and its safety issues and mechanism of action do not overlap with others, so it is often considered to be added to the combination.
This year, oncolytic virus T-VEC (IMLYGIC) combined with chemotherapy drugs anthracycline and paclitaxel showed positive phase 2 clinical results for the indication, which made the market have new expectations for T-VEC: 37 patients with triple negative breast cancer received T-VEC oncolytic virus combined with standard chemotherapy before surgery, and 89% of patients did not ** within 2 years, and the safety was not significantly different from standard chemotherapy. This again suggests that there is strong immune activation within the tumor and that T-VEC binding to the current chemoimmunity*** triple negative breast cancer is necessary.
In addition to combination chemotherapy,In the clinical research of oncolytic viruses, more than half of the global studies are designed to combine oncolytic viruses with immunosuppressantsHowever, it is not easy to achieve the desired combination efficacy, for example, Oncorus, which went bankrupt this year, went downhill after the failure of the core pipeline and the K drug combination trial.
T-VEC has also started clinical trials in combination with drug K and obtained breakthrough efficacy data in the early stage, but the report of the late-stage expanded sample study at the 2021 ESMO Congress showed that the phase 3 clinical trial of the study did not meet the primary endpoint.
In 2019, Sillajen, a South Korean biotech company, also announced that the Phase 3 clinical trial of its oncolytic virus drug JX-594 in combination with the small molecule drug sorafenib** hepatocellular carcinoma was terminated early due to the inability to meet the clinical endpoint as assessed by an independent data evaluation committee.
These joint ** are all very promising in theory, but lack the concept of "system". When PD-1 antibody is combined with imlygic, if it is administered at the same time, it may not be possible to achieve "triple overlap" due to the lack of coordination of a series of anti-tumor immune mechanisms such as antigen-presenting cells and tumor killer cells, resulting in the failure to reflect the combined efficacyWhen sorafenib is used in combination with oncolytic vaccinia virus drugs, it may destroy the replication basis of oncolytic vaccinia virus in tumor cells to a certain extent, resulting in the inability of the virus to multiply in the tumor and release holographic antigens, which cannot ensure the "smooth flow of the three channels".
Dr. Cai Jinlu, general manager of Kangwanda, said that the clinical trial design of big pharma companies is carefully considered, and its setbacks can give more inspiration to future studies to improve the probability of success. For example, Kangwanda's most representative core product, oncolytic vaccinia virus TT3, uses bioinformatics big data to screen non-human targets, design a guided oncolytic virus, effectively label tumor cells, and combine precision drugs (such as CAR-T, ADC, etc.) to achieve the killing of labeled tumor cells, and achieve the anti-tumor effect of "internal and external" integration.
For the exploration of joint design, Dr. Cai Jinlu summarized several points:
1) Choose the appropriate joint object. For example, the combination of vaccinia virus and antibodies or cells** is effective, or the combination of adenovirus and radiotherapy is effective.
2) Optimize the dosing sequence and time interval. Oncolytic viruses should be administered first, and the synergistic effect should be ensured in time.
3) Matching dosage administration. Fully explore the optimal dose of single agents and combination drugs, and cannot simply stack them.
4) Dynamically adjust the scheme. Track data, evaluate efficacy, and improve dosing regimen design as necessary.
There are also companies trying to do new combinations, such as the combination of oncolytic virus and mRNA vaccine, using mRNA vaccine to establish peripheral system anti-tumor immunity, and at the same time using oncolytic virus to break intratumoral immunosuppression and improve tumor microenvironment. On the one hand, the anti-tumor immune activity of mRNA vaccines can better play a role in tumors, and on the other hand, more tumor antigens are exposed through the lysis of tumor cells, thereby strengthening the effect of tumor immunity. At present, Funuojian has built a number of mRNA tumor vaccines.
The research and application potential of joint ** is huge, but it still needs a "hot model" to be born. Some people in the industry proposed: "The multi-channel exploration of the combination of oncolytic virus and immunity** is an important topic. The combination of dosing sequence and dosage will affect the efficacy of oncolytic virus, which requires a large number of preclinical and clinical studies to confirm. Of course, the first step is for the oncolytic virus to run out of a single drug. ”
The situation of oncolytic viruses may be similar to previous ADCs, the world's first ADC drug Mylotarg was used for ** acute myeloid leukemia, but it was unfortunately withdrawn from the market in 2010 due to severe hepatotoxicity and no obvious survival benefit. Since then, many ADC drugs have failed, and ADC drugs have fallen into a trough for a long time.
Daiichi Sankyo's DS-8201 completely subverted the ADC field, but it took a long time before the DS-8201 was unveiled with stunning results, and a large number of studies and experiments were carried out on toxins, coupling methods, connections, DAR, and sidekill effect modules, which also broke the original understanding of many ADC fields.
For example, Daiichi Sankyo believes that toxin molecules do not necessarily need to be active at the PM level, but can be compensated by linking multiple toxin molecules and bystander effects on a single monoclonal antibody, which makes the selection range of small molecule toxins at the nm activity level without having to find highly active small molecule toxins, which opens up the situation for the subsequent development of the ADC field.
After 2015, with the first oncolytic virus approved by the FDA on the market, various MNCs began to compete in this track: in 2016, BMS ended with 9US$3.6 billion worldwide commercial license for NG-348 developed by Psioxus Therapeutics;February 2018 Merck 3$9.4 billion acquisition of Viralytics;In May 2018, Johnson & Johnson won with 10$400 million acquisition of Benevir.
However, with the lack of exciting new research results for several years, and the mediocre sales of the marketed product IMLYGIC, the MNC gradually shifted its attention to the field of oncolytic viruses.
Oncolytic viruses are obviously more complex than ADCs, but excellent monotherapy is not an insurmountable problem in the field of oncolytic viruses.
"The approval of a single drug for marketing does not have to be a very earth-shattering achievement, but it can also solve the clinical needs of some patients, and the priority approved monotherapy indication can become the cornerstone of the follow-up exploration and innovation of the joint ** program. Even PD-1 antibodies were initially approved for a small range of indications. "One of the next trends is that digital means such as immunomics and genomics can be used to design individual protocols, and select suitable populations with high sensitivity to specific oncolytic viruses, which can greatly improve the accuracy and effect of oncolytic viruses." ”
With the domestic oncolytic virus research and development heat, Chinese companies are expected to seize the opportunity in this field. In addition, China is a global leader in regulation: the FDA does not yet have guidelines for oncolytic viruses, and the CDE is already one step ahead. In February 2021, in order to guide and standardize the clinical trial design of painlytic virus drugs, the CDE issued the "Guiding Principles for Clinical Trial Design of Oncolytic Virus Drugs (Trial)". In February this year, in order to standardize and guide the pharmaceutical research and development, production and registration of oncolytic virus products, the CDE promulgated the Technical Guidelines for Pharmaceutical Research and Evaluation of Oncolytic Virus Products (Trial).
In addition, domestic genetic engineering technology is an important foundation for the development of oncolytic viruses. For example, CGT CDMO and Meta Biotech, the first company on the Science and Technology Innovation Board, are mainly engaged in oncolytic viruses and gene ** vectors, and its large-scale production technology of oncolytic viruses is in a leading position in the industry, and new detection technologies are used to control the risks that cannot be detected before monitoring.
The research and development of oncolytic viruses has indeed experienced a long period of silence, but in recent years, G47Δ has been approved for marketing in Japan, the company has soared when RP1 announced the phase I clinical results, and CG0070 has also obtained very good phase 3 interim data. There is a growing body of evidence demonstrating the superiority of oncolytic viruses. Dr. Liu Binlei, the founder of Binhui Biotechnology, mentioned in a previous interview.
The industry believes that with the continuous innovation and breakthroughs of enterprises in the track in the combination of oncolytic viruses and intravenous administration, it is not entirely impossible for oncolytic viruses to appear the next "hit". It's just that in this frontier field, exploration and failure are symbiotic, and new drug research with scientific value and enlightening significance should be respected, rather than being "shunned" in the current environment because of innovation.