Under the new industry cycle, the competition of innovative pharmaceutical companies has entered the second half. The original R&D competition rules around target tracks and technology platforms are no longer fully applicable, and the industry has higher expectations for the commercialization, BD and internationalization capabilities of enterprises.
Despite this, the core of the competition has not changed, and the ability to differentiate with the times is still the key to success. Every innovative pharmaceutical company will embrace differentiation as a survival strategy, but the reality is that bubbles are glamorous, and there are not many truly visionary pioneers.
The story of Connova's establishment and growth may serve as a representative case of Biotech's pursuit of differentiation. In 2016, when tumor immunotherapy was in full swing, Chen Bo and Wang Changyu, two pioneers of tumor immunity at home and abroad, resolutely turned around and chose a path from scratch to found Connova, cutting into the relatively neglected field of autoimmunity in China at that time.
Nowadays, more and more domestic pharmaceutical companies are rushing to lay out the field of self-exemption, and Kangnuoya has been stuck in this blue ocean. With the acceleration of the priority review, spalzimab is expected to be approved for marketing this year, becoming the first domestic and the second IL-4Rα monoclonal antibody marketed in the world.
On the road from 1 to 10, Kangnuoya still has more cards, covering new modalities such as bispecific antibodies, ADCs and small nucleic acid drugs, and its clinical development progress is almost in the top three in China and even in the world.
Some of the clinical pipelines that are ahead of the curve
While expanding the R&D system in an orderly manner, Connova's capabilities are also evolving in an all-round way. BD has achieved fruitful results, and more than half of the clinical pipeline has achieved external authorization; At the commercialization level, Connaught is working hard and is forming an elite team; In-house large-scale production capacity has also been put in place. Quietly, the prototype of Biopharma has emerged.
The shot is the "king bomb"
When the industry enters the cycle of adjustment, the competition after the bubble bursts becomes more and more cruel. It is precisely such a shuffle moment full of changes, the easier it is for powerful players to qualify, and the more valuable products with real gold content can be highlighted.
Connoya is about to play his first trump card. Empzizumab has been declared for marketing at the end of 2023 and is intended for the treatment of moderate to severe atopic dermatitis in adults.
The choice of the IL-4Rα track was not accidental. At the time of the establishment of Keynova, Humira, the best-selling product in the field of autoimmunity, had been on the market for more than ten years and was entrenched in the throne of medicine. If you cut into the TNF-α track, it may be too late. Even if the most popular track is avoided, it is also the most homogeneous track, and it is not easy to dig out high-quality targets from countless targets. Changyu Wang, co-founder and head of preclinical evaluation and translational research at Kangnuoya, has a background in immunology and has an in-depth understanding of the mechanism of action of targets and diseases.
"Drugs in the early field of autoimmunity were mainly used to treat type 1 inflammation, and there were few new drugs for type 2 inflammation at that time, and allergic diseases basically belonged to type 2, and the market was very large." Wang Changyu analyzed from the source that in type 2 inflammation, that is, the Th2 pathway, IL-4Rα occupies a core position, which not only affects the differentiation of Th2 cells, but also controls IL-4 and IL-13 signaling, and regulates the conversion of IgE allergic antibodies.
The importance of the mechanism has given spalzimab the possibility of a wide range of allergic diseases, and Keynova has taken the lead in targeting the disease area of moderate to severe atopic dermatitis, which has an extremely large patient base and urgent clinical needs.
According to the survey, the number of patients with moderate to severe atopic dermatitis in China reached 18.7 million in 2020, and the prevalence is increasing year by year, and the patient population will expand to about 20.9 million by 2025 [1]. At present, the only biologic agent approved for the treatment of atopic dermatitis in China is imported dupilumab.
From the non-head-to-head data, the efficacy of spalzimab in the treatment of moderate to severe atopic dermatitis is not inferior to that of dupilumab. Phase III data showed that at least 75 percent of patients in the spalzimab group achieved at least a 75 percent improvement from baseline in eczema area and severity index at 16 weeks of treatment (EASI-75) [2]. In contrast, in the phase III SOLO 1 study, 51 percent of patients treated with dupilumab for 16 weeks achieved EASI-75 [3].
As for the longer-term 52-week data, it may be officially disclosed soon. Wang Changyu couldn't hide his anticipation, he said: "The result is even better than we imagined. ”
The reason why it can achieve good clinical benefits is inseparable from the advantages accumulated by Keynova in antibody design and screening. Some multinational companies have started clinical trials of IL-4Rα monoclonal antibody earlier, but the results are not satisfactory. Wang Changyu pointed out that the main reason is that the biological activity is not strong enough, which is a key indicator to evaluate the quality of antibody drugs. "We have decades of experience and have done a particularly thorough and in-depth job in bioactivity assessment. Our antibodies are tested with a number of different assays to ensure they have best-in-class (BIC) potential. ”
The color and texture of a product is ultimately subject to market inspection. Biotech's commercialization ability is inherently weak, so Connoya has worked hard and began to plan and pave the way 3 years ago. When carrying out clinical trials, Keynova gives priority to covering the top three institutions, hoping to achieve rapid expansion of post-marketing products by giving priority to covering the top core hospitals. The commercialization team is growing rapidly, covering core departments such as marketing, medicine, access, sales, and commerce.
Taking adult moderate to severe atopic dermatitis as the first indication is only the first step for spalzimab to enter the market. In the first half of this year, Keynova has launched a phase III clinical trial of atopic dermatitis in adolescents over 12 years old, and clinical studies for children aged 6 and above are also being planned.
The development of phase III clinical trials of sparkzimab
* Data from clinicaltrials.gov website registration information
In addition, the Phase III study for the treatment of chronic sinusitis with nasal polyps has also been successful, and Keynova plans to submit a marketing application for this indication this year. Previous Phase II studies of this indication showed that after 16 weeks of treatment, spalzimab significantly reduced nasal polyps and significantly reduced nasal congestion, thereby significantly improving patients' quality of life, which was published last year in the journal eClinicalMedicine. In the future, this indication may become another breakthrough in the volume of spalzimab.
"The therapeutic potential of spridzimab is very high, and we will take it step by step to win the indications with urgent clinical needs. After all, Connaught is still a biotech, and it is impossible to become a fat man in one bite. ”
Find a way to break out
On the road from 1 to 10, Connova has focused on the dual tracks of autoimmunity and tumors, and the differentiated pipeline pattern has gradually taken shape.
CM313 is the first domestic CD38 monoclonal antibody approved for clinical trial in China, and is currently advancing to Phase II clinical trial. Two CD38 monoclonal antibodies, Johnson & Johnson's daratumumab and Sanofi's isatuximab, have been launched globally, and the approved indications are concentrated in multiple myeloma (MM).
The strategy adopted by Keynova is to actively explore the path of breaking through serious autoimmune diseases such as systemic lupus erythematosus and immune thrombocytopenia while laying out the indications related to hematologic tumors.
Returning to the target characterization, CM313 does have the potential to achieve "crossover" therapy for tumors and autoimmunity. "The pathogenesis of MM is closely related to plasma cell proliferation, and CD38 is highly expressed in plasma cells. As a clearing antibody, CM313 can kill plasma cell tumors, including MM. Wang Changyu went on to explain: "Many autoimmune diseases are caused by autoantibodies, and most of the antibodies are produced by plasma cells. For these autoimmune diseases, CM313 achieves therapeutic goals by removing plasma cells equivalent to removing the root cause of the disease. ”
Data from an investigator-sponsored clinical study evaluating CM313 for the treatment of primary immune thrombocytopenia in adults with primary immune thrombocytopenia were presented in a poster at the 65th American Blood Association (ASH) Annual Meeting last year, showing that 7 of the 21 enrolled patients completed 8 treatments with a follow-up period of at least 8 weeks. Of the seven patients, 100.0% (7/7) achieved platelet counts of ≥50×10^9/L within 8 weeks of the first dose, with a median time to remission of 1 week (range 1-3). This result demonstrates the therapeutic potential of CM313 in autoimmune diseases such as primary immune thrombocytopenia in addition to myeloma and lymphoma.
Based on the antibody discovery platform, Keynova has also developed the TSLP monoclonal antibody CM326 and MASP2 monoclonal antibody CM338 to further expand the autoimmune product pipeline. In the field of oncology, a number of bispecific antibodies and ADC drugs have emerged.
CM336, CM350 and CM355 are CD3 bispecific antibodies that are used in combination with different targets for different tumor indications. Among them, BCMA/CD3 bispecific antibody CM336 and CD3/CD20 bispecific antibody CM355 are used for hematologic tumors, and the subdivision indications are different. CM336 targets MM, and CM355 targets lymphoma.
Such a layout also reflects Connaught's strategic thoughtfulness. CD3 bispecific antibody has the potential to cover and replace the range of hematologic tumor diseases treated by CAR-T in clinical practice, and CD3 bispecific antibody does not require in vitro cell culture, which is simpler, more convenient and less costly than CAR-T.
"Compared to similar products, our CD3 bispecific antibody may be BIC." Severe side effects of cytokine storm (CRS) are common with prior CD3 bispecific antibody therapy. Through structural optimization, the R&D team ensures that CRS is minimized when maximizing the activation of T cell killing. "Our bispecific antibody is a natural IgG molecular structure, and its stability, druggability, and pharmacokinetic activity are very good."
Wang Changyu bluntly said that many CD3 bispecific antibody platforms use non-natural structures, adding single chains or nanobodies, and the druggability is poor. Keynova chose the structure of natural antibodies, which is also the key to the stability and druggability of bispecific antibodies. "Antibodies in vivo have evolved over hundreds of millions of years to become the best choice. It's not that making something relatively new is better than a natural one. ”
The treatment of solid tumors with bispecific antibodies is also the trend of the times, and GPC3/CD3 bispecific antibody CM350 carries the hope of Kangnuoya - to fill the unmet needs of liver cancer treatment in China. There are 300,000-400,000 new cases of liver cancer in China every year, and there is still a lack of effective treatment. GPC3 is an ideal target for the treatment of liver cancer, and high expression of GPC3 has been observed in approximately 75% of liver cancers [4].
"It's not just about following the path that others have already taken, we also want to explore some more cutting-edge directions." GPC3 has not yet become a drug, and there are uncertainties behind it as well as great opportunities. At present, Keynova is leading the development of GPC3/CD3 bispecific antibodies, and is expected to launch an impact on the first-in-class.
In the current hot ADC track, Keynova has been planning its layout since 2017, and the potential world's first ADC drug targeting CLDN18.2 CMG901 is the answer.
Wang Changyu told us that in the development of CLDN18.2 target, Keynova did not take monoclonal antibody as the end point at the beginning, but built it into an ADC in one step. Recently, Astellas' CLDN18.2 monoclonal antibody zolbetuximab was approved for marketing in Japan, but its monotherapy effect is limited, and the regimen approved by the Japanese Ministry of Health, Labor and Welfare is also combined with chemotherapy. Connaught's vision goes without saying.
It is worth mentioning that CMG901 was the first to obtain CDE Breakthrough Therapy Designation and U.S. FDA Fast Track Designation using only Chinese clinical data, becoming the only CLDN18.2 targeted therapy in China to receive Breakthrough Therapy Designation. CMG901 is favored by the industry, and last year it licensed the global rights to AstraZeneca for a total of nearly $1.2 billion, and AstraZeneca will fully fund the follow-up research and development, which will undoubtedly continue to accelerate the development of the drug. Now, with the protection of AstraZeneca, CMG901/AZD0901 has rapidly advanced to global phase III clinical trials.
Based on the development of CMG901, Keynova is also constantly building and enriching its own ADC technology and product pipeline, and several new ADC drugs may be submitted for clinical trials this year.
Small nucleic acid drugs are also the future focus of Kangnuoya. "Most of the antibody targets are located in the cell membrane, and small nucleic acid drugs can penetrate deep into the cell, and the two are complementary." In addition to the development of conventional small nucleic acid drugs, Keynova will also explore new modalities of antibody-conjugated small nucleic acid (AOC) to break through the limitations of liver-targeted delivery. "If we can use antibodies to target specific cells or targets, we will have more advantages than companies that purely make small nucleic acid drugs."
Always move forward like a biotech
"We must keep up with the direction of the development of the industry and not rest on our laurels. We can't just stay on antibodies just because our antibodies are good, and they may be eliminated slowly, so we are constantly learning new technologies. ”
From monoclonal antibodies, to bispecific antibodies, ADCs, and then to small nucleic acid drugs, Keynova has upgraded and expanded its technology platform with the times, and actively raised the threshold of its own competition. Cutting into a new technology track, Connaught has its own advantages. There seems to be a large span between different tracks, and in essence, they can be more or less associated with antibodies.
When expanding the field of diseases, Kangnuoya also fully exerts its strengths to make layout. Aβ fibrillary antibody CM383 has been declared for clinical trial, trying to overcome the field of Alzheimer's disease, the "R&D Death Valley". Previously, Hengrui was the only domestic pharmaceutical company that had the courage and ability to advance the self-developed Aβ monoclonal antibody into clinical trials. The experience advantage in antibody research and development constitutes the biggest confidence for Keynova to advance into the field of Alzheimer's disease.
Unlike Aduhelm, which was approved for marketing earlier and clears all Aβ proteins, CM383 specifically clears pathological Aβ aggregates. By extending the half-life, CM383 has the potential to achieve a lower dosing frequency than Leqembi.
In the ever-changing R&D race, speed and efficiency are also critical for businesses. With the shortening of the life cycle of new drugs, the development of the same target may only be competitive in order to strive for the top three in the market. The development progress of Connova's clinical pipeline is almost in the top three in China and even in the world.
"Drug development relies heavily on experience. We have more experience and knowledge in R&D, so we do it relatively quickly. Wang Changyu said: "This also has a certain relationship with leadership, and organizational structure and decision-making ability are all comprehensive considerations. Chen Bo, CEO of Kangnuoya, has started many businesses, is not only a successful scientist, but also good at development and company management from 0 to 1, and makes the team work result-oriented and rapid from top to bottom.
Connova's capabilities are evolving across the board. BD has achieved fruitful results, and more than half of the clinical pipeline has been externally licensed. In terms of cooperation rights and interests, Kangnuoya has made flexible trade-offs, such as choosing to license CM310 and CM326 respiratory indications to CSPC Pharmaceutical Group, which has rich resources and experience in this field, but based on market and its own advantages and insights, it retains indications such as atopic dermatitis and rhinitis. During the trough period of the industry when cash was king, a number of BD transactions really brought incremental funds.
Of course, if you want to go further in the industry, relying too much on BD is not a long-term solution, and the preferred channel for biotech to go up is to achieve self-transfusion through product sales.
For Connaugh, 2024 is a pivotal year. Starting with spalzimab as a starting point, Keynova will embark on a new journey of commercialization. The internal large-scale production capacity has been put in place, and the Chengdu production base can provide 18,600L of biologics production capacity, which can meet the needs of 5-15 antibody drugs for commercial production at the same time, and the prototype of biopharma has appeared.
"Whether in terms of products, market value or influence, Connaught now has a certain foundation, but we will always regard ourselves as a biotech, continue to learn and move forward."
- Swipe up and down to view references -
[1] Connaught Prospectus
[2] Zhang J et al. 2023 EADV poster P0414: Efficacy and Safety of Stapokibart (CM310) in Adults with Moderate-to-Severe Atopic Dermatitis: Results of A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial
[3] Simpson EL, Bieber T, Guttman‐Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis [J]. N Engl J Med, 2016, 375(24): 2335‐2348.
[4] Fanching Lin, Renee Clift, Takeru Ehara, et al. Novel GPC3-targeting radiopharmaceutical therapy for hepatocellular carcinoma [J]. Hepatobiliary Cancer, 2024.
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