Technological iteration, and the reorganization of technology is expected to usher in a new era for botulinum toxin

As early as the last century, botulinum toxin was used for therapeutic exploration in areas such as strabismus, blepharospasm, and wrinkle removal. In 1989, the US FDA approved botulinum toxin for the treatment of blepharospasm and strabismus; in 2002, the US FDA approved the world's first botulinum toxin product - BOTOX.^®It is used to improve moderate to severe forehead wrinkles. Currently, there are more than 10 natural botulinum toxin products on the market worldwide.

Natural botulinum toxin is produced by the fermentation of Clostridium botulinum, and its quality highly depends on the characteristics of the bacterial strain. At the same time, due to the high biological risk associated with live Clostridium botulinum, related production is restricted or even prohibited in most countries. Moreover, the investment cost of production facilities is high, and the production process of natural botulinum toxin is complex with limited output, which limits the industry's development. Additionally, botulinum toxin products are different from traditional drugs and can be used in clinical treatment and medical aesthetics. The sales performance in the medical aesthetics market depends more on consumers' perception of products and brands. Therefore, the production access and commercial competition threshold for the botulinum toxin track are high, resulting in a relatively concentrated market. Currently, globally, the main producing regions of botulinum toxin are concentrated in a few countries such as the United States, Europe, China, and South Korea, with market share dominated by BOTOX.^®Primarily occupied by 5 - 6 brands.

Natural botulinum toxin products have achieved considerable sales in the medical aesthetics market. ISAPS survey data shows that the volume of botulinum toxin treatments has consistently ranked first among non-surgical medical aesthetic procedures over the past five years, increasing from 6.271 million cases in 2019 to 8.878 million cases in 2023, a growth of about 40% within five years, continuously expanding the market size.

According to the company's annual report information, in 2023, Allergen's BOTOX^®The product has achieved sales of $2.68 billion and $3 billion in the medical aesthetics and clinical treatment sectors respectively; Ipsen's Dysport^®Sales reached approximately $710 million; Hugel's Letybo^®Sales amounted to $120 million. BOTOX^®Relying on its advantage of being the first to go public, excellent product quality, and high brand recognition, SK-II surpassed other botulinum toxin brands with sales of $5.68 billion in 2023, taking a leading position globally. In addition, South Korea has the most production enterprises and brands in the botulinum toxin field, mainly used in the medical aesthetics industry. However, the sources of botulinum toxin strains from several Korean brands have not been certified by relevant institutions, resulting in multiple patent disputes and even product licenses being revoked. Overall, the strength, capabilities, and quality of South Korea's botulinum toxin production enterprises vary widely, and their share in the global botulinum toxin market remains relatively low.

Data source: Annual report of the company, analysis by Frost & Sullivan

In the Chinese market, according to information from the National Medical Products Administration (NMPA), as of September 13, 2024, six types of botulinum toxin type A natural products have been launched, namely BOTOX developed by Allergen.^®(Botox^®), Heng Li from Lanzhou Institute of Biological Products in China^®Dysport developed by Ipsen^®(Jishi^®), Letybo developed by Hugel^®(LetiBPo)^®), as well as XEOMIN from Germany Merz, which went public in February 2024^®(Xima) and Darciplatin (Daxifei), a new drug approved in September by Fosun Pharma and introduced by it^®(Daxxify^®). Among them, BOTOX^®Relying on its advantages in the medical aesthetics field, such as being a pioneer in listing, brand influence, and marketing capabilities, it has consistently ranked at the top of the AHA/BHA botulinum toxin market share in China for many years.

Source: NMPA, analysis by Frost & Sullivan

At the same time, multiple A-type botulinum toxin products from several companies are in clinical Phase III and application for market launch stages, including Daxiong Pharmaceutical, Aimeik (which has introduced the Korean-made Huons), Inibio, and Yuyan Pharmaceutical; the already marketed botulinum toxin products from Allergan and Lanzhou Biotech are in clinical Phase III expanding their indications. Among them, Yuyan Pharmaceutical's YY001 pipeline is the world's first innovative recombinant A-type botulinum toxin that uses recombinant protein technology and has entered clinical trials. Recombinant A-type botulinum toxin has advantages such as low biological risk, high purity, low immunological risk, high production efficiency, and controllable capacity. It can break through the limitations of natural A-type botulinum toxin and become a new generation of botulinum products, potentially changing the existing landscape of the A-type botulinum toxin market.

Source: NMPA, analysis by Frost & Sullivan

Botulinum toxin still has great room for expansion in innovative technology iterations. Traditional natural botulinum toxin type A has largely been developed in its main application scenarios due to its determined molecular structure. Recombinant botulinum toxin type A can be further combined with techniques such as molecular isomerization and fusion proteins in recombinant protein technology. By analyzing and regulating the molecular structure and action targets of botulinum toxin type A, new types of botulinum toxins with faster onset, longer duration, more precise injection, easier use, and adjustable diffusion can be developed according to actual needs.

Type A botulinum toxin belongs to Zn²⁺The dependent proteolytic enzyme family consists of a 100 kD heavy chain and a 50 kD light chain. The heavy chain of botulinum toxin type A can specifically bind to the nerve cell envelope and enter the cell, while the light chain can specifically hydrolyze SNAP-25 protein on the presynaptic membrane, thereby affecting the activity of SNARE proteins involved in intracellular endocytosis and exocytosis functions. It hinders the fusion of neurotransmitter vesicles such as acetylcholine with the presynaptic membrane, preventing the release of neurotransmitters, causing chemical denervation effects such as muscle relaxation and inhibiting glandular secretion.

Type A botulinum toxin is used in different scenarios, including medical aesthetics institutions for improving facial and neck skin conditions, local shaping, or treating hair loss, as well as in neurology and rehabilitation departments of hospitals. It plays a therapeutic role by regulating functions such as nerves, muscles, and glands.

In the field of medical aesthetics, botulinum toxin type A is a popular minimally invasive cosmetic treatment method that is widely accepted by consumers. It can be used for scenarios such as facial and neck wrinkle removal, contour shaping, facial rejuvenation, improving glandular secretion, treating hair loss, and preventive treatment.

• Facial and Neck Wrinkle ReductionBotulinum toxin type A can improve dynamic facial wrinkles by blocking the impulse transmission between nerves and muscles, relaxing overly contracted small muscles. Botulinum toxin type A is commonly used for the improvement of facial and neck wrinkles such as crow's feet, forehead lines, trapezius lines, nasolabial folds, perioral folds, marionette lines, and horizontal neck lines.

   

• Contour shapingBotulinum toxin type A prevents the release of acetylcholine at the neuromuscular junction, causing the nerves to lose control over muscle movement. As a result, the muscles atrophy and shrink due to loss of function, achieving the purpose of sculpting contour lines. Botulinum toxin type A can be used for facial slimming injections into the masseter muscle, leg slimming injections into the gastrocnemius muscle, and for improving shoulder and neck lines by injecting into the trapezius muscle.

   

• Facial rejuvenationInjecting botulinum toxin type A into the superficial muscle fibers of the facial depressor muscles can weaken their muscle pull, giving the lifting effect a dominant role, thereby achieving the purpose of lifting. Botulinum toxin type A can lift the sagging outer corners of the eyes and the ends of the eyebrows. Injecting into the platysma muscle can reduce its traction on the middle and lower face skin, lifting the lower part of the face and making the contour of the mandibular margin clearer.

   

• Improve glandular secretionSebaceous glands express alpha-7 nicotinic acetylcholine receptors (alpha-7nAChR), therefore botulinum toxin type A can effectively reduce sebum production and shrink pores by blocking cholinergic signaling and inhibiting neural regulation. The main site for botulinum toxin micro-dose injection is the seborrheic area, with related studies often focusing on the forehead.

   

• Treating hair lossAndrogenetic alopecia is associated with dihydrotestosterone (DHT) and insufficient microcirculation. Botulinum toxin can relax the scalp muscles, improve local blood perfusion and oxygen content, thereby clearing accumulated DHT locally and reducing its production, thus alleviating the effect of androgens on susceptible hair follicles and reducing hair loss.

   

• Prophylactic treatmentThe SAMCEP consensus points out that as people recognize the significant role of botulinum toxin injections in the prevention and treatment of facial wrinkles as well as facial stability (mainly at the temples and corners of the mouth), more and more people are requesting botulinum toxin injections at an earlier age. Rivkin and others have found that long-term, continuous use of botulinum toxin can remodel the skin and epidermis, prevent the formation of wrinkles, and has potential benefits in improving skin quality.

Botulinum toxin has a potent neuroblocking effect and may be an effective symptomatic therapy for diseases related to abnormal movement or posture due to excessive muscle contraction, pain, or hyperactive autonomic nervous system.

• Treatment of movement disorders:Botulinum toxin has the effect of reducing muscle tension in spastic muscles, improving the frequency and intensity of spasms. It can be used to treat diseases such as blepharospasm, hemifacial spasm, cervical dystonia, laryngeal dystonia, limb dystonia, tremors, tic disorders, and oromandibular dystonia.

   

• Improve spasticity:Botulinum toxin can be used for upper and lower limb spasticity caused by upper motor neuron damage. For example, in cases of upper limb spasticity due to stroke, botulinum toxin can reduce muscle tone or the degree of spasticity in the affected wrist and finger flexor muscles, thereby alleviating disability; for lower limb spasticity secondary to upper motor neuron injury in adults, botulinum toxin can reduce muscle tone, decrease painful spasms of the lower limbs caused by multiple sclerosis, and improve passive function.

   

• Regulate autonomic nervous system dysfunction:Injecting botulinum toxin into both parotid or submandibular glands can improve the frequency of salivation in patients, reducing saliva secretion volume and severity. Injecting botulinum toxin into the armpits and palms and soles can inhibit sweat gland activity controlled by cholinergic nerves, thereby treating hyperhidrosis. In addition, botulinum toxin can improve neurogenic overactive bladder, enhancing bladder capacity, compliance, and detrusor muscle stability.

   

• Analgesia:Botulinum toxin can be used for preventive treatment of chronic migraines (with or without medication overuse headaches), reducing the number of headache days; it is also used for neuropathic pain such as trigeminal neuralgia, postherpetic neuralgia, and diabetic peripheral neuropathy, where patients experience improved or complete relief of pain after injection.

   

• Prevention and treatment of scars:Botulinum toxin has been used for the prevention and treatment of pathological scars, but the specific mechanism is not clear. It may be related to botulinum toxin's effects such as reducing fibroblast proliferation, decreasing collagen fiber deposition, inhibiting inflammatory factor release, and reducing angiogenesis. For preventive treatment, it is recommended to administer botulinum toxin injections within 14 days after surgery; intradermal injection of botulinum toxin combined with glucocorticoids for the treatment of hypertrophic scars or keloids may be due to the effect of monospecific glucocorticoid therapy.

   

• Treatment for chronic rhinitis:Botulinum toxin type A can improve symptoms of chronic rhinitis, especially for runny nose, with safety and efficacy, and a long-lasting therapeutic effect. The mechanism of action may include: inhibiting the release of acetylcholine from presynaptic cholinergic nerve endings in the nasal or sphenopalatine ganglia, inducing apoptosis of nasal mucosal gland cells, inhibiting the release of inflammatory mediators in the nasal mucosa, reducing eosinophil infiltration and capillary dilation in the nasal mucosa.

According to differences in production technology, botulinum toxin type A can be divided into two categories: natural botulinum toxin type A and recombinant botulinum toxin type A.

• Natural botulinum toxin type A: Produced by fermentation of Clostridium botulinum, natural botulinum toxin type A is obtained after purification.

   

• Recombinant botulinum toxin type A: By expressing the gene sequence of botulinum toxin type A in engineered bacteria such as Escherichia coli, the engineered bacteria ferment to produce botulinum toxin precursor proteins. After activation, recombinant botulinum toxin type A is obtained.

Source: Public information, Frost & Sullivan analysis

The representative company for overseas restructuring of botulinum toxin is Ipsen. According to official website data, Ipsen currently has only one botulinum toxin pipeline, IPN10200. IPN10200 is an E-type botulinum toxin, driven by the unmet long-term treatment needs of patients, used to treat muscle stiffness, spasm, and pain related to the nervous system; through engineered design, it enhances the receptor affinity of botulinum toxin, strengthens endocytosis, reduces the risk of botulinum toxin spreading to surrounding tissues, and improves user tolerance. IPN10200 entered clinical research in 2021, and as of March 2024, two indications for this pipeline are in phase II clinical trials, namely moderate to severe upper facial wrinkles and adult upper limb spasm.

There are few domestic companies that have reorganized their botulinum toxin technology layout. According to data from the Center for Drug Evaluation (CDE) of the National Medical Products Administration, as of September 13, 2024, only three recombinant type A botulinum toxin pipelines have entered clinical trials: Yuyan Pharmaceutical's YY001 pipeline, Junhemin Biotech's JHM03 pipeline, and Dixinchenke's DN001 pipeline. The research and development progress of these three companies is not uniform, and there are also differences in the technical processes of their product pipelines:

• Yuyan PharmaceuticalAccording to CDE data, Yuyan Pharmaceutical's YY001 was approved in March 2022 for clinical Phase I/II trials, targeting moderate to severe forehead wrinkles. It is the world's first recombinant botulinum toxin type A product to enter clinical trials. The Phase I/II clinical trial was completed in May 2023. Meanwhile, CDE data shows that the Phase III clinical trial of this pipeline was initiated in December 2023. According to the company's disclosed information, YY001 held a clinical summary meeting on September 12, 2024, announcing the completion of Phase III clinical trials and the initiation of BLA application filing. This pipeline uses Escherichia coli as an engineered bacterium to simulate the natural production process of botulinum toxin. The produced recombinant botulinum toxin type A YY001 is highly consistent with natural botulinum toxin type A in terms of molecular structure, physicochemical characterization, biological activity, etc.; moreover, its purity is as high as over 99%, far exceeding the natural botulinum toxin type A, which currently accounts for the vast majority of sales in the market; clinical trials have shown better efficacy and safety. In addition, YY001 was also approved by CDE in July 2024 to conduct clinical trials on adult upper limb muscle spasms and announced the enrollment of the first subject on September 14, 2024. This is an important milestone globally as it marks the first application of recombinant botulinum toxin type A in the medical field.

   

• Junhe Alliance:Following Yuyan Pharmaceutical, Junhemei's recombinant botulinum toxin pipeline JHM03 was approved by the CDE for Phase I/II clinical trials in December 2023, targeting moderate to severe nasolabial folds. According to the company's disclosed information, the Phase II clinical trial of JHM03 is currently nearing completion. Both Junhemei and Yuyan Pharmaceutical use Escherichia coli fermentation to produce botulinum toxin, but according to professional analysis, their process technology differs from that of Yuyan Pharmaceutical. This process is different from the natural production of botulinum toxin; instead, it involves separate expression of heavy and light chains followed by disulfide bond formation, which may lead to changes in molecular structure. Molecules with altered structures may not be completely equivalent to natural botulinum toxin, and there is still a need for extensive long-term clinical application to verify its effectiveness, safety, and immunogenicity.

   

• Dixinchenke:The recombinant botulinum toxin type A product DN001 from Dixinchenke received CDE approval for phase I/II clinical trials in August 2024, targeting moderate to severe forehead wrinkles. No further disclosures about this product line have been made publicly available.

According to public information, domestic companies deploying in the botulinum toxin recombination track include Ruoyi Biotech and Yaohainuo Xin, with their pipelines all in the preclinical stage:

• Ruoyi Biology:By independently establishing a new production process platform for insect cells-rhabdovirus, we are committed to developing self-suppressing and attenuated botulinum toxin type A. We have currently completed the development of upstream, downstream, formulation, and other process steps and entered commercial batch-scale production. We expect to submit an IND application in Q4 2024.

   

• Yaohainuoxin:The official website shows that the company initiated the development of recombinant botulinum toxin in January 2024, including two types: type A and type E. The recombinant type A botulinum toxin has completed strain screening and pharmacological studies, with a purity exceeding 97% and an activity of 2×10⁷>U/mg or above.

Yuyan Pharmaceutical develops using gene recombination and protein expression technology, utilizing engineered Escherichia coli for the development of recombinant botulinum toxin type A. The production process of YY001 is consistent with that of natural botulinum toxin. It first uses engineered Escherichia coli to ferment and produce single-chain proteins, which are then cleaved by proteases into a heavy chain protein and a light chain protein. The heavy and light chains are connected by a disulfide bond to form a 150 kDa single active double-chain protein, which is the recombinant botulinum toxin. The molecular structure of YY001 is identical to that of natural botulinum toxin type A. Given that natural botulinum toxin type A has been used for over thirty years, it ensures that YY001 with the same molecular structure has the same biological functions and pharmacological effects as natural botulinum toxin.

Yuyan Pharmaceutical has innovatively designed a triple filtration technology. The YY001 product has high purity, high specific activity, and significant reaction rates. The proportion of 150 kDa neurotoxin can be as high as over 99%, which is significantly higher than that of most natural botulinum toxins (usually accounting for 13%-15% of the preparation). The high purity of YY001 can reduce the local dosing dose. Phase I/II/III clinical trials have shown no specific antibody production, better safety, and lower immunological tolerance.

In addition, the company has built production facilities that comply with GMP standards. The designed annual basic capacity of YY001 freeze-dried preparations is 2 million bottles, which began to be put into use in the first quarter of 2023. In the future, after YY001 is launched on the market, Yuyan Pharmaceutical's YY001 production capacity can be flexibly adjusted according to market demand. The production capacity reserve can meet more than 20% of the total market demand within 5 years after YY001 is commercialized.

YY001 has multiple potential indications, including forehead wrinkles, upper limb muscle spasms, blepharospasm, masseter hypertrophy, as well as potential scars and pain. At the Phase III clinical summary meeting for completed moderate to severe forehead wrinkle indications on September 12, 2024, Yuyan Pharmaceutical announced clinical data showing that YY001 demonstrated a high degree of consistency with the completed Phase I/II clinical results in large-scale population Phase III clinical trials. Its effectiveness, safety, immunogenicity, and other aspects all met the established clinical endpoints, outperforming the data of the control drug. In addition, Yuyan Pharmaceutical, leveraging its recombinant protein technology platform, global expert talent in the botulinum toxin field, and years of accumulated rich R&D experience, can further optimize and upgrade botulinum toxin type A, while developing more subtypes of botulinum toxin; and through techniques such as molecular isomerization and protein fusion, it is expected to develop more clinically valuable and widely applicable iterative innovative products.

It is reported that after successfully completing the Phase III clinical trial of YY001, Yuyan Pharmaceutical will soon submit a marketing application to the National Medical Products Administration (NMPA). The development of recombinant botulinum toxin type A is progressing the fastest globally, with an obvious first-mover advantage. Compared with the registration application times for botulinum toxin products approved for marketing in China in recent years, such as Jisi^®Registration and declaration period is about 22 months, Lepidium^®Registration and declaration period is about 16 months, Dashiwei^®The registration and application process takes about 17 months. Considering that Yuyan Pharmaceutical, as a domestic manufacturer, has more convenience in document preparation and communication compared to foreign manufacturers, it is expected that the listing application for YY001 will be achieved more efficiently, potentially becoming the world's first recombinant botulinum toxin type A product to be launched on the market. This would continue its first-mover advantage in commercial sales and is more conducive to YY001's market performance after listing.

In November 2023, Huadong Medicine signed an exclusive distribution agreement with Yuyan Pharmaceutical, obtaining the exclusive distribution rights for YY001 in the medical aesthetics indication areas of Mainland China, Hong Kong, and Macau.

Huadong Medicine's business covers the entire pharmaceutical industry chain. Its medical aesthetics segment focuses on the global high-end medical aesthetics market, including multiple subsidiaries such as Sinclair and Xinkeli Aesthetics. It has research and development centers and production bases in many countries around the world, established a professional marketing team of nearly 300 people, and built a globalized medical aesthetics marketing network. Its product sales have covered more than 80 countries and regions worldwide. Among them, Xinkeli Aesthetics serves as Huadong Medicine's domestic market operation platform. Under its promotion, the regenerative filler Ellansé...^®Yiyan Shi^®In less than three years since its launch, YY001 has achieved a partnership with over 600 hospitals and trained and certified more than 1,100 doctors. Utilizing the medical aesthetics marketing platform of Huadong Medicine, YY001 is expected to rapidly penetrate medical aesthetics institutions nationwide after its launch, rewrite the domestic botulinum toxin competition landscape, and become a global botulinum toxin brand with its outstanding efficacy.

In the field of recombinant botulinum toxin, Chinese enterprises are at the forefront of research and development globally. In the future, it is expected that with YY001 being approved for marketing as the world's first recombinant botulinum toxin, China will become a major producer and exporter of recombinant botulinum toxin, leading the global botulinum toxin industry into a new era.