What it is
LetibotulinumtoxinA is a type of botulinum toxin (type A). It is made by Hugel, a company in South Korea. In the United States it is sold as Letybo. The FDA approved Letybo in February 2024 for one cosmetic use. That use is softening moderate to severe frown lines between the eyebrows in adults. In South Korea and many other countries, the same toxin has been sold for years as Botulax.
Like other botulinum toxins, it is a protein made by bacteria. It is injected into a muscle. There, it blocks the signal that tells the muscle to tighten. The frown muscles relax for a few months. Then they recover. The strength of this product is measured in its own Units. The label says these Units cannot be compared with, or turned into, the Units of any other botulinum toxin.
LetibotulinumtoxinA (US proper name letibotulinumtoxinA-wlbg) is described in the label as a 900 kDa botulinum toxin type A produced by fermentation of Clostridium botulinum. The sponsor’s trial protocol specifies the complex as a 150 kDa neurotoxin, a 130 kDa non-toxic non-haemagglutinating protein and haemagglutinins of 17 to 48 kDa, purified from strain CBFC26, whose toxin-encoding sequence is reported to be identical to the Hall A reference strain. The formulation contains human albumin and sodium chloride.
Mechanism is shared across the type A class. After intramuscular injection the toxin is internalised into cholinergic nerve terminals, the light chain translocates into the cytosol, and its zinc-dependent protease activity cleaves SNAP-25, preventing docking and release of acetylcholine vesicles and producing a dose-dependent decrease in muscle function. Recovery follows degradation of the toxin and formation of axonal sprouts. The label states that no formal pharmacodynamic studies were conducted and that the product cannot be detected in peripheral blood after intramuscular injection at recommended doses.
Who made it and when
Hugel is based in Chuncheon, South Korea. It developed the toxin. South Korea first approved it, as Botulax, in March 2009. More Korean approvals came later. In 2016 these included stiff, tight arm muscles after a stroke. They also included a foot problem in children with cerebral palsy.
For Europe and the United States, Hugel worked with Croma-Pharma, a company in Austria. Croma-Pharma ran three large final-stage (Phase 3) trials. They were called BLESS I, II and III. Sales in Europe under the Letybo name began in 2022. The US approval took three years. The FDA sent the application back twice, in March 2022 and April 2023. Reports said both times were about how the product was made, not about the trial results. The FDA then approved Letybo on 29 February 2024.
According to the Croma-Pharma BLESS III protocol, BoNT/A-DP (Botulax) was first authorised to Hugel in the Republic of Korea on 13 March 2009, with Korean approvals in 2016 for post-stroke upper limb spasticity in adults and for equinus foot deformity in children with cerebral palsy; the protocol lists authorisations in 24 further countries at the time it was written. Hugel and Croma-Pharma formed a joint venture in 2018 for European development and commercialisation.
In the US, the biologics licence application (BLA 761225, Hugel Inc.), first submitted in March 2021, received complete response letters in March 2022 (additional facility documentation and data, per Korean trade press) and April 2023 (after an inspection of the Chuncheon plant). FDA approved the application on 29 February 2024, with the proper name letibotulinumtoxinA-wlbg and a single indication in glabellar lines. The label restricts retreatment to no more often than every three months and states that the product is not approved for spasticity or any condition other than glabellar lines. Hugel markets Letybo in the US through its own subsidiary.
What the data say
The US approval is based on three matching trials: BLESS I, II and III. Together they included 1,276 adults with moderate to severe frown lines. People were assigned by chance to a group. Three in four got one 20-Unit treatment, spread over five injection spots. One in four got a dummy treatment (placebo).
The trials checked results after four weeks. Success meant two things. The lines had to be rated “none” or “mild”. They also had to improve by at least two grades. Both the researcher and the patient had to agree. Success rates were 47%, 49% and 65% in the three trials. With the placebo, they were 0 to 2%.
Most people in the trials were women (91%). Their average age was 50. Headache was the most common side effect, in 2% of treated people. A drooping brow or eyelid happened in under 1%. Later, some people got repeat treatments. In that part, everyone knew they were getting the real drug. Side effects looked much the same.
A 2026 review that pooled 3 trials with 1,272 people found that far more people improved with letibotulinumtoxinA than with placebo at 4 weeks, the difference was still clear at 12 and 16 weeks, and side effects were not more common than with placebo.
BLESS I (NCT02677298), BLESS II (NCT02677805) and BLESS III (NCT03985982) were randomised 3:1, double-blind, placebo-controlled, multicentre trials of identical design (label: 957 active, 319 placebo; full analysis set 954 and 317). Participants aged 19 to 75 received 4 Units per site at five sites (one procerus, two per corrugator), 20 Units total. The primary endpoint was the week-4 composite of GLS 0 or 1 with at least a 2-point improvement on both investigator and subject assessment. Treatment differences were 47% (95% CI 43 to 51), 45% (36 to 54) and 65% (59 to 71). Investigator-only responder rates reached 66%, 75% and 79%.
In the pooled safety population (911 active, 310 placebo), headache occurred in 2% versus 1%; brow ptosis (3 subjects), eyelid ptosis (3) and blepharospasm (2) were each under 1%. In the open-label extension, 1,129 subjects received a median of three treatments over 48 weeks with no rise in adverse reaction incidence. Among 1,195 treated subjects, 4 (0.3%) developed anti-drug antibodies and none of the samples tested further contained neutralising antibodies.
Masood et al. (Aesthetic Plast Surg 2026;50(9):3427-3437; PMID 41501424) pooled 3 randomised controlled trials (n = 1,272) of letibotulinumtoxinA-wlbg versus placebo: the week-4 composite responder risk ratio was 59.47 (95% CI 14.95 to 236.52), efficacy remained significant at weeks 12 and 16, and there was no significant increase in serious, non-serious or overall treatment-emergent adverse events.
Regulatory picture
In the United States, Letybo is the only FDA-approved product with letibotulinumtoxinA. It is licensed to Hugel. Its only approved use is frown lines between the eyebrows in adults. The same toxin may be brought in or sold online as Botulax or under another name. That product is not FDA approved, even though it is licensed in South Korea and other countries.
The FDA has taken action on this. In November 2025 it announced 18 warning letters to websites. These sites sold botulinum toxin products that were not approved and were wrongly labelled. At least one letter named products sold as Botulax. In April 2024, the FDA had already warned about fake botulinum toxin. That fake product reached patients in several states. Pharmacies cannot make their own copies of a licensed biologic medicine like this one.
LetibotulinumtoxinA-wlbg is licensed under BLA 761225 under section 351 of the Public Health Service Act. As a biological product it sits outside the 503A bulk drug substances framework, and no lawful route exists for a pharmacy to compound a copy, so the compounding field is recorded as not applicable. The label carries the class boxed warning for distant spread of toxin effect and the statement that its Units are not interchangeable with other botulinum toxin products.
A US licence attaches to the approved product, its labelling and its manufacturing controls, not to the molecule wherever it is sold. FDA’s 3 November 2025 warning letter to one website stated that, although FDA-approved botulinum toxin products are on the US market, no approved application was in effect for the Botulax-branded products offered, which were therefore unapproved new drugs under section 505 and misbranded under section 502 of the FD&C Act. The letter was part of the 18-letter action announced on 5 November 2025.
