What it is
LetibotulinumtoxinA is the generic name of a botulinum toxin type A made by the South Korean company Hugel. In the United States it is sold as Letybo, which the FDA approved in February 2024 for one cosmetic use: 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 under the name Botulax.
Like other botulinum toxins, it is a bacterial protein that, once injected into a muscle, blocks the chemical signal telling that muscle to contract. The frown muscles relax for a few months and then recover. Its strength is measured in Units that belong to this product alone; the label says they cannot be compared with or converted 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, based in Chuncheon in South Korea, developed the toxin and first received Korean authorisation for it, as Botulax, in March 2009. Korean approvals for further uses followed, including arm spasticity after stroke and a foot deformity in children with cerebral palsy in 2016.
For Europe and the United States, Hugel worked with the Austrian company Croma-Pharma, which ran the three large Phase 3 trials, called BLESS I, II and III. European launches under the Letybo name began in 2022. The US application took three years: the FDA sent back complete response letters in March 2022 and April 2023, both reported as concerning manufacturing rather than the clinical results, before approving 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 rests on three matched trials, BLESS I, II and III, which together randomised 1,276 adults with moderate to severe frown lines. Three in four participants received a single 20-Unit treatment spread over five injection points, and one in four received a placebo. Four weeks later, the share rated “none” or “mild” with at least a two-grade improvement by both the investigator and the participant was 47%, 49% and 65% in the three trials, against 0 to 2% on placebo.
Most participants were women (91%) and the average age was 50. Headache was the most common side effect, in 2% of treated participants. Drooping of the brow or eyelid was reported in under 1%. An open-label extension with repeat treatments reported a similar side-effect pattern.
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.
Regulatory picture
In the United States the only FDA-approved product containing letibotulinumtoxinA is Letybo, licensed to Hugel, and its only approved use is frown lines between the eyebrows in adults. The same toxin sold under the name Botulax, or under any other name, and brought in for import or online sale is not an FDA-approved product, even though it is licensed in South Korea and elsewhere.
The FDA has acted on this directly. In November 2025 it announced 18 warning letters to websites selling unapproved and misbranded botulinum toxin products, and at least one of those letters named products marketed under the Botulax name. The agency had already warned in April 2024 about counterfeit botulinum toxin reaching patients in several states. Pharmacy compounding does not apply to a licensed biologic 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.
