CKD BiO(063160) is joining hands with U.S. partner Hillis Therapeutics to take on the development of a botulinum toxin treatment for major depressive disorder (MDD). This is an area where development was halted after global drugmaker Allergan failed to meet the key endpoint in phase 2.
CKD BiO recently received U.S. Food and Drug Administration (FDA) approval for an investigational new drug (IND) application for a phase 1 trial of its own botulinum toxin formulation "Tymbus" 100 units for MDD. Hillis will conduct the trial in the United States, and CKD BiO will manufacture and supply the investigational drug at its Osong plant in North Chungcheong.
If the potential of botulinum toxin to treat MDD is proven, a therapy that approaches depressive symptoms differently from existing antidepressants will emerge. Unlike existing antidepressants, which act on neurotransmitters in the brain, botulinum toxin blocks signals at the neuromuscular junction—the interface between peripheral nerves and muscles—to see if it can affect depressive symptoms.
According to global market research firm Research and Markets, the global MDD treatment market is expected to grow from about $6.4 billion (about 9 trillion won) in 2026 to about $7.5 billion (about 10.6 trillion won) in 2030.
However, this phase 1 is an early stage to assess safety and tolerability in healthy adults, and whether it has an antidepressant effect in actual patients with depression must be verified in subsequent trials.
◇ Nine years after Allergan's failure… CKD BiO tries again with a "different formulation"
The history of developing toxin antidepressants goes back to 2006. It began when Eric Finzi, M.D., a cofounder of Hillis, released an early case series applying botulinum toxin to MDD. Allergan subsequently jumped into development and advanced to phase 2 in 2017.
Allergan's phase 2 enrolled 255 adult women with MDD. It was a 24-week study comparing Botox 30 units and 50 units with placebo, respectively, with the primary endpoint being change in the Montgomery–Åsberg Depression Rating Scale (MADRS) at week 6 after dosing.
The results were mixed. In the 30-unit group, depressive symptoms improved by 3.7 points more than in the placebo group, but the prespecified threshold for statistical significance was not met. The 50-unit group also showed no significant difference from placebo.
However, statistically significant differences were observed in the 30-unit group at weeks 3 and 9.
The program did not proceed to phase 3. Allergan was acquired by AbbVie in 2020, and AbbVie did not resume development.
Hillis took over the rights to the discontinued program. In 2022, Hillis secured an exclusive license from AbbVie to key patents related to treating MDD with botulinum toxin, and in Jan. 2024 it signed a supply agreement with CKD BiO for a botulinum toxin type A formulation.
Allergan's Botox and CKD BiO's Tymbus are both botulinum toxin type A formulations, but they differ in excipients. Botox uses human serum albumin (HSA) and sodium chloride, while Tymbus uses L-histidine and other excipients instead of HSA.
CKD BiO said, "Tymbus is a non-animal product that excludes animal-derived raw materials and excipients," and noted, "We expect it could lower concerns about blood-borne pathogen transmission or allergy induction."
However, recent studies have suggested that formulations containing HSA spread relatively less within tissue after injection than those without HSA, raising the possibility that formulation may affect toxin diffusion.
This is a variable that warrants attention, as injections are given to areas like the glabella where multiple muscles involved in eyebrow and eyelid movement are concentrated. If the toxin affects adjacent muscles beyond the intended target muscle, it can lead to local side effects such as ptosis or changes in eyebrow position.
◇ The injection leaves visible signs… setting a "placebo" is also a challenge
From phase 2 in patients, another hurdle called "blinding" awaits.
The rationale for using botulinum toxin to treat depression includes the "facial feedback hypothesis." It is the theory that physical sensory signals generated by facial expressions are transmitted to the brain and can influence emotions.
Botulinum toxin type A suppresses acetylcholine release at the neuromuscular junction, preventing muscle contraction. When injected into the glabella, even if the brain sends signals to frown, the muscle does not respond normally. The idea is to weaken the cycle of negative emotions by blocking sensory feedback from facial expressions back to the brain.
The problem is that patients injected with botulinum toxin actually see their glabellar lines smooth out. In other words, patients are more likely to realize whether they received the drug.
If patients perceive that they received the actual drug, expectations about efficacy can influence symptom assessments. Evaluators, too, may introduce bias in the assessment process if they infer whether dosing occurred.
There have been cases where the trial design itself was changed to avoid this problem. A representative example is the "OnaDEP" clinical study released in 2024 by a team led by Caroline Ceolato-Martin, M.D., at Limoges University Hospital and Esquirol Hospital in France.
The researchers administered botulinum toxin to all patients instead of placebo but varied the injection site. They divided 58 patients with treatment-resistant depression into two groups, injecting one group in the glabella (corrugator and procerus), known as the target area for treating depression, and the other in the orbicularis oculi that forms the lateral canthal lines at the outer corners of the eyes.
Because both sites receive botulinum toxin, it is hard for patients to distinguish "whether they received the drug," and both sites show visible changes in wrinkle improvement. Instead, patients were not told which site was effective for treating depression. The researchers in charge of evaluations likewise were blinded to the injection site. Rather than "active drug versus placebo," the comparison was "a site expected to be effective versus one not expected to be."
CKD BiO said, "As this is an early clinical stage, it is still difficult to share specific plans," and added, "We will work closely with Hillis so that Tymbus can establish itself as a new treatment option for MDD beyond the aesthetic field."
References
Toxins (2026), DOI: https://doi.org/10.3390/toxins18030142
Depression and Anxiety (2024), DOI: https://doi.org/10.1155/2024/1177925