New botulinum toxin clinical trials: results and open questions

The arrival of a new toxin raises a legitimate question: what evidence is it based on? This page complements our overview of the new botulinum toxin and what sets it apart. It describes the published trials, what they measure, their results and, above all, what they do not yet tell us.

How is a medicine like this evaluated?

Before it is approved, a medicine goes through several stages of trials in humans. Phase 1 trials check tolerability and how the product behaves in a small number of people. Phase 2 trials look for the right dose and give a first idea of efficacy. Phase 3 trials, which are larger, confirm efficacy and tolerability, in this case against a placebo, meaning an injection with no active product.

For frown lines, efficacy is measured on a four-point severity scale, from "none" to "severe", at maximum frown¹. A patient is called a "responder" when their lines improve by a given number of points: at least two in the primary endpoint of the phase 3 trials¹. This detail matters, because a response rate only makes sense in light of how it is defined.

The first trials

A first phase 2 trial in humans, published in 2018, tested a short-acting botulinum toxin (serotype E) at increasing doses in frown lines⁵. It already described a fast-acting, short-lived effect, and its authors saw this profile as a lead for uses where a brief effect is precisely what is wanted⁵.

More recently, a phase 2b trial, also with increasing doses, was used to select the dose⁴. At the highest dose, 16.1% of patients responded at 8 hours, 41.9% at 24 hours and 93.3% on day 7, before a fall to 33.3% by day 14⁴. These figures show both how quickly the effect starts and how brief it is. They concern a single dose group and a demanding endpoint: they cannot be applied as such to all patients.

The two phase 3 trials

The European approval rests mainly on two identical phase 3 trials, randomised, double-blind and placebo-controlled, in adults whose frown lines were moderate to severe and had a psychological impact on them¹. Neither the patients nor the assessing doctors knew who had received the active product.

Together, the two trials enrolled 725 adults aged 20 to 81 (mean age 46), most of them women¹. The published trial, with 309 participants, only included people who had never received botulinum toxin³.

The main result, one week after injection

On day 7, 72.1% and 73.6% of treated patients had an improvement of at least two grades according to the investigator, compared with 0.8% and 0% on placebo¹. Pooling the two trials, the European Medicines Agency reports 72.6% of responders compared with 0.5% on placebo².

Patients also rated their own lines, without knowing the doctor’s assessment: 61.0% and 67.9% of them saw an improvement of at least two grades, compared with 0.8% and 0% on placebo¹. In the published trial, the main endpoint was stricter still: both the investigator and the participant had to rate the lines as none or mild, with a gain of at least two grades. 65.7% of treated patients met this endpoint, compared with 1.2% on placebo³. The figures therefore vary with who assesses and how a response is defined, not because the product changes.

Finally, a questionnaire measured how bothered people felt by the appearance of their lines. On day 7, the score had improved by at least 20 points out of 100 in 66.6% and 61.9% of treated patients, compared with 8.5% and 7.9% on placebo¹.

In the first few hours

In one of the two trials, the effect is observed from hour 8³. At 12 hours, 59.5% of participants had an improvement of at least one grade according to the investigator, and nearly 90% at 48 hours³. These figures use a less strict criterion (one grade instead of two) than the main result: they show that the effect starts early, not that it is already complete.

The trials also measured satisfaction at 24 hours: 58.7% and 68.5% of treated patients said they were mostly or very satisfied, compared with 16.2% and 9.9% on placebo¹. This is a feeling, not a measurement of the lines.

How long does the effect last?

The product information states that recovery generally occurs within 2 to 3 weeks, as the nerve endings recover¹. In the published phase 3 trial, the lines had returned to moderate or severe severity by around day 21³. In both trials, a new injection could be offered from day 43 if the lines were moderate to severe again, and the response rate was similar from one treatment to the next¹. To compare this duration with that of the long-acting toxin, see our comparison of the two families of toxins.

What about tolerability?

The adverse reactions reported in the trials were a drooping eyelid (0.17% of patients), a drooping eyebrow (0.13%) and an upward lift of the outer end of the eyebrow, known as the Mephisto sign (0.04%)¹. In the published phase 3 trial, adverse events of any cause were reported in 21.1% of treated patients and 23.2% of patients on placebo; those the investigators considered related to treatment affected 7.5% and 8.5% of them³. Most were mild. A single serious event occurred, unrelated to treatment, and no case suggesting distant spread of the toxin was observed³. These figures come from a trial of a few hundred people: they say nothing about rare effects.

The studies also looked for antibodies against the toxin, which could make it less effective. No patient developed neutralising antibodies, but the product information states that data are still limited¹.

What the studies do not yet tell us

A trial answers the question it asks, not the others. Several points have no published answer yet:

• No direct comparison with type A toxin. The pivotal trial has no active comparator, because no serotype E product was marketed yet³. Claims such as "more effective" or "better tolerated" are therefore unfounded.
• Trials funded by the manufacturer. The manufacturer funded the published phase 3 trial and took part in its design³; the phase 2b trial was also published together with the manufacturer⁴. This is usual for a new medicine, but it is a reason to wait for independent studies.
• Few data after 65. Only 7% of patients in the phase 3 trials were 65 or older, and their response rate on day 7 was lower: 58% according to the investigator, 37% according to the patients¹.
• Repeat treatments not evaluated. More than 3 consecutive injections beyond 18 weeks, or injections less than 6 weeks apart, have not been evaluated¹.
• Switching to a type A toxin. A type A toxin injected less than 30 days afterwards has not been evaluated¹; in a study of 90 subjects, an injection on day 30 had a similar effect to that seen after placebo¹.
• A single area. The trials concern frown lines, the only approved indication¹. The forehead, crow’s feet and other areas are not approved.
• Pregnancy and breastfeeding. Data during pregnancy are limited, it is not known whether the toxin passes into breast milk, and use is not recommended in either situation¹.

What the authors conclude

The authors of the phase 3 trial present the short-acting toxin as an option that may appeal to people who have never received a toxin or who hesitate to do so, and describe it as a trial treatment before possibly moving on to a longer-lasting toxin³. They also acknowledge that its shorter duration may be a disadvantage for those seeking a longer effect, and that it is not intended for long-term use³. These are hypotheses from authors linked to the manufacturer, not official indications.

From trial to approval

On the basis of these data, the short-acting toxin was approved in the European Union on 15 July 2026², and it has also been approved in Canada since 22 June 2026⁶.

To place these results in the history of botulinum toxins and their different serotypes, our page on the science of botulinum toxin covers the basics. And whichever toxin is being considered, the decision is made with your doctor, who knows your situation.