Christopher Bunick, MD, PhD: Efficacy, Safety of TMB-001 in Treating Congenital Ichthyosis

Christopher Bunick, MD, PhD

Credit: Yale School of Medicine

Adult and adolescent patients—in the age range of 12-64 years—saw positive results from the use of the investigational drug TMB-001 (topical isotretinoin) for moderate-to-severe X-linked and autosomal recessive congenital ichthyosis (CI), according to new late-breaking data.

These phase 3 findings were part of the open-label maximum use arm of the ASCEND study. The data were presented by Christopher Bunick, MD, PhD, at the 2024 American Academy of Dermatology (AAD) Annual Meeting in San Diego.

Bunick is known for his research and his role as associate professor of dermatology at the Yale School of Medicine. He spoke with the HCPLive editorial team about these new findings and their implications for patients with congenital ichthyosis, a group of rare genetic keratinization disorders which often result in thickened, dry, and scaling skin.

HCPLive: Can you provide an overview of the study design employed in the ASCEND trial, including the methodology used to assess safety, efficacy, and pharmacokinetic data?

Bunick: We actually had 2 arms. The data I presented was on the open label maximum use arm. This means these were our patients with moderate-to-severe, either X-linked recessive or autosomal, recessive, congenital ichthyosis that had moderate-to-severe disease and covering 75 - 90% of their body surface area. So they were applying the study medication over almost 90% of their body surface area.

This particular open label, maximum use arm is a distinct arm from the other arm. This trial also has a randomized blinded vehicle controlled component to the phase 3 ASCEND trial, and this is really important. So a lot of our efficacy data will come from the blinded, randomized, vehicle-controlled arm.

The maximum use arm was largely designed to understand the safety the pharmacokinetics, what is happening in the body when you apply it over so much surface area, and we got some really interesting results that are very reassuring to the safety of TMB-001 for congenital ichthyosis patients.

HCPLive: What were the key findings or preliminary results presented in the late-breaking session at the AAD Annual Meeting, observed in the open-label maximum use arm of the trial?

Bunick: So big picture, the preliminary findings were very positive for TMB-001. This investigational, new therapy for moderate-to-severe X-linked and autosomal recessive congenital ichthyosis. Before we get into the results, I just want to mention that what's really unique about this topical isotretinoin formulation, as it involves polyethylene glycol, there's a special delivery vehicle designed for ichthyosis patients to help improve hydration and lubrication of the skin with this polyethylene glycol technology.

This is something that no one else has used before in the design of a topical isotretinoin. I think it gives TMB-001 a distinct advantage compared to past attempts to try to create a topical isotretinoin. So I think this is really unique, and it distinguishes why this medicine seems to be working so well in ichthyosis patients…The goal of the open-label maximum use arm was really first to look at safety and the metabolism of the topical isotretinoin. Was there any systemic absorption of the isotretinoin or its metabolites? That was the main goal of the maximum use arm.

HCPLive: What were some of the major takeaways observed in terms of the safety profile?

Bunick: What we did was, in this particular group of data, we had 17 adolescent and adult patients. They received the topical TMB-001 ointment at Day 0 and for 14 days, twice a day. Throughout that time period, samples were taken from the blood to then look for systemic absorption of isotretinoin and its metabolites. So we're particularly looking for isotretinoin, 4-oxo-isotretinoin, tretinoin, and 4-oxo-tretinoin.

I can say that for tretinoin and 4-oxo-tretinoin, those two metabolites, the levels were so low that it was basically not detectable. That's amazing. When we look at isotretinoin itself, and the 4-oxo-isotretinoin, the levels that were seen in the blood were incredibly low. In order to provide a comparison, we had some healthy volunteers that received oral isotretinoin 180 milligrams. So a single dose of oral isotretinoin, 80 milligrams, was actually at times 60 to almost 280-fold higher systemic absorption in the blood than 1 dose of the topical TMB-001, 0.05% ointment.

So there was a massive difference in systemic absorption between the topical therapy and a single dose of oral isotretinoin, 80 milligrams. So what does this tell us? This is telling us that the TMB-001 pointment for congenital ichthyosis appears to be very safe and have minimal absorption of the isotretinoin or its primary metabolite the 4-oxo-isotretinoin. It is at substantially lower levels than what dermatologists experienced with oral isotretinoin. This is a very positive development, and a much needed one because it's important to remember that there are no specific treatments that are approved by the United States Food and Drug Administration for congenital ichthyosis patients.

HCPLive: Would you go into the efficacy component of some of these findings?

Bunick: The randomized, blinded, vehicle-controlled arm of the phase 3 ASCEND trial is where we will get our main efficacy data. But we were able to analyze the efficacy of the 17 patients that demonstrated such high safety to the topical TMB 001.

When I speak to the safety, what I'll say is that we already talked about the systemic absorption of metabolites. The main adverse events that we're seeing in these patients were very tolerable, mild, localized skin reactions such as redness, and itch. This was very manageable, from the trial from a provider perspective.

Regarding efficacy, we really did find that there was substantial improvement among these 17 participants in the open label, maximum use arm. Remember, they were putting it on anywhere from 75 - 90% of their body surface area.

So if we look at different measurements by different ways, one of the main inputs that we're looking at was the Investigator Global Assessment, composite scaling and fissuring…and when we look at 12 weeks of using twice-daily dosing of the TMB-001, 0.5% ointment, we saw a decrease in the Investigator Global Assessment score from 3.2 to 1.6, which was statistically statistically significant.

So another way to look at that data is that over that same 12 week timeframe, 60% of our patients achieved a 2-point or greater decrease in their IGA scores from baseline. This is amazing. And if we look at a 1-point improvement…we had 82% that demonstrated a clinically significant 1-point or greater improvement in their IGA composite scores from baseline. This is astounding.

This is a disease that has no FDA-approved therapies, and here we are seeing results of anywhere from 60 - 80% improvement, clinically, along with this high safety bar that I have mentioned already. This is truly speaking, in my opinion, to the transformational nature that TMB-001 can be for congenital ichthyosis patients.

The quotes used in this summary were edited for the purposes of clarity.