New pharmacokinetic phase 3 data will be presented at the 2023 Society for Pediatric Dermatology meeting next week.
Timber Pharmaceuticals recently announced the interim pharmacokinetic (PK) analyses from its phase 3 ASCEND clinical trial of TMB-001 0.05% for the potential treatment of congenital ichthyosis (CI).1 The phase 3 ASCEND (NCT05295732) results show that interim PK analyses indicate minimal systemic absorption of isotretinoin or its major metabolites in patients with moderate to severe forms of CI who were treated with TMB-001 0.05% ointment. The full PK phase 3 data will be presented at the 2023 Society for Pediatric Dermatology Annual Meeting in Ashville, North Carolina, July 13-16.
To further discuss the importance of the phase 3 PK data, Dermatology Times® spoke with Alan Mendelsohn, MD, the chief medical officer of Timber Pharmaceuticals.
"If [TMB-001] is successful, this will be the first form of isotretinoin, oral or topical, that will actually be able to be used in children under 12. And this is obviously an important issue when we're talking about a congenital disease where many of these children manifest significant symptoms, soon after their birth," said Mendelsohn.
Mendelsohn: My name is Alan Mendelsohn, and I'm the chief medical officer of Timber Pharmaceuticals, the sponsor of the ASCEND trial program in congenital ichthyosis.
Dermatology Times: Can you please provide an overview of the phase 3 data of TMB-001 0.05% that is being presented at the 2023 Society for Pediatric Dermatology meeting?
Mendelsohn: Great, thanks for this opportunity. The ASCEND program is either the largest or one of the largest development programs ever in congenital ichthyosis, particularly the 2 forms, we're studying. Congenital ichthyosis, ostensibly, if you think of the skin is a wall, and a wall is made up of mortar and bricks, congenital ichthyosis is a disease where there are genetic mutations where either the mortar or the bricks aren't acting appropriately. In all cases, however, the reaction of the body is the same. And that's to really increase the number of cells and the thickness of the skin to the point where in many cases, patients can't sweat. They have the physical appearances, that unfortunately in society, lend themselves to derogatory comments. They can have terrible itching, and shedding of their skin. And because it's genetic, there really are no cures. So most of the treatments that currently are used right now are really descaling agents, whether that's things like urea, or physical loofa sponges, or other agents that are like emollients, that actually soften the skin. So it makes it less itchy and in a sense, more tolerable. But because as I said, it's a genetic disease, there really hasn't been an accurate or an active treatment that's actually gotten at the root of what causes the disease. And that's what we're studying in our program. So we will have at least 142 subjects with, as I mentioned, the 2 different forms of congenital ichthyosis, one that's more common, called X-linked ichthyosis that occurs predominantly in males, occurs probably around one to 2000 to 5000 male patients, and then a less common, but potentially more severe disease called arci, or autosomal, recessive congenital ichthyosis of the lamellar type. And we are studying 9 different genetic mutations in that group. In total of all of the congenital ichthyosis mutation subtypes, there are probably well over 30 different mutations that can lead to very similar types of appearances. And so the total of at least 142 patients are divided up into 2 separate groups. There's a 110 patient cohort, that is a classic vehicle control trial, where 2 out of every 3 patients get randomized to TMB-001 0.05%, which is our proprietary form of topical isotretinoin. And the other 1/3 of patients are randomized to vehicle which is everything, including the emollient parts of TMB-001 0.05%, but without the isotretinoin. And then after that first 12 week period, we extended the trial for an additional 12 weeks in terms of looking at the maintenance period, meaning how long and how well will the drug do after the first initial 12 weeks? How do patients tolerate it? What is the safety profile look like? Because as a genetic disease, this is going to require chronic treatment. And that's one of hopefully the major advances that we hope to bring forward and we'll discuss today about TMB-001 as opposed to oral isotretinoin is the fact that this presentation at the Society for Pediatric Dermatology is really our first and potentially biggest step in showing a major differentiating factor from oral isotretinoin, which is a well-known compound to the vast majority of dermatologists with a well-known safety profile, which we hope we will actually be able to improve upon. But the additional 32 patients of the 142 are entered into an open-label maximal use study. And these are potentially the 32 worst patients that we could find in terms of the severity of their disease. So by definition, to get into this open-label portion, they have to have at least 75% of their total body surface area with the exclusion of their face and their scalp, and other parts of their body, the back of their hands, for example. So at least 75% of their body has to be covered by these scales, and the amount of scaling and severity of the scaling has to either be moderate or severe. Additionally, these patients start to apply TMB-001 0.05% twice a day, every day, [for the first 14 days] during which we obtain pharmacokinetic data, which allows us to look at what is the peak concentration that one achieves with this topical formulation, when you ostensibly apply it to your whole body? How long does it potentially stay in your body, how much drug gets accumulated over the course of time, and after that first 2 weeks of mandatory 2 times a day application, patients then can continue to apply the drug, preferably twice a day, but maybe once a day, depending on how they tolerate it, for an additional 10 weeks, so that we will have additional safety and efficacy data for 12 weeks on those patients.
Dermatology Times: As someone so involved in the development of a treatment for congenital ichthyosis, what data points or results are you most pleased with from the ASCEND trial?
Mendelsohn: Well, we're very, very excited about these data. Because as I just mentioned, this really is a turning point, certainly in many parts of the world that have no access to this type of topical retinoid, because while we were able to show in the first 9 of the 32 patients that are going to be in the maximal use study, again, ranging from 12 to 62. And that's what also makes this trial and program so unique is that we will be enrolling children, as young as 6 years of age all the way up to in fact, our oldest patient right now is 81 years of age. So that in and of itself is a major move forward. Because isotretinoin in the vast majority of places in the world is only on-label to be used in children over the age of 12. So if this is successful, this will be the first form of isotretinoin, oral or topical, that will actually be able to be used in children under 12. And this is obviously an important issue when we're talking about a congenital disease where many of these children manifests significant symptoms, soon after their birth. And what we were able to show in these 9 patients who are applying the drug literally all over their body, almost analogous to when you take an oral isotretinoin, and the drug gets completely distributed throughout your whole bloodstream is that in fact, we are achieving 40 to 80 times lower concentrations in the blood with the topical form, as compared to historical control, like Accutane, which is pretty much well known in the medical and patient community is treatment and oral treatment for acne. So we're able to achieve extraordinarily low concentrations, but still, in many cases achieve the same, if not potentially better efficacy than one would achieve with oral isotretinoin. We don't yet have any head-to-head data to support that. But at least in terms of safety, we didn't have any of the major safety issues that you might see with oral isotretinoin, such like cheilitis, dry mouth, and dry lips. More severe things like hair loss that can happen with oral isotretinoin. And even chronically, particularly in children, issues around abnormal stunted growth, abnormal bone growth in children can occur with isotretinoin. So we didn't see any of those kinds of things. And in fact, what we're going to show in the actual presentation, is a 12-year-old young man with X-linked ichthyosis, who had at least 80% of his body covered with these scales, who after applying the TMB-001 twice a day for the full 12 weeks, achieves nearly complete clearance of his disease, and his maximum serum concentration is at about 5.03 nanograms per milliliter. So just to put that into perspective, if you were to look at the Accutane label, the Accutane label would say that the average serum concentration that you would achieve with an 80 milligram dose of isotretinoin is 864 nanograms per milliliter. So we are hopefully achieving the same results that you would get with an isotretinoin concentration in the hundreds or 1000s with a serum concentration that's in the single digits. So that's obviously very, very exciting.
Dermatology Times: From the data, it was found that there was minimal absorption of isotretinoin when TMB-001 was applied to 75% to 90% of BSA. What do these results mean for moving toward the approval of TMB-001?
Mendelsohn: Well, I mean, the answer is really bifunctional, which is there's the practical issue. And then there's the potential issue. The practical issue is obviously if we applied this drug, as I just said, to the entire body surface and the serum concentrations that we achieved by applying it to the skin were the same as you achieve with an oral isotretinoin compound, there really wouldn't be any benefit at all to the topical isotretinoin because you'd get the same serum concentrations and therefore, you get the same safety profile. So number one, that's a major practical issue is that we were actually able to show that there's far less absorption of isotretinoin when it's applied topically as TMB-001, then you would get with historically and 80 milligram dose of oral isotretinoin. This fulfills one of the major criteria that we need to fulfill for the FDA, because as part of the FDA approval process for this product, they've asked us to repeat some of the oral isotretinoin data in 15, healthy adult male volunteers. And so as far as the FDA and approval is concerned, in the next few months, we're going to take the data from these 15 healthy volunteers compared to the 16 adults who are in the maximal use study, and use that to show to the FDA, that in fact there are these differences, and that the FDA will then hopefully allow us from a practical standpoint to actually proceed to move forward with presenting to them the efficacy and safety data that we're currently collecting. So this is a huge first step for us even being able to make a submission to the FDA for approval, which we still hope to do sometime in 2024. From a potential standpoint, what this shows is it opens up many potential avenues of treatment for topical isotretinoin in conditions where oral isotretinoin has been used and been shown to be effective. So other forms of congenital ichthyosis, potentially psoriasis; isotretinoin has been shown to work in psoriasis and cousins of psoriasis, like PRP. So the list is sort of one can go on. Particularly, I mean, we only focus on rare diseases. So we are really not very much interested in lots of diseases that have other treatments. But it opens up a whole potential for other treatment modalities or other diseases, where oral isotretinoin may be used, because we, for example, has been able to show that you can get very similar if not better effects with a topical isotretinoin without a lot of the safety issues.
Dermatology Times: For physicians unfamiliar with TMB-001 or the high dose of isotretinoin used, what would you like them to know about TMB-001s safety and efficacy?
Mendelsohn: Well, we've been very fortunate, we've been able to show again, in terms of safety, that we can achieve very low serum concentrations by applying topically without a lot of the safety issue. So just for example, in our program, we have had no serious adverse events that have been attributable to the drug. So we've had no deaths, no hospitalizations, no cardiovascular events, no malignancies, really the only safety issues we've had predominantly are skin reactions, so things like burning or itching. And once that happens, and patients can tolerate the drug, those effects go away. I mean, the other effects we've had are some people with colds, some people will gastroenteritis, intestinal flu, and things like that. But nothing major. Nothing else that has caused patients to stop. The success is evident and we really appreciate the support of the patient groups and the dermatology community that has supported our efforts, and has allowed us to publish our data in prestigious journals such as the Journal of the American Academy of Dermatology, Dermatology and Therapy, Clinical and Experimental Dermatology, where all of the phase 2a and phase 2b program data can be found in the literature. And we really appreciate the fact that the Society for Pediatric Dermatology is actually allowing us to now present the first data from this phase 3 program that will hopefully be the stepping stone next year towards a full approval and then being able to help patients who really don't have any other medical treatment right now. All they really have are, as I said, keratolytics like urea, or emollients. So it's a very exciting time.
Dermatology Times: Do you have any closing remarks or comments?
Mendelsohn: Just really want to thank Dermatology Times for the opportunity to discuss the trial and the results. We look forward to meeting all members of the SPD, and anybody else who wants to speak to us at the SPD, between July 13 and the 16th, where we'll be presenting the full dataset and please contact Dermatology Times. If you have any questions and you know how to find me.
[Transcript edited for clarity]