Trial of Novel TYK2 Inhibitor Hits Its Endpoint in Plaque Psoriasis

The efficacy and safety results from the phase IIb clinical trial of TAK-279 (formerly NDI-034858), a novel allosteric tyrosine kinase 2 (TYK2) inhibitor in patients with moderate-to-severe plaque psoriasis, were presented at the American Academy of Dermatology (AAD) annual meeting.

MedPage Today brought together three expert leaders in the field: moderator Melinda Gooderham, MSc, MD, a clinical researcher from Peterborough, Ontario, is joined by Jennifer Soung, MD, a dermatologist and director of clinical research at Southern California Dermatology in Orange County, and Geeta Yadav, MD, founder of FACET Dermatology in Toronto, for a virtual roundtable discussion. This first of four exclusive episodes focuses on the results from the phase IIb trial of TAK-279.

Following is a transcript of their remarks:

Gooderham: Hello, I'm Melinda Gooderham. I'm a dermatologist and clinical researcher from Peterborough, Ontario, at the SKiN Centre for Dermatology and an assistant professor at Queen's University. I wanted to welcome you to this roundtable discussion on top news from the AAD 2023, and I'm delighted to have with me today Dr. Geeta Yadav, who is the founder and medical director at FACET Dermatology in Toronto and a lecturer at the University of Toronto, and Dr. Jennifer Soung, who is the director of clinical research at Southern California Dermatology and is a clinical faculty at Harbor-UCLA.

So thank you both -- on your very busy AAD schedules, it's amazing that we were able to connect all at the same time to go over some of the top news that was presented.

And I wanted to start with TYK2 excitement at the late breakers. So we have a new medication that's been approved that inhibits TYK2, and there was another late breaker presentation on yet another TYK2 inhibitor.

So Dr. Soung, could you tell us your take on the efficacy and safety results from the randomized double-blind placebo-controlled phase IIb trial of the TYK2 inhibitor NDI-034858, which is now called TAK-279 since it was acquired by Takeda, in moderate-to-severe psoriasis. What did you think about this one?

Soung: Thank you, Dr. Gooderham. I think it's clear that this mechanism of action and JAKs [Janus kinase inhibitors] are here to stay and really reconfirming the specificity of how TYK2 is a key component in the psoriasis inflammatory pathway. So, remember JAKs have several enzymes, JAK1, 2, and 3, as well as TYK2. And this really reconfirms the specificity of the allosteric inhibition of TYK2. And the hope is that this is not only more efficacious, but shows similar efficacy.

So let's take a look at the study design first. These were adult psoriasis patients that were included in the trial -- so your usual suspects. Had to have a diagnosis of plaque psoriasis for at least 6 months, a PASI [Psoriasis Area and Severity Index] ≥12, a PGA [physician global assessment] ≥3, and a body surface area of at least 10%.

There were six arms in the study -- so looking at a dose-ascending study starting from 2 mg to 5, 15, and 30, and then placebo. The study was for 12 weeks with a 4-week follow up, and the primary endpoint was PASI 75 at week 12 with several other secondary endpoints.

So let's take a look at the demographics of these patients. Pretty typical for your psoriasis population, with slightly more male patients, average age around mid-40s, and a distribution of mostly white patients -- about 86% -- with a little bit of Asian and African American. In terms of overall weight, we know that our psoriasis patients can be a little heavier, in the BMI [body mass index] around 31, duration of psoriasis 12 up to 17 years.

And when we look at the severity of psoriasis that these patients started with, around two thirds to three quarters of patients were in the moderate range, so a PGA of 3. And about 20-40% were severe. So when you look at body surface area, average about 20-24% body surface area. And the DLQI [Dermatology Life Quality Index] being at least 10, up to around 12 -- so definite impact on life.

Something else I like to look at is bioexperience. Certainly we now have many treatment options for our psoriasis patients. So giving us an idea of whether they have had biologics prior to participating in this trial for an oral medication.

Okay, so let's take a look at the primary endpoint. This was measured at week 12, and we see a clear dose-ascending response over that 12-week time period, with the highest dose groups 30 mg and 15 mg achieving the highest PASI 75. So you see 68% of patients in the 15 mg once-daily dose achieved PASI 75; similar results in the 30 mg group -- 67.3% of patients achieving a PASI 75.

What are your thoughts, ladies, looking at this efficacy at week 12?

Gooderham: Yeah, I think it's great efficacy. It's interesting that you're not seeing, it's like you've hit a plateau that the higher dose does not give you a higher PASI 75 response. But I think this is an oral medication. It's giving pretty good results. If you actually look at some of the secondary endpoints, the PASI 90, PASI 100, you see a bit of a difference in the PASI 100 rates with the higher dose that you're not seeing with PASI 90 and PASI 75.

So again, with an oral medication to get PASI 100 in about a third of patients is something we haven't seen before. So I think it's pretty exciting.

Yadav: And I think to your point, Melinda, about that you might see some bigger gains on the efficacy side with the higher dose when looking at that PASI 100 performance. To go hand in hand with that, one thing that we worry about, and I think increasingly so, we're looking at safety as an important sort of marker of what it means to have an effective therapy in psoriasis.

We've kind of gotten a bit comfortable with that concept of safety, but now we have to look at that a little bit more carefully. And from this poster, there isn't a big difference between those higher doses from a safety perspective, and that's kind of reassuring and nice to see those AEs [adverse events] also plateau, along with that PASI 75.

Soung: Great point. Let's briefly review the safety. So when we look at the five different groups in terms of serious adverse events, there was only one in the 15 mg group. Overall, the adverse events were numerically similar to each other in the groups. In fact, the most frequent adverse event was COVID-19 infection. And the other adverse events we're seeing were acne, acneform dermatitis -- so not unexpected for a JAK medication.

In terms of the hematologic parameters in CPK [creatine phosphokinase], as you noted, Geeta, similar to what we've seen with the other TYK2s in this class, a tiny signal with CPK that was not clinically significant -- otherwise no laboratory abnormalities or adverse trends in these cell counts.

Yadav: I think it is really nice that we're sort of getting to a place where having a variety of medications, JAK, TYK2s, and getting kind of a common approach to how we're going to monitor those drugs. It sort of gives people a little bit more comfort in starting to prescribe in that class, because we're seeing these similarities in terms of probably monitoring requirements, or expectations for laboratory results, as patients kind of continue on these therapies for a longer duration.

Gooderham: Yeah, I think it's important with these oral therapies too, because I think one of the things patients and clinicians like about biologics is they don't have to do the monitoring and the blood work. And at least with the first TYK2 inhibitor that's been approved, we don't have that monitoring requirement. So it's nice to see this field developing in this way.

Anything to add there?

Soung: What struck me the most was an increase in the efficacy without any further new or increase in safety signals. So I think that really reaffirms the importance of this pathway for psoriasis pathophysiology and definite continued interest probably in honing or understanding this pathway and target.

Gooderham: Awesome, yeah, thanks. Thanks a lot, guys. It's really interesting to see this move into a phase III program, so look forward to that.

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