This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.  

Tuning In to TYK2: Innovation in Oral Psoriasis Treatment for NPs and PAs

Veronica Richardson (University of Pennsylvania Health System): As I mentioned, we are going to be talking about psoriasis pathogenesis and JAK-STAT family signaling.

[00:07:50]

Patient Perspective: My Experience With Moderate to Severe Psoriasis

First, what is most important, and it is why we are here today is for the patient. We want to hear from a patient. We are going to hear from a real patient, Monica. This is just under a 2-minute video. We are going to go ahead and hear about Monica's experience with moderate to severe psoriasis.

Monica: When I started having issues with psoriasis, I was in my teens, and at first, was not really sure what was happening. The skin was getting dry, red, irritated. Started on my knees and my elbows. I did get some on the back of my scalp. It was a constant itch. At first, I tried over-the-counter cortisone and moisturizers of all sorts. It did not help. When my sleeping was not real good, I would wake up in the night wanting to scratch. During the day, it was the same. Affected me as far as I was embarrassed, insecure. I thought people were staring.

I went ahead and I went to see a dermatologist. At that time was still not sure what was going on. I was diagnosed with psoriasis. They started me on a steroid ointment, which I would use twice a day. It helped. It took the itch away, as long as I used it like I was supposed to, and I would use moisturizer on top of that, which helped as well.

You could still see some areas. It did not take it completely away. When you are young like that in your teens, the way you look and the way you dress, it all affects you in your life.

[00:10:09]

Epidemiology of Psoriasis

Veronica Richardson: Hearing Monica's story is impactful. Monica is not alone. More than 8 million individuals in the United States over the age of 20 are living with psoriasis. We tend to see psoriasis affect males and females pretty equally. We see it most commonly in Caucasian patients.

What I really want to highlight here is that patients with skin of color do get psoriasis. In fact, although psoriasis is a clinical diagnosis, meaning you do not need to do a biopsy to diagnose psoriasis. Patients with skin of color who have psoriasis are 3 times more likely to actually have gotten a biopsy to diagnose their psoriasis than their Caucasian counterparts. That is primarily because we, as clinicians, especially in dermatology, are not very good at being able to recognize inflammation in darker skin tones. That is primarily because many of the clinical trials, as many of the textbooks and the photos and textbooks show inflammatory diseases in white skin, which looks very different than more deeply pigmented skin.

That is something I really want to highlight. There is a lot of educational initiatives going on for that. But please think about psoriasis in your skin of color patients as well. There is often a delay in diagnosis. Really making sure you are able to identify inflammation in skin of color is incredibly important.

The other thing we often think about with psoriasis is that there is a bimodal peak in terms of the onset of the disease. Over the course of one's life, we tend to see 2 time periods where psoriasis tends to pop up.

Now, it can happen at any point in the lifetime, but we tend to see in the second and third decades of life, and then again in the 50s and 60s we can see peaks of psoriasis develop. This is a very common condition that we see.

All of you here tonight are understanding that psoriasis is more than a skin disease. This is a systemic inflammatory condition with primarily cutaneous manifestations, but also has a whole host of other comorbidities associated with it.

[00:12:24]

Increased Morbidity and Mortality With Psoriasis

Information that has come out over the past 15, 20 years have really honed in on those comorbidities, especially cardiovascular disease. This is just 1 of a number of studies that have looked at comorbidities with patients who are living with psoriasis. This 1 is really impactful. That is why we have it up here.

This study actually showed increased morbidity and mortality in patients with psoriasis. In fact, patients with psoriasis lived, on average, 6 years less than their non-psoriasis counterparts. Mortality was due to a number of causes. The most prevalent cause of death was related to cardiovascular disease. All of you primary care providers, I am sure you are aware that psoriasis is closely linked with cardiovascular disease, or patients are at greater risk of cardiovascular disease and metabolic syndrome.

I always am making sure that my patients with psoriasis have a primary care provider that they are seeing because this is so incredibly important.

[00:13:33]

Moderate to Severe Psoriasis Is Undertreated/Untreated

If you take a look at this pie chart, you see the type of treatments that patients have received in the prior year. This was a survey study that was done. Again, this is old data now. The survey was done between 2007 and 2012 and published almost 10 years ago at this point. I anticipate that some of these percentages have changed a bit.

The bottom line that I really want to highlight here is this bottom figure, because I think this is probably still pretty similar. Of the patients treated in the past year, 50% were no longer being treated.

Now, psoriasis is a chronic disease. We do not have a cure. That means patients were on a treatment and they abandoned their treatment, whether it be topicals or phototherapy or oral medications or biologics. We want to know why. That tells us that patients are not 100% satisfied with their treatment options.

[00:14:30]

Patient-Reported Burden of Therapy for Psoriatic Disease

When you look at conventional oral therapies, and what I mean by that are medications like methotrexate, acitretin, cyclosporin. Cyclosporin really is just used as a rescue medication, so I do not consider that a long-term treatment for psoriasis. When we think about methotrexate and acitretin, again, this study was published in 2016, but data was up until 2014 before any other oral medications like apremilast had come out.

The primary concerns that patients had about conventional oral therapy were the risk of abnormal lab tests or cumulative toxicity, adverse events. So the safety essentially of those medications.

Then on the other side, on the graph to the right, these are the concerns patients have about biologic therapy. Now biologic therapy are administered with injections. By and large, the most common concern patients have about biologics and I have this discussion with my patients every day, is needle phobia. Patients do not like the idea of having to give themselves an injection.

A close second behind that needle phobia was again adverse events and abnormal lab tests. That tells us that there is a gap. There is an unmet need here for a therapy that is not only efficacious, but it is easy, does not require a ton of lab monitoring, and is not given by injection.

[00:15:56]

Challenges With Biologic Therapy for Psoriasis

Biologics have absolutely changed the game when it comes to treating patients with psoriasis. When I first started in dermatology in 2011, we had 2 biologic drugs that were FDA-approved for psoriasis. We had a third that was not FDA-approved, but we used it anyway off-label.

Now we have 12 biologics to choose from. Our toolbox is essentially exploding with options from a biologic standpoint, but they are not accessible to everyone. Whether it be cost or insurance, there are definitely barriers when it comes to getting patients started on biologics.

Cost is a big one. Insufficient knowledge on the part of the patient, not understanding a lot about biologic therapy, and then therefore, maybe being hesitant. Then also healthcare providers.

I know that there are even some dermatologic providers who are hesitant to give patients biologic drugs because of their lack of knowledge. That is why we do CME events such as this, to educate providers about the different therapies for psoriasis to make them more comfortable and more confident.

[00:17:05]

Challenges With Traditional DMARDs

Some of the challenges that we face with the conventional oral therapies like methotrexate and acitretin. One, they are not great in terms of efficacy. They offer about anywhere from 30% to 45% likelihood of getting a patient 75% better. That is mediocre in today's standards. We also know with drugs like methotrexate, for example, there are a number of drug-drug interactions. You can have cumulative toxicity in the liver. You can actually have methotrexate-induced pulmonary toxicity.

The really long-term use of methotrexate is not ideal, especially in our patients with psoriasis who are more likely to have ventral obesity and fatty liver, which puts them at greater risk of hepatotoxicity.

Then the other challenge with the traditional drugs like acitretin and methotrexate is the frequency of monitoring. When we start patients on methotrexate, we are often checking labs pretty frequently. Then they space out to every 3 months, which is still pretty burdensome for patients.

As you can see, we have challenges across the board when it comes to the different treatments for psoriasis. The biggest challenge is beating this disease and what is happening.

[00:18:26]

Pathogenesis of Psoriasis

On a higher level, in terms of the pathogenesis of psoriasis, I mentioned earlier, this is a chronic disease. It is an inflammatory disease with primarily skin manifestations. It can look different in different patients, plaque psoriasis being the most common phenotype. You can have guttate psoriasis, inverse psoriasis. We know it is driven by an overactive immune system. It is this complex interplay between our cytokines. So pro-inflammatory cytokines like IL-17, IL-23, TNF-alpha and then our T-cells and predominantly Th17 cells.

[00:19:04]

Inflammatory Cascade of Psoriasis

For those more visual learners here, this is a nice little schematic of what happens and what is happening in the epidermis and the dermis in terms of the inflammatory cascade in psoriasis. I mentioned earlier when I first started practicing, we had 2 FDA-approved biologics and both of them were TNF-alpha inhibitors. The thought back then was let us target TNF-alpha, which you can see down here towards the left bottom after the plasmacytoid dendritic cell, which is that reddish pink cell.

We targeted TNF-alpha, and they are very effective drugs. As research has continued and research has advanced, we have identified that the IL-23, Th17 axis is really critical. That is actually the driving force behind psoriasis inflammation.

What happens is you get these keratinocytes. You have essentially an insult to them, whether it is inflammation. You have a trauma to the keratinocyte. Then what happens is they released a whole host of signals to the plasmacytoid dendritic cells, which release type I interferons and TNF-alpha. Those work on the dermal dendritic cells to then essentially release IL-12 and IL-23.

Now IL-23 needs that JAK-STAT pathway in order for it to do its dirty work. That is where the JAK-STAT pathway comes in. IL-23 relies on the JAK-STAT pathway in order to basically send its message. IL-23 is a cytokine. It is chemical messenger from outside of the cell into the cell, into the nucleus to then create a host of changes that result in transcription and further driving of Th17 and Th17 development of pro-inflammatory cytokines like IL-17.

[00:21:14]

JAK–STAT Pathway in Psoriatic Disease

We will take another look at this here in terms of digging down deeper into the JAK-STAT pathway in psoriatic disease.

As I mentioned, the JAK-STAT pathway, think of it as a bridge from outside of the cell into the cell. It is essentially a conduit. What the JAK-STAT pathway does is essentially translates messages from the cytokine.

If you look all the way over to the right, let us take a look at IL-12 and IL-23. IL-12 and IL-23 are cytokines that are incredibly important in the development of psoriasis. IL-12 and IL-23 need a way to communicate into the cell into the nucleus. They attach to this receptor here. Then we rely on TYK2.

TYK2 is a protein, that is essentially something that is going to basically drive inflammation. I will show you in our next page.

[00:22:21]

TYK2 Inhibitor Selectivity in Psoriasis

We really want to see TYK2 being blocked, because TYK2 is incredibly specific towards psoriasis cytokines. If you block TYK2, you are being very specific and very selective to psoriasis.

TYK2 inhibitors, they block TYK2. TYK2 inhibitors bind to what we call the regulatory domain or the inactive domain rather than the active or the catalytic domain.

What happens when you target the inactive or the regulatory domain, it essentially locks TYK2 in an inactive state. Then that chemical message cannot continue into the nucleus. By inhibiting TYK2, you are stopping that process and you are no longer driving production of IL-12, IL-23 and type I interferons.

[00:23:21]

TYK2 Inhibitor Selectivity in Psoriasis (cont’d)

Here is another way to look at it. As I mentioned earlier, we have this initial skin injury, say, koebnerization, that causes the plasmacytoid dendritic cells to produce type I interferon. We know, if we go back to our slide here, TYK2 is also involved in type I interferon. We have this blockade of TYK2 that then impacts the ability of type I interferons and IL-12 and IL-23 to do their dirty work, if you will.

Then if you look further down this, the dermal dendritic cells that are producing IL-12 and IL-23, again, you have TYK2 blocking IL-23’s ability to get into the nucleus of the cell and cause additional inflammation.

[00:24:19]

JAK–STAT Selectivity of Deucravacitinib and Tofacitinib

JAK-STAT selectivity. The first JAK inhibitor to come out was something called tofacitinib. There is a family of JAK inhibitors, JAK1, JAK2, JAK3 and TYK2. Those are the 4 members of the JAK family, if you will.

The first JAK inhibitor to come to market, it is not approved for psoriasis is a drug called tofacitinib. Tofacitinib has primarily JAK1 and JAK 3 inhibition. It also has the ability to inhibit JAK2. We call it a pan-JAK inhibitor because it hits all of those JAKs. There is tiny bit of TYK2.

What we know is that because of this pan JAK activity, yes, it is very good for some diseases in terms of really suppressing these pro-inflammatory cytokines. So it is approved in conditions like rheumatoid arthritis and ulcerative colitis and psoriatic arthritis. What happens is because it is a pan-JAK inhibitor, again its immunosuppression is more broad. Therefore, we have more off target effects. So you have more side effects. You have a heftier side effect profile, a riskier side effect profile.

If you compare that to deucravacitinib, which is a TYK2 inhibitor. Again, it is highly selective for TYK2. You can see on the chart here, its activity is against TYK2. Very little impact on JAK1, JAK3 and JAK2. It is highly selective for TYK2.

If you take a look over to the table on the left and you look at the TYK2 kinase signal, you can see its impact is directly on Th1, Th17 differentiation, which again, Th17 plays a paramount role in the development of psoriasis. If you are able to again functionally block TYK2, which is incredibly important for psoriasis, you are going to have disruption in the ability for those cytokines to drive psoriatic inflammation but you are not going to have any other off-target effects, which is why TYK2 inhibitors were developed.

They identified that if you inhibit TYK2 and you do it through the regulatory domain, which is what we call allosteric inhibition, you can basically stop the further activity without any off-target side effects.

[00:26:49]

Clinical Impact of JAK–STAT Selectivity

This is really just summarizing what I mentioned that the first-generation JAK inhibitors, pan-JAK, which is tofacitinib. You have a number of adverse events compared to your more selective JAK inhibitors and more selective TYK2 inhibitors. You have greater specificity, less side effects. We needed that pan-JAK to really learn from and drill down and get better therapeutics, very similar to when we just had TNF inhibitors. Then we learned more that it was really IL-23 and IL-17, Th17 axis, which was critical. Then we focused our therapies and our targets on that.

[00:27:35]

Patient Case 1: John, 56 Yr Old

We are going to get into our first case. This is John. He is 56 years old. He has a 14-year-history of plaque psoriasis. He has 15% body surface area affecting scalp, elbows and knees. He has previously used topical therapies but with little effect. He has not used them as frequently as prescribed. He has been getting adalimumab, which is a TNF inhibitor, for the past 2 years, and he has not missed a dose. He is understandably frustrated. He has a lot of psoriasis despite being on a TNF inhibitor. He would like to try a different therapy. He is asking us about oral options.

[00:28:11]

Case Discussion

What are some of the common patient preferences and concerns that we think about regarding psoriasis treatment, and which needs remain unmet for this population?

I ask my patient, “What are you looking for in a treatment for your psoriasis?” I want to know about adverse effects. I want to know how do they feel about needles? He has made it clear he is really interested in thinking about oral options. I want to know, and I am sure the patients want to know, how well does this work? What is the duration of the therapy in terms of how long does it work well for? These are all things we like to think about when we are thinking about switching patients to medications.

I would say, though, the most important thing that you really want to think about are comorbidities. You want to be thinking about comorbidities of your patient. Your patient is not going to be thinking about those, but you, as the clinician, need to be thinking about those.

Our patients are concerned about convenience and safety and how well it works. We need to make sure we are giving the right drug to the right patient.

[00:29:19]

Latest Safety and Efficacy Data: Oral Small Molecules for Psoriasis

In thinking about, okay, does this medication work and how well does it work, we are going to be looking at the latest efficacy and safety data when it comes to 2 of the small molecule inhibitors that are currently on the market.

[00:29:32]

Poll 3

Here is a polling question before we get started. What factors do you consider when determining if a patient is appropriate for oral small molecule therapy in the management of moderate to severe psoriasis? You can go ahead and type in your answer.

[00:30:02]

ESTEEM 1/2: Apremilast for Difficult to Treat Nail Psoriasis

Okay. Let us dig into the data. This is the ESTEEM 1 and 2 trials. This was with apremilast, also known as Otezla. With any medication that comes out now for psoriasis, because we have such a plethora of options, it behooves the pharmaceutical companies to look at what we call special site data. Because we know that patients who have scalp psoriasis, nail psoriasis, genital psoriasis, those patients have high impact sites. They may not have a large body surface area, but there is a huge impact on their quality of life. It is really important for us to be able to look at treatments and understand, okay, what works well for different areas.

What the ESTEEM trials did is they pulled also data on nail psoriasis and how well apremilast works for nail disease. They use something called the NAPSI, which is the Nail Psoriasis Severity Index, which is a measure of how severe nail disease is. You can see at both the short-term and the long-term in both ESTEEM 1 and 2, that apremilast did a really nice job at improving and reducing the nail severity index score. Apremilast is a nice option for patients with psoriatic nail disease.

Just a piece of information for you. Patients who have scalp psoriasis, nail psoriasis, and genital psoriasis are at greater risk for developing psoriatic arthritis. They have increased odds ratio of developing psoriatic arthritis. If you are caring for patients with psoriasis, which about 25% of patients with psoriasis get all of their dermatologic care from their primary care provider. Thank you for caring for our patients. It is important to know what to look for. Do not forget to look at the nails.

[00:31:58]

ESTEEM 1/2: Apremilast for Difficult to Treat Nail Psoriasis (cont’d)

Then what this shows, this is also in the same pivotal trial, ESTEEM 1 and 2. This really just highlights that the nail improvement really tracks with the skin improvement. As the PASI score improves, the nail disease also improve, which makes sense and is not a surprise here. PASI greater than 90 means more than 90% improvement in their psoriasis.

[00:32:27]

ESTEEM 1/2: Apremilast for Difficult to Treat Scalp Psoriasis

The other special site that these trials looked at was scalp psoriasis. You can see the gentleman on the right what his baseline score was. Then at 16 weeks, so 4 months later, a score of zero, meaning no psoriasis in his scalp.

I will say scalp is 1 of the more challenging types of psoriasis to treat, tends to be quite recalcitrant to treatment and has a significantly negative impact on quality of life for our patients.

Again, you see compared to placebo, very nice results at week 16. Relatively quick for scalp psoriasis for patients being treated with apremilast.

[00:33:11]

Apremilast Efficacy: A Real‑world Retrospective Study

Then in terms of efficacy, what this is essentially looking at is anything that is plotting to the right of the midline, it means they are more likely to achieve that particular outcome, whether it is a BSA of less than or equal to 1% at 6 months, all the way down to PASI 75 at 12 months. This is compared to topical therapy.

What this really highlights here is topical therapy as monotherapy is okay maybe for a patient with 1% body surface area like on their back or something very, very limited disease and not necessarily a high impact site. If you have someone with more than 3 palms worth of psoriasis, full body psoriasis, we are not using topicals as monotherapy. Of course, they can be used as adjunct therapy to either biologics or oral systemic agents, but really should not be used as monotherapy for high impact sites or severe disease.

[00:34:13]

POETYK PSO-1/2: Deucravacitinib (TYK2 Inhibitor) in Patients With Moderate to Severe Psoriasis

Let us change gears here to looking at the data behind deucravacitinib, which is a TYK2 inhibitor. The deucravacitinib pivotal trials were POETYK 1 and 2. This is looking again at 16-week and 24-week. This is looking at a skin clearance. We are looking at the PASI 75. What PASI 75 means is 75% improvement in their psoriasis at Week 16 and at Week 24.

You can see here the nice thing with the POETYK trial is that besides just comparing to placebo, it is an active comparator. It is a head-to-head trial. This was looking at deucravacitinib vs apremilast to see which medication was more efficacious at meeting the primary endpoint of a PASI 75 at either Week 16 and at Week 24. You can see in both POETYK 1 and 2, deucravacitinib was a clear winner.

[00:35:11]

Deucravacitinib (TYK2 Inhibitor) Impact on QoL in Patients With Moderate to Severe Psoriasis

It is no surprise that as we improve patient’s skin and reduce the burden of psoriatic skin lesions, their quality of life improves. We have something called the DLQI, which is the Dermatology Life Quality Index, which is a standard measure of quality of life impact. It goes from zero to 30, with 30 being the most impactful on the patient's daily living.

In a more recent NPF, National Psoriasis Foundation survey that was just done in 2024, about 40% to 50% of patients scored 27. So huge impact on quality of life. You can see here with deucravacitinib, standard dose is 6 mg twice a day. You can see that really nice increase in terms of as their PASI increases. If you look all the way here PASI 100 means the skin is clear and you have 80% of patients with DLQI score of zero or 1, meaning their disease is not impactful at all on their daily life vs very minimally impactful.

That is what we want to see. That is why we do what we do.

[00:36:28]

POETYK PSO-1/2: Deucravacitinib Safety

Safety. We always want to know about safety. Is what we are prescribing to our patients safe. From the deucravacitinib safety, the POETYK 1 and 2, we have deucravacitinib and then data on apremilast as well, and of course placebo. Really very, very clean data with definitely some side effects, but minimal serious adverse events. We will go a little bit into detail what we need to be worried about in terms of apremilast and in terms of deucravacitinib.

[00:37:06]

Short-term Efficacy of Targeted Therapies vs Placebo*

The next couple slides we are going to be looking at short-term efficacy vs long-term efficacy. A lot of colors on this slide. What is this? This is essentially a bar graph showing the estimated PASI response from weeks 10 to 16, so early short-term efficacy when it comes to non-biologic therapies and biologic therapies.

You can see non-biologic oral therapies here in orange. Then our newer biologic therapies like our IL-17 inhibitors and IL-23 inhibitors. You have our first-generation biologics which are TNF-inhibitors and our 1 IL-12/23 inhibitor, ustekinumab. Then our second-generation biologics, which again really focus on that IL-23, Th17 axis. You can see higher rates of efficacy in those medications. Again, they are more targeted, actually have fewer side effects and really great efficacy.

It is important to know that these are not head-to-head trials. This is essentially just taking the PASI 75 response scores from the package insert and plotting it on a graph.

[00:38:20]

Long-term Efficacy of Targeted Therapies vs Placebo

Then you see very similar results when it comes to long-term efficacy as well, again, with our IL-23 and IL-17 biologics really outperforming the others.

[00:38:38]

Safety Considerations With TYK2 and PDE-4 Inhibitors

When we think about prescribing an oral small molecule inhibitor, whether it be deucravacitinib, which is a TYK2 inhibitor, or apremilast, which is a phosphodiesterase-4 inhibitor, we absolutely have to be thinking about safety. It should be noted that TYK2 inhibitors do not have an FDA boxed warning, nor do PDE4 inhibitors.

TYK2, however, is in the JAK family. There is a warning on the package insert that you should be cautious in patients with cardiovascular risk, history of clots because JAK inhibition of JAK1 and JAK3 and JAK2, we can see venous thrombosis. We can see major adverse cardiac events. This is a caution, but it is not a black box or a boxed warning.

Things that I think about when I am talking to patients about deucravacitinib. I say, “Listen, upper respiratory tract infections, very common. You can also see increased herpes simplex, whether that be genital herpes or cold sore on the mouth.” So being aware of that. We see a lot of folliculitis and acne with deucravacitinib as well as with other JAK inhibitors.

There have been some reports of increased CPK, which has resolved with discontinuation of the medication, but that is quite rare. But it is recommended that you do check a baseline CPK and follow that up.

In terms of cautions and considerations, it does suppress the immune system. So you are not going to use it in the setting of active infection, and you are going to avoid live vaccines. There can be increased risk of certain cancers like lymphoma. Although it may not be in the package insert to routinely check a CBC, I, as part of my practice, am checking a baseline CBC as well as periodic CBCs and doing a review of systems to make sure patients are not having any symptoms of malignancy like night sweats, unintentional weight loss or whatnot.

When it comes to apremilast, this does not suppress the immune system. It is more of an immune modulator, if you will. You can get live vaccines on this medication. We do not see any issues with serious infections, but we do see a lot of GI side effects. This is very common. Diarrhea, nausea. Also see a lot of headaches in patients on apremilast. They can get some upper respiratory tract infections. Patients in the clinical trials, the main things they saw were nausea, diarrhea, unintentional weight loss of up to 10% of the patient's body weight. So asking patients about their weight as well.

They also saw mood changes in some patients. So increased thoughts of suicide or suicidal ideations. It is something that you do again want to be screening patients for. Again, that is another comorbidity that is associated with psoriasis, is increased rates of depression and anxiety. That should be a conversation that we are having with all of our psoriasis patients. That is in general some of the safety considerations that we think about before prescribing or while we are prescribing medications like deucravacitinib or apremilast.

[00:41:54]

Poll 4

We have a polling question. How would you counsel patients about the safety of TYK2 inhibitors for psoriasis?

1. TYK2 inhibitors require monthly CBCs for everyone;
2. We will screen for tuberculosis first and avoid TYK2 inhibitors in the case of an active infection;
3. Because there are no infection risks at all, you do not need to call for a fever or spreading redness; or
4. TYK2 inhibitors increase risk of cardiovascular events.

Great. In addition to testing for tuberculosis prior to starting a TYK2 inhibitor, I am screening patients. This is again not in the package insert. This is my personal practice to screen patients for HIV, hepatitis B and C, in order to make sure they do not have any underlying infections that I was not aware of.

[00:43:02]

Emerging Oral Small Molecule Therapies in Psoriasis

This is an exciting time to be a small molecule when it comes to treating psoriasis. There are a number. There are 4 drugs here and probably several others in the pipeline, 3 of them being TYK2 inhibitors, again, because of that functional selectivity on TYK2 and really reducing off-target effects. We have 3 TYK2 inhibitors that are in the pipeline.

Then there is actually an oral IL-23 inhibitor, with Johnson & Johnson, which should be coming out very soon. So all very exciting things and more options are always better. Because like I said, not 1 therapy fits all for every patient. It can be very nuanced based on their comorbidities, based on their preferences. Always nice to have more options to get more patients clear or almost clear.

[00:43:55]

Patient Case 2: Laura, 36 Yr Old

We are going to go into another patient case. This is Laura. She is 36. She reports intermittent psoriasis, mostly on the scalp, progressed her elbows and knees. She was diagnosed with psoriatic arthritis last year. She was on an IL-17 inhibitor without full response, and she started a different IL-17 inhibitor about a year ago. It initially worked and then lost response. Her recent lab results reveal anti-drug antibodies.

[00:44:22]

Case Discussion

What therapies would you consider for Laura? What are the pros and cons of using a TYK2 inhibitor that you would consider? What risk mitigation strategies might you use?

[00:44:37]

APP Considerations for Managing Patients on Oral Small Molecule Therapies

Patient Perspective: My Experience With Transitioning to Oral Small Molecule Therapy

Let us take a look at this. Let us talk about this patient, Monica, again in terms of her experience with transitioning to oral small molecule therapy.

Monica: As my disease progressed and the dermatologist prescribed me steroid ointments, at the time, I have had pretty good insurance and the insurance was covering. They did give me a couple of different samples of ointments to try, and then called in a prescription. The treatment did work. I mean, it helped. It did not take it completely away. Maybe helped with the itching. Of course, the skin got really dry, but I was able to use moisturizers and that helped.

I did that all through my teens. Then as I got older, got busy with work and my son just life, I got where I was not doing the ointments like I should and the psoriasis was flaring. I went back to the dermatologist, and at that point, they put me on an oral medication. Luckily, my insurance covered it, and I am trying to think maybe I had to have pre-authorization, but anyways, it did end up covering it and the oral medication was wonderful. It pretty much is stable. I do not have any problems right now. There is no itching.

I still use moisturizer every day. Sometimes twice a day. Take my medicine like I am supposed to and able to not think about it as much as I did when I was using the ointments when I was younger, it was something that was constantly on my mind. The oral medications have given me quite a bit more freedom as far as what I can wear and how I feel out in public.

It has been life-saving to me.

Veronica Richardson: Life-saving, life changing. These are words that we hear all the time in clinic when we hear patients and we see patients back who have had success with their treatments. Monica's story is a success story. We have a lot of those. We are very fortunate to have a lot of those because we have a lot of options for treatment.

[00:47:32]

Poll 5

Here is a poll. What barriers do you encounter in your practice when considering small molecule therapies for patients with psoriasis? Is it:

1. Insurance approval;
2. Patient adherence;
3. Adverse events;
4. Treatment cost; or
5. Complexity of dosing.

The other thing that Monica said, which I think really rings true for a lot of our patients, is that it gave her some freedom. Being on an oral therapy, for example, taking a pill, gave her some freedom. A lot of patients feel really tied and almost in jail with their topical medications. They are reminded every day, twice a day when they are using topicals because they are putting it on their psoriatic lesions that they have psoriasis.

In a way, when a patient is taking an oral medication, not that much of a reminder that they have the disease. There is not that tangible of touching the psoriatic lesions and having such a negative impact and a reminder on a day to day basis.

In terms of poll, these are absolutely barriers that we all encounter, whether it be insurance approval, adherence, adverse events, treatment costs and complexity of dosing. I would say oral therapies tend to be a little bit easier in terms dosing. Again, hearing from our patient what they like and what they do not like about their therapy, is very important because we are really partnering with them to get them to the place that they want to be.

[00:49:09]

Patient Candidacy for Oral Small Molecule Therapies

Who is a candidate for oral small molecule therapy? The way I think about it. One is they have to have failed topicals or they have too much disease for a topical medication. They have moderate to severe disease, at least 3% body surface area or they have involvement of special sites. We talked about face, scalp, nails, genitals, palms and soles.

Maybe they did not respond to prior topical treatment or phototherapy. The patients many times prefer oral medications over injectables.

The other thing I really want to highlight is knowing whether or not a patient has psoriatic arthritis, that really does impact your treatment choices and knowing what pattern of psoriatic arthritis that they have. Because different patterns of psoriatic arthritis whether it is axial disease vs peripheral disease might respond better to one therapy vs another. Do not forget to include if you are managing patients with psoriasis and you are thinking about starting a systemic therapy, whether it be an oral therapy or a biologic. And you know they have psoriatic arthritis or you are concerned they may have psoriatic arthritis, please make sure you are getting those patients into rheumatology, because different therapies have different efficacy levels when it comes to different types of psoriatic arthritis.

We really want to be treating as many domains as possible. If someone has psoriasis and psoriatic arthritis, we want to make sure their joints are best covered. Typically, the skin will follow in most instances. It is really important to not practice in a silo when it comes to patients with psoriasis, with psoriatic arthritis, and also patients with psoriasis that have inflammatory bowel disease.

[00:51:00]

Patient-Related Factors to Consider Regarding Oral Small Molecule Therapies

What are some of the patient-related factors that we should really be considering when we are talking about oral small molecule inhibitors?

What I think about are comorbidities, multiple medications, polypharmacy. Are there any drug-drug interactions with medications, for example, the older ones like methotrexate. We talked about end-organ toxicity like liver toxicity. In older adults, we can see renal toxicity as well. So really not a great option for older adults.

We are really trying to tailor these therapies to the patient that is in front of us. Then we know, as I mentioned, that psoriasis is associated with a number of comorbidities, especially cardiovascular disease. We want to make sure we are not using a therapy that could potentially enhance that cardiovascular risk.

[00:51:56]

Treatment-Related Factors to Consider Regarding Oral Small Molecule Therapies

When I think about treatment-related factors that I consider when I am thinking about putting a patient on an oral small molecule, I want to know if it works, and I want to know if it works for all of the domains. We just talked about, okay, I know what it does for their psoriasis. How does it work in psoriatic arthritis if they have psoriatic arthritis? Or what if they also have psoriasis and inflammatory bowel disease, which is also something that we can see very commonly due to shared immune pathways?

I may not reach for an oral small molecule inhibitor, because I may know that starting a patient on a biologic, with psoriasis and inflammatory bowel disease, they are actually going to have better control that way. I think about safety. Again, major adverse cardiac events, clot risk. In patients who have a history of clot, I may be choosing 1 therapy or another or avoiding 1 therapy because of potential risk of increased risk of clot.

Duration of response. The 1 thing that we have for biologics that we do not have with the newer oral small molecule therapies is really long-term data. We have a lot of long-term data with our biologic therapy. We see how well they work and how well they work over years. We do not have that same robust data when it comes to oral small molecule therapies. It does not mean we would not and it does to mean they do not necessarily work. But that is something we need to keep in mind when we are treating patients with psoriasis because we are treating them over the lifespan. This is a long-term chronic disease.

We may have periods of time where therapies lose their response and we need to think of what to do next. The way we decide on what to do next is how did they respond to that prior therapy, what class of drug did they respond to?

Then, of course, which many times is out of our control, is the cost of the medication and what medication is going to be covered by the patient's insurance? Many times there are hoops that need to be jumped through in order to get a medication that we want for a patient into the hands of the patient.

[00:54:00]

Patient Case 3: Payton, 25 Yr Old

Let us go to another case. This is a 25-year-old patient who has plaque psoriasis for the past 10 years. They were diagnosed at age 15. She has a thick silvery scales on the knees, scalp and elbows. She has a BSA, body surface area of 23%. Her primary care provider prescribed some dandruff shampoo, some moisturizers and a moderate potency topical steroid. She had little improvement with that. She has been taking an injectable biologic recently that is working well, but she has needle phobia, and she would really like to try and get off of the biologic.

She had like an oral option, but she is hesitant about older oral therapies due to safety concerns. Well, I think that is reasonable. I tend to avoid using methotrexate in general because I always ask myself, what is the endpoint? What is the end game with that? Eventually, they are going to need to get off of it. So it is not a great long term.

I also am not a fan of using it in women of childbearing potential. It is a therapy that is not absolutely not safe to take in the setting of pregnancy with really only 1 biologic being most studied in pregnancy, which is certolizumab.

The other point I want to make with about the older systemic agents is absolutely do not prescribe acitretin to any female of childbearing potential. That can stay in the system for 3 years after discontinuation of the drug, potentially longer if the individual drinks alcohol. It is a no-no. It is an absolute contraindication. Do not prescribe acitretin in any patient of childbearing potential.

[00:55:35]

Case Discussion

What I would say to Payton is, “Hey, what are you looking for in your treatment? Are you absolutely against a needle? If you want to do an oral therapy, let us talk about your 2 options. We have apremilast. We have deucravacitinib. Let us weigh the pros and cons of each. Which 1 sounds best to you? What is your risk appetite? What concerns do you have?”

That is how I approach that with patients. I often give them 2, maybe 3 options and go through the pros and cons with each of them.

[00:56:11]

Putting it All Together: Choosing Optimal Small Molecule Therapies

How do we put it all together? We know that oral small molecules have really expanded the treatment armamentarium. As we can see from that pipeline slide, we have 4 more oral medications coming down the pike. That toolbox is going to be further exploding with options.

We know TYK2 inhibitors are very selective and they target those key inflammatory cytokines like IL-23 and IL-12. They are preferred over those broader JAK inhibitors because they have less collateral damage and less severe side effects. For example, less impact on bone marrow, no issues with leukopenia or anemia.

When we are choosing an optimal small molecule therapy, we have to consider disease severity. We have to consider comorbidities. What other comorbid conditions do they have? what have they been treated with before? How did they respond to it and what are their preferences for their treatment?

[00:57:15]

Posttest 1

We are going to get into the post-test questions. A 35-year-old man with moderate to severe psoriasis failed methotrexate and phototherapy. You want to consider an oral selective TYK2 inhibitor. Which best explains the role of TYK2 inhibitors in the JAK-STAT pathway?

1. TYK2 inhibitors bind to ATP sites similar to other JAK inhibitors;
2. TYK2 inhibitors can be allosteric rather than ATP competitive, yielding functional selectivity;
3. TYK2 inhibitors pair with gamma C cytokines; or
4. TYK2 inhibitors act on the T-cells and neutrophils.

[00:58:02]

Posttest 1: Rationale

Excellent. 67% got the correct answer. TYK2 inhibitors can be allosteric rather than ATP competitive. Traditional JAK inhibitors that target JAK1, JAK2, JAK3, they compete for the ATP that active catalytic domain vs TYK2 inhibitors, they bind to the regulatory domain. They have this allosteric inhibition which creates this conformational change actually changes the structure of the protein to prevent any further downstream signaling.

[00:58:37]

Posttest 2

Post test question number 2. This is our 33-year-old woman with moderate to severe psoriasis. BSA of 16%, failed topical steroids and phototherapy. Did not tolerate apremilast due to weight loss and nausea. She declines injections. She had LFT abnormalities with methotrexate. Her blood pressure is borderline. She has normal kidney function and triglycerides. She wants to become pregnant in 6-12 months and travels frequently for work, preferring an oral medication. What do you recommend? Would you:

1. Restart methotrexate with folate;
2. Start cyclosporin;
3. Start acitretin; or
4. Start deucravacitinib.

This one, we were evenly split in the responses. Let us see how you all answer now.

[00:59:40]

Posttest 2

Great. Deucravacitinib is absolutely the best option out of these here. Restarting methotrexate. She previous had LFT abnormalities, I would not touch it again. Cyclosporin should be used on the order of weeks, not months and years. It should be used for rescue therapy only. Acitretin should never be used in a woman of childbearing potential. Absolutely not.

Deucravacitinib has great efficacy. It is safe. It has a relatively short half-life. We do not have pregnancy data on deucravacitinib. It is recommended that you stop in the setting of pregnancy, but it is absolutely contraindicated as it is with acitretin and methotrexate.

[01:00:31]

Posttest 3

Post-test 3. How confident are you now in your ability to personalize treatment plans for patients with moderate to severe psoriasis?

About 46% or 50% of us in the audience were not confident at all. Hopefully, we have seen that number go up even just a little bit.

Good. There are no longer non-confidence in the group. That is great. We have moved to somewhat confident, confident, a very confident person, which is great.

I will take maybe 1 or 2 questions if we have any, Tammy, if you think we can.

[01:01:35]

Poll 3

With our poll question 3 earlier on when you were asked to state which factors you consider when determining if a patient is appropriate for oral small molecule therapy. Some of the answers, comorbidities, excellent. Financial attitude and knowledge, compliance, risk factors, other conditions like pregnancy, comorbidities, history, cost.

Excellent. These are all the right things we want to be thinking about. Any other questions?

[01:02:20]

Go Online for More Coverage of Psoriasis!

Well, thank you all for joining this evening. I appreciate your time, your attention, and being here to learn a little bit more about psoriatic disease as well as management of patients with psoriasis with oral small molecule inhibitors.