Pearls in Psoriasis: Oral Small Molecules

In this episode, Dr Larry Green interviews Dr George Han about current and future oral small molecules for psoriasis.

Dr Han is the assistant medical director for dermatology at Mount Sinai Health System, assistant professor and chief of telederamtology for the department of dermatology at the Icahn School of Medicine at Mount Sinai in New York City.

Dr Green is the section editor of The Dermatologist's Psoriasis Center of Excellence and a clinical professor of dermatology at George Washington University in Washington, DC.

Transcript

Dr Larry Green: Hi, everyone. Welcome to another podcast. My name is Larry Green. I’m Section Editor of the Dermatology Psoriasis Center of Excellence and a Clinical Professor of Dermatology at George Washington University in Washington, DC.

I’m honored to have here with us on this podcast Dr George Han, who is the Assistant Medical Director for Dermatology at Mount Sinai Health System and the Assistant Professor and Chief of Teledermatology for the Department of Dermatology at the Icahn School Medicine at Mount Sinai in New York City, as well as current Vice President of the Dermatologic Society of Greater New York, and a member of the board of the National Psoriasis Foundation.

George, I think that means you’re next to be president of the Dermatologic Society of Greater New York, doesn’t it?

Dr George Han: Unless there’s a coup or military takeover. You never know.

Dr Green: That seems to be popular these days, so you never know. Keep it in the back of your mind. Anyway, today, we’ll be discussing the latest oral small molecule therapies for psoriasis, as well as new therapies in the pipeline.

We’ll talk about oral small molecules in psoriasis, and it’s an expanding field. That’s what we’re going to get into on this podcast. Let’s start with what oral small molecule therapies are available for psoriasis and also psoriatic arthritis.

Dr Han: Thank you for having me. It’s really exciting to talk about this subject, especially because of what’s coming in the pipeline. Certainly, we have a number of medications that we’ve used for a long time in terms of oral medications for psoriasis.

There’s methotrexate, cyclosporine, acitretin, apremilast, and tofacitinib. In Europe, they have fumaric acid esters, but certainly, we don’t have that here as of yet. There’s some concerns with progressive multifocal leukoencephalopathy, so might be a pretty big hindrance for that.

There’s a number of things on the market right now. We’ll get into the details, I think, in a little bit. Certainly, a couple of options. They all have their benefits, risks, and side effects, but a lot of options right now and the different ways that we can use them.

Dr Green: Yeah, so let’s talk about some of the older oral small molecules first, before we get into aprimelast, which is relatively new. The pros and cons of the available oral small molecules, and how the dermatologists will choose among them, and for what types of psoriasis. How do you break them down?

Dr Han: I think first, you have to think about just basically when you’re looking at the patient and thinking about what’s appropriate treatment for them, thinking about oral small molecule, versus an injectable or a topical therapy.

I think for somebody who needs a systemic, somebody who we think has moderate to severe psoriasis, candidate for systemic therapy or phototherapy, or perhaps psoriatic arthritis as well, people have this concept that injections have some kind of connection with aggressiveness, danger, or somewhat that’s a bigger step.

I think the truth is it’s just a matter of how the drug is delivered, based on what types of medication. Approaching drug like the biologics would never be stable in a pill formulation or ingested orally. When we think about the complexity of the medication, both in production and development, a small molecule drug is like a tricycle, and a monoclonal antibody is like a spaceship, basically.

It’s really different things we’re talking about. As a protein drug, you have to deal with the interactions. There are some advantages, really, to the small molecules. There’s more predictable drug distribution. It’s usually easier to taper on and off for a lot of the medications, due to shorter half-lives, and there’s no requirements for storage in terms of refrigeration, and the cost of production is a lot less.

A small molecule drug can be quickly discontinued if a patient needs an operation or has a reaction to a medication, rather than being around some of our biologics that have half-lives well over 20 days, and the drug will still stick around for quite some time.

I think, though, the biggest advantage of an oral small molecule is the fact that patients understand the concept better. They think, “I’m sick, or, “I have a medical issue,” and take a pill. It’s very straightforward. Then as soon as you mention injection, a lot of people just start shying away.

Very few patients come into me thinking, “OK, I have a skin problem. Let me get an injection.”

Dr Green: Yeah, that’s so true, when you think about it. Regardless of the true safety, a pill always seems safer than an injection to the patient, which as you just mentioned, isn’t necessarily the case. It doesn’t always work that way. It’s interesting how our brains are wired.

Let’s go back and talk about methotrexate and cyclosporine. How do you use those medications in this day and age, and for what type of patient would you use them?

Dr Han: Yeah, I think, when thinking about those older medications, there’s a lot of compromises. I think it’s important to understand them. If we’re going to start with methotrexate, it’s a good medication. We have to keep in mind it’s actually not approved for psoriatic arthritis. It hasn’t been shown to inhibit progression of joint disease.

Other drawbacks, it shouldn’t be used in women who may get pregnant. It should be avoided with heavy alcohol intake, has been linked to liver fibrosis, of course. That’s an interesting point. The liver issues with methotrexate are a subject of considerable disagreement.

It’s clear that methotrexate can cause toxicity to the liver, leading to elevated liver enzymes in a significant way. It’s been estimated in a couple of studies around 15% of patients will get actually over a double, twofold increase of the upper limit of normal in liver enzymes, so something we keep an eye on.

The result of that is a little less clear. What does that really mean in the long time? We think about these things like liver fibrosis, but overall risk seems to be fairly low. I know that the rheumatologists take a fairly cavalier attitude towards methotrexate.

I think, in general, for dermatology, we’re a bit more cautious with it, especially when we consider that there are a lot of comorbid conditions that we might be dealing with -- fatty liver disease, alcoholism -- that could contribute to these liver issues as well.

I think we generally think of psoriasis patients at risk, especially after reaching a cumulative dose above three or four grams, and further studies have proven. In the old days, we had the liver biopsy. Now, we have noninvasive techniques, like the FibroScan, or a vibration-controlled transient elastography.

To put it into perspective, I think compared to other choices we have nowadays for systemic treatment of psoriasis, at least in my practice, methotrexate has largely been supplanted by other medications.

I think, in terms of where it has a definitive role, is more when a patient who’s a secondary non-responder, or a serial secondary non-responder -- so somebody who improves on a biologic, but consistently starts developing issues or having recurrence of it, somewhere between six months to two years later.

I have some patients who do this over and over and over again. If we hypothesize that antibody formation is the reason for this, low-dose methotrexate has been shown to help prevent that antibody formation. That’s one way that can be used in conjunction for somebody who just needs a little extra coverage, for whatever reason.

That might be a role, but there’s other medicines that are also better for that, I think. Switching over to cyclosporine, I think it’s nice, because it works quickly, and it has been for a long time our treatment of choice for patients who really need to get clear fast.

It works rather well for subtypes of psoriasis, which is good. It’s pretty consistent in treating guttate, generalized pustular psoriasis, palmoplantar psoriasis, we’d reach for cyclosporine, but the kidney toxicity is considerable.

There’s lab monitoring that’s necessary, and obviously, we can’t really keep patients on this for very long, for longer than a year or so. It’s good when you need a bridge to something else, or somebody’s coming in, and you have a hospital consult, or who may need erythrodermic, that you need to just something started on right away.

But taken alone, I don’t find it terribly useful. It’s a bridge to nowhere in that sense. If you build a bridge to somewhere, then it can be helpful, but maybe not so much. Nowadays, cyclosporine really doesn’t have much of a role, because for the speed, you have biologics that work very fast, and it’s not a long-term treatment, either.

There just really isn’t as much use for it, except when you really just can’t get a biologic, say, for somebody who’s erythrodermic, and you just really need to put them on something quickly. Acitretin, on the other hand, is still used with some frequency.

I like that it’s a free add-on, in some ways, because there’s really no immunosuppression with it. Actually, you get the benefit of chemoprevention for non-melanoma skin cancers, so on that front, it’s quite nice. It’s very good for pustular psoriasis and palmoplantar pustulosis.

It’s a little faster for those two conditions, usually, than for general plaque psoriasis. We often have to wait several months for good effects, so that’s one of the downsides, really. It’s a great adjuvant therapy when you need a little extra efficacy, though it doesn’t work on the joints at all, so that’s important to keep in mind.

You really shouldn’t use it at all in women in child-bearing age or with alcohol intake, as it forms a metabolite, etretinate, that can stay in the system for years. I’ve usually reached for acitretin in older patients, especially for those who can’t get on a biologic for reimbursement issues.

Side effects, including liver function abnormalities, hair loss, and just general dryness, can be significant. Sometimes, we’re not able to push the dose as much as we’d like for that reason, but it definitely has a place in our treatment armamentarium, I believe.

Dr Green: Thanks, George. It’s all really interesting going through the oral small molecules, pretty much before 2010. Let’s talk about some of the new oral small molecules, specifically apremilast and tofacitinib. Let’s start with apremilast, and also talk about the difference between them, how you would select one or the other, and how you position them and the risks versus benefits to them.

I’ll go ahead and let you take over.

Dr Han: Apremilast, oh, boy, apremilast. The idea certainly is nice. There’s a medication that affects phosphodiesterase-4, and it inhibits Th1 and Th17 interference. Sounds really nice. Seems to be relatively safe in patients with a prior history of malignancy or immunosuppression, but the efficacy really leaves a lot to be desired.

The PASI-75 members in the pivotal trials were around 30%, so if you’re counting on apremilast to do any kind of real heavy lifting in treating plaque psoriasis, it’s a setup for disappointment. I think it does have a role.

The areas where I stick to it nowadays, and it has real wins for, are in scalp psoriasis, so patients with scalp psoriasis, or even just really severe, if you believe in it, sebopsoriasis. It seems to work better, above its weight class for that.

Palmoplantar psoriasis as well, a good treatment for that, and to some degree, guttate psoriasis as well. For these specific forms of psoriasis, I think it works better than it does for the rest of the body, so that’s one area where we might reach for it.

It makes a nice option as an additive treatment, so what’s good is that so far, it doesn’t seem to really any add any significant degree of immunosuppression, so we’re able to add apremilast onto a biologic. If you have somebody that they’re pretty happy, they need a little efficacy additionally either on the skin of the joints or both.

You may be able to add apremilast without subjecting the patient to many more risks. That being said, these days, honestly, for the most part, I’m more likely to switch the patient to a different biologic that’s already available, rather than adding any kind of second agent to get a little more clearance.

For me, unless a patient really is just so, so wary of getting an injection, or maybe they don’t just have much psoriasis, but they still need a systemic treatment, especially if they have involvement of the hands that interferes with their activities of daily living, I’m more liable to guide them towards to a biologic. Certainly, some of those patients are reasonable candidates to try with apremilast first.

Dr Green: Yeah, if I can add, it’s interesting, George, you mentioned on apremilast and scalp psoriasis. I’ll just tell everyone some anecdotal experience I’ve had apremilast in the scalp. For people who have primarily scalp psoriasis who may not be severe enough for a biologic, I’ve had success with PBMs getting apremilast for that patient.

Because a lot of times, they want methotrexate failure come to having moderate to severe psoriasis before something like apremilast, or even a biologic, but there is no good data showing methotrexate works well in scalp psoriasis.

We have good data showing that, like you mentioned, apremilast does work well, so that like you mentioned with scalp psoriasis, I think it does have utility there and it certainly plays. I’ve had success getting it approved through PBMs and through step therapy.

Dr Han: Right, for sure, that SPOUSE study was really helpful in really delineating that efficacy there.

Dr Green: Right. Let’s move onto tofacitinib, which is something we as dermatologists aren’t quite as familiar with this medication. Why don’t you enlighten us and tell us a little bit how you use it and your experience with it?

Dr Han: Yeah, certainly, [laughs] we reach for it less, because it’s approved only for psoriatic arthritis, not for plaque psoriasis. Its efficacy seems to be pretty similar if you’re just trying to draw comparisons across trials. Pretty similar to adalimumab for psoriatic arthritis, at least, so it actually works pretty well.

We do have some limited data on skin psoriasis. The PASI-75 numbers for the approved dose were around 40%. At higher dosing, it can be more effective. Doubling the dose pushed the the PASI to clearance up 20% to 60%, but it comes with a higher incidence of side effects.

Really, that just encapsulates, I think, to me, the idea of JAK inhibition, especially pan-JAK inhibition. You start thinking about all of these other effects on the immune system, as well as things like getting blood clots, anemia, lipidemia, GI perforations, not to mention the warning mentioning lymphoma.

We don’t want to get too much into the weeds with JAK inhibitors on this podcast, I think, but that suffice it to say that these are good examples of drugs with relatively narrow therapeutic windows. I don’t think it’s wise to push the dose and inhibition of these pathways too much.

For the patient who has bad psoriatic arthritis who that outweighs the skin complaints, if they do end up seeing a dermatologist for that, I think it’s certainly a reasonable option if they really just want an oral medication, and they go into it understanding the risks and benefits.

But other than that, I don’t think it’s going to be first on anyone’s list for treatment of our patients that we primarily manage in dermatology, but for the patients with severe joint disease, where they just are so resistant to going on injectable, maybe that might be something to introduce the idea of.

Dr Green: Thanks, George. That’s a good bridge, tofacitinib, to talk about some of the new therapeutic options in the pipeline that maybe we’ll be seeing in the next year or two, dermatologists. What oral options would you like to talk about that are in the pipeline that can certainly help us?

Dr Han: I think the most exciting medication that everybody’s talking about, of course, is deucravacitinib. This used to be known as BMS 986165. It finally got named recently, yay, but it’s an oral small molecule that targets Tyk2.

Tyk2, T-Y-K-2, is somewhat related to the JAK inhibitors, but the nice thing about Tyk2 and inhibition of Tyk2 specifically, is that it seems to have a much cleaner side effect profile. If you think about the whole JAK/STAT signaling pathway, you start to get into those issues that we mentioned earlier with tofacitinib.

You start talking about the effects on the hemoglobin, the white blood cells, and the blood clotting. You really avoid a lot of those by just targeting Tyk2 by itself, which is nice. That being said, when we’ve looked at patients with deficiency of Tyk2, there were some issues, some issues with getting infections.

Some patients, for example, got the disseminated BCG infection when they got the BCG shot and other infectious issues. Now, I would keep in mind that, when we’re using a small molecule, we’re not going to be approaching those levels of suppression of Tyk2, but it is important to, again, think about the therapeutic window here.

The good thing, I think, that at least is from the early studies, it seems that we aren’t seeing much of that, any major issues in terms of immunosuppression with the doses of the Tyk2 inhibitors that seem to be effective for treating psoriasis.

Specifically, when you look at deucravacitinib, there was a bunch of papers looking at the selectivity for Tyk2, and it seems to be very good on that front. In terms of the phase II trials for efficacy, there were over 250 patients who entered these trials, and the patients on the higher doses got up to over 70% PASI-75 reduction.

If we compare, if we think back to apremilast at around 30%, most of the other oral medications top out at around 40 to 50%. This is a pretty big step up from that. PASI-75 of 75% puts it squarely in the neighborhood of a biologic.

Certainly, probably an older class of biologic, something like adalimumab, but nonetheless, this is much better than anything we’ve ever seen from an oral small molecule. Adverse events were reported in varying degrees.

Certainly, in the treatment group, it tended to be several percent higher. It was usually things that you might think that you would find with any of our treatments for psoriasis. Some cases of nasopharyngitis, some cases of headache, a few cases of diarrhea in the highest dose, but that didn’t seem to be too consistent.

So we’ll to see what the phase III trials show in terms of the GI side effects, but hopefully, that’s not something as consistent or as bothersome as we certainly saw with apremilast. The interesting thing that came out of the deucravacitinib trials is that there were some cases of mild to moderate acne seen in the active treatment groups.

It did seem to be definitely higher than placebo, and it did seem to be some degree related to the dose. It’s not really clear why that is. Certainly, you think about the subtle changes in the skin microbiome might be leading to some mild acne, but it remains to be seen how that plays out in the larger phase III trials.

Basically, I would summarize that as saying it seems to be pretty effective, with good numbers of PASI clearance, with very little trade-off in terms of any side effects that you’d be worried about. I think a couple of hurdles still remain.

Of course, that phase III trial. We want to make sure that A, the efficacy holds up. B, there’s no new safety signals, and I think the third part that we should also think about is what the label’s going to look like.

Certainly, I think that the FDA has been rather conservative with their approach towards JAK inhibitors in terms of dosing, in terms of labeling. I can’t see that it’s really logical to put on a class statement regarding issues that we have with JAK inhibitors onto this drug, but I guess you never know.

Hopefully, reason will win out, and they’ll go with the data, but the data looks pretty good, I would say.

Dr Green: That’s really interesting, George. Thanks for that really great summary about deucravacitinib. We don’t have the phase III, but like you said, it seems like we may have our first oral option with real good efficacy compared to the biologics, which we don’t see with other oral small molecules like methotrexate or apremilast.

George, what about the future beyond deucravacitinib? Any other oral small molecules you would like to mention?

Dr Han: Yeah, there’s a couple in the pipeline that I think are worth calling out. There’s another Tyk2 inhibitor made by Pfizer that went through a phase II trial as well. Seems to look pretty similar to deucravacitinib, so we’ll see if that ends up getting further development.

The other one that I think probably is the most interesting one is ponesimod. It’s S1P1 or sphingosine-1-phosphate receptor 1 immunomodulator. The sphingolipid seems to modulate a wide variety of functions by G-protein-coupled receptors.

With regards to psoriasis, it seems to act on the initial step of lymphocyte activation, so that’s, I think conceptually, the really interesting thing about it. Rather than target that canonical IL-23, Th18, IL-17, and TNF-α pathway, it goes to that first lymphocyte activation.

It seems to leave the innate immune system alone, more or less. The immunosuppression is less of an issue. The interesting about this, it also modulates heart rate. An important side effect, especially early on in treatment, is bradycardia and the possibility of arrhythmia.

We’ll see if it’s safe and effective in phase III trials, but the phase II data shows the PASI-75 in about half of the patients. A couple other ones, some other JAK1 inhibitors, filgotinib and upadacitinib are being studied for psoriatic arthritis, so we’ll see how that pans out.

That’s about it. There was something being studied for the pruritis of psoriasis, but that doesn’t look like it’s going to really play out very well, the neurokinin receptor, serlopitant. I think that about wraps it up. We got a couple of really interesting things that are going to come out that really, I think, have a good role in our armamentarium.

Dr Green: Yeah, it sounds like the future for oral small molecules is quite interesting, and you never know what’s going to play out. Even for the near future, we know about deucravacitinib and its potential to change our thoughts about oral small molecules to be more effective for moderate to severe psoriasis than we currently are used to having.

Anything in conclusion you’d like to add? You’ve given us such a great summary of the past, the present, and the future.

Dr Han: Thank you. I’m just excited to think that soon we’re going to have numerous new agents available for the treatment of psoriasis and small molecules available orally. Our standards, really, for psoriasis treatments have increased over the years in terms of both risk tolerance and clearance.

These new molecules are going to be held to a higher standard of both safety and efficacy, but a number of them do have a pretty good chance of satisfying those expectations and really surpassing them. I’m looking forward to seeing more data and getting these new treatments into our hands.

Dr Green: Thank you. Thanks, George. Thanks, Dr Han, and thank all of you for listening. Don’t forget to submit any comments or questions in the feedback box below. We really appreciate that, and we thank you for listening to the podcast.