Immune thrombocytopenia, or ITP, is an autoimmune disorder where the immune system attacks platelets, resulting in thrombocytopenia with a platelet count of less than 100,000. There is no gold standard test for diagnosing ITP, so it remains a diagnosis of exclusion. The diagnostic workup is really about excluding other potential causes of thrombocytopenia.

The major symptom that, of course, we think about is increased risk of bleeding. That risk is very heterogeneous, with some patients presenting with severe or life-threatening bleeding, and others having minimal bleeding or no bleeding at all.

ITP can be primary, that is occur in isolation, or it can occur secondary to a predisposing condition. If you look at the pie chart here, you will see that about 80% or so of cases are primary, and the other 20% are secondary. They can be secondary to a variety of conditions, broader autoimmune diseases like lupus, antiphospholipid syndrome, Evans syndrome, immune deficiencies like common variable immune deficiency, lymphoproliferative disorders like CLL, infections like HIV and hepatitis C.

ITP: Epidemiology

This is one slide on the epidemiology of ITP. Depending on when you did your training, you might have learned that ITP was predominantly a disorder of young women. It turns out that it is more complicated than that. This is a slide that shows you the incidence of ITP per 100,000 person-years over the lifespan. The blue bars are males. The orange bars are females. What you can see is that there is a bimodal distribution or two peaks. There is a peak in early childhood between ages one to five, and then a peak in the elderly patients greater than 75 years old.

Interestingly, for both of those peaks, ITP is more common in males than females. On the other hand, it does occur at all ages. If you do look at young adults, you will see that ITP is more common in women than men at those ages. The annual incidence of ITP in adults is estimated to be 1.6 to 3.9 cases per 100,000 person-years.

ITP Pathophysiology: Antibody-Mediated Platelet Clearance

What about the pathophysiology of ITP? We have long recognized that ITP is a disorder of accelerated platelet clearance due to antiplatelet autoantibodies. The person who first showed this was William Harrington, when he did these famous, or infamous, experiments in Washington University in the 1950s, where he and his colleagues withdrew blood from a patient with ITP and injected it into themselves.

You can see what happened to their platelet count in this figure. The platelet count fell. There was something in the patient's blood that was causing the platelet counts to be cleared or destroyed. We now know that those were antiplatelet autoantibodies. Fortunately, everybody who received this patient blood, their platelet count ultimately recovered, but you could never get away with doing an experiment like this today, certainly.

ITP Pathophysiology: Impaired Platelet Production

We now know that ITP pathophysiology is more complex than just antibody-mediated platelet clearance. It turns out that platelet production is also impaired in ITP. The reason for that is that many of the same antigens that are on the surface of mature platelets are also on megakaryocytes. These antiplatelet antibodies and anti-autoactive T lymphocytes not only affect mature platelets, but they also bind to megakaryocytes. They cause megakaryocyte apoptosis and thus impaired platelet production. ITP is a disease of both impaired platelet production and accelerated platelet clearance.

More Than a Bleeding Disorder: Impact on QoL

We talked about bleeding being the primary symptom of ITP. But ITP is more than a bleeding disorder. It has a profound impact on quality of life. This was really underscored by the ITP World Impact or I-WISh Survey. This is a survey that was taken by about 1,500 patients with ITP from 13 countries around the world.

What you can see from this figure here that a very substantial percentage of patients reported that ITP impacted in a negative way their energy levels, their capacity to exercise, their ability to undertake daily tasks, their work life or their school life, their ability to enjoy hobbies, their social life, their sex life. So, ITP, far more than a bleeding disorder, has far reaching effects on a patient's quality of life.

Fatigue

Probably the most prominent symptom that impacts quality of life in ITP, is not bleeding, it is actually fatigue. This figure also comes from the I-WISh Survey. On the y-axis, we have the percentage of patients reporting a certain sign or symptom. You can see a higher percentage, 50% reported fatigue more than any other sign or symptom, including bleeding or bruising.

Then on the x-axis we have, of the patients who reported that symptom, the percentage that reported it as being severe. You can see that about two-thirds of the patients who reported fatigue reported it as a severe symptom with a dramatic impact on their quality of life.

Mechanism of Fatigue in ITP

Why do patients with ITP have so much fatigue? I think we do not have a full understanding of that question, but it is probably multifactorial. Some patients restrict their activity, perhaps due to fear of bleeding, and as a result, they become deconditioned. Depression is not uncommon in patients with ITP. Patients with ITP may have bleeding and, as a result, iron deficiency and anemia, which can contribute to fatigue. They may be on medications like steroids, which can disturb their sleep and contribute to fatigue. They may have psychosocial stressors, co-morbidities like hypothyroidism that can contribute to fatigue.

Finally, ITP ultimately is an inflammatory disorder. Inflammation makes us feel like we want to stay in bed. We have all had this feeling, for example, when we have the flu. That is called sickness behavior. That probably also contributes to the fatigue experienced by ITP patients.

Improving Fatigue Is a Priority for Patients With ITP

It turns out that not only is fatigue common in patients with ITP, but making it better is a priority. Here again, our data from the I-WISh Survey, where patients were asked about their most important treatment goals. You can see that third one on the list, increasing my energy levels. 41% of patients in the survey listed that among their top three goals, and 20%, one-fifth, listed it as their main goal, even over reducing bleeding or improving platelet counts.

ITP Life Quality Index (ILQI)

How can we measure fatigue? How can we measure quality of life impact in our patients with ITP? There are various validated tools available. One such tool is called the ITP Life Quality Index or ILQI, and this is a 10 question questionnaire where patients are asked to provide answers based on their experience over the last month. You can see the questions are things like, how often has your ITP impacted your work life or your school life? Never, sometimes, more than half the time, all the time. How often have you taken off time from work? How often has your ITP impacted your ability to concentrate? How often has it impacted your social life, your sex life, etc.? This is a very simple tool that patients can respond to that can give you a sense about how the ITP is impacting their quality of life.

Posttest 4

We will come back to one of our pretest questions, but now it is a posttest question. Approximately what proportion of patients with chronic ITP report fatigue as a symptom of their disease and may therefore benefit from evaluation using available fatigue assessment tools?

I will give you a moment to key in your answer here.

The correct answer here is 50%. As I showed you, we learned from the I-WISh Survey that 50% of patients with chronic ITP report fatigue as a symptom. Actually, that is the most common symptom reported among patients with ITP.

Conventional Treatment Paradigm for Primary ITP in Adults

Let us talk a little bit about treatment. The main goal of treatment is not to normalize the platelet count in ITP, but to achieve and maintain a hemostatic platelet count, which for most patients and situations, is a platelet count of greater than 20 to 30, while at the same time minimizing side effects from treatment.

A secondary goal, of course, is to improve things like fatigue and quality of life. If the patient's platelet count is above 50, treatment is rarely required, they can just be observed. On the other hand, if the platelet count is less than 30, most of the time they are going to need treatment. First-line treatment is with corticosteroids supplemented as needed with IVIG or anti-D.

Many patients, most patients, will have a good response to first-line treatment, and some of them will be able to maintain that response even after first line therapy is tapered off, and in those patients, we just observe. Most patients will either not respond to first-line treatment or they will respond, but then they will relapse after the first line treatment is tapered off. Those patients are candidates for second-line treatment. The typical second-line treatments are thrombopoietin receptor agonists and rituximab. More recently, fostamatinib and rilzabrutinib have been added to this list.

It is the relatively rare patient who does not respond to any second-line treatments or cannot tolerate those second-line treatments. In those folks, we need to move to third line or salvage therapies. Examples of such treatments include immunosuppressive agents like azathioprine, cyclosporine, danazol, dapsone, mycophenolate, mofetil. Sometimes in these patients, we will use combination therapy, combinations of second-line drugs. Then splenectomy is also an important option. We traditionally considered splenectomy as second-line therapy, but with the availability of more and better medical therapies, we now tend to use splenectomy later in the disease course in more refractory patients.

Recommendation

This is a recommendation from the ASH guidelines, ITP guidelines, surrounding first-line therapy with steroids, and it reads as follows: In adults with newly diagnosed ITP requiring corticosteroids, the ASH guideline panel suggests either prednisone 0.5 to 2 mg/kg per day, or dexamethasone 40 mg a day for four days for initial therapy. This is a conditional recommendation based on very low certainty in the evidence of effects.

There is an important remark that comes with this, and that is that if rapidity of platelet count response is important, dexamethasone may be preferred over prednisone. Why is that? ITP:

Response Rates With Dexamethasone vs Prednisone

Here are data from a systematic review and meta-analysis comparing response rates with prednisone and high-dose dexamethasone at seven days and at one month. What you can see is that response rates at seven days were higher in the dexamethasone group, 73.2% versus 55.8% for prednisone. By the time you got to one month, the response rates were essentially equal. That is why, if you need a rapid response, you might prefer high-dose dexamethasone.

ITP: The Folly of Steroids

I want to talk now about what I see as the folly of steroids in ITP. Steroids represent a very important rescue therapy or first-line therapy for patients with ITP. There is a certain folly to their use. What do by that?

Take a look at the figure on the left side. This represents a study of patients with newly diagnosed ITP treated with steroids. On the y-axis, we see the probability of a first remission, and the orange line represents complete plus partial responses. The blue line complete response. You can see that the vast majority of patients, about 86% of patients, will achieve a response with steroids. That is the good news.

The bad news is that those responses tend not to be sustained. We cannot keep people on steroids forever, and so we need to taper them off. What happens when we taper them off? Most of them relapse. That is what is shown on the right side of the figure. Here we have data from a study of newly diagnosed patients with ITP who responded to steroids. What happened? As the steroids were tapered off, they relapsed. The 10-year relapse-free survival rate was only 13%. The vast majority of patients respond to steroids, but then the vast majority relapse when the steroids are tapered off.

If you squint your eyes and imagine these two curves together, it is almost like we are putting the patient on a roller coaster with steroids. We bring their platelet count up, but then we taper it, and their platelet count falls back down.

Steroids Are Toxic

That roller coaster is a toxic roller coaster. Steroids have tons of nasty side effects, you know this. Our patients hate steroids. This is a figure from a survey. It is an older study where patients were asked about side effects from their ITP treatments. The orange bars represent the percentage of patients who reported at least one side effect, the blue bars represent the percentage of patients who said they were highly bothered by a side effect, and the black bars represent the percentage of patients who said they needed to stop or reduce a treatment due to side effects. Those percentages were higher with corticosteroids than they were with any of the other ITP treatments that the patients asked about. Again, the folly of steroids. We bring the platelet count up, but then we taper steroids, and the platelet count falls, and all the while we expose the patients to these nasty side effects.

Duration of First-line Corticosteroids

One of the ways that we can minimize these side effects is by limiting the duration of exposure to steroids. Here is the corresponding recommendation from the ITP ASH guidelines. In adults with newly diagnosed ITP, ASH guideline panel recommends a short course, that is, that no more than six weeks of prednisone, rather than a prolonged course. This is a strong recommendation based on very low certainty evidence.

An important remark that comes with this is the justification. There is no evidence for a benefit with a longer duration of steroids, and there is a high-quality indirect evidence for cumulative toxicity with the use of longer courses of steroids. A corticosteroid duration of six weeks represents a reasonable duration to provide a standard maximum 21 days of treatment, plus additional time for the taper.

Second-line Therapies for ITP

What do we do when our patients relapse after we taper their steroids or they do not respond to steroids? Then we have to go to second-line therapy. Here are the key players in terms of second-line therapy. Rituximab, which of course is an anti-CD20 monoclonal antibody, so it depletes B lymphocytes and inhibits autoantibody production. We have fostamatinib and splenectomy again, now more conventionally considered a salvage therapy. These are treatments that inhibit antibody-mediated clearance of antibody-coated platelets. Then, finally, there are thrombopoietin receptor agonists, which stimulate the bone marrow to make more platelets.

Let us take a look at each of these treatment options one by one.

Rituximab

We will start with rituximab. Many of you have extensive experience prescribing rituximab. You know that it is a pretty well-tolerated drug, but patients can experience infusion reactions. Other side effects include serum sickness. There is a small increase of infection risk, including reactivation of hepatitis B. There is also a risk of hypogammaglobulinemia, and patients who receive rituximab have a blunted response to immunizations for the next six to 12 months.

One of the limitations of rituximab is that it work right away. The median time to response in ITP is about six weeks, and so patients often need to be bridged with steroids or some other treatment while you are waiting for the rituximab to work. Another limitation of rituximab is that the long-term response rates are relatively modest. Overall, about 60% of patients will respond to rituximab, but people tend to lose those responses. By 12 months, the response rate is down to about 40%, and by five years it is down to about 20%.

Splenectomy

What about splenectomy? This is the oldest treatment that we have for ITP, and it is highly effective. Based on older studies, we know that about 70% of patients will have a complete response with normalization of their platelet count. I do want to point out, though, that those older studies, splenectomy was used earlier on in the disease course and less refractory patients. Now that we are using it later on in more refractory patients, the response rates with contemporary use may be somewhat lower.

One of the frustrating things about splenectomy is that we are not great at predicting who will respond and who will not. We do know that younger patients have an increased potential for response. Then, also individuals who have what is called a splenic sequestration pattern on a nuclear medicine study called indium labelled autologous platelet scanning.

Splenectomy, of course, has important side effects. There is a lifelong increased risk of infection and overwhelming sepsis, which we can mitigate with vaccination and antibiotic prophylaxis. There is also a modest, lifelong increased risk of thrombosis.

We prefer, when possible, to avoid splenectomy in the first year after diagnosis, because if the patient is going to have a spontaneous remission, it is most likely to occur in that first year, and it would seem a shame to remove the spleen of somebody who is destined to remit anyway.

Thrombopoietin Receptor Agonists (TPO-RAs)

What about the thrombopoietin receptor agonists? There are three FDA-approved options. Romiplostim, which is given as a weekly subcu injection, and eltrombopag and avatrombopag, which are daily oral medications. These drugs have durable response rates anywhere between 50% and 90%.

Patients tend to respond fairly quickly, usually within one to two weeks of starting the drug. Interestingly, patients who do not respond to one thrombopoietin receptor agonist may respond to another. This was underscored by a study of switching to avatrombopag. This was a study of 44 patients who switched from either eltrombopag or romiplostim to avatrombopag, and if you look in the table here, under the total population column, you will see that 93% of these patients achieved a platelet count of 50 or higher, and 86% of 100 or higher after switching to avatrombopag.

If you look at just the subgroup of 14 patients who switched because of lack of effectiveness with romiplostim or eltrombopag, even there, a substantial fraction of patients responded when switching to avatrombopag. The lesson here is, just because you do not respond to one TPO-RA, does not mean that you will not respond to the whole class, so it can be worth trying another member of the class.

Limitations of TPO-RAs

Now TPO-RAs do have some important limitations. There are challenges with administration. Eltrombopag has some dietary restrictions. It needs to be taken several hours removed from polyvalent cations in order to maximize absorption. A small percentage of patients will also experience liver toxicity. Romiplostim can be inconvenient for patients because, again, it is a weekly subcu injection that needs to be administered in a physician's office. Avatrombopag overcomes some of these convenience issues. It is an oral agent that have the same dietary restrictions of eltrombopag.

These drugs are expensive, and for most patients, they are not curative therapy, they are chronic therapy. However, there is pretty good evidence now that about a third of patients who respond to a TPO-RA will ultimately be able to discontinue the drug and maintain a safe platelet count off all treatment. We do not know yet whether it is the TPO-RAs that are inducing those treatment-free responses, or whether that is just the natural history of ITP.

ASH 2019 Guidelines for Immune Thrombocytopenia

How do you choose among these really disparate second-line treatment options, which have their own pros and cons? Here is a nice figure from the ASH ITP guidelines that considered second-line treatment options with TPO-RA, rituximab, and splenectomy.

The first thing to do when you are thinking about what treatment to recommend to your patient is assess the duration of ITP. If the patient has that ITP for less than 12 months we prefer to avoid splenectomy. The primary treatment options, that is these orange boxes on the left side, are rituximab and thrombopoietin receptor agonists.

The next thing to do is assess the patient's values and preferences. If the patient places a high value on achieving a durable response, you might want to go with a TPO-RA, because they have better long-term response rates than rituximab. On the other hand, if the patient places a high value on avoiding long-term medication, then rituximab may be preferred.

If the patient has had ITP for more than 12 months, then the options include not only rituximab and thrombopoietin receptor agonists, but also splenectomy. You can see the figure on the right side in blue, showing again how you use patient values and preferences to help your patient arrive at a decision that best aligns with their treatment goals.

Fostamatinib

Fostamatinib is a newcomer to this second-line treatment options. It is an oral inhibitor of an enzyme called splenic tyrosine kinase. It was studied in two Phase 3 randomized controlled trials, which collectively enrolled 150 subjects. The overall response rate in these trials was 43% in the fostamatinib group versus 14% in the placebo group. You may say, well, 43%, that is not a very impressive response rate, I would agree, but it is important to realize that many of the patients in this trial were quite refractory, heavily pre-treated patients.

If we looked at just the subgroup of 32 patients for whom fostamatinib was truly second-line therapy, meaning all that they had previously had was first-line therapy with steroids. In that particular subgroup, the response rate to fostamatinib was quite high at 78%.

The most common adverse effects with fostamatinib are diarrhea, hypertension, so you need to monitor blood pressure, nausea, some patients complain of dizziness, and you also have to monitor LFTs.

Posttest 1

Circling back to our post questions. Remember this question. A patient presents with a platelet count of six and mucocutaneous bleeding. You review the blood smear, which shows decreased numbers of normal appearing platelets without clumping. Red cells and white cells are normal. You suspect ITP and decide to initiate treatment.

Which of the following approaches best reflects the most appropriate treatment in a patient with newly diagnosed ITP? I read you these options before. I do not need to read them again, but let me give you a little time to key in what you think the best answer is.

Still a smattering of responses a little different than before. I would actually argue that, and then maybe we can go to the next slide, which I think provides the rationale, that the best answer to this question is prednisone 1 mg/kg with a four-week taper.

This is a tricky question with tricky answer choices. The idea here is that, of course we are going to use steroids for first-line therapy, but in accordance with the ASH guidelines, we want to limit the course of steroids to six weeks or less. Choice A and choice C involve longer courses of steroids.

That said, choosing dexamethasone for a single cycle would have been a very reasonable answer had that been a choice option. Maybe you think that because this patient's platelet count is only six, that it is really imperative to get that platelet count up quickly, and we know that we can achieve more rapid responses with high dose dex, so a single cycle of high dose dex would have also been a fine choice, just not four cycles, which would have been more prolonged steroid exposure than is recommended.

Posttest 2

Here is your next posttest question. A patient with recently diagnosed ITP initially responds to prednisone, but during the taper, her platelet count falls to 15. She reports worsening fatigue and steroid-related adverse effects that are affecting her daily activities. Which of the following is the most appropriate next step?

1. Cyclosporin 50 mg a day;
2. Splenectomy;
3. Avatrombopag 20 mg daily; or
4. Pulse dose dexamethasone.

I will give you time to key in your answers.

I agree with the majority of you who said avatrombopag.

Avatrombopag is a thrombopoietin receptor agonist. It is a great choice for second-line therapy in this patient. The idea is we want to implement second-line therapy sooner rather than later to minimize our cumulative steroid exposure.

She is fairly recently diagnosed with ITP. Has not had it for a year or more, so we would prefer to avoid splenectomy. Cyclosporin is a salvage therapy that we use further down the line. Dexamethasone, yes, we could probably bring her platelet count up with dexamethasone, but then we are just giving her more steroids. She is already having steroid side effects, and so we would prefer to move on to something steroid-sparing.

Evolving Paradigms in ITP Management: New and Emerging Therapies in Immune Thrombocytopenia

We are now going to shift gears and talk about new and emerging therapies in the ITP space

ITP: From Steroids, Splenectomy, and Salvage to Numerous Targeted Therapies in 2 Decades

This is a figure that just highlights some of the drugs that we are going to talk about: efgartigimod, rilzabrutinib, ianalumab, and anti-CD38 antibodies like mezagitamab.

Effects of BTK Inhibition

Let us start with rilzabrutinib, but I heard you talking about Bruton tyrosine kinase inhibitors in the last talk on CLL. We are going to talk about this class of drugs again. It turns out that BTK inhibitors not only work in CLL, but they also work in ITP. How do they do this? They block B cells and plasma cells, so it can block autoantibody production. Then they also inhibit monocytes and macrophages, so they can inhibit phagocytosis of those antibody-coated platelets.

BTK Inhibitor for ITP: Rilzabrutinib

Many of you had probably experience with the early generations of BTK inhibitors like ibrutinib. You might recall that one of the side effects of ibrutinib is increased bleeding. That is due to inhibition of platelet function. It seems like a really bad idea to give a drug that inhibits platelet function and increases bleeding. To somebody with ITP. We would not want to use ibrutinib for ITP, but rilzabrutinib is a much more selective BTK inhibitor.

Rilzabrutinib Does Not Impact Platelet Function, Unlike Other BTK Inhibitors

What that means is that it does not have the same platelet inhibitory effects that ibrutinib does. If you look at the figure on the very left side of the slide, this is the percent of maximum platelet aggregation in healthy volunteers who took ibrutinib with different platelet agonists. What this shows is that ibrutinib inhibits platelet aggregation with collagen. Then, if we give those same healthy volunteers, that is panel B, or patients with ITP, panel C, rilzabrutinib it has no effect on platelet function. This is a much safer BTK inhibitor to give to patients with ITP.

LUNA 3: Rilzabrutinib, a BTKi in Persistent/Chronic ITP

Rilzabrutinib was studied in patients with persistent and chronic ITP in the LUNA-3 trial. This was an international double blind randomized Phase 3 trial where patients with ITP were randomly assigned to receive either rilzabrutinib 400 mg twice a day or placebo from weeks one to 24, and then patients could enter an open-label extension study. The primary endpoint was a durable platelet response.

LUNA 3: Platelet Counts Are Significantly Higher on Rilzabrutinib vs Placebo

Here, what you see is mean platelet count. The orange curve represents patients treated with rilzabrutinib, the grey curve placebo, and so you can see that, those who got randomized to rilzabrutinib had higher platelet counts throughout the study. Actually, the difference increased over time.

LUNA 3: Time to Platelet Response Is Much Faster With Rilzabrutinib vs Placebo

The time to response is actually fairly quick with rilzabrutinib. Here on the y-axis we have the time to first platelet count response. Much quicker in the rilzabrutinib arm than in the placebo arm. Patients with rilzabrutinib can respond within the first two weeks of starting treatment, sometimes even more quickly. [00:42:03]

LUNA 3: Much Less Therapy Required for Rilzabrutinib vs Placebo

Because of high response rates, you will not be surprised to know that patients who were randomized to rilzabrutinib required less rescue therapy with things like steroids or IVIG than those in the placebo group.

LUNA 3: Substantial Improvements in Fatigue (ITP-PAQ) With Rilzabrutinib vs Placebo

Interestingly, rilzabrutinib not only improved platelet counts, but it also improved fatigue. Fatigue was assessed using something called the ITP PAQ tool. You can see that the scores were the same at baseline but higher in the rilzabrutinib-treated patients than in the placebo-treated folks.

LUNA 3: Safety of Rilzabrutinib

What about safety? Rilzabrutinib generally quite well tolerated the most common side effects experienced were diarrhea and nausea.

Posttest 3

Here is your next posttest question. It is now 18 months later. The patient did not respond to avatrombopag, romiplostim or fostamatinib and had only a transient response to rituximab. She underwent splenectomy three months ago and did not have a sustained response.

She is currently receiving romiplostim at the maximum dose, 10 micrograms per kilogram per week, and prednisone 10 milligrams daily, and her platelet count is still only 12. She has ongoing mild mucocutaneous bleeding. Which of the following agents is FDA-approved for treatment of ITP with insufficient response to prior therapy?

1. Daratumumab;
2. Cyclosporine;
3. Ianalumab; or
4. Rilzabrutinib.

We will give you a little time to key in your answer.

Almost all of you said rilzabrutinib, correct. Rilzabrutinib was approved, I believe, in July of 2025, and it is the only drug on this list that is FDA-approved for ITP. Daratumumab and ianalumab show promise, but they remain investigational therapies for ITP. Cyclosporin again does have ITP activity, but that is not FDA approved for this disease, and it is a salvage therapy.

Ianalumab (VAY736) in ITP

Speaking of investigational therapies, let us talk about ianalumab. This is a monoclonal antibody that has a dual mechanism of action. How does it work? First it works by blocking something called the BAFF receptor. In doing so, it prevents activation and differentiation of B cells and induction of long-lived plasma cells, and it may therefore overcome some of the resistance that we see in patients treated with rituximab.

Its second mechanism of action is that it enhances ADCC-mediated B cell depletion. Basically, the antibody coats B cells, and these B cells are then removed from circulation by the reticulo endothelial system. It thus provides more potent sustained B cell depletion in blood and tissues than rituximab does.

VAYHIT2: Ianalumab + Eltrombopag in ITP After Failure on IL Corticosteroids

Ianalumab was studied in something called the VAYHI2 trial. This trial enrolled adults with primary ITP who had been treated with steroids and now needed something else. They had only received steroids and nothing else relatively early on in their disease course. They were randomized to one of three treatment groups.

Ianalumab 3 mg/kg, or ianalumab 9 mg/kg in combination with eltrombopag. I should clarify, the ianalumab was given as a every four-week infusion times four. Then there was also a placebo group where the placebo infusion was given in combination with eltrombopag.

The primary endpoint was the time to treatment failure. That was defined as the time to either a platelet count less than 30, or need for rescue therapy greater than eight weeks from randomization, the need to start new ITP therapy, or inability to taper or stop eltrombopag after eight weeks, or death. That was the primary endpoint.

VAYHIT2: Time to Treatment Failure (Primary Endpoint)

Here we can see the time to this primary endpoint of treatment failure. Essentially, time to treatment failure was significantly longer in the ianalumab groups than in the placebo group. The median time to treatment failure was 13 months with the ianalumab 9 mg group, was not reached with the 3 mg group, and it was 4.7 months with the placebo group. Essentially, what we were seeing with ianalumab is a prolonged time to treatment failure, and patients basically being off all treatment for months without relapsing.

VAYHIT2: Efficacy of Ianalumab

This is the number and proportion of patients who achieved a response defined as a platelet count of 50 or higher, or a complete response, a platelet count of 100 or higher. The blue bars represent the ianalumab 9 mg group, the orange bars, the 3 mg group, and the grey bars, the placebo group. You can see that there were higher response and complete response rates with ianalumab than the placebo group, with something of a dose response seen.

VAYHIT2: Changes in Fatigue Measurements Over Time

Like rilzabrutinib, ianalumab, not only improved platelet counts, but it also improved fatigue as measured by a tool called the PROMIS-Fatigue score.

VAYHIT2: Any-Grade Bleeding Events per WHO Bleeding Scale

Not surprisingly, ianalumab, in improving platelet counts, also reduced bleeding. You can see that bleeding rates were fairly high at baseline. By week 25, the bleeding rates were lowest in the ianalumab 9 mg group, and it is lower in the five 3 mg group compared with placebo.

VAYHIT2: Safety of Ianalumab

Ianalumab tended to be well tolerated. With a drug like this, you might worry about an increased risk of infections, but there did not seem to be numerically more infections in the ianalumab groups than in the placebo group. There were a small number of patients in the ianalumab arms that had neutropenia, although that did not seem to result in infections, and a few patients with infusion related reactions and one patient with hypogammaglobulinemia.

VAYHIT 3: Efficacy of Ianalumab Primary ITP Following ≥Prior LoT

This drug ianalumab, is also being studied in a Phase 2 trial called the VAYHIT-3 trial. This is looking at the efficacy of ianalumab in patients who are more treatment refractory. They have had at least two prior lines of therapy and need something else.

What you can see here, when you look at confirmed response, I can see that the colors got a little changed on this particular slide, but 44% of patients had a confirmed response. 24% of these patients had a stable response lasting at least six months. Of these 10 patients who had a stable response, nine of them had a complete response, meaning normalization of their platelet count.

This is promising data from a Phase 2 trial that ianalumab may have activity as a later line of therapy as well.

Posttest 5

Here is your next posttest question. A 54-year-old man with primary ITP diagnosed three months ago presents to clinic with petechiae and fatigue. He previously completed a six-week course of prednisone to which he had a complete response. However, today's platelet count is down to 16.

He asks if there are any new treatments when added to standard therapy that could provide a treatment-free interval and possibly make his disease less likely to come back in the future. Based on currently available evidence, which of the following investigational ITP medications has demonstrated this potential?

1. Povetacicept;
2. Mezagitamab;
3. Efgartigimod; or
4. Ianalumab.

I will give you a little time to key in your answer.

Correct. The answer here is ianalumab based on the data that we have so far, for this investigational drug. It looks like giving this treatment early on may improve the potential for patients to have sustained remission or response off treatment. We need longer follow-up, but the hope is potentially, if we give it early on, even mitigate the long-term course of the disease or cure the disease in patients who otherwise might have been destined to develop chronic ITP.

VAYHIT1: Ianalumab + 1L Corticosteroids in Primary ITP

I do want to briefly mention that ianalumab is being studied in a third trial the VAYHIT trial, where it is actually being given upfront with steroids as part of initial combination therapy. Again, with the goal of potentially mitigating the long-term course of the disease. This trial is still ongoing, so we do not have results to share with you yet.

Efgartigimod Competitively Inhibits FcRn

Briefly mention efgartigimod. This is a small molecule that inhibits something called the neonatal endothelial receptor, FcRn. The job of FcRn is to recycle IgG molecules, which allows them to have a long half-life of 25 days in our blood. If we take a drug like efgartigimod and block FcRn, that targets IgG molecules for degradation in the lysosomes rather than recycling, and greatly shortens their half-life. By giving this drug we are diminishing levels of IgG, including antiplatelet antibodies.

ADVANCE IV: Efgartigimod vs Placebo in Previously Treated Primary ITP

Efgartigimod was studied in the ADVANCE IV trial. In this particular trial, adults with chronic or persistent ITP were randomized to receive efgartigimod IV 10 mg/kg, given every week to two weeks based on the platelet count versus placebo.

ADVANCE IV: Platelet Count Changes Over Time

If you look at the platelet counts in orange, that represents the efgartigimod group, grey represents the placebo group, and what we actually have on the y-axis is not platelet count, but mean change in platelet count from baseline. You can see that there was a bigger improvement in platelet count in the efgartigimod group than in the placebo group.

ADVANCE IV: Targeted Reduction in IgG Levels

As expected, based on the mechanism of action of this drug, efgartigimod reduced IgG levels. That is what we see on the y-axis here is mean percent change in IgG levels. You can see that they were dramatically reduced in the efgartigimod arm, and they remained stable in the placebo arm.

Mezagitamab (TAK-079) to Treat ITP

Another investigational drug to discuss is mezagitamab. Mezagitamab is a monoclonal antibody that targets CD38 on plasma cells, very similar to daratumumab. The idea is we can maybe deplete plasma cells, which are the cells that give rise to these antiplatelet autoantibodies.

Mezagitamab for ITP: Rapid, Sustained Improvement in Platelet Counts Persisted Through Wk 16

Mezagitamab was studied in a Phase 2 trial that was just published last week in the New England Journal of Medicine. In this phase two trial, adults with ITP were randomized to receive placebo or three different doses of mezagitamab. What you see on the y-axis here is the mean change from baseline in platelet count, and you can see that there were improvements in platelet count with the mezagitamab arms, but not with placebo, that is the grey bar. There was something of a dose-response relationship. The higher mezagitamab arms had greater increases from baseline in platelet count.

Mezagitamab for ITP: Fewer Patients With Bleeding Events With Mezagitamab vs Placebo

This is a table that just shows you bleeding events in the patients in this Phase 2 trial. Essentially, if you look at the different columns, you will see that, percentage-wise, there were more bleeding events, a higher percentage of bleeding events, in the placebo arm than in the mezagitamab arms. Not only does mezagitamab improve platelet count, but it seems to reduce bleeding events as well.