CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 23, 2023
Expiration: March 22, 2024
Marshall Mazepa, MD:
ITP is an acquired autoimmune disorder marked by decreased platelet counts, increased bleeding risk, fatigue, and reduced QoL.31-34
Most patients with ITP have pathogenic immunoglobulin G (IgG) autoantibodies targeting glycoproteins expressed on platelets and megakaryocytes.35-37 For this reason, ITP traditionally has been treated with immunosuppressant therapies.
During the COVID-19 pandemic, it was challenging to find therapies for patients with ITP that would keep them safe from infection with normal vaccine response. Overall, treatment strategies shifted toward the thrombopoietin (TPO) receptor agonists, which are the most commonly used approved therapies that are not immunosuppressant in nature. We are in a time when patients are much more concerned about the effects of long-term immune suppression.
It is well established across multiple sets of guidelines to treat patients with either bleeding symptoms or a platelet count <30 x 109/L, but the reality of practice is that even with the tools we have, there are many patients whose platelet counts do not sufficiently respond, so there certainly is still an unmet need. For those more frequently treated patients, it would be great to add a non‒immune-suppressing treatment to that menu of therapy options. The reality is that the risk of emerging infections is going to be with us a long time, so I do not think that patient fear is going to go away.
Marshall Mazepa, MD:
At ASH 2022, we saw data presented for the multicenter, double-blind phase III ADVANCE IV trial of IV efgartigimod, a human IgG1 Fc fragment that competitively binds to FcRn to prevent recycling of IgG and hence reduce pathogenic IgG autoantibodies, vs placebo in adults with primary, persistent, or chronic ITP. Patients enrolled on this study are among the hardest to treat, with chronic or persistent ITP that met the criteria for treatment but did not respond well (2 platelet counts <30 x 109/L).
ADVANCE IV has a very reasonable study design. What is unusual about ITP is that there are spontaneous remissions, such that patients may have a platelet count of 20 x 109/L one week and 40 x 109/L the next, for example. Thus, a placebo arm was necessary to account for the natural tendency of the disease to have platelet counts go up and down across the cutoff point of 30 x 109/L. Patients were randomized 2:1 to receive IV efgartigimod at 10 mg/kg or placebo. The primary endpoint was the proportion of patients with ITP with sustained platelet count response. Participants discontinuing were followed for 4 weeks, and those not discontinuing could roll over to the open-label extension.
Marshall Mazepa, MD:
There was nothing concerning or unusual in the baseline characteristics. The arms are remarkably well balanced considering it is a rather small, randomized study. It also is expected that most patients receiving stable chronic therapy for ITP in the efgartigimod arm and the placebo arm concurrently were receiving corticosteroids (25.6% and 26.7%), other immunosuppressants (9.3% and 13.3%), or TPO receptor agonists (23.3% and 20.0%) at baseline.
Marshall Mazepa, MD:
The result for the primary endpoint of proportion of patients with sustained platelet count response in ≥4 of 6 visits during 19-24 weeks without intercurrent events in the chronic population was very exciting. The investigators consciously chose a timepoint at 19-24 weeks after the initial start of treatment because immunoglobulin levels would not be expected to fall rapidly. The desired outcome is a clinically sustained response ≥50 x 109/L, which will encourage patients to continue on with treatment. Approximately 22% vs 5% of patients in the efgartigimod arm vs the placebo arm had a sustained response, which was statistically significant (P = .0316). Patients essentially achieved a 4-fold improvement in platelet count response. Again, I think the endpoint was well chosen to have ≥4 of the 6 visits, a few months into treatment, be ≥50 x 109/L, as this is always a treatment goal. Other secondary endpoints—such as cumulative weeks of disease control, sustained platelet count response, and durable sustained platelet count response—also were significant.
Bleeding is pretty uncommon in this disease. Patients who are followed for a long time appear to accumulate very low platelet counts, but for patients at the time of presentation, I am not surprised to see that there was no statistical difference in bleeding in this study (P = .8287).
Marshall Mazepa, MD:
I found the data on platelet count change over time quite helpful. From a management standpoint, we are always curious to know with a new therapy what kind of response can be expected because every patient starts at a different baseline. In these data, there seems to be a range of approximately 20 x 109/L to 30 x 109/L.
In the clinic, if a patient has a single digit platelet count, you might hope to achieve 50 x 109/L or above, but it is much more likely that 50 x 109/L is achievable if the initial platelet count is closer to 30 x 109/L. What this chart does not show, as is typically true with trial reporting, is that you cannot see individual patients who had great responses compared with those who effectively had no response. What I find most exciting is the rapid rate of response seen within the first 4 weeks of treatment.
When efgartigimod eventually receives FDA approval, it will be useful to know, from a management standpoint, how fast response should be expected. This knowledge also helps patients understand what to expect of therapy.
Marshall Mazepa, MD:
In terms of degree of response, from a practical perspective you do not necessarily need a CR. However, investigators presented data showing that there will be a group of patients who have very robust responses to this therapy. Overall, 51% vs 20% of patients experienced a response with efgartigimod vs placebo. Approximately 28% vs 4% of patients in the efgartigimod vs placebo arm experienced a CR, respectively.
In this trial, those patients who maintained sufficient platelet counts could have treatments spaced out to every 2 weeks. For patient adherence and acceptance of this therapy, spacing out treatment is likely to be really important to keeping patients on therapy and in remission.
Marshall Mazepa, MD:
It was a bit unfortunate to see a drop-off in responses over time. It is difficult to know what to expect if this therapy comes into approval and regular clinical use, but if this loss of response is seen in real-world use, it will be interesting to see how efgartigimod falls into the treatment paradigm. It is probably too early to make any conclusions about this other than to say there is a trend toward a loss of response over the course of 6 months. Additional data will be needed to better understand what this means
Marshall Mazepa, MD:
The subgroup analyses for sustained platelet count response show that no one group in particular lacks response, which is very fortunate. In selecting efgartigimod for the next line of therapy, an HCP would not have to worry whether a patient has received rituximab or a TPO receptor agonist.
Marshall Mazepa, MD:
With the mechanism of action of efgartigimod, there is a theoretical risk of lowering IgG levels to an unsafe range and creating risk of infections. Several questions were raised on this topic at the live presentation. However, efgartigimod already is approved for myasthenia gravis38 and has undergone trials in other diseases. At this point, and certainly from this trial, it does not look like the IgG levels fell to an unsafe range
Marshall Mazepa, MD:
AEs leading to treatment discontinuation were low (4.7% vs 2.2%). In addition, the AEs reported did not show any concerning signals for risk of opportunistic infections, with any infection event seen as comparable between arms.
Overall, the treatment was quite well tolerated, which is encouraging. The most common treatment-emergent AEs in the efgartigimod arm vs placebo included headache (16.3% vs 13.3%), asthenia (7% vs 0%), and hypertension (5.8% vs 0%).
Marshall Mazepa, MD:
I agree with the conclusions from investigators that efgartigimod was associated with clinically and statistically significant improvements in sustained platelet count recovery compared with placebo. In addition, and as expected, total IgG levels were lowered, but the range still seems to be safe and did not significantly cause immune suppression. I would group efgartigimod with the category of treatment options that do not increase the risk of infections.
If efgartigimod is approved for ITP, it will give patients more treatment options if we want to avoid immunosuppressants or if we had tried and failed multiple agents. Obviously, we are always looking for new agents for these difficult-to-treat subsets of ITP, but fortunately this is a smaller patient population.
Much of the treatment selection in this particular group of patients is about patient preference—even the most recent guidelines talk about involving the patient in treatment selection. There are differences in the durations for different treatments; for example, rituximab is given as 4 doses and then observation, whereas other agents, such as TPO receptor agonists and efgartigimod, are given indefinitely. Thus, HCPs can work with patients on which treatment regimen will be acceptable for them, in addition to which is most likely to be efficacious.
Realistically, I think indefinite weekly IV efgartigimod infusions will be a big burden for patients, so efgartigimod may not be appropriate for everyone. I think patients who can move to every other week administration will be much more accepting. There is an ongoing SC administration study, so in the future this treatment has the potential to be given at home (NCT04687072). Moving this therapy from the clinical trial setting to real-world, at-home administration would be an important step to make this more accessible for patients, as well as more acceptable.
It will be interesting to see whether SC administration offers the same kind of response as intravenous administration. I suspect it will be more acceptable to patients, but you never really know until you take it to the clinic and start talking to patients about it.
Overall, it is exciting to have a new class of agent potentially on the horizon for ITP. This treatment landscape is a bit crowded these days, but it is exciting to have options for those most difficult-to-treat patients and options to include in the nonimmunosuppression category, as well as an option with low toxicity.
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