CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 23, 2023
Expiration: March 22, 2024
David Dingli, MD, PhD:
PNH is a rare, chronic hematologic disorder characterized by intravascular hemolysis, thrombophilia, and marrow failure that is caused by acquired mutations in the PIGA gene in hematopoietic stem cells, leading to dysregulation of the complement alternative pathway.7,8 The complement cascade can be activated by 3 pathways: classical, alternate, and lectin. The classical pathway essentially is not relevant in PNH, but the alternate pathway is critical because it is continuously active at a low level via the so called tick-over mechanism. Formation of active complement 3 convertase (C3) is critically dependent on the activity of factor B and factor D. Once C3 is activated, it can activate the formation of the complement 5 convertase, which then can lead to formation of the membrane attack complex, resulting in red blood cell lysis.
The current standard of care in PNH consists of anti–complement 5 blockade with either eculizumab or ravulizumab9,10 or the C3 inhibitor pegcetacoplan.11 Eculizumab and ravulizumab are very effective at inhibiting intravascular hemolysis, but they do not effectively prevent extravascular hemolysis, such that, in time, many patients with PNH accumulate complement 3b on the surface of red blood cells, which renders them “optimized” for extravascular hemolysis in the reticuloendothelial system of the spleen and liver.12 As a consequence, many patients (approximately 66%) receiving standard of care therapy for PNH remain anemic, and a considerable fraction are transfusion dependent, largely because of persistent extravascular hemolysis.12
Preliminary data from a small multicenter phase II study previously showed that iptacopan (LNP023)―a first-in-class oral, selective inhibitor of factor B, a key component of the alternative pathway―can significantly improve hemoglobin levels in patients who continued to have anemia despite receiving eculizumab treatment.13
We are entering an exciting new phase in the treatment of PNH with the potential availability of oral complement inhibitors, also called proximal complement inhibitors. I would like to highlight 2 key studies presented at ASH 2022 relating to novel therapies for PNH.
David Dingli, MD, PhD:
At ASH 2022, De Latour and colleagues1 reported primary efficacy and safety data from the phase III APPLY PNH study of iptacopan vs standard of care with eculizumab or ravulizumab in patients with PNH who had residual anemia and extravascular hemolysis (mean hemoglobin: <10 g/dL, reticulocytes: ≥100 x 109/L) while receiving standard therapy. Patients were randomized either to receive iptacopan 200 mg twice daily orally or maintain baseline IV anti‒complement 5 standard of care therapy (eculizumab or ravulizumab). The study had 2 phases: an initial 24 week randomized treatment period and then an extension period, in which patients who were initially randomized to continue with complement 5 inhibitor therapy could switch to oral iptacopan. The primary endpoint was hematologic response, defined as a hemoglobin increase of ≥2 g/dL from baseline or hemoglobin ≥12 g/dL in the absence of red blood cell transfusions. Secondary endpoints included transfusion avoidance, change in baseline hemoglobin levels, FACIT Fatigue scores, absolute reticulocyte count, and lactate dehydrogenase (LDH) levels, as well as the occurrence of major adverse vascular events and other safety profile of iptacopan.
In this report, data from the first 24 weeks of therapy were made available. The study was powered to look at potential superiority of iptacopan compared with complement 5 inhibition.
David Dingli, MD, PhD:
The baseline characteristics of patients in this trial were very similar between the 2 groups. The median age was 51 years, 67% of patients were female, and the mean time from diagnosis was 12.5 years. The majority of patients enrolled were receiving eculizumab (65%), and 57% of patients were transfusion dependent before enrollment. Mean baseline hemoglobin was 8.9 g/dL, and LDH was 270 U/L. Only 7% of patients had an LDH >1.5 times the upper limit of normal (ULN), which suggests that the anemia was likely due to extravascular hemolysis. Mean baseline absolute reticulocyte count was 192 x 109/L.
David Dingli, MD, PhD:
Iptacopan was superior to standard of care, essentially across all endpoints studied. In these initial results, 82.3% of patients receiving iptacopan achieved a ≥2-g/dL improvement in hemoglobin vs 2% of patients receiving standard of care complement 5 inhibitor therapy. In addition, 68.8% of patients receiving iptacopan reached a hemoglobin of ≥12 g/dL without transfusions vs 1.8% of patients receiving standard of care complement 5 inhibitor therapy. Both of these results were highly statistically significant (P <.0001).
David Dingli, MD, PhD:
Looking at transfusion avoidance, patients who were randomized to receive iptacopan had a transfusion avoidance of 96.4% vs 26.1% for the patients receiving complement 5 inhibitor therapy. Again, this difference is quite substantial and highly statistically significant (P <.0001). Superiority of iptacopan over complement 5 inhibitors also was confirmed in post hoc sensitivity analyses (96.7% vs 38.9%; P <.0001).
David Dingli, MD, PhD:
The responses to iptacopan were quite rapid, with hemoglobin increasing to >12 g/dL within approximately 4 weeks of initiation of therapy. The average change in hemoglobin from baseline compared with standard of care was 3.59 g/dL, and that response was sustained for the 24-week duration of the study reported in this presentation.
David Dingli, MD, PhD:
In parallel to the improvement in hemoglobin, there was an improvement in the mean FACIT-Fatigue score, with results reaching the normal range for a healthy adult population. The absolute difference in the FACIT-Fatigue score was an improvement of 8.29 points with iptacopan compared with complement 5 inhibition— and a difference of 5 points is generally considered to be clinically meaningful.
David Dingli, MD, PhD:
As hemoglobin improved, the absolute reticulocyte count decreased and settled in the normal range for the majority of patients receiving iptacopan vs complement 5 inhibitor. Again, this finding was consistent with control of both intravascular and extravascular hemolysis and improved the lifespan of red blood cells.
David Dingli, MD, PhD:
Perhaps as expected, there was no difference in LDH levels between patients receiving iptacopan vs standard of care complement 5 inhibitor therapy, showing that both approaches are equally effective at inhibiting intravascular hemolysis.
David Dingli, MD, PhD:
The risk of breakthrough hemolysis―a potential complication that is very important in PNH―was lower with iptacopan than with complement 5 inhibitor therapy, with 2 of 62 patients receiving iptacopan having clinically significant breakthrough hemolysis vs 6 of 36 patients receiving standard of care complement 5 inhibitor therapy. Again, this difference was statistically significant (P = .0118). Of importance, there was no difference between iptacopan and complement 5 inhibitor therapy with respect to major adverse vascular events (P = .3173). This is again an important observation given the risk of thrombosis in patients with PNH.
The authors disclosed that there was 1 serious treatment emergent adverse event (AE) in the iptacopan arm―transient ischemic attack―but this was considered to be unrelated to iptacopan. That patient had sick sinus syndrome and has continued receiving therapy with iptacopan despite this event.
David Dingli, MD, PhD:
The most common treatment-emergent AEs with iptacopan vs complement 5 inhibitor therapy were headache (16.1% vs 2.9%) and diarrhea (14.5% vs 5.7%), and most of these were mild.
As previously stated, breakthrough hemolysis was more common in patients receiving complement 5 inhibitor therapy (17.1%) vs iptacopan (3.2%). Of importance, no serious infections were caused by encapsulated bacteria, and no patient needed to discontinue therapy, except for 1 patient who became pregnant and had to discontinue iptacopan. There were no deaths during the observation period.
David Dingli, MD, PhD:
The study showed that oral iptacopan is a highly active agent in patients with PNH and residual anemia while receiving stable complement 5 inhibitor therapy.
Iptacopan was shown to be very effective at controlling both intravascular and extravascular hemolysis, with a high proportion of patients achieving hemoglobin ≥12 g/dL in the absence of red blood cell transfusions.
Most patients became transfusion independent, and there was concomitant improvement in patient-reported fatigue. The safety profile of iptacopan was found to be very favorable, with no serious AEs or breakthrough hemolysis compared with complement 5 inhibitor therapy.
The investigators concluded that iptacopan monotherapy may change management of patients with PNH with residual anemia receiving stable anti‒complement 5 standard of care therapy.
Complement 5 inhibitor therapy with either ravulizumab or eculizumab is very good at blocking intravascular hemolysis and reducing LDH levels to essentially normal. With iptacopan we expect control of intravascular hemolysis, so LDH is expected to similarly decrease, and in fact LDH levels were no different between these treatments. What is different between these 2 drugs is that although eculizumab or ravulizumab does not prevent extravascular hemolysis because of accumulation of complement 3b on the surface of red blood cells, iptacopan does.The end result is that iptacopan inhibits intravascular hemolysis as effectively as eculizumab or ravulizumab and blocks extravascular hemolysis, whereas eculizumab and ravulizumab do not, which explains why hemoglobin is higher compared with eculizumab and ravulizumab.
Iptacopan provides a potential new therapy involving an oral agent without the need for parenteral therapy. I expect more information to come on this drug and similar agents for PNH.
David Dingli, MD, PhD:
The second study from ASH 2022 that I would like to highlight is that of vemircopan, an oral factor D inhibitor. Similar to factor B inhibition with iptacopan, there is rationale for vemircopan to prevent both intravascular and extravascular hemolysis by inhibiting the proximal complement cascade in the alternate pathway and disrupting the amplification loop, which is critical for rapid activation of complement and formation of membrane attack complex.14
Previously, the first-in-class oral factor D inhibitor danicopan showed improved control of extravascular hemolysis in patients with PNH who were receiving complement 5 inhibitor therapy with eculizumab.15,16 However, danicopan exhibited unfavorable pharmacokinetic and pharmacodynamic blockade of factor D.
The advantage of the second-in-class agent vemircopan is that it has higher potency and binding affinity to factor D and is being developed as a potential monotherapy in patients with PNH.14
David Dingli, MD, PhD:
At ASH 2022, Browett and colleagues14 reported data from a phase II study of vemircopan in 11 patients 18 years of age or older with treatment-naive PNH. Patients were required to be anemic with hemoglobin <10.5 g/dL, elevated absolute reticulocyte count (≥100 x 109/L), and LDH 1.5 times ULN because of intravascular hemolysis. Patients were started on vemircopan at 120 mg twice daily, and the dose could be escalated to 180 mg twice daily if hemoglobin did not increase by ≥1 g/dL by Week 4, in which case the patient also would receive transfusions, or if LDH was still >1.5 times ULN by Day 14 in 2 consecutive assessments. The study had 2 phases: a treatment period of 12 weeks and a long-term extension of 96 weeks. The primary endpoint was change from baseline hemoglobin at Week 12. Secondary endpoints were transfusion avoidance and change in LDH, absolute reticulocyte count, and FACIT-Fatigue score from baseline.
David Dingli, MD, PhD:
The median age was 44 years, and most patients were of Asian descent (approximately 73%). Median baseline hemoglobin was 8.2 g/dL, and median LDH was 1743.0 U/L (range: 544.0-2358.3), which are values compatible with active untreated PNH. Only 1 patient had a history of aplastic anemia, and none of the patients had a history of thrombosis.
David Dingli, MD, PhD:
Therapy with vemircopan was associated with a fairly rapid improvement in hemoglobin, increasing by approximately 3.9 g/dL by Week 12. At Week 6, hemoglobin reached 10.7 g/dL and continued to improve over the duration of the observation period, reaching almost the lower limit of normal at 11.8 g/dL. With the improvement in hemoglobin, LDH decreased to approximately 1-1.5 times ULN, showing that the drug is quite effective at inhibiting intravascular hemolysis. The LDH reduction also was maintained over the duration of the observation period. By Week 12, mean reticulocyte count also decreased, almost reaching ULN.
In addition to the improvement in hemoglobin and reduction in hemolysis, patients reported an improvement in fatigue corresponding to a 13.3-point increase in FACIT Fatigue score, where an improvement of 5 points is considered to be clinically meaningful.
David Dingli, MD, PhD:
This is a small study with 11 patients, but overall the drug was very well tolerated; 7 of 11 patients needed dose escalation from 120 mg twice daily to 180 mg twice daily. Most AEs were mild to moderate in severity (grade 1-2) and generally considered unrelated to the study. There were no reported deaths, thrombotic events, seizures, or meningococcal infections.
David Dingli, MD, PhD:
This small study suggests exciting responses with vemircopan as monotherapy in patients with previously untreated PNH, including impressive improvement in hemoglobin of approximately 3.9 g/dL by Week 12 compared with baseline, improvement in FACIT Fatigue scores, and an acceptable safety profile.
The investigators concluded that the efficacy and safety findings provide proof of concept for vemircopan in PNH and warrant phase III studies of this factor D inhibitor.
These are exciting times for patients with PNH. We are now on the cusp of soon having oral agents―iptacopan and vemircopan―that potentially can yield clinically meaningful disease control. The advantages of an oral agent are that patients do not require parenteral therapy, which gives them the ability to plan their lives with much more freedom. Although we still need longer follow-up on these agents, so far the data look quite exciting.
Back
