CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: February 22, 2024
Expiration: February 21, 2025
Paroxysmal Nocturnal Hemoglobinuria
Next, I would like to talk about studies presented for a much rarer hematologic disorder known as PNH. PNH is a rare, long-lasting hematologic disease caused by somatic mutations in PIGA gene in hematopoietic stem cells. PNH is characterized by severe hemolysis and life-threatening thrombosis via aberrant activation of the complement alternative pathway.11,12
Anti─C5 blockade with either eculizumab or ravulizumab is the current standard of care treatment for PNH, but up to 82% of patients receiving these therapies remain anemic and transfusion dependent, largely due to persistent C3-mediated extravascular hemolysis.13,14
At the 2023 ASH annual meeting there was much excitement about novel therapies targeting complement in PNH.
Iptacopan in Patients With PNH and Residual Anemia With Anti-C5 Therapy (APPLY-PNH Final Results)
The first study I wish to highlight is that of iptacopan, an oral newly FDA-approved, first-in-class, selective inhibitor of factor B, a key component of alternative pathway that inhibits C3 convertase activity, reducing C5 convertase formation.15,16
In a previous report, iptacopan demonstrated efficacy and safety in phase III trials in anti-C5–treated patients with PNH and persistent anemia (APPLY-PNH); and in anti-C5–naive patients with PNH (APPOINT-PNH).13,17
At ASH 2023, we saw the final results for the multicenter, randomized, open‑label phase III APPY-PNH of iptacopan in patients with PNH and residual anemia with anti-C5 therapy.18 The trial enrolled adult patients with PNH and csEVH while receiving standard of care therapy, which included anti‑C5 therapy. Patients were randomized to either maintain their current anti‑C5 therapy or to receive iptacopan and then they either stayed on iptacopan or, if they started on anti-C5 therapy, they switched to iptacopan during the maintenance part of the study. The dual primary endpoints were an increase in hemoglobin of ≥2 g/dL from baseline in the absence of RBC transfusions, or a hemoglobin ≥12 g/dL in the absence of RBC transfusions. Secondary endpoints included Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue scores, markers of hemolysis including LDH, and safety (including breakthrough hemolysis [BTH] and major adverse vascular event [MAVES]).
APPLY-PNH Final Results: Baseline Characteristics
The mean age of patients enrolled was approximately 50 years, 69% were females, 65% were on eculizumab, 35% were on ravulizumab, and the vast majority had been on those treatments for more than 3 years. The mean baseline hemoglobin was approximately 9 g/dL. Mean baseline LDH was 270 U/L, mean baseline absolute reticulocyte count (ARC) was 192.3 109/L, and mean FACIT-fatigue score was 33.4.
APPLY-PNH Final Results: Changes in Hb, ARC, FACIT-Fatigue, and LDH
When we look at the efficacy summary data, we see that iptacopan demonstrated an improvement in hemoglobin up to 12 g/dL with an adjusted mean change increase from baseline to Week 48 of +3.35 g/dL for the arm that started on iptacopan and +3.36 for those who switched to iptacopan from anti-C5 therapy.
The adjusted mean change decrease in ARC from baseline to Week 48 was -106.26 109/L for those who started on iptacopan and -107.95 for those who switched to iptacopan from anti-C5 therapy.
FACIT-fatigue scores were also improved for those starting iptacopan (+9.80) and those who switched from anti-C5 therapy (+10.96) from baseline through Week 48. However, LDH remained unchanged which would suggest that there may be some small amount of EVH continuing.
APPLY-PNH Final Results: Transfusion Avoidance and Breakthrough Hemolysis Events
Patients who started on iptacopan largely avoided RBC transfusions from Week 2 through Week 24 (95.2%) and from Week 2 through Week 48 (91.9%). Similarly, patients who switched from anti-C5 therapy to iptacopan avoided transfusions from Week 2 through Week 24 (40.0%) and from Week 26 through Week 48 (94.1%).
There were fewer BTH events for those starting on iptacopan from Week 1 through Week 24 (3.2%) and from Week 24 through Week 48 (8.2%). BTH events were also fewer in those who switched from anti-C5 to iptacopan from Week 1 through Week 24 (17%) and from Week 24 through Week 48 (2.9%). It is important to remember that patients whose anemia and extravascular events were not well controlled on anti-C5 therapy were having BTH, which is why they were enrolled on the study. And so, patients who started or later switched to iptacopan monotherapy have a lower rate of BTH.
The adjusted annualized rate of clinical BTH during iptacopan monotherapy was 0.11 (95% CI: 0.05-0.23). All clinical BTH events during iptacopan monotherapy were mild to moderate in severity and resolved without iptacopan discontinuation.
APPLY-PNH Final Results: Clinical Breakthrough Hemolysis at 48 Wk in APPLY and APPOINT-PNH
The table on the right show the final results for BTH in patients who received iptacopan monotherapy with low rates of BTH with iptacopan in the APPOINT-PNH and APPLY-PNH trials and compared to those receiving anti-C5 standard of care therapy.
Overall, of 136 patients treated with iptacopan monotherapy only 10 had a clinical BTH event. In APPOINT-PNH, 2 patients in the iptacopan arm experienced a clinical BTH (2 total events).
Of the 96 patients in APPLY-PNH, 7 patients receiving iptacopan had a clinical BTH (8 total events). In APPLY-PNH, despite a 5 times higher exposure with anti-C5 therapy than with iptacopan monotherapy, 6 of 35 patients receiving standard of care experienced a clinical BTH (11 events) during the 24-week randomized period.
APPLY-PNH Final Results: MAVES
One of the potential concerns for using iptacopan is that it is a twice daily oral medication and there is potential for lower patient compliance and for increased susceptibility to hemolysis. However, that did not appear to be borne out in iptacopan clinical trials. MAVES occurred in only 3 patients, 1 during the randomized period and 2 during the treatment extension period, and all 3 were deemed to be unrelated to iptacopan. One of the 3 patients had sick sinus syndrome and a transient ischemic attack; 1 had a portal vein thrombus attributed to discontinuation of heparin; and 1 had a transient ischemic attack that presented as dysarthria.
APPLY-PNH Final Results: Safety Summary
Most common treatment-emergent AEs with iptacopan included COVID-19 (29%), headache (19.4%), diarrhea (16.1%), nasopharyngitis (14.5%), nausea (12.9), arthralgia (11.3%), urinary tract infection (11.3%), BTH (9.7%), LDH elevation (9.7%), and abdominal pain (8.1%). Of importance, no serious infections caused by encapsulated bacteria were noted, including Streptococcus, Neisseria, and Hemophilus. There were no discontinuations due to treatment‑emergent AEs, and there were no deaths reported on the trial. Iptacopan safety profile remained consistent with what was seen at Week 24.
APPLY-PNH Final Results: Conclusions and Takeaways
The main takeaway from the APPLY-PNH study of iptacopan was that patients who started on iptacopan—as well as those who switched from anti-C5 therapy to iptacopan who were having extravascular hemolysis—experienced control of their extravascular hemolysis. There were no new safety concerns and iptacopan was well-tolerated. BTH events occurred infrequently on iptacopan monotherapy and these were generally clinically mild to moderate.
Long‑term data for iptacopan demonstrate a durable response with control of both intra- and extravascular hemolysis. Based on the results from APPLY-PNH and APPOINT-PNH, iptacopan is now FDA approved for the treatment of patients with PNH.16
Ravulizumab or Eculizumab + Add-on Danicopan or Pbo in Patients With PNH and csEVH (ALPHA Long-term Data)
The other study presented at ASH for PNH that I would like to highlight is the randomized, double-blind, placebo-controlled phase III ALPHA trial of ravulizumab or eculizumab plus add-on danicopan, an investigational oral, complement pathway factor D inhibitor, or placebo in patients with PNH and csEVH.19,20 Dr Kulasekaraj presented the long-term data for the ALPHA study. This trial enrolled patients who were having csEVH despite receiving stable eculizumab or ravulizumab for ≥6 months. Patients were randomized 2:1 to receive their anti-C5 therapy plus add-on danicopan or placebo, and patients on placebo were later able to switch over to danicopan therapy after Week 12. After Week 12, patients on anti-C5 plus danicopan (n = 60) were treated for an additional 12 weeks and could enter a 2-year long-term extension, which is the bulk of the data presented at the 2023 meeting. The primary endpoint of the study was change in hemoglobin from baseline to Week 12. Secondary endpoints included change from baseline to Week 24 for hemoglobin, ARC, LDH, C3 deposition on PNH RBCs, and FACIT-fatigue scores. Other endpoints included proportion of patients with transfusion avoidance or hemoglobin increase ≥2 g/dL without transfusion, and safety.
ALPHA Long-term Data: Baseline Characteristics
The mean age of patients enrolled in the study was approximately 53 years (range: 20-82 years), approximately 60% of were women who had a mean hemoglobin at baseline around 8.0 g/dL. Mean baseline LDH was modestly elevated (286-304 U/L), and patients required a median of 2 transfusions in the 6 months prior to screening. In the study arm receiving danicopan at the start, approximately 63% of patients were taking ravulizumab and 37% were taking eculizumab. In the arm that initially received placebo and later received danicopan, 52% of patients were taking ravulizumab and 48% were taking eculizumab. Patients had been on their anti-C5 therapy for a mean of 5 years.
ALPHA Long-term Data: Change in Hb
Looking at changes in hemoglobin, patients in the danicopan treatment period 1 to period 2 arm had a least squares mean change in hemoglobin of 2.94 g/dL at Week 12 and 3.17 g/dL at Week 24 compared to baseline. In the placebo to danicopan arm, patients had a least squares mean change in hemoglobin of 0.50 g/dL at Week 12 and 2.26 g/dL at Week 24. Increases in hemoglobin levels were maintained through Week 48.
ALPHA Long-term Data: Change in ARC
If we look at ARC levels in the danicopan treatment period 1 to period 2 arm, here as well we can see that patients achieved a least squares mean reduction of -83.8 109/L at Week 12 and -80.2 109/L at Week 24 compared with baseline.
If we look at ARC levels in the placebo to danicopan arm, here we see that patients achieved a least squares mean of 3.5 109/L at Week 12 compared to baseline and a -65.2 109/L at Week 24 compared with baseline. Here also we see that improved ARC levels at Week 12 in the danicopan-treated arm vs placebo-treated arm were maintained through Week 48.
ALPHA Long-term Data: Transfusion Avoidance and C3 Fragment Deposition
Looking at transfusion avoidance and C3 fragment deposition, we can see that the proportion of patients who avoided transfusions was much higher by Week 12 (85% vs 38%) for those receiving danicopan at the start vs placebo. Of importance, this benefit was maintained through Week 24.
Regarding C3 fragment deposition, here as well we note a decrease in the amount of C3 fragment deposition on RBC for those who received danicopan from baseline through Week 12 compared with those receiving placebo (12% vs 37%).
ALPHA Long-term Data: Change in LDH
Long‑term changes in LDH are as you would expect. Because danicopan acts to inhibit extravascular hemolysis, the patient’s LDH values are expected to go down. The least squares mean change in LDH was -23.49 from baseline to Week 12 and -17.79 from baseline to Week 24 for those starting danicopan. By contrast, the least squares mean change in LDH was -2.92 from baseline to Week 12 and -6.03 from baseline to Week 24 for those starting on placebo and later switching to danicopan at Week 12.
ALPHA Long-term Data: Safety Summary
Looking at the safety data, we can see that there were a number of treatment‑emergent AEs. Similar to the previous study we discussed, the most common treatment-emergent AEs included COVID-19 (21.3%), diarrhea (15.0%), headache (15.0%), pyrexia (13.8%), nausea (12.5%), and fatigue (10.0%).
Grade ≥3 treatment-emergent AEs occurred in 28.8% of patients (53 events). Treatment-emergent AEs leading to discontinuation of study drug occurred in 5.0% of patients (6 events). The median treatment exposure was 37.7 weeks. There were no meningococcal infections, no patient deaths, and no treatment discontinuations due to hemolysis. There were 4 BTH events, which resolved in 30 days or less.
ALPHA Long-term Data: Conclusions and Takeaways
The long‑term data from the phase III ALPHA trial is encouraging with clinically meaningful and significant improvements in hemoglobin and ARC levels with the addition of danicopan to anti-C5 monotherapy in patients with csEVH. Of importance, these improvements were maintained.
We saw a favorable benefit–risk profile through Week 24 and in the long‑term extension period. No new safety signals were identified from what was previously reported.19
We have good options available for patients with PNH. We have a couple of therapies that work on inhibiting the alternative pathway iptacopan as a single-agent and an add‑on therapy to C5 inhibition with danicopan.
Choosing between these treatments will depend on multiple factors, but mostly patient preference. Are patients going to be committed to the twice daily oral requirement with iptacopan to maintain the efficacy that we have seen in the clinical trials? Would patients rather receive an infusion-based therapy like ravulizumab or eculizumab? Those are all questions we have to discuss with patients as we are thinking about what is going to be the best therapy for managing their PNH.
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