ASH 2022: Updates on management of aHUS and PNH

Dr. Andrew Siedlecki
Brigham and Women’s Hospital
Boston, Massachusetts, US
Dr. Morag Griffin
St James’s University Hospital
Leeds, UK
Dr. Peter Browett
University of Auckland
New Zealand
16 Mar 2023
ASH 2022: Updates on management of aHUS and PNH

Intravenous (IV) infusions of the complement component 5 (C5) inhibitors eculizumab and ravulizumab are currently approved treatments for patients with rare complement dysregulation disorders (ie, atypical haemolytic uraemic syndrome [aHUS] or paroxysmal nocturnal haemoglobinuria [PNH]). Meanwhile, novel agents for aHUS and PNH, such as the oral factor D inhibitor, vemircopan, are in the pipeline. This article summarizes select presentations on aHUS and PNH from the 64th American Society of Hematology Annual Meeting and Exposition (ASH 2022), including results from the Global aHUS Registry and clinical trials involving complement inhibitors for PNH.

Patient characterization in Global aHUS Registry
“aHUS is a rare complement-mediated thrombotic microangiopathy [TMA], which may or may not be associated with a prior triggering event or medical condition,” said Dr Andrew Siedlecki of the Brigham and Women’s Hospital in Boston, Massachusetts, US. “Additionally, approximately 50–60 percent of patients with aHUS may also present with anti–complement factor H [CFH] autoantibodies or pathogenic gene variants associated with the complement system that may impair regulation of the alternative pathway.” [Siedlecki AM, et al, ASH 2022, poster 1173]

Study background
“In the ongoing Global aHUS Registry, which is the largest cohort of real-world data in patients with aHUS, we assessed the frequency and clinical characteristics of patients with aHUS with triggering events or associated conditions at clinical presentation and correlated it with presence [positive cohort] or absence [negative cohort] of genetic variants and/or anti-CFH antibodies,” Siedlecki continued.

Among 1,947 patients enrolled in the registry, 349 patients were noted to have triggering events or associated conditions. Only patients with a single triggering event or associated condition were included in the analysis population (n=307). An additional 118 patients were then excluded due to unknown pathogenic complement variant and/or anti-CFH antibody status.

Study results
Results showed that patients with pathogenic variants in complement genes/anti-CFH autoantibodies were younger, with a median age of 26.8 years vs 36.5 years among those in the negative cohort. (Table)

Incident triggering type or associated conditions were similar in the two cohorts. The most common triggering events or associated conditions were pregnancy and acute infection in the positive cohort, vs malignancy and pregnancy in the negative cohort. (Table) TMA frequency was also comparable between pathogenic variant/anti-CFH antibody–positive and –negative patients, alongside similar numbers of subsequent TMAs and proportions of patients experiencing extrarenal manifestations following aHUS onset.


“In both cohorts, estimated glomerular filtration rates [eGFRs] were generally similar and suppressed except for those with acute infections,” said Siedlecki. Median eGFRs at aHUS onset for those with acute infection were lower in the negative vs positive cohort (9.8 mL/min/1.73 m2 vs 86.2 mL/min/1.73 m2).

Within each triggering event or associated condition, the median time from the event/condition to aHUS onset was similar in both cohorts, except for those with autoimmune disease (58.0 months in the positive cohort vs 78.8 months in the negative cohort) or chronic infection (60.9 months vs 42.4 months).

In the positive cohort, 82 patients (93.2 percent) had at least one pathogenic variant, while 22 (24.4 percent) tested positive for anti-CFH antibodies. A total of 16 patients (17.8 percent) had both pathogenic variant and anti-CFH antibodies.

“In summary, our study showed that the presence of triggers or associated conditions does not exclude concurrent pathogenic complement gene variants and/or anti-CFH antibodies in patients with aHUS,” Siedlecki said. “Clinical presentations were also similar in both cohorts. The longer intervals between certain associated triggers or conditions [eg, autoimmune disease and chronic infection] and aHUS onset may be due to the presence of subclinical or undetected disease following the initial triggering/associated event, which may be followed by subsequent clinical presentation.”

“Characterization of aHUS subcategories will hopefully provide information that will accelerate disease management even prior to aHUS diagnosis,” Siedlecki concluded.

Switching from eculizumab to ravulizumab well tolerated in PNH
“Eculizumab and ravulizumab are current standards of care in PNH,” said Dr Morag Griffin of the St James’s University Hospital in Leeds, UK. [Ther Adv Hematol 2022;13:20406207221091046; Eur J Haematol 2022;109:205-214] “However, up to 15 percent of patients with PNH treated with eculizumab experience insufficient inhibition of intravascular haemolysis [IVH] towards the end of the fixed-dosing interval [900 mg Q2W].” [Blood 2008;112:3441]

Study background and methods
“There are currently no recommendations or clinical trial data regarding the impact of switching patients with PNH from eculizumab to ravulizumab,” Griffin continued.

In the ongoing, single-arm, multicentre phase IV Study 401, Griffin and her colleagues aimed to assess the safety of switching from high-dose IV eculizumab (≥1,200 mg Q2W) to the approved, weight-based dose of IV ravulizumab (Q8W) in adult patients with PNH (age ≥18 years; n=18). [NCT04320602; Griffin MM, et al, ASH 2022, abstract 1251; Soliris Hong Kong Prescribing Information; Ultomiris Hong Kong Prescribing Information]

At least 3 months before screening, patients received highdose IV eculizumab treatment, which they continued throughout the 3month screening period before switching to weight-based IV ravulizumab. Patients received weight-based loading and maintenance doses of ravulizumab according to the approved prescribing information. [Griffin MM, et al, ASH 2022, abstract 1251; Ultomiris Hong Kong Prescribing Information]

The primary endpoint of the study is the proportion of patients who experience free C5–associated breakthrough haemolysis (BTH) up to day 351 (ie, at least one new or worsening symptom or sign of IVH with lactate dehydrogenase [LDH] level at least twice the upper limit of normal [ULN; ≥562 U/L] and free C5 concentration of ≥0.5 μg/mL). Key secondary endpoints include change in free C5 concentration and LDH level, and the proportion of patients with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). [Griffin MM, et al, ASH 2022, abstract 1251]

Interim analysis results
Data from 10 of the 18 enrolled patients were available at the interim analysis (median follow-up, 183.0 days [range, 176–190 days]). The mean age at PNH diagnosis was 40.9 years, while the mean age of patients at study entry was 52.6 years. [Griffin MM, et al, ASH 2022, abstract 1251]

Baseline mean free C5 concentration was 0.02 μg/mL, while baseline LDH level was 246.4 U/L. From baseline to day 183, no instances of free C5–associated BTH were reported, while free C5 concentrations remained <0.5 μg/mL for all patients at all study time points. (Figure 1) Similarly, LDH levels remained ≤1.5 times the ULN in all patients at all time points. (Figure 2)


In the interim analysis, no instances of meningococcal infections were reported. Of the analyzed patients, no TESAEs were reported, while seven patients had TEAEs, which were either mild or moderate in severity. None of the documented TEAEs led to death or study withdrawal.

BTH occurred in one patient, who had a laboratory-reported LDH level of 492.0 U/L. However, this was deemed to be vaccine-related since the patient received both COVID-19 and influenza vaccinations the day prior to the event. Since no elevated free C5 levels or decreased haemoglobin levels were detected after the event, the patient was able to continue ravulizumab treatment without any changes in the dose or dosing interval.

“Based on a small sample of patients with PNH, our interim analysis showed that switching treatment from high-dose IV eculizumab to standard, weight-based IV ravulizumab was well tolerated, with minimal changes in laboratory measures associated with PNH symptoms,” said Griffin. “No free C5–associated BTH was reported, and the safety profile of ravulizumab was considered comparable to previously published studies, with no instances of meningococcal infection or TESAEs reported.”

Oral vemircopan safe and effective in treatment-naïve patients with PNH
“Eculizumab and ravulizumab have greatly improved treatment outcomes of patients with PNH,” said Dr Peter Browett of the University of Auckland in New Zealand. “However, up to 20 percent of patients who receive these treatments may still develop clinically significant extravascular haemolysis [EVH] that may require blood transfusions.” [Blood 2014;124:2804-2811; N Engl J Med 2006;355:1233-1243; Blood 2019;133:530-539; Browett PJ, et al, ASH 2022, abstract 294]

“There is also a need for an effective oral-based alternative to currently available injectable C5 inhibitors,” Browett commented.

An emerging target in PNH treatment is pharmacologic inhibition of factor D, the rate-limiting enzyme of the complement alternative pathway. [Protein Sci 1996;5:553-564; Haematologica 2017;102:466-475] Previously, the oral factor D inhibitor, danicopan, demonstrated efficacy as monotherapy and add-on treatment to eculizumab. However, residual IVH may still occur with monotherapy. [Blood 2021;138:1928-1938; Haematologica 2021;106:3188-3197]

Study background and methods
“Vemircopan is a second-in-class oral factor D inhibitor with the same mechanism of action as danicopan, but with increased potency and binding affinity for factor D,” explained Browett. “It also achieves immediate, complete and sustained alternative pathway inhibition with twice-daily administration.” [Browett PJ, et al, ASH 2022, abstract 294]

“In our ongoing phase II proof-of-concept study, we aim to assess the efficacy and safety of vemircopan monotherapy in adult patients with PNH,” Browett shared. [Browett PJ, et al, ASH 2022, abstract 294]

The study consists of a 60-day screening period, a 12-week treatment period, and a 96-week long-term extension with three patient groups, namely, treatment-naïve, eculizumab switch, and danicopan monotherapy rollover groups. Results from the interim analysis presented at ASH 2022 focus on efficacy and safety data from the treatment-naïve group.

Patients received oral vemircopan 120 mg BID, which was escalated to 180 mg BID per investigator discretion based on guidelines in the protocol. The primary endpoint is change from baseline to week 12 in haemoglobin (Hb) levels. Key secondary endpoints include changes from baseline to week 12 in LDH levels and Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) score.

Interim analysis results: Treatment-naïve patients
As of data cut-off on 30 April 2022, 11 treatment-naïve adult patients were enrolled. Nine patients who completed 12 weeks in the study were included in the interim analysis.

From baseline to week 12, mean Hb level increased by 3.9 g/dL. (Figure 3) Mean LDH levels decreased by approximately 81 percent (from 1,688.0 U/L at baseline to 328.3 U/L at week 12), which may indicate rapid and sustained control of IVH. There was also a 13.3-point clinically meaningful improvement in mean FACIT-Fatigue score from baseline to week 12.


“Treatment with vemircopan was generally well tolerated,” continued Browett.“A total of 31 TEAEs and no TESAEs were reported. Most of these TEAEs [25/31; 80.6 percent] were considered as unrelated to vemircopan. No grade ≥3 TEAEs, discontinuations, deaths, thrombotic events, seizures, or meningococcal infections were reported.”

“In treatment-naïve adult patients with PNH, our interim analysis showed that monotherapy with oral vemircopan may help improve Hb levels and reduce LDH levels, which may be suggestive of clinically significant EVH prevention and IVH control, respectively,” said Browett. “No new safety signals were identified during the 12-week evaluation period, providing a proof of concept for vemircopan in patients with PNH and supporting the need for phase III trials for further evaluation.”

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