German Real-World Experience of Patients with Diverse Features of Acute Intermittent Porphyria Treated with Givosiran

Abstract

Background/Objectives: Acute intermittent porphyria (AIP) is a metabolic disease characterised by neurovisceral crises with episodes of acute abdominal pain alongside life-altering, and often hidden, chronic symptoms. The elimination of precipitating factors, hemin therapy, and pain relief are strategies used to treat porphyria symptoms, but are often reserved for patients suffering recurrent, acute attacks. Givosiran (siRNA) is an emerging AIP therapy capable of silencing delta-aminolevulinic acid synthase-1 (ALAS1) and, in turn, reducing the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that precede porphyria symptoms. The aim of this study was to investigate the efficacy and safety of givosiran administration in patients with both acute and chronic AIP burden, who were poorly responsive to current therapies, using a personalised medicine approach. Methods: Real-world data were collected in consecutive patients treated with givosiran at an accredited German Porphyria Clinical Center. Biochemical, clinical, and HR-QoL outcomes were monitored alongside adverse events (AEs). Results: Twenty-eight patients treated between 2018 and 2024 were sub-categorised into groups corresponding to Ipnet terms 13 'Sporadic Attacks, 5 'Symptomatic High Excretors', 5 'Prophylactic Heme', and 5 "Recurrent Attacks'. The mean time from diagnosis to treatment was 9.2 years (range in months 1-324), and the mean duration of treatment was 30 months (range 3-68). After 6 months of monthly givosiran injection (2.5 mg/kg), all patients' ALA levels reached <2ULN, and 60% of patients attained PBG levels < 2ULN (p < 0.001). These biochemical responses were not different between sub-groups (p > 0.05). Clinically, 75% of patients' chronic and acute porphyria symptoms improved. The total patient populations' annualised attack ratio (AAR) improved; Historical AAR: 2.9 (0-12.0) vs. Givo AAR: 0.45 (0-3.0) (p < 0.01). During follow-up, nine patients experienced minor breakthrough episodes. Of these, three patients required hemin infusion. An association between clinical success and a shorter interim period between diagnosis and treatment was evident (r = -0.522, p = 0.0061). All patients' indices of HR-QoL improved under givosiran, including mental health (38%, p < 0.0001) and pain (38%, p < 0.0001). Patient-reported health (givosiran 77.9% vs. baseline 37.1%, p < 0.0001) and clinical outcome scores (86.9%: good-very good) were also positive. Two patients withdrew from treatment <6 months, citing fatigue, which was a common side effect. A mild elevation in liver enzymes (AST and/or ALT < 1.5ULN, 15.4%) and reduced glomerular filtration rates (GFR, 11.5%) were also evident, but no life-threatening adverse events (AEs) were attributed to givosiran treatment. Conclusions: Givosiran is effective in preventing severe acute attacks and reducing the chronic health burden in patients with acute intermittent porphyria. Importantly, HR-QoL improved in patients suffering chronic AIP burden with few incidences of historical attacks. All patients experienced substantially improved mental health, ease of living, and self-perceived health.

Keywords: AHP; AIP; ALA; ALAS1; Fatigue Assessment Scale (FAS); HR-QoL; Ipnet; PBG; chronic symptoms; fatigue; givosiran; siRNA; sporadic attack.

Figure 1

Overview of study timeline and design.

Figure 2

Therapeutic siRNA givosiran alters the urinary biochemical profile of ALA and PBG in patients with AIP. Urinary metabolites (A) delta-aminolevulinic acid (ALA) and (B) porphobilinogen (PBG) were measured following givosiran administration, presented as mean ± SD (μmol/mmol of creatinine) at 0 months (baseline), 3 months and 6 months treatment. Patients’ individual biochemical response, (C) ALA (n = 5), and (D) PBG (n = 5), following breakthrough porphyria symptoms (multiple events are numbered sequentially as 1, 2, and 3) under givosiran during follow-up (months). Dashed lines (----) represent biochemical thresholds (2ULN: ALA 5.32 μmol/mmol of creatinine, PBG 2.02 μmol/mmol of creatinine). Statistical significance was assessed via t-test (*** = p < 0.0001 (compared to baseline), δ = p < 0.05 (3 months vs. 6 months), n = 24–28).

Figure 3

Givosiran treatment is similarly efficacious in its reduction in urinary metabolites ALA and PBG across phenotypically distinct AIP patients. Results after 6 months of givosiran treatment in 26 patients with AIP. Comparison of reduction (fold reduction) of urinary metabolites (A) delta-aminolevulinic acid (ALA) and (B) porphobilinogen (PBG) among phenotypically distinct AIP patients, divided into four groups according to Ipnet definitions. Group definitions: Group 1—Sporadic Attacks (n = 11), Group 2—Symptomatic High Excretor (n = 5), Group 3—Prophylactic Heme (n = 5), and Group 4—Recurrent Attacks (n = 5). Phenotypes are presented separately and collectively as Group 1–2 (n = 16) and 3–4 (n = 10) to demonstrate efficacy in patients (Group 1–2) who were excluded so far from givosiran treatment in other porphyria studies owing either to the sporadic nature of their attacks or chronic symptoms. Values are expressed as a fold reduction relative to baseline levels. Higher values indicate a higher reduction in ALA/PBG. Statistical significance was assessed via one-way ANOVA with Tukey’s multiple comparison test (p > 0.05). Two patients withdrew from givosiran at month 3 and are not included.

Figure 4

Factors affecting the biochemical and clinical outcome of givosiran treatment in patients with AIP. The effect of (A) prior prophylactic heme treatment (i,ii:—none, +regularly, or iii: the total amount historically infused in grammes), or (B) givosiran treatment length (i,ii <12 months or >12 months, or iii: 0–70 months), or (C) Time between AIP diagnosis and givosiran treatment (i,ii <5 years, >5 years, or iii: 0–350 months): on (i) ALA-level fold reduction at 6 months, (ii) PBG-level fold reduction at 6 months, or (iii) clinical outcome (measured on 1–5 scale, worst–best, respectively). For biochemical analysis, individual patient data point distribution is presented as a scatter plot with a median value, and statistical significance was assessed via unpaired, t-test, p > 0.05, n = 26. Simple linear regression with Spearman’s correlation coefficient represents the goodness of fit (r) and statistical significance (** = p < 0.01, n = 26), ns (not significant, p > 0.05).

Figure 5

Givosiran reduces the incidence of acute attacks in patients with distinct porphyria phenotypes. The historical annualised attack rate (AAR) is compared with the AAR under givosiran after 6 months in patients with phenotypically distinct AIP patients divided into four groups according to Ipnet definitions. Group definitions ‘All patients’ (n = 24, based on the availability of historical data); Group 1—‘Sporadic Attacks’ (n = 11) and Group 2—‘Symptomatic High Excretor’ (n = 5), Group 3—‘Prophylactic Heme’ (n = 4), and Group 4—‘Recurrent Attacks’ (n = 4). Paradoxically, patients in Groups 1–2 display a high mean AAR due to a number of attacks in their total disease history (>24 months before givosiran initiation), regardless of their Ipnet classification exclusively employing a timeframe of 2 years. ‘Breakthrough Patients’ are the subset of patients experiencing porphyria attack symptoms under givosiran (“Givo”) after 6 months (n = 9). Statistical significance was assessed via a one-way ANOVA with Dunnett’s test for multiple comparisons ** = p < 0.01, * = p < 0.05 (mean historical AAR vs. mean Givo AAR), ns (not significant, p > 0.05).

Figure 6

Patient versus physicians’ perception of clinical success under givosiran. Clinical outcome was measured on a patient- or physician-reported scale of 1–5 (1 = poor, 2 = unsatisfactory, 3 = satisfactory, 4 = good, 5 = very good). Data are presented together: all patients (n = 23) or as collective groups: 1–2 (n = 14), Group 3–4 (n = 9), versus physicians (n = 27). We assessed statistical significance via two-way ANOVA with multiple comparisons (p > 0.05).

Figure 7

Givosiran improved all aspects of the quality of life in AIP patients. The effect of givosiran treatment on self-reported aspects of QoL in all patients (n = 18–25, some lost to follow-up), using the EQ-5D-5L Questionnaire measuring the following: (A) Agility, (B) Ease of everyday tasks, (C) Anxiety and depression, (D) Self-care, or (E) Pain/discomfort; expressed on a scale of 1–5 (1 = best, 5 = worst). (F) Overall Health Scale (patient-perceived wellness) is expressed as a percentage of optimal health (100%) in collective groups 1–2 vs. 3–4 (n = 9–16, n = 7–9, respectively); at baseline (0 months), 6 months, 12 months, and on final assessment (+). Statistical significance was assessed via one-way ANOVA, with Dunnett’s test for multiple comparisons comparing all measurements to baseline values (0 months) (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** p < 0.0001), ns (not significant, p > 0.05).

Figure 8

Fatigue is variable in AIP patients undergoing givosiran treatment. We measured (A) fatigue scores and categorised this by (B) severity (‘none’ <21, ‘mild–moderate’ >22–34, and ‘severe’ >35); expressed as fatigue score (A), or percentage of patients (%) (B), respectively. All measurements were assessed at baseline (0 months), 3 months, and 6 months under givosiran treatment (n = 15–19, some data lost to follow-up). Statistical significance was assessed using one-way ANOVA with repeated measures (p > 0.05), with arrows indicating a trend of improvement in fatigue at month 6.