Novel treatment options for acute hepatic porphyrias

Abstract

Purpose of review:

Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the neurotoxic porphyrin precursor delta-aminolevulinic acid (ALA). Patient with frequent recurrent acute attacks have been difficult to treat and these patients sometimes require liver transplantation. Recent developments in siRNA-based therapy led to the development of an effective prophylactic treatment for patients with frequent recurrent attacks. This review will describe treatment options for AHP and highlight management in light of new treatment option.

Recent findings:

Givosiran is a novel siRNA-based therapy targeted specifically to hepatocytes to inhibit ALA synthase 1, the first and rate-limiting step in heme biosynthesis. Patients with frequent recurrent attacks treated with givosiran had durable normalization of ALA and significantly reduced numbers of acute attacks and need for hemin treatment. The overall safety profile for givosiran was comparable to placebo and the drug was recently approved by the FDA for treatment of AHP patients.

Summary:

Givosiran is an effective treatment for prevention of acute porphyria attacks in AHP patients with frequent recurrent attacks.

Introduction:

Porphyrias are inherited disorders in the heme biosynthesis pathway. Heme is an essential molecule that carries out a wide array of functions necessary for aerobic life. It is synthesized through eight enzymatic steps, and mutations that lead to partially defective activity in heme synthesis enzymes result in the eight inherited porphyrias (Table 1) [1, 2]. Symptoms for the porphyrias are due to the specific intermediates that accumulate prior to the defective enzymatic step. The four acute hepatic porphyrias (AHP), acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and 5-aminolevulinic acid dehydratase deficiency porphyria (ALAD) present with identical episodic acute neurovisceral attacks due to abnormal accumulation of the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).

Table 1:

List of porphyrias and the corresponding defective step in heme biosynthesis

Types of Porphyria	Enzyme (Gene)	Clinical pearls:
X-linked protoporphyria	ALA synthase 2 (ALAS2)	Cutaneous porphyria with same clinical presentation as EPP
ALA-Dehydratase Deficiency Porphyria (ADP)	ALA-dehydratase (ALAD)	Rarest of the acute porphyrias. Biochemically shows elevated ALA with normal PBG.
Acute Intermittent Porphyria (AIP)	Hydroxymethylbilane Synthase (HMBS)	Most common form of acute hepatic porphyria.
Porphyria Cutanea Tarda (PCT)	Uroporphyrinogen Synthase (UROS)	Cutaneous porphyria that presents with skin fragility and skin blisters. Most common form of porphyria and the only porphyria that can be acquired. About 20% of patients have familial PCT. Homozygous UROS mutations lead to the rare hepatoerythropoietic porphyria (HEP)
Congenital Erythropoietic Protoporphyria (CEP)	Uroporphyrinogen Decarboxylase (UROD)	Presents with severe photosensitivity with or without hemolysis. Severe forms can lead to disfiguring photomutilation.
Hereditary Coproporphyria (HCP)	Coproporphyrinogen Oxidase (CPOX)	Can present with both acute attacks and blistering skin lesions.
Variegate Porphyria (VP)	Protoporphyrinogen Oxidase (PPOX)	Has high prevalence in South Africa due to founder effect from a Dutch settler
Erythropoietic Protoporphyria (EPP)	Ferrochelatase (FECH)	Acute burning sensation in skin after sun exposure. Typically presents in early childhood.

Pathophysiology of acute porphyria attacks:

The heme biosynthesis pathway is shown in Figure 1. Though all cells in the human body synthesize heme, it is predominantly formed by erythroblasts in the bone marrow (75 to 80%) and hepatocytes in the liver (15 to 20%) [2]. The pathway is controlled by the first and rate-limiting step, the conversion of glycine and succinyl coenzyme A to ALA by the mitochondrial enzyme ALA synthase (ALAS). There are two forms of ALAS. In non-erythroid cells, including hepatocytes, ALAS1 is expressed. In the liver, ALAS1 is subject to feedback regulation by heme through several different mechanisms to ensure that production of ALA is matched to the demand for heme [2–4]. ALAS2 is the isoform made in bone marrow and is regulated by iron, rather than heme [5].

Figure 1:

The pathway of heme synthesis. (ALA = delta-aminolevulinic acid; PBG = porphobilinogen; URO = uroporphyrin; COPRO = coproporphyrin; PROTO = protoporphyrin.)

In the AHPs, ALAS1 typically remains the rate-limiting step in the liver even with a partially defective enzyme downstream, and there is no accumulation of ALA and PBG. Under conditions of increased hepatic heme demand, ALAS1 expression increases, and the defective enzymatic step becomes the rate-limiting step. This results in abnormal accumulation of ALA and PBG, as well as insufficient heme production, which further activates ALAS1. In ADP, only ALA is elevated. In HCP and VP, the accumulation of the porphyrins coproporphyrinogen III and protoporphyrinogen IX, respectively, inhibits the function of hepatic hydroxymethylbilane synthase (also known as PBG deaminase) [6]. This is the metabolic setting for an acute attack.

Porphyrin precursors, in particular ALA, are neurotoxins, whereas porphyrins are light absorbing chemicals that act as photosensitizers, resulting in skin damage. Several lines of evidence show excess hepatic ALA production as the mediator of neurotoxicity in acute attacks. Acute attacks are always accompanied by elevated urine ALA, and effective therapy correlates with decreased ALA levels [7]. In non-porphyria conditions with identical symptoms as AHP, lead intoxication and hereditary tyrosinemia, ALA (but not PBG) is elevated. Liver transplantation, which does not affect heme synthesis deficiency in neurologic tissue, is curative for AHPs [8] while domino liver transplantation of AIP livers with elevated ALA production is sufficient to cause acute attacks in recipients who have otherwise normal heme synthesis [9].

All four AHPs present with identical clinical symptoms of episodic, severe neurovisceral attacks [10]. In variegate porphyria (VP) and hereditary coproporphyria (HCP), both porphyrin precursors and porphyrins accumulate, and patients with these types can present with both neurovisceral attacks and cutaneous symptoms. The most common symptoms are listed in Table 2. During an acute attack, patients present with severe non-focal abdominal pain typically associated with nausea, vomiting and constipation. Neurologic symptoms are present in up to 70% of acute attacks [10]. All levels of the nervous system can be affected [11, 12], and the wide range and non-specific nature of the symptoms contributes to the difficulty in diagnosing acute porphyria attacks. The rate of symptom progression is variable but can be rapid, progressing to flaccid tetraplegia and respiratory paralysis within days. Prolonged or frequent attacks can lead to permanent neurologic damage and chronic pain and neuropathy, causing significant morbidity and severely affect qualify of life [13].

Table 2.

Symptoms and signs in acute hepatic porphyria at presentation

Symptom/Signs	Frequency (%)
Abdominal pain	74
Nausea, vomiting	73
Weakness	63
Constipation	60
Anxiety/Depression	55
Palpitations	50
Hypertension	40
Diarrhea	29
Sun sensitivity	20
Seizures	9

Note: Data taken from Bonkovsky [52]. The findings in hereditary coproporphyria and variegate porphyria are similar [36].

Genetics and clinical presentation of AHPs:

AIP, HCP and VP are autosomal dominant disorders while ALAD porphyria is a very rare autosomal recessive disorder with only 8 reported cases in the world literature [14–17]. Disease-causing mutations in AHP genes result in at least 50% reduction of the activity in the corresponding enzyme. While all AHPs are rare diseases, recent data from population level genetic studies show that the prevalence of genetic carrier state for AHPs is between 1:1300 to 1:1785, much higher than previously thought 25 [18, 19].

The vast majority of genetic carriers of AHP do not experience symptomatic acute attacks in their lifetime. The estimated penetrance of symptomatic disease is ~1% of AIP gene carriers [19] with HCP and VP thought to be more often latent than AIP [20]. These patients have normal ALA and PBG levels and are not clinically affected by this disease. The low penetrance indicates the likely presence of additional factors that are required for symptomatic manifestation of AHPs, including precipitating factors, as well as likely unknown modifying genes and/or epigenetic factors [21, 22]. Sex hormones, in particular progesterone, are known to precipitate attacks. Approximately 90% of symptomatic AHP patients are women, and attacks are rare before the onset of menses or after menopause in these patients. Other common precipitating factors include medications and chemicals that induce cytochrome P450 enzymes in the liver, acute illness such as infection, stress, excess alcohol intake, and caloric deprivation. These factors all induce hepatocyte ALAS1 mRNA expression [23–26].

Within symptomatic AHP patients, more than 90% experience only one or a few acute attacks in their lifetime. These attacks are often precipitated by inducing factors, and outside of acute attacks these patients have normal ALA and PBG levels. An estimated 3–5% of symptomatic AHP patients experience frequent recurrent attacks, typically defined as having more than 4 attacks per year. These attacks are typically not associated with identifiable triggers, though some with attacks during the luteal phase of their menstrual cycles are believed to be triggered by progesterone. In addition to the acute attack symptoms described above, more than 50% of frequent recurrent attack patients have chronic neurologic symptoms, and 35% had a diagnosis of neuropathy [13, 27]. These patients have markedly impaired quality of life [28, 29], and are at higher risk for long-term complications of AHP, including liver disease, hepatocellular carcinoma [30] and chronic renal failure [31, 32]. ALA and PBG levels in frequent recurrent attack patients are elevated, even in between attacks [33]. It is unclear whether their chronic symptoms are due to unrecovered neurologic damage from frequent severe acute attacks or persistently elevated ALA.

Some individuals who carry an AHP mutation have elevated ALA and PBG but do not have acute attack symptoms. This group of asymptomatic high excretors (ASHE) may be at increased risk, relative to mutation carriers with normal ALA, for an induced acute attack or for chronic renal or hepatic injury [34, 35]. These patients may also have chronic, subacute neurologic symptoms [36]. It is unclear whether this is due to chronically elevated ALA levels.

Treatment of acute attacks:

The primary goals of treatment during an acute attack are to relief ALAS1 induction in the liver, leading to decreased production of ALA, and symptomatic management of the severe pain. Identifiable precipitating factors such as medications that induce cytochrome P450s are stopped. Carbohydrate loading is commonly used during early stages of acute attacks. Animal studies have shown that fasting induces the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which induces the expression of ALAS1 [24]. This is the basis for giving carbohydrates to patients in an acute attack [37].

The only definitive treatment for acute attacks is intravenous heme infusions [7, 38–41]. Heme rapidly down-regulates ALAS1 expression in the liver, thus stopping the continued accumulation of ALA and PBG. Symptomatic relief depends on elimination of excess ALA and PBG and typically takes 48–72 hours. The recovery rate of neurologic symptoms can vary, depending on the underlying pathology. Timely treatment with heme results in normalization of ALA and PBG levels, improvement of attack symptoms, and avoidance of long-term neurologic symptoms.

Despite the improvement in management of acute attacks, treatment for AHP patients with frequent recurrent attacks remains challenging. The majority of these patients are women during their reproductive years, and some have catamenial-associated attacks. These patients can be treated with hormonal suppression therapy, but the success is limited [42]. Off-label use of prophylactic intravenous heme infusions is commonly used [1]. While heme is clearly effective at stopping acute attacks, its effectiveness as prophylaxis against frequent attacks is less established. In addition, chronic heme use is associated with a number of complications. This includes the need for indwelling venous catheter which can be complicated by loss of venous access or sepsis. Secondary iron overload is common with frequent heme infusions. Access to frequent heme infusion can be difficult.

In some patients with frequent recurrent attacks not controlled by prophylactic heme infusions, liver transplantation has been used as a treatment of last resort [43, 44]. Liver transplant effectively restores heme synthesis pathway in the liver and is curative. However, given the shortage of donors and high risk of OLT, alternative treatment are needed.

Givosiran as prophylaxis for frequent recurrent acute attacks in AHP:

Recently, a novel siRNA based therapy against ALAS1 has been approved for patients with frequent recurrent attacks [45]. The therapy directly targets controlling hepatic ALAS1 induction. Givosiran is an ALAS1 specific siRNA covalently linked to N-acetyl galactosamine (GalNAc) that is administered subcutaneously and taken up selectively by hepatocytes via the asialoglycoprotein receptor (ASGPR) [46]. After uptake into hepatocytes, the siRNA is processed by the cellular enzyme Dicer into approximately 20 bp long single strands which bind to ALAS1 mRNA and targets it for destruction. The result is reduced translation of the ALAS1 protein and decreased production of ALA.

Givosiran was first studies in a multicenter, randomized, placebo-controlled phase I/II study conducted on 40 patients with AIP [33]. This study consisted of 3 parts. In parts A and B, 23 AIP patients with elevated urinary ALA and PBG but no attacks (ASHE) were treated with givosiran. Patients were randomly assigned in a 3:1 ratio to receive one of five ascending doses of givosiran or a single subcutaneous injection of placebo. 42 days after the injection, patients were found to have a dose-dependent decrease in urinary ALA and PBG of 91 and 96%, respectively, in the group receiving 2.5 mg/kg of givosiran (n = 3).

In part C of this study, 17 patients with >2 attacks within 6 months (defined as requiring hospitalization, urgent health care or IV heme admintration ) were randomized to receive givosiran monthly or quarterly for 12 weeks vs placebo. Monthly givosiran administration (n = 6) resulted in sustained lowering of ALA and PBG urinary excretion (>90% of baseline values) to normal levels, a 57% reduction in the annualized attack rate (AAR), and 48% reduction in annualized number of heme doses compared to baseline.

Serious adverse events (SAE) occurred in 6 of 33 patients (18%) who received givosiran compared with none in the placebo group. This included one spontaneous abortion and 1 case of hemorraphic pancreatitis, both determined to be unrelated to givosiran. The rates of adverse events (AE) were similar between the groups.

A larger, multinational phase III clinical trial on the safety and efficacy of givosiran for preventing frequent attacks of acute porphyrias was recently completed [45]. Patients with > 2 attacks within 6 months were eligible. A total of 94 patients were randomized in a 1:1 ratio to placebo (n = 46) or givosiran (n = 48), administered monthly for 6 months. In the givosiran arm, urinary ALA and PBG were 86% and 91% lower relative to baseline, respectively, and the reductions were sustained throughout intervention period. The givosiran group experienced a 74% reduction in annualized attack rates over 6 months when compared with patients on placebo: 12.5 vs 3.2. Additionally, 50% of patients on givosiran experienced no acute attacks during the study compared to 17% of patients on placebo. Heme use was significantly lower in the givosiran group compared with placebo, with a 77% reduction in the mean annualized number of heme use days.

Safety data about givosiran from the phase 3 study showed overall comparable rates of AEs in givosiran (90%) vs placebo (80%) arms. A higher rate of SAEs was reported in the givosiran group (21%) compared to the control (10%). The adverse events observed more frequently with givosiran include increased serum alanine aminotransferase (ALT), decreased eGFP, injection site reactions, nausea, rash and fatigue. Alanine aminotransferase increases of >3 times upper limit of normal was seen in 7 patients on givosiran (14.6%) compared to 1 patient in the placebo arm. One of the seven patients in the givosiran group discontinued the study drug due to a > 9-fold increase, five of the seven patients had normalization of their ALT without change in givosiran dose. Worsening renal function (increased serum creatinine with concomitant decrease in eGFP) was reported in five patients on givosiran, who had chronic renal insufficiency at baseline. The mean creatinine elevation of 0.08 mg/dL at 3 months in these patients either resolved or remained stable by the end of the double-blind phase of the trial.

Based on these results, givosiran was approved by the Food and Drug Administration in November 2019 for adults with AHP.

Conclusion and Future directions:

AHPs are a group of rare genetic diseases characterized by episodic acute neurovisceral pain episodes. The disease may be underdiagnosed as recent population genetic studies have shown that prevalence of mutations is much higher than previously thought. Prior to the development of heme therapy, AHP patients were at risk for increased mortality and severe neurological complications [47]. With improved recognition of acute attacks, avoidance of known pharmacological triggers, better critical care and heme treatment, the prognosis of AHP has improved dramatically. Overall, patients can have a good prognosis, especially if they are free of acute attacks or when the diagnosis is made in a timely fashion, acute attacks are managed rapidly, and future attacks prevented.

Despite this, the subset of AHP patients with frequent recurrent attacks have remained at risk for significant morbidity. The recent development of givosiran as a highly effective prophylactic therapy for this select patient population is an exciting and welcome treatment option. The hope is that suppression of repeated acute attacks will prevent the development of chronic pain and lead to significantly improved quality of life in these patients. An ongoing open label extension study will begin to answer some of these questions.

Looking ahead, the ability to normalize ALA and PBG levels long-term will allow us to determine whether the chronic sequelae in AHPs, including renal insufficiency and HCC can be prevented. Additional treatment options are also being developed in the horizon. This includes recombinant adeno-associated virus mediated transfer of human PBGD cDNA and administration of human PBGD mRNA packaged into lipid nanoparticles for treatment of AIP patients [48, 49].

Key bullet points:

• Acute porphyria attacks cause severe episodic abdominal pain.

• Treatment of acute attacks require prompt treatment with hemin.

• In patients with frequent recurrent attacks, treatment with monthly siRNA therapy is effective in drastically reducing the number of attacks and amount of hemin treatments needed.