RNA interference therapy in acute hepatic porphyrias.

The acute hepatic porphyrias (AHPs) are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks precipitated by factors that upregulate hepatic 5-aminolevulinic acid synthase 1 (ALAS1) activity. Induction of hepatic ALAS1 leads to the accumulation of porphyrin precursors, in particular 5-aminolevulinic acid (ALA), which is thought to be the neurotoxic mediator leading to acute attack symptoms such as severe abdominal pain and autonomic dysfunction. Patients may also develop debilitating chronic symptoms and long-term medical complications, including kidney disease and an increased risk of hepatocellular carcinoma. Exogenous heme is the historical treatment for attacks and exerts its therapeutic effect by inhibiting hepatic ALAS1 activity. The pathophysiology of acute attacks provided the rationale to develop an RNA interference therapeutic that suppresses hepatic ALAS1 expression. Givosiran is a subcutaneously administered N-acetylgalactosamine-conjugated small interfering RNA against ALAS1 that is taken up nearly exclusively by hepatocytes via the asialoglycoprotein receptor. Clinical trials established that the continuous suppression of hepatic ALAS1 mRNA via monthly givosiran administration effectively reduced urinary ALA and porphobilinogen levels and acute attack rates and improved quality of life. Common side effects include injection site reactions and increases in liver enzymes and creatinine. Givosiran was approved by the US Food and Drug Administration and European Medicines Agency in 2019 and 2020, respectively, for the treatment of patients with AHP. Although givosiran has the potential to decrease the risk of chronic complications, long-term data on the safety and effects of sustained ALAS1 suppression in patients with AHP are lacking.

Pharmacokinetic-pharmacodynamic model of urinary δ-aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria.

Givosiran, an RNA interference-based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I-III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA-induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ-aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035-5 mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5-mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.

[Acute hepatic porphyrias]. / Akute hepatische Porphyrien.

Acute porphyrias are caused by rare hereditary disorders of hepatic heme biosynthesis. Episodes of accumulating neurotoxic metabolites lead to multisystemic symptoms such as visceral pain, autonomic dysregulation, neurocognitive impairment, hyponatremia, and occasionally motor paralysis. In addition to protracted non-emergency courses, acute life-threatening crises can occur, often triggered by infection, medication, fasting, or hormonal stimuli. Since the clinical presentation is nonspecific and multifaceted, many patients have gone through a long odyssey until they receive a diagnosis. Acute attacks often lead to presenting initially to the emergency department, where acute hepatic porphyria (AHP) is easily overlooked in the differential diagnosis. Establishing the diagnosis requires a high level of genuine suspicion (e.g., cluster of signs and symptoms along with certain patterns of health care resource utilization). The initial diagnostic work-up requires the measurement of metabolites in the urine. Emergency management consists of infusions of glucose and heme arginate along with symptomatic therapy. However, porphyrinogenic agents must be strictly avoided ( www.drugs-porphyria.org ). After initial diagnosis, a thorough work-up should be done at a porphyria center (confirming the diagnosis, education, genetic counselling) and issuance of an emergency identification card is mandatory. If the frequency of relapses is high, new targeted prophylactic therapies have proven effective. Patients with known porphyria require special attention in any acute medical condition in order to avoid porphyrinogenic triggers and to exclude threatening differential diagnosis (e.g., sepsis) by consistent basic diagnostics.

Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review.

Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.

Petits ARN interférents : applications potentielles pour les néphrologues Small interfering RNA: potential applications for nephrologists.

Small interfering RNA (siRNAs) are double-stranded RNAs of around 20 base pairs in length that trigger RNAi machinery, which promotes degradation of a target mRNA avoiding protein translation. SiRNAs are liver-targeted, using tris N-acetylgalactosamine (GalNAc) as the targeting ligand. This discovery received the Nobel Prize for medicine and physiology in 2006 and lead to substantial therapeutic advances. Application field and development of these siRNA has been very fast. Indeed, patisiran has been released in 2018 for hereditary transthyretin amyloidosis. This first treatment showed the security and efficacy of such a product. Since, treatments have been developed for acute hepatic porphyria and primary hyperoxaluria. The current pipeline for new siRNA development is ambitious; clinical trial are ongoing in nephrology, as in the IgA nephropathy. Frequent diseases are also targeted such as hypertension or hypercholesterolemia. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.

EXPLORE B: A prospective, long-term natural history study of patients with acute hepatic porphyria with chronic symptoms.

One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (<3 attacks and no prophylaxis treatment) attacks. Patients in the total population (N = 136), and more (n = 110) and fewer (n = 26) attack subgroups, reported a median (range) of 3 (0-52), 4 (0-52), and 1 (0-2) acute attacks, respectively, in the 12 months prior to the baseline visit. Pain, mood/sleep, digestive/bladder, and nervous system symptoms were each experienced by ≥80% of patients; most received hemin during attacks. Almost three-quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.

Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran.

INTRODUCTION: Homocysteine is a sulfur-containing amino acid formed in the intermediary metabolism of methionine. Amino acid metabolism and heme biosynthesis pathways are complexly intertwined. Plasma homocysteine elevation, hyperhomocysteinemia (HHcy), has been reported in patients with acute hepatic porphyria (AHP), a family of rare genetic disorders caused by defects in hepatic heme biosynthesis. AREAS COVERED: This article summarizes published case series in which givosiran, a subcutaneously administered small interfering RNA approved for AHP treatment, appeared to exacerbate dysregulated homocysteine metabolism in patients with AHP. A comprehensive exploratory analysis of ENVISION trial data demonstrated that on a population level, givosiran increased homocysteine but with wide interpatient variations, and there is no proof of correlations between HHcy and changes in efficacy or safety of givosiran. EXPERT OPINION: The strong correlation and co-increase of homocysteine and methionine suggest that HHcy associated with givosiran is likely attributable to the impaired trans-sulfuration pathway catalyzed by cystathionine ß-synthase, which uses vitamin B6 as a cofactor. Data-based consensus supports monitoring total plasma homocysteine and vitamin B6, B12, and folate levels before and during givosiran treatment; supplementing with pyridoxine/vitamin B6 in patients with homocysteine levels >100 µmol/L; and involving patients with homocysteine levels >30 µmol/L in decisions to supplement.

Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy.

Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Acute hepatic porphyrias are a group of rare, inherited metabolic disorders, characterized by acute potentially life-threatening attacks as well as chronic symptoms with a negative impact on quality of life. It has four types, each associated with distinct enzyme defects in the heme biosynthesis pathway in the liver. By targeting the expression of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1], givosiran can down-regulate levels of toxic metabolites, leading to biochemical and clinical improvement. Givosiran selectively targets hepatocytes due to its linkage to N-acetylgalactosamine (GalNac) leading to its selective uptake via asialoglycoprotein receptors (ASGPR). We provide an up-to-date literature review regarding givosiran in the context of a clinical overview of the porphyrias, an overview of siRNAs for therapy of human disorders, the design and development of givosiran, key clinical trial results of givosiran for prevention of acute porphyric attacks, emerging concerns regarding chronic use of givosiran, and the overall management of acute hepatic porphyrias. These insights are important not only for the management of acute hepatic porphyrias but also for the emerging field of siRNAs and their role in novel therapies for various diseases.

Givosiran for the treatment of acute hepatic porphyria.

INTRODUCTION: Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients' quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression. AREAS COVERED: For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals. EXPERT OPINION: Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study.

BACKGROUND & AIMS: Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. AIMS: evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria. METHODS: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. RESULTS: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period. CONCLUSIONS: Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

A Drug-Drug Interaction Study Evaluating the Effect of Givosiran, a Small Interfering Ribonucleic Acid, on Cytochrome P450 Activity in the Liver.

Givosiran (trade name GIVLAARI) is a small interfering ribonucleic acid that targets hepatic delta-aminolevulinic acid synthase 1 (ALAS1) messenger RNA for degradation through RNA interference (RNAi) that has been approved for the treatment of acute hepatic porphyria (AHP). RNAi therapeutics, such as givosiran, have a low liability for drug-drug interactions (DDIs) because they are not metabolized by cytochrome 450 (CYP) enzymes, and do not directly inhibit or induce CYP enzymes in the liver. The pharmacodynamic effect of givosiran (lowering of hepatic ALAS1, the first and rate limiting enzyme in the heme biosynthesis pathway) presents a unique scenario where givosiran could potentially impact heme-dependent activities in the liver, such as CYP enzyme activity. This study assessed the impact of givosiran on the pharmacokinetics of substrates of 5 major CYP450 enzymes in subjects with acute intermittent porphyria (AIP), the most common type of AHP, by using the validated "Inje cocktail," comprised of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). We show that givosiran treatment had a differential inhibitory effect on CYP450 enzymes in the liver, resulting in a moderate reduction in activity of CYP1A2 and CYP2D6, a minor effect on CYP3A4 and CYP2C19, and a similar weak effect on CYP2C9. To date, this is the first study evaluating the DDI for an oligonucleotide therapeutic and highlights an atypical drug interaction due to the pharmacological effect of givosiran. The results of this study suggest that givosiran does not have a large effect on heme-dependent CYP enzyme activity in the liver.

[New therapeutic option for acute hepatic porphyrias]. / Neue Therapieoption für akute hepatische Porphyrien.

Givosiran is a small synthetic double-stranded siRNA (small interfering RNA) conjugated with N-acetyl-galactosamine (GalNAc) for specific hepatocyte targeting via the asialoglycoprotein receptor. A prospective randomized multicenter study (Envision) demonstrated the clinical efficacy of monthly subcutaneous injection of Givosiran for the prevention of attacks of acute hepatic porphyria (AHP). This leads to highly selective transcriptional inhibition of the key hepatic enzyme, aminolaevulinate synthase 1, that is overexpressed in AHP. The success of the Envision study has led to the approval of Givosiran in the US and Europe for the treatment of severe AHP. This innovative guided siRNA therapy has opened up the possibility to selectively inhibit the expression of any hepatocyte gene whose overexpression that causes pathology, which can be considered a milestone development in hepatology. However, currently this treatment with givosiran is very costly. Moreover, since some patients experience worsening of kidney function and elevated aminotransferases, monthly monitoring of these parameters is necessary in the first half year of treatment.

Multiple roles of haem in cystathionine ß-synthase activity: implications for hemin and other therapies of acute hepatic porphyria.

The role of haem in the activity of cystathionine ß-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5'-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.

Givosirana para o tratamento pacientes adultos com porfirias hepáticas agudas / Givosiran for the treatment of adult patients with acute hepatic porphyria

INTRODUÇÃO: As Porfirias Hepáticas Agudas (PHA) são doenças metabólicas, raras, hereditárias autossômicas, sendo os quatro tipos diferentes de PHA resultantes da deficiência de cada uma das enzimas envolvidas na biossíntese do heme, ocasionando assim, o acúmulo de precursores de porfirinas. Esse acúmulo de precursores de porfirinas se torna tóxico em altas doses, ocasionando dano aos tecidos. Essas crises agudas acometem os pacientes geralmente entre as idades de 15 e 45 anos, sendo mais comum em mulheres e com provável maior frequência durante ou após a gestação. Os dados epidemiológicos da PHA são escassos, não havendo no Brasil estimativas robustas. Contudo, o registro da Associação Brasileira de Porfiria (ABRAPO) identificou 293 pacientes com PHA entre 2007 e 2015. Atualmente não há Protocolo Clínico e Diretrizes Terapêuticas (PCDT) publicado sobre a porfiria hepática aguda. As opções de tratamento atuais para pessoas com PHA visam o manejo das manifestações clínicas das crises e a interrupção de potenciais desencadeadores das crises, uma vez que atualmente há poucos medicamentos destinados ao tratamento específico das PHA. TECNOLOGIA: givosirana. PERGUNTA: Givosirana é eficaz, segura e custo-efetiva para o tratamento de pacientes com porfirias hepáticas agudas? EVIDÊNCIAS CLÍNICAS: Dois Ensaios Clínicos Randomizados (ECR), um de fase I e um de fase III foram incluídos na seleção do demandante e da Secretaria Executiva da CONITEC. A givosirana ocasionou redução estatisticamente significante da taxa média anual de ataques de porfiria (com taxas de reduções em relação ao placebo de 57% e 74% nos ECR de fase I e II, repsctivamente) e dos níveis urinário de ácido aminolevulínico (redução percentual mediana da linha de base aos seis meses de tratamento foi de 86% p< 0,001) e porfobilinogênio (redução percentual mediana da linha de base aos seis meses de tratamento foi de 91% p< 0,001), quando comprado ao placebo. Alguns itens da qualidade de vida dos pacientes que utilizaram givosirana, mensurada pelo SF-12, PGIC e PPEQ, também aumentou significantemente em comparação aos pacientes que utilizaram placebo. Dessa forma, acredita-se que givosirana se mostrou mais eficaz que o placebo para o tratamento da porfiria hepática aguda. Contudo, o uso da givosirana também ocasionou maior frequência de eventos adversos, eventos adversos graves e descontinuação de tratamento devido a eventos adversos. Os ECR apresentaram baixo risco de vieses e os desfechos tiveram a qualidade da evidência julgada como moderada. AVALIAÇÃO ECONÔMICA: O demandante apresentou um modelo de Markov de análise de custo-efetividade (ACE) comparando os custos e benefícios da givosirana com o melhor cuidado assistencial no tratamento profilático de crises de PHA em adultos, sob a perspectiva do SUS. A distribuição dos pacientes pelos estados de saúde, probabilidades de transição, taxas anuais de crises agudas, comorbidades associadas e taxa de eventos adversos foram extraídas e extrapoladas do estudo ENVISION. O demandante assumiu como premissa a taxa de mortalidade da população geral por todas as causas, em todos os estados de saúde do modelo. Foi considerado ainda a redução da taxa de crises na menopausa e a desutilidades dos episódios de crise e os custos médicos diretos associados a givosirana e ao melhor cuidado assistencial. O demandante considerou o custo de aquisição da givosirana com o Preço Máximo de Venda ao Governo (PMVG) ICMS 0% de R$ 167.239,27, contudo, por se tratar de um medicamento que atualmente não apresenta nenhuma desoneração fiscal, a Secretaria Executiva da Conitec considerou mais adequado a utilização do ICMS do estado de origem, Goiás, ICMS 17%, ou seja, o valor do givosirana de R$ 202.938,13. O demandante realizou duas análises, uma considerando e uma desconsiderando os custos associados à hemina. Contudo, a Secretaria Executiva da Conitec optou por apresentar apenas a análise desconsiderando esses custos, uma vez que este tratamento não está incorporado no SUS. As razões de custo-efetividade incrementais (RCEI) estimadas pelo demandante e recalculadas considerando o ICMS 17% pela Secretaria Executiva da Conitec foram de R$2.892.086/QALY e R$ 3.538.767/QALY, respectivamente. Na composição dos custos observa-se que o custo de aquisição de givosirana é o mais representativo. Os resultados da análise de sensibilidade determinística mostram que a taxa de desconto dos desfechos clínicos e a desutilidade associada às crises são as de maior influência na RCEI. O modelo do demandante assume várias premissas de estudos conduzidos fora do país, sendo uma limitação importante, uma vez que estes dados podem apresentar variabilidade relevante entre diferentes populações. Ademais, o estudo ENVISION apresenta um curto período de seguimento em relação ao horizonte temporal, dessa forma, muitas extrapolações foram realizadas, o que gera incertezas. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O modelo de IO do demandante estimou os custos relacionados ao tratamento com givosirana em comparação com os melhores cuidados assistenciais. Foi adotado um horizonte temporal de 5 anos e foram considerados elegíveis os pacientes que apresentaram pelo menos uma crise nos últimos 12 meses. A distribuição dos pacientes pelos estados de saúde, probabilidades de transição, taxas anuais de crises agudas, comorbidades associadas e taxa de eventos adversos foram extraídas do estudo ENVISION. O demandante considerou a prevalência e incidência europeia de 9,9 casos e 0,23 novos casos para cada um milhão de habitantes e estimou que somente 20% desses pacientes estariam diagnosticados e que 50% desses teriam apresentado pelo menos uma crise nos últimos 12 meses. O cenário base atual considera a participação de mercado de givosirana é nula, já no cenário alternativo, o demandante estimou um Market share inicial de 5% no primeiro ano, com aumentos até 50% no quinto ano. O demandante considerou como o custo de givosirana, o PMVG com 0% de ICMS, que é de R$ 167.239,27, enquanto Secretaria Executiva da Conitec considerou o PMVG com ICMS 17%, de R$ 202.938,13. O demandante assumiu ainda o custo de administração da injeção subcutânea da givosirana. Dessa forma, os custos incrementais da incorporação de givosirana, acumulados em cinco, foram de 628,5 e 767,6 milhões de reais, estimados pelo demandante e pela Secretaria Executiva da CONITEC, respectivamente. Além das limitações já apontadas na ACE, uma limitação importante destacada pela Secretaria Executiva da Conitec foi a taxa de difusão no mercado que pode estar subestimada, o que poderia aumentar consideravelmente o impacto orçamentário da incorporação da givosirana no SUS. CONSIDERAÇÕES FINAIS: A partir das evidências avaliadas, sugere-se que givosirana é mais eficaz que o placebo para o tratamento da porfiria hepática aguda. Contudo, o uso da givosirana também ocasionou maior frequência de eventos adversos, eventos adversos graves e descontinuação de tratamento devido a eventos adversos. Na ACE, a givosirana se mostrou mais efetiva e mais onerosa em todos os cenários, com uma razão de custo-efetividade incremental importante. Na análise de IO, a givosirana ocasionou um importante aumento dos gastos. No caso de uma potencial incorporação da givosirana para o tratamento da porfiria hepática aguda no SUS, será necessário a elaboração do PCDT de porfiria hepática aguda. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes deliberaram 96ª reunião ordinária, realizada no dia 08 de abril de 2021, por unanimidade, que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à incorporação da givosirana para o tratamento de pacientes com porfirias hepáticas agudas, devido ao elevado valor da razão de custo-efetividade incremental. CONSULTA PÚBLICA: O relatório de recomendação inicial da CONITEC foi disponibilizado para contribuições por meio da consulta pública nº 28/2021 entre os dias 26/04/2021 e 17/05/2021. Foram recebidas 590 contribuições, sendo 86 contribuições de cunho técnico-científico e 504 contribuições de experiência pessoal ou opinião, destas 71,0% discordavam com a recomendação preliminar da Conitec. RECOMENDAÇÃO FINAL: A Conitec, em sua 98ª reunião ordinária, realizada no dia 10 de junho de 2021, deliberou por unanimidade à não recomendação da ampliação do uso da givosirana para o tratamento de pacientes com porfirias hepáticas agudas. Assim, foi assinado o Registro de Deliberação nº 634/2021. DECISÃO: Não incorporar a givosirana para o tratamento de pacientes adultos com porfirias hepáticas agudas, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 38, publicada no Diário Oficial da União nº 127, seção 1, página 143, em 08 de julho de 2021.

Givosirana para o tratamento pacientes adultos com porfirias hepáticas agudas / Givosiran for the treatment of adult patients with acute hepatic porphyrias

INTRODUÇÃO: As Porfirias Hepáticas Agudas (PHA) são doenças metabólicas, raras, hereditárias autossômicas, sendo os quatro tipos diferentes de PHA resultantes da deficiência de cada uma das enzimas envolvidas na biossíntese do heme, ocasionando assim, o acúmulo de precursores de porfirinas. Esse acúmulo de precursores de porfirinas se torna tóxico em altas doses, ocasionando dano aos tecidos. Essas crises agudas acometem os pacientes geralmente entre as idades de 15 e 45 anos, sendo mais comum em mulheres e com provável maior frequência durante ou após a gestação. Os dados epidemiológicos da PHA são escassos, não havendo no Brasil estimativas robustas. Contudo, o registro da Associação Brasileira de Porfiria (ABRAPO) identificou 293 pacientes com PHA entre 2007 e 2015. Atualmente não há Protocolo Clínico e Diretrizes Terapêuticas (PCDT) publicado sobre a porfiria hepática aguda. As opções de tratamento atuais para pessoas com PHA visam o manejo das manifestações clínicas das crises e a interrupção de potenciais desencadeadores das crises, uma vez que atualmente há poucos medicamentos destinados ao tratamento específico das PHA. TECNOLOGIA: givosirana. PERGUNTA: Givosirana é eficaz, segura e custo-efetiva para o tratamento de pacientes com porfirias hepáticas agudas? EVIDÊNCIAS CLÍNICAS: Dois Ensaios Clínicos Randomizados (ECR), um de fase I e um de fase III foram incluídos na seleção do demandante e da Secretaria Executiva da CONITEC. A givosirana ocasionou redução estatisticamente significante da taxa média anual de ataques de porfiria (com taxas de reduções em relação ao placebo de 57% e 74% nos ECR de fase I e II, repsctivamente) e dos níveis urinário de ácido aminolevulínico (redução percentual mediana da linha de base aos seis meses de tratamento foi de 86% p< 0,001) e porfobilinogênio (redução percentual mediana da linha de base aos seis meses de tratamento foi de 91% p< 0,001), quando comprado ao placebo. Alguns itens da qualidade de vida dos pacientes que utilizaram givosirana, mensurada pelo SF-12, PGIC e PPEQ, também aumentou significantemente em comparação aos pacientes que utilizaram placebo. Dessa forma, acredita-se que givosirana se mostrou mais eficaz que o placebo para o tratamento da porfiria hepática aguda. Contudo, o uso da givosirana também ocasionou maior frequência de eventos adversos, eventos adversos graves e descontinuação de tratamento devido a eventos adversos. Os ECR apresentaram baixo risco de vieses e os desfechos tiveram a qualidade da evidência julgada como moderada. AVALIAÇÃO ECONÔMICA: O demandante apresentou um modelo de Markov de análise de custo-efetividade (ACE) comparando os custos e benefícios da givosirana com o melhor cuidado assistencial no tratamento profilático de crises de PHA em adultos, sob a perspectiva do SUS. A distribuição dos pacientes pelos estados de saúde, probabilidades de transição, taxas anuais de crises agudas, comorbidades associadas e taxa de eventos adversos foram extraídas e extrapoladas do estudo ENVISION. O demandante assumiu como premissa a taxa de mortalidade da população geral por todas as causas, em todos os estados de saúde do modelo. Foi considerado ainda a redução da taxa de crises na menopausa e a desutilidades dos episódios de crise e os custos médicos diretos associados a givosirana e ao melhor cuidado assistencial. O demandante considerou o custo de aquisição da givosirana com o Preço Máximo de Venda ao Governo (PMVG) ICMS 0% de R$ 167.239,27, contudo, por se tratar de um medicamento que atualmente não apresenta nenhuma desoneração fiscal, a Secretaria Executiva da Conitec considerou mais adequado a utilização do ICMS do estado de origem, Goiás, ICMS 17%, ou seja, o valor do givosirana de R$ 202.938,13. O demandante realizou duas análises, uma considerando e uma desconsiderando os custos associados à hemina. Contudo, a Secretaria Executiva da Conitec optou por apresentar apenas a análise desconsiderando esses custos, uma vez que este tratamento não está incorporado no SUS. As razões de custo-efetividade incrementais (RCEI) estimadas pelo demandante e recalculadas considerando o ICMS 17% pela Secretaria Executiva da Conitec foram de R$2.892.086/QALY e R$ 3.538.767/QALY, respectivamente. Na composição dos custos observa-se que o custo de aquisição de givosirana é o mais representativo. Os resultados da análise de sensibilidade determinística mostram que a taxa de desconto dos desfechos clínicos e a desutilidade associada às crises são as de maior influência na RCEI. O modelo do demandante assume várias premissas de estudos conduzidos fora do país, sendo uma limitação importante, uma vez que estes dados podem apresentar variabilidade relevante entre diferentes populações. Ademais, o estudo ENVISION apresenta um curto período de seguimento em relação ao horizonte temporal, dessa forma, muitas extrapolações foram realizadas, o que gera incertezas. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O modelo de IO do demandante estimou os custos relacionados ao tratamento com givosirana em comparação com os melhores cuidados assistenciais. Foi adotado um horizonte temporal de 5 anos e foram considerados elegíveis os pacientes que apresentaram pelo menos uma crise nos últimos 12 meses. A distribuição dos pacientes pelos estados de saúde, probabilidades de transição, taxas anuais de crises agudas, comorbidades associadas e taxa de eventos adversos foram extraídas do estudo ENVISION. O demandante considerou a prevalência e incidência europeia de 9,9 casos e 0,23 novos casos para cada um milhão de habitantes e estimou que somente 20% desses pacientes estariam diagnosticados e que 50% desses teriam apresentado pelo menos uma crise nos últimos 12 meses. O cenário base atual considera a participação de mercado de givosirana é nula, já no cenário alternativo, o demandante estimou um Market share inicial de 5% no primeiro ano, com aumentos até 50% no quinto ano. O demandante considerou como o custo de givosirana, o PMVG com 0% de ICMS, que é de R$ 167.239,27, enquanto Secretaria Executiva da Conitec considerou o PMVG com ICMS 17%, de R$ 202.938,13. O demandante assumiu ainda o custo de administração da injeção subcutânea da givosirana. Dessa forma, os custos incrementais da incorporação de givosirana, acumulados em cinco, foram de 628,5 e 767,6 milhões de reais, estimados pelo demandante e pela Secretaria Executiva da CONITEC, respectivamente. Além das limitações já apontadas na ACE, uma limitação importante destacada pela Secretaria Executiva da Conitec foi a taxa de difusão no mercado que pode estar subestimada, o que poderia aumentar consideravelmente o impacto orçamentário da incorporação da givosirana no SUS. CONSIDERAÇÕES FINAIS: A partir das evidências avaliadas, sugere-se que givosirana é mais eficaz que o placebo para o tratamento da porfiria hepática aguda. Contudo, o uso da givosirana também ocasionou maior frequência de eventos adversos, eventos adversos graves e descontinuação de tratamento devido a eventos adversos. Na ACE, a givosirana se mostrou mais efetiva e mais onerosa em todos os cenários, com uma razão de custo-efetividade incremental importante. Na análise de IO, a givosirana ocasionou um importante aumento dos gastos. No caso de uma potencial incorporação da givosirana para o tratamento da porfiria hepática aguda no SUS, será necessário a elaboração do PCDT de porfiria hepática aguda. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes deliberaram 96ª reunião ordinária, realizada no dia 08 de abril de 2021, por unanimidade, que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à incorporação da givosirana para o tratamento de pacientes com porfirias hepáticas agudas, devido ao elevado valor da razão de custo-efetividade incremental. CONSULTA PÚBLICA: O relatório de recomendação inicial da CONITEC foi disponibilizado para contribuições por meio da consulta pública nº 28/2021 entre os dias 26/04/2021 e 17/05/2021. Foram recebidas 590 contribuições, sendo 86 contribuições de cunho técnico-científico e 504 contribuições de experiência pessoal ou opinião, destas 71,0% discordavam com a recomendação preliminar da Conitec. RECOMENDAÇÃO FINAL: A Conitec, em sua 98ª reunião ordinária, realizada no dia 10 de junho de 2021, deliberou por unanimidade à não recomendação da ampliação do uso da givosirana para o tratamento de pacientes com porfirias hepáticas agudas. Assim, foi assinado o Registro de Deliberação nº 634/2021. DECISÃO: Não incorporar a givosirana para o tratamento de pacientes adultos com porfirias hepáticas agudas, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 38, publicada no Diário Oficial da União nº 127, seção 1, página 143, em 08 de julho de 2021.

Nonclinical Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion of Givosiran, the First Approved N-Acetylgalactosamine-Conjugated RNA Interference Therapeutic.

Givosiran is an N-acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t1/2; less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor-mediated uptake, and the t1/2 in the liver was significantly longer (∼1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3' end of antisense strand, AS(N-1)3' givosiran, which was equipotent to givosiran. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, givosiran has a low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. SIGNIFICANCE STATEMENT: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous administration results in adequate exposure of givosiran to the target organ (liver). These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of acute hepatic porphyria.

Givosiran: A Review in Acute Hepatic Porphyria.

Givosiran (Givlaari®) is an δ-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) approved for the treatment of acute hepatic porphyria (AHP). In the phase 3 ENVISION trial, givosiran significantly reduced the annualized rate of composite porphyria attacks (i.e. attacks requiring hospitalization, urgent healthcare visit or intravenous hemin administration at home) compared with placebo in patients with recurrent acute intermittent porphyria (the most common type of AHP) attacks. Givosiran also improved several other outcomes, including hemin use and pain (the cardinal symptom of AHP). While generally well tolerated with an acceptable safety profile, the drug may increase the risk of hepatic and kidney adverse events. Givosiran offers the convenience of once-monthly subcutaneous administration. Available evidence indicates that givosiran is an important newer therapeutic option for patients with AHP and severe recurrent attacks.

Givosiran to treat acute porphyria.

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin.

BACKGROUND: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited. METHODS: We report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment. RESULTS: Circulating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 - an X-linked modifying gene in some other porphyrias - was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera. CONCLUSIONS: Elevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms.