Updates on new therapies in development for rare liver diseases

April 14, 2018, European Association for the Study of the Liver

Promising results for three drugs for the treatment of three rare liver diseases were presented today at The International Liver Congress 2018 in Paris, France. Sebelipase alfa, approved for treatment of lysosomal acid lipase (LAL) deficiency in 2015, showed sustained improvements and long-term tolerability in a diverse patient population. Preliminary findings with two investigational RNA interference (RNAi) therapeutics were also positive; givosiran substantially reduced the annualized attack rate in patients with acute intermittent porphyria (AIP), and ARO-AAT demonstrated positive preclinical safety and efficacy in alpha-1 antitrypsin (AAT) deficiency—pointing to the developing potential of this new therapeutic strategy in patients with few treatment options. LAL deficiency, an underappreciated cause of cirrhosis and severe dyslipidaemia, is a rare autosomal recessive disorder characterized by accumulation of cholesteryl esters and triglycerides in the liver.25 The age at onset and rate of progression vary greatly.25 Sebelipase alfa is a recombinant human LAL enzyme indicated for the treatment of LAL deficiency which was approved in 2015 following successful Phase 2/3 trials.

"It is exciting to see clinical benefits and good tolerability confirmed in this long-term follow-up across a diverse population of adult and paediatric with LAL deficiency," said Dr. Florian Abel from Alexion Pharmaceuticals, Inc., New Haven, CT, USA. "This population included patients who would have been ineligible to participate in previous clinical studies because of their age or prior transplant status."

Data were presented today for 31 patients who were enrolled in a multicentre, open-label study of sebelipase alfa 1 mg/kg by intravenous (IV) infusion every other week for up to 96 weeks. Permitted dose escalation/reduction was from a maximum of 3 mg/kg weekly to a minimum of 0.35 mg/kg every other week.

There were marked reductions from baseline in alanine aminotransferase (ALT; -44.4%) and aspartate aminotransferase (AST; -38.4%). There were also reductions from baseline in volume (-17.6%), liver fat content (-14.9%), and spleen volume (-16.5%). In the 7/13 patients with data available, liver fibrosis improved or did not progress. Most adverse events were mild to moderate in severity, three patients experienced infusion-associated reactions. Two patients were positive for anti-drug antibodies, on one occasion each, but neither developed neutralizing antibodies.

"We were pleased to see that long-term treatment with sebelipase alfa was well tolerated and that improvements in markers of liver injury were sustained," said Dr. Abel.

AIP is the most common form of acute hepatic porphyrias (AHPs), a family of rare, inherited metabolic diseases resulting in deficiencies in the liver enzymes responsible for haem biosynthesis.28 Central to the pathophysiology of all AHPs is the induction of aminolevulinic acid synthase 1 (ALAS1), which can lead to accumulation of the neurotoxic haem intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), which are causal for potentially life-threatening disease manifestations.29 RNAi is a naturally occurring cellular mechanism mediated by small interfering RNA (siRNA) that allows for the inhibition of protein synthesis through the cleavage and degradation of a specific mRNA.30 Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting liver ALAS1 to reduce ALA and PBG accumulation in patients with AHPs.

A Phase 1, multinational, randomized, placebo-controlled study of givosiran has been conducted in three parts; Part A: single ascending dose, Part B: multiple ascending dose and Part C: multiple dose (four cohorts of four to five patients each), to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of givosiran in patients with AIP (ClinicalTrials.gov Identifier: NCT02452372). The study has now been completed and givosiran was generally well tolerated, with no serious adverse events or clinically significant laboratory abnormalities related to the study drug.

Monthly dosing of givosiran led to rapid, dose-dependent, and durable silencing of induced ALAS1 mRNA of approximately 60%, with concomitant lowering of ALA and PBG by >80% in patients with recurrent attacks. Patients treated with a monthly dose of 2.5 mg/kg of givosiran had an 83% mean decrease in the annualized attack rate (requiring hospitalization, urgent care, or haemin) compared with placebo, and an 88% decrease in the number of haemin doses. Patients completing the Phase 1 study were eligible to enrol in an open-label extension study (NCT02949830). As of February 2018, the safety profile in patients in the open-label extension (n=16) was consistent with that observed in Part C. Patients that had received givosiran in Part C (n=12) had further reductions in annualized attack rate of 93%, relative to the 3-month run-in period.

"Givosiran has the potential to significantly lower liver ALAS1 levels in a sustained manner and to thereby decrease the accumulation of neurotoxic intermediates that potentially lead to severe or life-threatening neurovisceral attacks. We're very encouraged by our results, as treatment was associated with marked reductions in both annualized attack rate and haemin use," said Dr. Eliane Sardh from the Karolinska University Hospital, Stockholm, Sweden. "These results suggest that givosiran, which is currently being studied in a Phase 3 trial, has the potential to become a transformative treatment option for patients with hepatic porphyrias, a debilitating and potentially life-threatening disease." (NCT03338816).

AAT deficiency is an autosomal, co-dominant genetic disorder in which the PiZ mutation results in the misfolded protein (Z-AAT) that accumulates in hepatocytes and can lead to fibrosis, cirrhosis and hepatocellular carcinoma.31 The only current treatment option for AAT deficiency-related liver disease is liver transplant.31 ARO-AAT is a second-generation, subcutaneously adminstered RNAi therapeutic that replaces ARC-AAT, a first-generation intravenously administered RNAi therapeutic that previously demonstrated proof of concept in the PiZ mouse model expressing human Z-AAT, and achieved deep knockdown in healthy volunteers and patients.32,33

"ARO-AAT is a liver-targeted RNAi therapeutic that durably reduced Z-AAT liver mRNA and serum protein in PiZ mice. The degree of mRNA reduction correlated with the amount of siRNA in the liver," said Dr. Christine Wooddell of Arrowhead Pharmaceuticals, Madison, WI, USA. "We have also assessed the pharmacokinetics and biodistribution of ARO-AAT in rats, efficacy in PiZ mice, and pharmacological activity in non-human primates."

In the studies presented today, ARO-AAT in rats demonstrated high tissue distribution, with the highest exposure in the liver through Day 16, peaking at 4 hours. Repeat dosing (4 mg/kg once every 2 weeks, four times) of young PiZ mice reduced Z-AAT liver mRNA by 95%, plasma Z-AAT by 96%, monomeric liver Z-AAT by 98%, and polymeric Z-AAT by 41%. ARO-AAT prevented increases of Z-AAT polymer globules that were observed in untreated controls of the same age, with a 2.6-fold increase in number, an 8-fold increase in affected liver area, and a 3.3-fold increase in globule size. Non-human primates had a mean reduction of serum AAT of 89-91% that was sustained for more than 7 weeks after the second dose received, following administration of two doses of 3 mg/kg, 4 weeks apart. These results are supportive of monthly or less frequent dosing for ARO-AAT.

"We believe that the results from these studies strongly support advancement of ARO-AAT into the clinic," said Dr. Wooddell. "A Phase 1 single- and multiple-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and effect of ARO-AAT on serum alpha-1 antitrypsin levels in healthy adult volunteers started administering doses to subjects on 12 March 2018."

"Rare diseases are a greater challenge than you might expect, as apart from the difficulties in reaching a full diagnosis, there are often no effective treatments available," said Prof. Marco Marzioni from the University Hospital of Ancona, Italy, and EASL Governing Board Member. "For instance, the study investigating a treatment for LAL deficiency is important, as this is a disease that we only recently learned to identify."

Explore further: Phase 2 studies of two novel treatments for primary biliary cholangitis report encouraging results

Related Stories

Phase 2 studies of two novel treatments for primary biliary cholangitis report encouraging results

April 13, 2018
Preliminary results from two ongoing Phase 2 studies of novel agents under investigation for the treatment of primary biliary cholangitis (PBC) have suggested promising efficacy, safety and tolerability profiles in patients ...

NGM282—an engineered analogue of FGF19—shows promise in patients with primary sclerosing cholangitis

April 13, 2018
The fibroblast growth factor 19 (FGF19) engineered analogue, NGM282, inhibits bile acid synthesis, decreases markers of hepatic inflammation, and significantly improves markers of fibrosis in patients with primary sclerosing ...

Long-term obeticholic acid treatment leads to reversal or stabilization of fibrosis/cirrhosis in patients with PBC

April 13, 2018
The first results from the POISE biopsy sub-study have today confirmed that long-term treatment with obeticholic acid (OCA) leads to the reversal or stabilization of fibrosis/cirrhosis in patients with primary biliary cholangitis ...

New enzyme-replacement therapy shows promise for genetic lipid disease treatment

September 9, 2015
Of the more than 50 known lysosomal storage diseases (LSDs)-rare inherited metabolic disorders-only seven can be treated with approved enzyme-replacement therapies. Lysosomal acid lipase deficiency (LALD) is an LSD that causes ...

New therapy has potential to advance the treatment of pediatric cholestatic liver diseases

April 22, 2017
Results presented today from a study of a novel ileal bile acid transport inhibitor, A4250, demonstrated that it reduced levels of blood (serum) bile acids, which are characteristic of many liver diseases and often associated ...

New gene editing approach for alpha-1 antitrypsin deficiency shows promise

October 20, 2017
A new study by scientists at UMass Medical School shows that using a technique called "nuclease-free" gene editing to correct cells with the mutation that causes a rare liver disease leads to repopulation of the diseased ...

Recommended for you

Deadly Rift Valley fever: New insight, and hope for the future

July 19, 2018
Health control measures alone could be ineffective in the long term fight against the deadly Rift Valley fever which affects both humans and animals, a new study in the journal PNAS reports.

New guidelines to diagnose, manage rare endocrine disorders

July 19, 2018
International guidelines have been published for the first time to help doctors around the globe diagnose and manage patients with a very rare set of endocrine diseases known as pseudohypoparathyroidism and its related disorders, ...

Overuse of antibiotics not what the doctor ordered

July 19, 2018
With increased use of antibiotics worldwide linked to growing antibiotic resistance, a world-first study co-authored by a QUT researcher has highlighted the growing impact of non-prescription supply of antibiotics in community ...

Alcohol-related cirrhosis deaths skyrocket in young adults

July 18, 2018
Deaths from cirrhosis rose in all but one state between 1999-2016, with increases seen most often among young adults, a new study shows.

Hidden blood in feces may signal deadly conditions

July 17, 2018
(HealthDay)—Even if it's not visible to the naked eye, blood in the stool can be serious—a sign of a potentially fatal disease other than colon cancer, new research suggests.

Childhood abuse linked to greater risk of endometriosis, study finds

July 17, 2018
Endometriosis, a painful condition that affects one in 10 reproductive-age women in the U.S., has been linked to childhood physical and sexual abuse, according to findings published today in the journal Human Reproduction.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.