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ILC 2019: Promising results reported with givosiran in acute hepatic porphyria (AHP) and lanreotide in polycystic liver disease (PLD) associated with autosomal dominant polycystic kidney disease (ADPKD)

13 April 2019, Vienna, Austria


Two studies involving individuals with rare liver diseases have reported encouraging findings with investigational agents; givosiran, for the treatment of acute hepatic porphyria (AHP), and long-term lanreotide in polycystic liver disease (PLD) associated with autosomal dominant polycystic kidney disease (ADPKD). The studies, which were presented today at The International Liver Congress™ 2019 in Vienna, Austria, provide new evidence of the clinical benefits of these two treatments in liver conditions in which current treatment options are limited.

The first study was a Phase 3, randomized, double-blind, placebo-controlled study (ENVISION) that evaluated the investigational RNA interference (RNAi) agent, givosiran, in AHP1 – a rare and serious genetic condition caused by problems with the normal liver production of heme (a molecule required for the function of haemoglobin and some other proteins).2,3 The treatment has been designed to reduce levels of the enzyme, hepatic delta aminolevulinic synthase 1 (ALAS1) which, when induced, results in the build-up aminolevulinic acid (ALA) and porphobilinogen (PBG), toxic intermediaries of heme synthesis responsible for the potentially life-threatening, recurrent neurovisceral attacks and debilitating chronic symptoms of AHP.1

“The ENVISION study enrolled individuals diagnosed with AHP who were experiencing recurrent neurovisceral attacks” explained Manisha Balwani MD MS, Associate Professor of the Department of Genetics and Genomic Sciences and Department of Medicine at the Icahn School of Medicine at Mount Sinai and principal investigator of the ENVISION study. “Participants were randomized to receive subcutaneous (sc) givosiran 2.5 mg/kg or placebo once-monthly for 6 months. The primary endpoint of the study was the annualized rate of attacks requiring hospitalization, urgent care, or intravenous administration of hemin treatment at home in AIP patients. Secondary endpoints included urine levels of ALA and PBG; rate of hemin usage, a medication used to treat acute porphyria attacks; rate of attacks in AHP patients; symptoms and quality of life measures.”1

Givosiran significantly lowered the mean annualized rate of composite attacks by 74% relative to placebo (p=6.04 x 10-9). Furthermore, the median annualized rate of composite attacks was lowered by 90% relative to placebo, and 50% of patients treated with givosiran were attack-free compared with 16.3% for placebo. In addition, givosiran treatment resulted in significant reductions in levels of urinary ALA and PBG, and the usage of hemin, relative to placebo. Adverse events were reported for most patients (80.4% with placebo; 89.6% with givosiran), and serious adverse events were reported in 20.8% of givosiran and 8.7% of placebo patients. There was one discontinuation from treatment in a patient on givosiran due to a transaminase elevation, per protocol criteria. No deaths were reported on study. Ninety-three of 94 patients enrolled in the open-label extension phase of the study.

“Givosiran represents a novel approach to the treatment of this rare liver disease, for which there is a considerable unmet need,” said Dr Balwani.

The second study presented today evaluated the long-term efficacy of the somatostatin analogue, lanreotide, in PLD associated with ADPKD. Polycystic liver disease is the most common extra-renal manifestation of this rare genetic condition, and is characterized by the development of fluid-filled liver cysts that cause progressive and symptomatic liver enlargement.5

‘Lanreotide has been shown in previous PLD studies to reduce liver volume,6,7 however, there are no robust data on the long-term volume-reducing effects of this or other somatostatin analogues,’ explained Dr René van Aerts from Radboud University Medical Center in Nijmegen, the Netherlands. The study presented by Dr van Aerts involved a subanalysis of data from the DIPAK-1 study, which was a 120-week, randomized, open-label study to compare the renoprotective effect of lanreotide with standard-of-care (SOC) (i.e. blood pressure reduction measures) in 305 individuals with ADPKD.8 The new analysis included 175 individuals from the DIPAK-1 study who had PLD (93 received lanreotide 120 mg sc every 4 weeks, 82 received SOC).

At 120 weeks, the height-adjusted total liver volume (hTLV) decreased 1.99% (95% CI –4.21, 0.24) in the lanreotide treatment group, while it increased by 3.92% (95% CI 1.56, 6.28) in the SOC group (treatment difference: 5.91% (95% CI –9.18, –2.63; (p<0.001). A beneficial treatment effect was still evident 4 months after the last injection (hTLV –3.87%; 95% CI –7.55, –0.18; p=0.04). Lanreotide resulted in an even greater reduction in height-adjusted total liver and kidney volume compared to SOC (-7.18%, CI -10.25 to -4.12; p<0.001).

‘This study has provided the robust evidence we needed that lanreotide is associated with sustained reductions in liver growth in patients with PLD due to ADPKD,’ said Dr van Aerts. ‘The benefits of treatment were apparent even after treatment cessation. In patients with symptomatic PLD, long-term treatment with lanreotide should be considered. A patient-centered approach is needed to decide whether prolonged administration is warranted, based on individual liver volume-reducing effect, effect on symptoms, tolerability, and expected gender- and age-based disease progression.’

‘To perform clinical studies in rare diseases is always very challenging, since the task of enrolling an adequate number of patients is quite complex,’ said Professor Marco Marzioni from the Università Politecnica delle Marche, Ancona, Italy, and an EASL Governing Board Member. ‘The authors of these two studies are thus to be congratulated, since they were able to design and complete very solid studies that contribute to the need of our patients, namely the possibility of receiving a better cure.’


About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2019 will take place from 10­–14 April 2019 at the Reed Messe Wien Congress and Exhibition Center, Vienna, Austria.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.


For more information, please contact the ILC Press Office at:

Onsite location references

Session title: ‘General session 3’

Time, date and location of session: 10:15–10:30, 13 April 2019, Main plenary

Presenter: Manisha Balwani, USA

Abstract: ENVISION, a phase 3 study to evaluate efficacy and safety of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1, in acute hepatic porphyria patients (GS-14)

Session title: Clinical developments in rare liver disease

Time, date and location of session: 08:00–08:15, 13 April 2019, Strauss 3

Presenters: René van Aerts, the Netherlands

Abstracts: Lanreotide reduces liver growth in autosomal dominant polycystic kidney disease: Data from a 120-week randomized clinical trial (PS-192)

Author disclosures

Manisha Balwani (the Principal Investigator in the ENVISION study) receives financial compensation as an advisory board member for Alnylam (the study sponsor and manufacturer of the study drug givosiran). The Icahn School of Medicine at Mount Sinai (“ISMMS”) holds issued and pending patents related to the study drug givosiran and has licensed these patents to Alnylam. As part of the license to Alnylam, ISMMS will receive payments from Alnylam, including a payment when givosiran entered Phase 3 clinical studies, as well as future payments if givosiran becomes a marketed treatment for acute hepatic porphyria. ISMMS, as well as the ISMMS faculty that are named inventors on the licensed patents, will benefit financially.

René van Aerts has no relevant disclosures.


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