AI-generated summaries. Verify every claim with the cited sources before acting on them. Read our methodology

← Back to all reports

Acute Intermittent Porphyria

Recent research efforts aimed at curing Acute Intermittent Porphyria.

Last updated

Acute Intermittent Porphyria

Overview

Acute intermittent porphyria (AIP) is an inherited liver disorder caused by a harmful variant in the HMBS gene, which reduces activity of hydroxymethylbilane synthase (also called porphobilinogen deaminase, or PBGD), an enzyme needed to make heme. When liver heme production is pushed upward by triggers such as certain medicines, fasting, hormonal changes, alcohol, or illness, toxic precursors—delta-aminolevulinic acid (ALA) and porphobilinogen (PBG)—can accumulate and cause severe “neurovisceral” attacks, including abdominal pain, nausea, fast heart rate, weakness, neuropathy, and psychiatric or neurologic symptoms. Most people who inherit an HMBS variant never develop attacks; attacks usually begin after puberty and are more frequent in women. GeneReviews: Acute Intermittent Porphyria

The prognosis is often good when attacks are recognized quickly and triggers are avoided, but recurrent or poorly controlled disease can cause long-lasting nerve injury, chronic kidney disease, and increased risk of primary liver cancer. Standard care includes stopping triggers, carbohydrate support for mild attacks, intravenous hemin for significant acute attacks, symptom control, and givosiran for people with recurrent attacks. Liver transplantation is currently the only established curative intervention because replacing the liver removes the main source of excess ALA and PBG, but it is reserved for exceptional, severe cases. GeneReviews: Acute Intermittent Porphyria AGA Clinical Practice Update

Scope of Recent Research (2020–present)

Since 2020, AIP research has been active but concentrated in a relatively small number of specialist centers and companies. The dominant questions are whether durable suppression of toxic precursor production can prevent disease complications, and whether restoring PBGD directly in liver cells can provide an etiologic treatment—that is, one that corrects the biochemical defect rather than only controlling its downstream effects. Givosiran has substantially improved disease control but does not repair the inherited HMBS variant; the most important curative-direction advance is repeated lipid-nanoparticle delivery of PBGD messenger RNA (mRNA), which has produced encouraging results in non-human primates but remains preclinical. Final ENVISION results PBGD mRNA in non-human primates

Major Breakthroughs and Emerging Therapies

RNA interference: durable pathway suppression. Givosiran is a small interfering RNA (siRNA) medicine that lowers liver production of ALAS1, the first rate-limiting enzyme in heme synthesis. Lower ALAS1 activity reduces the buildup of ALA and PBG, preventing attacks without replacing the missing PBGD enzyme. In the phase III ENVISION trial, patients with AIP receiving givosiran had a 74% lower annualized attack rate over six months than those receiving placebo, alongside lower ALA and PBG levels, less hemin use, and better pain outcomes. Phase III givosiran trial

Longer follow-up has strengthened the evidence that RNA interference can convert recurrent AIP into a much more manageable condition. In the 36-month ENVISION analysis, the median annualized attack rate during givosiran treatment was 0.4, and 86% of continuously treated participants had no attacks by the end of the open-label extension. However, because treatment must be continued and does not restore normal HMBS function, it is best understood as highly effective disease control rather than a cure. Final ENVISION results

mRNA enzyme replacement: the leading etiologic strategy. Researchers are packaging mRNA encoding human PBGD into lipid nanoparticles, small fat-based delivery particles that preferentially enter liver cells. Once inside hepatocytes, the mRNA directs temporary production of functional PBGD, addressing the enzyme deficiency itself. A 2020 pharmacokinetic-pharmacodynamic modeling study integrated animal data on mRNA delivery, liver PBGD activity, and urinary precursors to help predict human dose and dosing schedules. mRNA therapy modeling for AIP

The most consequential recent experimental result came in 2025, when investigators created an AIP-like non-human-primate model by selectively reducing liver PBGD activity. Repeated systemic PBGD-mRNA treatment restored liver PBGD activity and protected the animals against induced attacks, precursor accumulation, liver metabolic abnormalities, and central nervous system changes. This is an important proof of principle because it tested repeat dosing in a model that reproduced pain, motor abnormalities, and biochemical features of human AIP; it is not yet evidence of safety or efficacy in people. PBGD mRNA in non-human primates

Gene replacement remains conceptually attractive but technically unresolved. Earlier liver-directed adeno-associated virus (AAV) gene therapy delivered a PBGD gene using an AAV2/5 vector. The phase I study found the approach acceptably safe, but it did not achieve metabolic correction at the doses tested, demonstrating that enough PBGD must be delivered to a sufficiently large fraction of liver cells to lower ALA and PBG reliably. That result has helped shift recent emphasis toward improved vectors, more potent PBGD constructs, and repeatable nonviral mRNA delivery. AAV-PBGD phase I trial

Clinical Trials and Experimental Approaches

The major recent clinical evidence concerns givosiran rather than a permanent cure. Alnylam Pharmaceuticals sponsored the phase III ENVISION trial in 94 patients with acute hepatic porphyria, including 89 with AIP; the study tested monthly subcutaneous givosiran against placebo, followed by an open-label extension. The final 36-month analysis found sustained reductions in attacks, hemin use, urinary ALA and PBG, and improvements in quality-of-life measures. Final ENVISION results A separate phase I/II open-label extension in 16 adults with AIP reported up to 48 months of follow-up, with 97% and 96% reductions in annualized attacks and hemin use, respectively; all participants were free of attacks requiring significant medical intervention during months 33 through 48. 48-month givosiran follow-up

The direct PBGD-replacement program remains at the animal-study stage. The earlier phase I AAV2/5-PBGD study is completed and demonstrated safety but insufficient biochemical efficacy, while the 2025 PBGD-mRNA study was performed in non-human primates rather than patients. AAV-PBGD phase I trial PBGD mRNA in non-human primates A currently recruiting Norwegian interventional study, NCT06273644, sponsored by Nordlandssykehuset HF, is testing high-carbohydrate dietary intervention and examining metabolic, inflammatory, microbiome, RNA-sequencing, and mitochondrial markers in AIP; it is not a gene- or enzyme-replacement cure trial. NCT06273644: carbohydrate-rich diet study

Methodologies and Scientific Approaches

AIP cure research increasingly combines mechanistic disease models with quantitative biomarkers. The most important treatment-response markers are urinary ALA and PBG, which directly reflect the toxic biochemical overflow from hepatic heme synthesis. Researchers also measure liver PBGD activity, attack frequency, hemin use, pain, quality of life, kidney and liver function, and—in advanced animal models—brain perfusion, glucose use, mitochondrial function, and liver metabolic pathways. PBGD mRNA in non-human primates AGA Clinical Practice Update

For delivery, the principal platforms are GalNAc-conjugated siRNA for targeted ALAS1 suppression, AAV vectors for one-time liver gene transfer, and lipid nanoparticles for repeatable mRNA enzyme replacement. Computational pharmacology is being used to connect nanoparticle release, mRNA translation, PBGD production, and reductions in ALA and PBG across mice, larger animals, and projected human dosing scenarios. Phase III givosiran trial mRNA therapy modeling for AIP

Leading Institutions and Funding

The University of Navarra’s Center for Applied Medical Research and associated Clínica Universidad de Navarra investigators have been central to both AAV-PBGD gene-transfer work and the newer PBGD-mRNA program. The 2025 non-human-primate mRNA study involved collaborators from Spanish academic and clinical institutions, the French Porphyria Center, and Moderna; the paper reports support from Moderna, Spanish Institute of Health Carlos III grants, European Union co-funding, and the Fundación Mutua Madrileña de Investigación Médica. PBGD mRNA in non-human primates

European public investment helped establish the gene-therapy infrastructure for AIP. The European Commission’s AIPGENE project, coordinated by Fundación para la Investigación Médica Aplicada in Spain, had a total cost of €4.35 million and an EU contribution of €3.31 million; it supported production and first-in-human testing of liver-directed AAV5-PBGD. Alnylam Pharmaceuticals has led the clinical development of givosiran with an international network of porphyria specialists. AIPGENE project record Final ENVISION results

Strengths, Limitations, and Challenges

The strongest recent advance is that researchers now have two biologically credible ways to reduce AIP toxicity: suppressing ALAS1 with givosiran and replacing deficient PBGD with mRNA. Givosiran has robust human trial evidence and durable benefit for recurrent attacks, while PBGD mRNA has directly corrected disease-related biochemical and neurologic abnormalities in a sophisticated primate model. Final ENVISION results PBGD mRNA in non-human primates

The limitations are substantial. Givosiran requires ongoing treatment and monitoring because liver-enzyme elevations, changes in kidney function, and elevated homocysteine can occur. AGA Clinical Practice Update PBGD-mRNA treatment will probably also require repeat dosing because mRNA and the protein it produces are temporary, and its human dose, durability, immunogenicity, and effect on chronic AIP complications remain unknown. AAV gene transfer offers the prospect of a one-time treatment but has not yet delivered sufficient metabolic correction in people, and redosing AAV can be difficult because of immune responses. AAV-PBGD phase I trial

Outlook and Future Directions

A non-transplant cure for AIP is not yet close to clinical use, but the field now has a credible etiologic candidate in liver-targeted PBGD mRNA. The milestones to watch are formal first-in-human testing of PBGD-mRNA replacement, evidence that repeat dosing safely normalizes ALA and PBG in patients, and demonstration that treatment prevents not only acute attacks but also chronic neurologic, renal, and liver complications. Until then, givosiran represents the major practical advance of the 2020–present period: not a cure, but a treatment that can greatly reduce disease activity for many people with recurrent AIP. PBGD mRNA in non-human primates Final ENVISION results

References

Don't see your disease? Request a report