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A corrective therapy for acute intermittent porphyria

Prof. Aurora Martinez, UiB; Dr Helene Bustad Johannessen, UiB; Dr James Hitchin, UNIVERSITETET I BERGEN; Dr Aasne Karine Aarsand, Helse Bergen; Dr Juha Kallio, UNIVERSITETET I BERGEN; Dr Marta Vorland, Helse Bergen; Dr Jarl Underhaug, UNIVERSITETET I BERGEN; Dr Lars Skjerven, UNIVERSITETET I BERGEN; Dr Karen Toska, Helse Bergen; Prof. Sverre Sandberg, Helse Bergen; Prof. Caroline Schmitt, The Assistance Publique – Hôpitaux de Paris; Dr Laurent Gouya, INSERM



Acute intermittent porphyria (AIP) is a dominantly inherited genetic disease caused by mutations in the gene coding for the enzyme HMBS, which is involved in the biosynthesis of heme. In AIP, mutations often result in a defective protein with incorrect folding. All nucleated cells synthesize heme, and heme is necessary for critical functions such as oxygen transportation in blood, myoglobin and cytochrome P450 function. Reduced HMBS activity causes an accumulation of the heme building blocks (ALA and PBG), which are toxic to the nervous system and trigger acute life-threatening neuropsychiatric attacks. Patients suffering from severe recurrent attacks with long hospitalization, a high disease burden, low quality of life and potential deadly outcome are today without sufficient treatment options. Symptomatic patients as well as predictively tested mutation carriers have an increased risk of long-term complications such as hepatocellular carcinoma and kidney failure. Treatment options for all settings are at present merely palliative and only provide transient reduction of toxic building blocks.


Pharmacological chaperones (PC) specifically stabilize a target protein and represent a novel therapeutic approach to correct the enzyme defect by recovering a functional native-like structure and stability. We have identified PCs that increase HMBS levels both in vitro, in cells and in an AIP mouse model, in the latter where our best hit compounds also yield decreased excretion of urinary ALA and PBG. PCs provide a corrective treatment with the potential to both being curative for acute attacks, and function prophylactically to impede recurrent acute attack. Symptomatic patients and predictively tested HMBS carriers have a normal WT gene in addition to the mutated gene. This shows a universal treatment potential for the PCs independently of the specific mutation. AIP thus represents a generic model system for the development of stabilizing and function-activating therapies for other diseases where a WT gene is present.

Commercial Opportunity

AIP has a variable prevalence, from 1:10 000 to 1:75 000, reflecting geographic variations, founder effects and probably diagnostic delay. A PC treatment represents a great market potential, based on a for-life treatment for 40–50 % of the patients being treated with doses of 3–5 mg/kg/day. Our analysis with a conservative price point of c.$300.000 per patient in the US and c$150.000 in 5EU, a combined patient population of c.2000-3000 and penetration of 40%-50% would result in combined US/5EU sales of c.$180m-$335m.

Development Status

We are in a hit to lead phase, testing our compounds in vivo. More experiments in mice will be done in 2021.

Patent Situation

A priority patent was filed in November 2019 and a PCT patent in November 2020

Further Reading

Yuste-Checa, P., et al., Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. Hum Mutat, 2017. 38(2): p. 160-168

Bustad, H.J., et al., Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria. Biosci Rep, 2013. 33(4)


A corrective therapy for acute intermittent porphyria