Phase I Gene Therapy Clinical Trial Using the Vector rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria

Overview

This is a Phase I trial aimed to determine the safety of the investigational gene therapy product (rAAV2/5-PBGD) for the treatment of Acute Intermittent Porphyria (AIP). Up to eight patients fulfilling the eligibility criteria will participate in this multicentre, open label, single dose, dose-ranging Phase I clinical trial. The enrolled patients will be followed up to assess the safety profile of the investigational gene therapy product and to establish the maximum therapeutic safe dose to be administered in future confirmatory/pivotal clinical trial(s). In addition, the biological and clinical response to the treatment with rAAV2/5-PBGD in AIP patients will be assessed. A complete evaluation of the clinical (symptoms and quality of life assessment) and laboratory (blood and urine) data will be performed.

Acute Intermittent Porphyria (AIP) is inherited as an autosomal dominant disorder of the heme biosynthesis pathway. AIP is caused by a genetic defect in porphobilinogen deaminase (PBGD), a key enzyme for heme synthesis. AIP is characterized by acute episodes and asymptomatic periods. Neuropathic symptoms are predominantly in these attacks, which may be related to the toxic effect produced by the precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), accumulated because the enzyme deficiency. It occurs with very low prevalence (1 in 50,000), but figures for prevalence based on clinical manifestations (i.e., acute attacks) greatly underestimate the number of patients with latent AIP. Abdominal pain is the most common symptom, sometimes with constipation. Paresthesia and paralysis also occur, and death may result from respiratory paralysis. Other symptoms, including seizures, psychotic episodes, and hypertension, develop during acute attacks. They may be precipitated by porphyrogenic drugs such as barbiturates, progestogens and sulfonamides, some of which are known to induce the first rate-controlling step in heme synthesis, ALA synthesis. Other known precipitants are alcohol, infection, starvation, and hormonal changes; attacks are more common in women. Acute attacks rarely occur before puberty. This is a Phase I clinical trial mainly aimed to evaluate the safety of a recombinant adeno associated vector with a liver-specific promoter for the PBGD expression (rAAV2/5-PBGD), for the treatment of Acute Intermittent Porphyria. The patients will be enrolled in an adaptive dose-escalation, multicentre trial to assess safety profile, and to establish the maximum therapeutic safe dose to be administrated to patients in further confirmatory or pivotal clinical trial. This clinical trial is preceded by an "Observational study of acute intermittent porphyria patients" (DIG-API-2011-01). In this observational study, severe AIP patients have been followed for 6 to up to a maximum 24 months. During this time, the clinical and laboratory (blood and urine biochemistry) conditions of the patients were evaluated, in order establish clinical and biological baseline and history to compare the future results of this clinical trial. During this clinical trial, the safety will be evaluated by the Adverse Events (AEs) and Serious Adverse Events (SAEs) assessment. A complete evaluation of the clinical and laboratory (blood and urine) data will be collected. The study will also investigate as secondary endpoints the effect of this treatment to modify other aspects of the patient condition. Due to the heterogeneity of genetic mutations and inter-individual variation, clinical symptomatology and ALA/PBG levels in AIP subjects showed an evident variability in urine samples both during acute attacks and during remission; each subject will be its own control, so this study will be an intra-individually controlled clinical trial. At the end of the clinical trial the efficacy evaluation will be performed based on the clinical and biochemical changes compared to the baseline established in the previous observational study.