Phase I Gene Therapy Clinical Trial Using the Vector rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria
Condition: Acute Intermittent Porphyria
MeSH terms: Porphyria, Acute Intermittent; Porphyria, Erythropoietic; Porphyrias
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): rAAV2/5-PBGD vector dosage 1; rAAV2/5-PBGD vector dosage 2; rAAV2/5-PBGD vector dosage 3; rAAV2/5-PBGD vector dosage 4
Intervention type(s): Genetic; Genetic; Genetic; Genetic
Intervention description(s): Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.; Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.; Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.; Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Porphyria; Gene therapy; AAV; Liver gene transfer