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

Brief Title

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

Official Title

Phase I, Multicentre, Open Label, Single Dose, Dose-ranging Clinical Trial to Investigate the Safety and Tolerability of a Gene Therapy rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria

Brief 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Number of patients with Adverse Events and Serious Adverse Events

Secondary Outcome

 Effect of the treatment on porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) urinary level.

Condition

Acute Intermittent Porphyria

Intervention

rAAV2/5-PBGD vector dosage 1

Study Arms / Comparison Groups

 Cohort A
Description:  rAAV2/5-PBGD vector dosage 1

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Genetic

Estimated Enrollment

8

Start Date

November 2012

Completion Date

November 2014

Primary Completion Date

July 2014

Eligibility Criteria

        Inclusion Criteria:

          -  Patient's written Informed Consent

          -  Age between 18 and 64 years, inclusively.

          -  Patients with confirmed diagnosis of Acute Intermittent Porphyria(AIP), as confirmed
             by clinical, biochemical data and genetic confirmation of porphobilinogen deaminase
             (PBGD) gene mutation. The patient must have a severe AIP condition, with at least two
             hospitalizations during the previous year due to acute attacks (clinical
             manifestations of acute porphyria), or at least four hospitalizations during the
             previous year due to the requirement of hospital treatment administration (including
             day-hospital and home hospital program)

          -  Previous participation in the "Observational study of acute intermittent porphyria
             patients" for at least six months.

          -  Ability to follow instructions and cooperate during the study conduct

        Exclusion Criteria:

          -  Pregnant women, as confirmed by a positive urine pregnancy test, or with intention of
             becoming pregnant

          -  Female subjects of childbearing potential who are not using barrier methods of
             contraception, at least during the study.

          -  Male subjects with partners of child bearing potential who are not using barrier
             contraceptive methods, at least during the study

          -  Acute or chronic liver disease of viral, autoimmune or metabolic causes

          -  History of acute or chronic severe gastrointestinal dysfunction (different than those
             typical gastrointestinal symptoms associated with an acute attack of AIP), in the
             opinion of the principal investigator

          -  Kidney disorder (renal impairment defined as plasma creatinine > 2 mg/dl (150
             µmol/l)), severe respiratory disease, severe autoimmune disease or severe acute active
             infection

          -  Evidence of active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection as
             reflected by HBs antigen or HCV-antibodies positivity (in case of HCV-antibodies
             positivity a HCV-RNA test should be performed in order to confirm active viral
             replication)

          -  Positive human immunodeficiency virus (HIV) serological test

          -  History of drug use (cannabis, cocaine, amphetamines, barbiturates) or alcohol abuse
             or addiction, during the three months preceding the selection visit

          -  Presence of neutralizing antibodies against adeno-associated serotype 5 (AAV5)

          -  Current or previous (within the previous 12 months) participation in a gene therapy
             trial.

          -  Previous participation (at any time) in a gene therapy trial using AAV vectors

          -  Any other disease or condition that, in the opinion of the principal investigator,
             contraindicates the participation in the study because it can expose the patient to a
             risk or because it disqualifies the patient to complete the schedule of the study.
      

Gender

All

Ages

18 Years - 64 Years

Accepts Healthy Volunteers

No

Contacts

Juan Ruiz, MD, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT02082860

Organization ID

AAVPBGD-AIP-001

Secondary IDs

2011-005590-23

Responsible Party

Sponsor

Study Sponsor

Digna Biotech S.L.

Collaborators

 Porphyria Centre Sweden

Study Sponsor

Juan Ruiz, MD, Study Chair, Digna Biotech S.L.


Verification Date

December 2014