The manufacturer of an experimental gene therapy drug for inflammatory arthritis said yesterday, Monday 26th November, that the US Food and Drug Administration (FDA) has allowed the phase I/II trial of the drug to resume following an investigation into the death of a patient.
Targeted Genetics Corporation said the action followed the agency’s review of the trial’s safety data on 127 participants and that surrounding “a fatal serious adverse event” in particular.
According to press reports at the time, 36-year old Jolee Mohr died in July this year, just after having the experimental drug injected into her right knee. She was reported to have died of organ failure from an overwhelming and sudden infection; some experts were reported to have said she should not have received such a large dose of the experimental drug.
In a statement released on 26th July this year, the FDA said that following a report from Targeted Genetics Corporation of Seattle on 24th July, about the death of a patient who received “an investigational gene therapy product in a clinical trial”, even though the causes were unknown, it placed the trial on clinical hold; that is no further product was to be administered to patients already on the trial and no new participants were to be enrolled.
The gene therapy drug being tested, experimental name tgACC94, is based on a recombinant adeno-associated virus (AAV) derived vector that carries a Tumor Necrosis Factor Receptor (TNF-receptor) gene to block a key mediator of inflammation.
The drug, or placebo, was injected directly into affected joints, which in Mohr’s case was the right knee.
The FDA said it was not aware of similar adverse events happening on other gene therapy trials, involving this product or any other that used AAV vectors, but as a precaution it is reviewing all ongoing trials using AAVs.
According to the company’s statement, the investigation showed that tgAAC94 did not contribute to the patient’s death, which was due to disseminated histoplasmosis, a fungal infection that usually affects the lungs but can occasionally spread to other parts of the body.
Tests results were presented to the 71st annual meeting of the American College of Rheumatology (ACR) earlier in November. These showed it was unlikely that the AAV vector used in the trial had spread to other parts of the patient’s body as a result of the experimental drug. Only trace amounts of the AAV virus DNA were found in tissues outside of the treated joint, and the amount of TNF-alpha antagonist protein (the receptor blocker) circulating in the patient’s bloodstream was as expected.
Apart from the experimental drug, the patient was also taking adalimumab, methotrexate and prednisone, which are known to suppress the immune system, and also increase known risk factors for infection by the histoplasma fungus, said the company.
As a result of the FDA investigation Targeted Genetics said it will be changing the informed consent procedure used in the Phase I/II trial to include information about the patient death, and it will also change the trial protocol to incorporate suggestions from the FDA. This involve getting re-consent from the 35 patients who have still to receive the second dose of the drug.
President and chief executive officer of Targeted Genetics, H. Stewart Parker, said the company will be working closely with practitioners on the trials:
“To ensure we resume development in the most efficient manner possible with patient safety, as always, of paramount importance.”
“We anticipate having full data from the Phase I/II trial in the second half of 2008. In the meantime, we believe we have the information needed from this trial to simultaneously plan initiation of a Phase II trial of tgACC94 in the second-half of 2008,” added Parker.
The purpose of the Phase I/II study is to assess the safety and potential efficacy of different doses of tgAAC94 injected directly in the affected joints of patients with inflammatory arthritis. Participants already on the trial will continue to be monitored, said the company.
The trial started in October 2005 when 127 patients received a first dose of active drug or placebo into the affected joint. Among these participants the affected joint could be a knee, ankle, wrist, metacarpophalangeal (finger joint) or elbow. 74 of the patients have now received a second dose, of which 52 have taken two doses of the active agent.
Interim results reported to the ACR meeting showed that a higher percentage of patients on the active drug showed improvements to joint symptoms, function and pain, compared to patients who were injected with the placebo only. The most common adverse events were reactions at the injection site, which affected 10 per cent of treated patients.
Inflammatory arthritis, also known as rheumatoid arthritis, is an extremely painful and debilitating disease where the immune system attacks the joints. It affects more than 2 million Americans and patients with this serious disease experience chronic pain, permanent damage to nerves, joints and bones, which in some cases leads to death.
Some drugs alleviate the symptoms but they weaken the immune system, bringing with them side effects, including infections. tgAAC94 is being tested as a potential alternative therapy that reduces inflammation without the systemic side effects.
Click here for information about Inflammatory/Rheumatoid Arthritis (Arthritis Foundation).
Written by: Catharine Paddock