Clinical Safety of Adenoviral Vector Products

Most of the completed and ongoing adenoviral vector clinical trials are early, uncontrolled trials. The absence of an internal control group limits the ability to draw definitive conclusions about the contribution of the adenovirus vector product to an adverse event. Despite this caveat regarding causality assessments, administration of replication defective adenovirus is associated with an acute cellular and cytokine mediated inflammatory response. Individuals have experienced systemic reactions such as fever, chills, hypotension, and laboratory findings consistent with disseminated intravascular coagulation, including thrombocytopenia. An overwhelming systemic inflammatory response, to which has been attributed, at least in part, the death of a volunteer in a trial of ornithine transcarbamylase (OTC) deficiency who received intrahepatic artery injection of a high dose of adenovirus-containing product, has not been observed in other clinical trials, including those that employ systemic administration of similar doses of adenovirus vector. See also discussion in section XVI.

The route of administration appears to play a key role in determining the type of and occurrence of adverse events. Toxicities have been particularly prominent in organs that are the sites of adenovirus injection, including the lung, brain, and liver [13, 23, 24], In addition to route of administration, other variables associated with the clinical trial may influence the nature, frequency, and severity of an adverse event. Such factors include the adenovirus construct, transgene, dose, and frequency of product administration, and host factors such as the underlying disease, other comorbidities, and use of concomitant medications. A committee of experts convened to discuss adenovirus safety in December 1999 questioned the role of the transgene in the toxicity profile and suggested employing null adenovirus vectors as controls when possible to tease out the relative toxicities of the transgene from the vector [25].

Preexisting antibody to adenovirus and/or the development of an antibody response following administration of an adenovirus-containing product may play a role in product safety, although a clear relationship has not been established [24]. The limited data available have not suggested a correlation between high baseline levels of neutralizing antibody and adenovirus toxicity (or activity). Moreover, in a study that involved repeat administration of an adenovirus-containing product, participants developed large spikes in serum levels of neutralizing antibody after the initial dose. However, the toxicity profiles of the first and subsequent doses were similar, again suggesting a lack of correlation. It is important that clinical investigators continue to characterize the immune status of study participants at baseline and following adenovirus vector administration, and attempt to correlate adverse events with levels of or changes in antibody titer. Ultimately, such information could be utilized in patient selection criteria or in clinical monitoring to enhance safety and effectiveness.

The long-term safety of gene transfer is under active discussion. Concerns about late adverse sequelae such as new malignancies occurring years or decades following administration of replication-competent, integrating viruses resulted in FDA guidance regarding testing for replication-competent retrovirus (RCR) in product and patient's serum and for lifelong clinical monitoring [26], These recommendations are currently limited to retroviral vector INDs. Although adenovirus can become replication competent, the FDA had not previously recommended that patients exposed to this class of product be followed long term. Long-term follow-up of gene therapy products was discussed at recent meetings of the Biologies Response Modifier's Advisory Committee [8, 9, 9a]. FDA will revise the recommendations for long term follow up of recipients of gene transfer products including adenovirus-containing products, pending additional public discussions.

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