British zebrafish technology company Summit and a small number of big pharma companies this month met with officials from the US Food and Drug Administration in an agency-sponsored seminar to discuss the merits of using the model organism to glean toxicology data in drug-development studies, and possibly to include these data as part of IND submissions.
“What we have detected is that the industry is using [zebrafish] so much now, and we have been a big part of that equation, that the FDA [had] invited us to consult with them [in November], and talk seriously about [zebrafish technology’s] positioning within the industry,” Summit CEO Steven Lee said last week during an earnings call for the six-month period ended July 31.
Lee said that should the FDA decide to accept zebrafish data as part of IND submissions, “just this platform itself would create significant value for us, because it would be difficult to see who [else] big pharma would go to, or even other biotech companies would go to, if it was a recommended set, and certainly if it was a required set, of information.”
David Jacobson-Kram, associate director of pharmacology/toxicology at the agency’s Center for Drug Evaluation and Research, told CBA News this week that although the agency has no plans to require or accept zebrafish data in IND filings, the FDA is “curious about how pharmaceutical companies use zebrafish data in their decision-making processes.”
Jacobson-Kram stressed that information presented at the meeting, which took place on Nov. 3, will have no immediate regulatory impact.
A transcript of the meeting or other details about it were not immediately available.
The seminar came out of a workshop Summit hosted on zebrafish screening at March's Society of Toxicology Conference in Seattle, Richard Pye, investor relations for Summit, told CBA News via e-mail this week. He said officials from the FDA attended the workshop and were impressed by the company’s toxicological data.
“Having been aware of the technology for some time, [the FDA officials] approached us to meet with a wider audience within the FDA to update them on the recent advances in the technology,” Pye said.
At the Nov. 3 meeting, Adrian Hill, head of toxicology at Summit, presented an overview of the company’s model, including results from a recent study on hepatotoxicity undertaken with Johnson & Johnson. In addition, AstraZeneca presented results from a consortium with Summit, Roche, and others on using the zebrafish to study developmental toxicity.
“Summit was delighted to be invited to this seminar, and will be happy to continue to work with the FDA to further the understanding of how the zebrafish model can be implemented in drug discovery to minimize safety-related drug attrition,” said Pye.
The FDA is “curious about how pharmaceutical companies use zebrafish data in their decision-making processes.”
Jacobson-Kram said that although pharmaceutical companies may use zebrafish data as an early indicator of some kind of problem, it does not appear that they make “go/no go” decisions based on the results in zebrafish.
“I think [zebrafish data] just supports the evidence [that pharmaceutical companies] use in making a decision,” he said.
“The bottom line is that there is not enough data for the FDA to change its regulatory requirements, but ultimately, our hope is that will be the case, which is why we are working on it,” Calum MacRae, an assistant professor of medicine at Massachusetts General Hospital and a consultant to Summit and the FDA, told CBA News.
In September, MacRae and his colleagues at Mass General began the final year of a four-year, NIH-funded study to develop a model of drug-induced cardiac repolarization abnormalities in larval zebrafish (see CBA News, 9/12/08).
Working with a $414,000 grant from the National Institute of General Medical Sciences, the investigators are developing a panel of reporter fish modeling repolarization reserve, and several human proarrythmic disease states, MacRae said.
The Mass General researchers are using these reporter fish to generate a profile of repolarization responses for cardiotoxic or non-cardiotoxic drugs in order to identify features that could help predict proarrythmia in human patients.
The FDA has an interest in this particular area because the agency found that the current techniques “really do not predict toxicity very effectively at all in many situations,” MacRae said.
Most of the technologies used by researchers to help predict drug-induced toxicity are geared almost exclusively toward trying to find evidence of toxicity that has previously been reported. Mass General’s technology, by comparison, is more geared toward trying to find new forms of toxicity and to overcome some of the limits of current approaches, such as in vivo mouse and rat models and cell-based assays, said MacRae
He added that investigating the ability of zebrafish data to predict toxicity in humans is a worthwhile investment of the agency’s time and money. “There is absolutely no doubt that the current methodologies are useless,” he said.
MacRae added that no good methods exist to predict toxicity in general. Current methods, such as animal testing and cell-based screens, are extremely expensive and are predictive for some types of toxicity, but not all. And they are largely based on what has happened before, rather than on detecting novel forms of toxicity. “I think ultimately, [zebrafish technology] will be a fairly powerful strategy for finding some forms of toxicity,” he said.