The rasH2 Evolution: Taconic's Innovative Drive in Action

Taconic Biosciences took the lead in bringing to market a model that's the gold standard for small molecule drug carcinogenicity testing. Our history of staying ahead of industry needs and driving innovation continues with the evolution of the rasH2 mouse model.

Pharmaceutical companies are under tremendous pressure to ensure their drug candidates are safe, but they're equally strained to deliver study results faster to speed time to market with new therapeutics. Yet, for many years, drug carcinogenicity testing was a lengthy process requiring a two-year rat and mouse bioassay. Besides the delays in bringing novel therapeutics to market, this testing approach didn't always detect human-relevant carcinogens, raising concerns that it didn't accurately gauge human safety risks.

Thirty years ago, Taconic led the way to faster and more accurate drug carcinogenicity testing by helping to evaluate the rasH2 and other mouse models as a shorter-term testing alternative. Today, Taconic is again advancing carcinogenicity testing with an initiative that combines the rasH2 model with genomic technologies—aiming to enable test results that are available earlier in the process and more predictive of human outcomes.

The Quest to Speed Carcinogenicity Testing

The rasH2 Evolution: Taconic's Innovative Drive in Action In the early 1990s, the research community identified the possibility that genetically engineered models (GEMs) could detect human-relevant carcinogens faster and with low background tumor rates, making them a potential alternative to the two-year bioassay. And while the potential impact was significant, the solution wasn't straightforward. What the industry was lacking was a catalyst to serve as a driving force to support the much-needed transformation of drug carcinogenicity testing. Taconic proved to be that catalyst.

At that time, initial evaluations at research centers around the world—including the US National Toxicology Program and the Central Institute for Experimental Animals (CIEA) in Japan—had moved transgenic models to the forefront of the discussion. In particular, CIEA's rasH2 model was found to detect both genotoxic and non-genotoxic compounds on a six-month timeline.

"It became clear that the rasH2 model was one option with the potential to serve as a faster, more human-relevant alternative to the two-year bioassay," said Taconic Vice President of Innovation Donna Gulezian.

Taconic began rallying support for validating transgenic mouse models for use in shorter-term carcinogenicity testing. First, Taconic and representatives from the Health and Environmental Sciences Institute (HESI) branch of the International Life Sciences Institute organized a roundtable on the topic, soon followed by forums at many other industry events globally.

With industry representatives worldwide acknowledging the limited utility of conventional carcinogenicity studies and calling for a better alternative, HESI established an international Alternatives to Carcinogenicity Testing (ACT) committee to lead a large-scale evaluation of transgenic mouse models for short-term testing. Given the significant ramifications, HESI had strong interest in sponsoring the initiative and providing the structure for major players across the globe—including pharmaceutical companies, academic research institutions, and animal model providers—to come together and advance carcinogenicity testing.

Paving the Way for Model Access

Two transgenic mouse models were considered the most relevant for evaluation in short-term testing: the TSG-p53® knockout mouse model and the Tg.rasH2 transgenic mouse model. But before the evaluation phase could proceed, it was necessary to clear any obstacles to the models' use in these studies.

Here again, Taconic took a lead role by approaching DuPont, which held the Oncomouse intellectual property (IP) that covered the use of the two models specifically for carcinogenicity testing. "Taconic has always been committed to removing the IP hurdles that can constrain research, so we were well-equipped to work with DuPont to clear the way for access to these models for the evaluation phase of the ACT project," Gulezian said.

Once DuPont agreed to licensing terms enabling the models' use in the ACT initiative, a series of retrospective and prospective studies got underway, designed to assess whether these models could deliver equal or better result reliability and the same or better insights into carcinogenic mechanisms, within a shorter timeframe. The prospective study alone involved 30+ organizations worldwide and 50+ studies over a four-year period.

While the p53 knockout model was able to detect genotoxic compounds, the rasH2 model was able to detect both genotoxic and non-genotoxic carcinogenic compounds, confirming the model's validity for use in a six-month bioassay. The International Council for Harmonisation (ICH), an organization focused on harmonization of regulatory requirements for global pharmaceutical development, issued guidelines recommending a six-month carcinogenicity assay using this transgenic model as an alternative to the two-year test.

Ensuring Model Consistency and Integrity

But before global regulators like the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) could feel confident accepting the six-month bioassay, it was necessary to demonstrate that the rasH2 model could be bred anywhere in the world with consistent integrity and quality and that it would be easily accessible to researchers.

With more than five decades of experience taking models from validation through commercialization at that time, Taconic spearheaded the effort of ensuring investigators could obtain the model readily and with consistent health standards and quality on a global basis. With many of our GEMs available with a simple label license, Taconic is adept at simplifying access for commercial research use, removing hurdles that can keep models out of reach, and helping investigators bring novel therapies to market faster.

Ensuring the rasH2 model would be widely accessible required coordination and cooperation among all three entities involved, each offering unique value:
  • CIEA provided the intellectual property and technical knowledge gained during its research on the model
  • DuPont agreed to grant the rights to use the model for carcinogenicity testing
  • Taconic leveraged its extensive breeding and distribution capabilities to scale up generation of the rasH2 model, ensuring it was ready for global adoption
Scientists at Taconic and the Central Laboratory for Experimental Animals (CLEA) also collaborated to develop and adopt globally harmonized production methods and quality control measures to assure the model's consistency and stability. Global harmonization across multiple breeding locations has proven essential to the rasH2 model's widespread adoption for regulatory application.

Evolving Carcinogenicity Testing Once Again

While carcinogenicity testing took a giant leap forward with these efforts, the industry's needs never stop evolving. Investigators remain under pressure to further reduce costs, use fewer animals, obtain results that are more predictive of the human response, and make better decisions sooner. With new and enhanced technologies constantly emerging, there is always the potential to move the needle further—and that's why Taconic is always on the move.

This time Taconic is playing an even more prominent role in improving carcinogenicity testing, participating more directly in the research. We're the primary stakeholder in a significant initiative that brings together some of the world's leading pharmaceutical companies and other industry providers to validate use of the rasH2 model with TwinStrand Biosciences' powerful duplex sequencing technology, a type of error-corrected next-generation sequencing.

"Combining Taconic's rasH2 model with TwinStrand's technology has the potential to make the model more powerful, more predictive of human outcomes earlier in drug discovery, and even avoid the need to advance to the tumor stage to identify carcinogenic compounds," Gulezian said. "Because we believe this work can be truly transformative, Taconic is making significant investments of our own and attracting investments from other sources."

To date, the proof-of-concept phase has demonstrated encouraging signs that it's possible to further reduce both the timeline and animal usage needed to arrive at carcinogenicity testing results, without having to proceed as far as tumor development.

"When it comes to improving mouse model predictability and translatability, there is never an endpoint," Gulezian noted. Through a combination of new technologies and new partners, Taconic is continuing to explore new ways to help researchers obtain more human-relevant data per animal, faster, at a lower cost, earlier in their decision-making process.

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