– Results demonstrate antitumor activity of IONIS-KRAS-2.5Rx in multiple KRAS mutant tumor models –
KRAS is one of the most frequently mutated genes in cancer and is therefore a highly attractive target for cancer therapeutics. However, targeted inhibition of KRAS has been a challenge in cancer research for more than 30 years, and to date, no drugs directly targeting KRAS have been evaluated in clinical studies. Ionis scientists discovered the first antisense drug to selectively inhibit KRAS, which was licensed by AstraZeneca in December of 2016. IONIS-KRAS-2.5Rx, also referred to as AZD4785, is a Generation 2.5 antisense drug entering clinical development for the treatment of cancer.
“IONIS-KRAS-2.5Rx incorporates Ionis’ Generation 2.5 chemistry, which we developed to increase the potency of antisense drugs by increasing affinity for the target RNA. This advancement creates opportunities for drugs like IONIS-KRAS-2.5Rx to effectively target traditionally ‘undruggable’ targets, like KRAS, in tumors” said Brett Monia, senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis Pharmaceuticals. “We are excited to work with AstraZeneca to bring IONIS-KRAS-2.5Rx to the clinic as the first anticancer drug targeting KRAS.”
Preclinical study results were published in the recent issue of Science Translational Medicine (Ross et al. 2017) and highlighted in AstraZeneca’s article, demonstrating that treatment with IONIS-KRAS-2.5Rx selectively targets KRAS mRNA to reduce levels of the corresponding KRAS protein, leading to the death of tumor cells harboring KRAS mutations. In preclinical cancer models, systemic delivery of IONIS-KRAS-2.5Rx resulted in antitumor activity in a range of KRAS mutant human cell line-derived and patient-derived tumor xenograft models. Moreover, treatment with IONIS-KRAS-2.5Rx was well tolerated in preclinical studies in mice and monkeys, suggesting that a good therapeutic window exists for this approach. These results build on recent clinical successes of other Generation 2.5 antisense drugs, which have shown evidence of therapeutic benefit in clinical studies in cancer (Hong et al. 2015).
“It has been fantastic working at the forefront of antisense technology with Ionis. AZD4785 offers an exciting potential to overcome challenges faced in developing inhibitors of KRAS through traditional platforms,” says Sarah Ross, oncology lead biologist of AstraZeneca’s IMED Biotech Unit. “We used a selection of patient-derived xenograft models with KRAS gene mutations, and for the first time were able to directly show reduction in the growth of a lung tumour as a result of a KRAS targeted molecule. This, together with data from other in vivo models helped us build a body of evidence to support progression to clinical first-time-in-man testing for AZD4785.”
By employing Ionis’ advanced antisense technology and AstraZeneca’s cancer expertise, Ionis and AstraZeneca have identified an attractive, novel therapeutic with promising potential to address the high unmet clinical need in mutant KRAS-driven cancers.
For more information on Ionis’ collaboration with AstraZeneca to develop IONIS-KRAS-2.5Rx, please see Ionis’ press release here.
- Ross S., et al. “Targeting KRAS dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.” Science Translational Medicine. Published online June 14, 2017.
- Hong D., et al. “AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.” Science Translational Medicine. Published online November 18, 2015.