Pfizer has selected the final two targets in a two-year-old, up-to-$911 million collaboration with Wave Life Sciences to develop new treatments for metabolic hepatic diseases, including nonalcoholic steatohepatitis (NASH), Wave said today.

Pfizer has nominated the fourth and fifth targets of the collaboration, designed to apply Wave’s stereochemistry platform across antisense and single-stranded RNA interference (RNAi) modalities, along with the aminosugar N-acetylgalactosamine (GalNAc) and Pfizer’s hepatic targeting technology for delivery to the liver.

Details on the two new targets were not included in Wave’s announcement of the milestone. Pfizer and Wave declared two targets—one of them disclosed, apolipoprotein C-III (APOC3)—when the collaboration was launched in May 2016 with the goal of developing nucleic acid therapies for metabolic diseases. Three months later, Pfizer nominated its third target, which was undisclosed.

Pfizer was eligible to select a maximum of five targets to advance from discovery through candidate selection with Wave. Upon development of the candidates, Pfizer may elect to exclusively license the programs, Wave said.

“The designation of these final two targets marks another milestone in a highly productive collaboration in which we have further established the benefits and versatility of our stereochemistry platform while making meaningful progress toward potentially addressing metabolic diseases of the liver,” Paul Bolno, M.D., MBA, CEO and president of Wave Life Sciences, said in a statement. “We look forward to continuing to advance all five programs and delivering differentiated stereopure candidates to our partners at Pfizer.”

Through the collaboration, Wave said, it has been able to further explore the therapeutic potential of single-stranded RNAi.

Wave has said its stereopure GalNAc-conjugated APOC3 antisense oligonucleotide has shown a seven- to tenfold improvement in potency and an increase in durability in vivo compared with stereorandom GalNAc-conjugated APOC3 antisense oligonucleotides. And in November 2017, Wave showed what it termed significant activity of stereopure GalNAc-conjugated APOC3 antisense oligonucleotides over stereorandom oligonucleotides in in vivo studies and meeting other milestone criteria.

These advancements are expected to extend RNAi-mediated silencing to tissues beyond the liver, Wave said.

Wave has also generated in vivo data showing significant activity of stereopure GalNAc-conjugated antisense oligonucleotides over stereorandom GalNAc-conjugated oligonucleotides.

“Based on encouraging preclinical in vivo data generated through this collaboration, we believe that Wave’s unique stereochemistry platform can augment our targeting technology and enhance the profile of potentially therapeutic oligonucleotides,” added Morris Birnbaum, M.D., Ph.D., CSO with Pfizer’s Internal Medicine Research Unit. “We are pleased to have identified five important and druggable hepatic targets and fully expect to maintain this momentum as we collaborate with Wave on candidate selection.”

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