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Two ways to look at it
BASEL, Switzerland—Buoyed by continuing progress in antisense technology by others and its own promising, if fledgling, "brain shuttle" program, Roche formed an alliance in early April with Carlsbad, Calif.-based Isis Pharmaceuticals Inc. to develop treatments for Huntington's disease (HD).
Under the terms of the agreement, Roche will make an upfront payment of $30 million to Isis, with total payments related to license fee and pre- and post-licensing milestone payments reaching as much as $362 million. In addition, Isis will receive tiered royalties on sales of the drugs should they reach the market.
The work will be based on Isis' antisense oligonucleotide (ASO) technology, with the idea being to combine Isis' antisense expertise with Roche's scientific expertise in developing neurodegenerative therapeutics and central nervous system (CNS) research in general. In addition to the goal of finding therapies for HD, Isis and Roche also will be collaborating to combine Isis' ASOs and Roche's proprietary brain shuttle program, the objective being to increase the brain penetration of ASOs with systemic administration.
"Central to the partnership is Roche's brain shuttle program, which we see as highly complementary to Isis' drug development work," said Shafique Virani, Roche Partnering's global head of neuroscience, cardiovascular and metabolism, in the news release about the deal. "This dual-track development program ensures whichever candidate compound proves to be most promising—Isis' lead target or Roche's brain shuttle version—can be taken forward to pivotal clinical trials."
Interviewed by ddn, Virani was unable to share details about the brain shuttle program because of intellectual property concerns around the "still maturing technology," but he does say, "our portfolio is agnostic to large or small molecules, and the brain shuttle program is key to getting large molecules into the brain. After about four or five years of pursuing this program, we have a sense of comfort that we can finally get large molecules into the brain at decent concentrations and exposure, though we still have a lot of work beyond that to understand the effects on the brain of doing that, in terms of homeostasis and other factors."
Virani says that discussions between Roche and Isis around HD treatment and Isis' ASO technology began almost a year ago at a JP Morgan conference, adding, "we have a few key areas in CNS and neurodegenerative disease—Alzheimer's, ALS, Parkinson's and Huntington's—and we're always on the lookout for new advances or insights into the biological pathways for these diseases. We learned about Isis' technology, and once we became familiar with their ASO platform, we thought it might be good for some of the more intractable targets."
Discussions about an actual alliance began around the beginning of 2013, Virani recalls, noting that the two companies have not worked together directly before; however, they've had many informal discussion on various issues through the years at different meetings around the world.
Roche has the option to license the drugs from Isis through the completion of the first Phase I trial. Prior to any exercise of that option, Isis is responsible for the discovery and development of an antisense drug targeting the huntingtin (HTT) protein. Roche and Isis will work collaboratively on the discovery of an antisense drug utilizing Roche's brain shuttle program. If Roche exercises its option, it will be responsible for global development, regulatory and commercialization activities for all drugs arising out of the collaboration.
Initial research will focus on Isis' lead drug candidate that blocks production of all forms of the HTT protein, the protein responsible for HD, which offers the potential to treat all HD patients if it works. But there is also the potential for treating subsets of HD patients, as Isis is also conducting research into treatments that specifically block production of the disease-causing forms of the HTT protein. In parallel, Roche will combine its proprietary brain shuttle technology with Isis' ASO technology and, if that is successful, it should allow systemic administration of antisense drugs to treat asymptomatic patients.
"We believe that Roche's expertise in developing CNS drugs, along with their clinical development experience, will greatly enhance our development efforts for this program and allow us to move forward more rapidly," noted B. Lynne Parshall, chief operating officer of Isis, in an official statement. "By partnering our more complex and nuanced research and development programs earlier in development, like our Huntington's disease CNS program, we add value and resources with partners that bring unique benefits."
Because financial and scientific support from the CHDI Foundation, a nonprofit foundation exclusively dedicated to the development of therapies that slow the progression of HD, has played a significant role in Isis' progress with HD research, that foundation will also benefit from the Roche deal.
"Together, Isis and CHDI demonstrated that antisense compounds can be used to inhibit the production of HTT protein in both brain and peripheral tissues," notes Isis in the news release about the Roche deal, "and that the inhibition of normal HTT protein was well tolerated."
Over time, CHDI will be reimbursed for its support of Isis' program out of the milestone payments received by Isis, and the foundation will receive $1.5 million in the short run associated with the signing of the Roche agreement. CHDI reportedly will continue to provide advice to Isis and Roche on the development of antisense drugs to treat patients with HD.