Two ways to look at it

BASEL, Switzerland—Buoyed by continuing progress inantisense technology by others and its own promising, if fledgling, "brainshuttle" program, Roche formed an alliance in early April with Carlsbad,Calif.-based Isis Pharmaceuticals Inc. to develop treatments for Huntington'sdisease (HD).

Under the terms of the agreement, Roche will make an upfrontpayment of $30 million to Isis, with total payments related to license fee andpre- and post-licensing milestone payments reaching as much as $362 million. Inaddition, Isis will receive tiered royalties on sales of the drugs should theyreach the market.

The work will be based on Isis' antisense oligonucleotide(ASO) technology, with the idea being to combine Isis' antisense expertise withRoche's scientific expertise in developing neurodegenerative therapeutics andcentral nervous system (CNS) research in general. In addition to the goal offinding therapies for HD, Isis and Roche also will be collaborating to combineIsis' ASOs and Roche's proprietary brain shuttle program, the objective beingto increase the brain penetration of ASOs with systemic administration.

"Central to the partnership is Roche's brain shuttleprogram, 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. "Thisdual-track development program ensures whichever candidate compound proves tobe most promising—Isis' lead target or Roche's brain shuttle version—can betaken forward to pivotal clinical trials."

Interviewed by ddn,Virani was unable to share details about the brain shuttle program because ofintellectual property concerns around the "still maturing technology," but hedoes say, "our portfolio is agnostic to large or small molecules, and the brainshuttle program is key to getting large molecules into the brain. After aboutfour or five years of pursuing this program, we have a sense of comfort that wecan finally get large molecules into the brain at decent concentrations andexposure, though we still have a lot of work beyond that to understand theeffects on the brain of doing that, in terms of homeostasis and other factors."

Virani says that discussions between Roche and Isis aroundHD treatment and Isis' ASO technology began almost a year ago at a JP Morganconference, adding, "we have a few key areas in CNS and neurodegenerativedisease—Alzheimer's, ALS, Parkinson's and Huntington's—and we're always on thelookout for new advances or insights into the biological pathways for thesediseases. We learned about Isis' technology, and once we became familiar withtheir ASO platform, we thought it might be good for some of the moreintractable targets."

Discussions about an actual alliance began around thebeginning of 2013, Virani recalls, noting that the two companies have notworked together directly before; however, they've had many informal discussionon various issues through the years at different meetings around the world.

Roche has the option to license the drugs from Isis throughthe completion of the first Phase I trial. Prior to any exercise of thatoption, Isis is responsible for the discovery and development of an antisensedrug targeting the huntingtin (HTT) protein. Roche and Isis will workcollaboratively on the discovery of an antisense drug utilizing Roche's brainshuttle program. If Roche exercises its option, it will be responsible forglobal development, regulatory and commercialization activities for all drugsarising out of the collaboration.

Initial research will focus on Isis' lead drug candidatethat blocks production of all forms of the HTT protein, the protein responsiblefor HD, which offers the potential to treat all HD patients if it works. Butthere is also the potential for treating subsets of HD patients, as Isis isalso conducting research into treatments that specifically block production ofthe disease-causing forms of the HTT protein. In parallel, Roche will combineits proprietary brain shuttle technology with Isis' ASO technology and, if thatis successful, it should allow systemic administration of antisense drugs totreat asymptomatic patients.

"We believe that Roche's expertise in developing CNS drugs,along with their clinical development experience, will greatly enhance ourdevelopment efforts for this program and allow us to move forward morerapidly," noted B. Lynne Parshall, chief operating officer of Isis, in anofficial statement. "By partnering our more complex and nuanced research anddevelopment programs earlier in development, like our Huntington's disease CNSprogram, we add value and resources with partners that bring unique benefits."

Because financial and scientific support from the CHDIFoundation, a nonprofit foundation exclusively dedicated to the development oftherapies that slow the progression of HD, has played a significant role inIsis' progress with HD research, that foundation will also benefit from theRoche deal.

"Together, Isis and CHDI demonstrated that antisensecompounds can be used to inhibit the production of HTT protein in both brainand 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 willreceive $1.5 million in the short run associated with the signing of the Rocheagreement. CHDI reportedly will continue to provide advice to Isis and Roche onthe development of antisense drugs to treat patients with HD.