Ionis Pharmaceuticals said today it has received a $10 million milestone payment from Biogen for launching a Phase I/IIa trial of the antisense drug the companies are codeveloping for mild Alzheimer's disease (AD)—a disorder riddled in recent years with clinical failures.

IONIS-MAPTRx is designed to selectively reduce the production of microtubule-associated protein tau (MAPT) in the brain. The three-month randomized, placebo-controlled, dose escalation clinical study (NCT03186989) is designed to evaluate the safety and activity of IONIS-MAPTRx in approximately 44 mild AD patients.

The study’s estimated primary completion date is January 31, 2020, Ionis disclosed at, on a page last updated October 2.

Biogen has an option to develop and commercialize IONIS-MAPTRx., formerly known as IONIS-BIIB4Rx.

The companies are hoping to buck what has been a strong tide of clinical failure in AD by drug developers, which have long struggled to create successful new drugs for the disease.

Only a handful of drug successes have ever won marketing approvals, and those treatments have only slowed progression of symptoms by 6 to 12 months. Most recently in July, Fujifilm’s AD drug candidate T-817MA failed a Phase II trial, though the company vowed that it would continue to develop the drug. Over the past year,  pharma giants Merck & Co. and Eli Lilly have been among companies to acknowledge clinical failures for AD candidates.

A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for AD drug candidates between 2002 and 2012. That study found high attrition rates for AD treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

Five Other Alzheimer’s Candidates

Biogen’s pipeline lists five other drug candidates for AD. Two of these are in Phase III: aducanumab (Aβ mAb), an antibody designed to bind to and reduce brain amyloid plaques, developed in collaboration with Neurimmune, and E2609, a small-molecule inhibitor of β-secretase, a protein that cleaves β-site amyloid precursor protein cleaving enzyme 1 (BACE1), being developed in collaboration with Eisai.

Rounding out the Biogen pipeline for AD are another Eisai-partnered candidate in Phase II, BAN2401 (Aβ mAb), and two Phase I candidates, the tau-targeting antibody BIIB076 and BIIB092, an extracellular tau-targeting antibody licensed from Bristol-Myers Squibb.

IONIS-MAPTRx will be administered as a once-monthly intrathecal injection directly into the cerebral spinal fluid, similar to how the marketed spinal muscular atrophy (SMA) treatment Spinraza® (nusinersen) is administered.  Biogen markets Spinraza, for which it agreed last year to pay Ionis $75 million upfront, and up to $225 million overall, to license global rights.

Spinraza and IONIS-MAPTRx are among treatments being developed by Biogen and Ionis under a broad strategic collaboration intended to develop novel therapies for neurological disorders by combining Biogen's expertise in neurology with Ionis' know-how in antisense technology.

Also through the collaboration, Ionis and Biogen are developing IONIS-SOD1Rx for amyotrophic lateral sclerosis and three antisense candidates for undisclosed neurodegenerative disease—IONIS-BIIB5Rx, IONIS-BIIB6Rx, and IONIS-BIIB7Rx. The companies are also evaluating “numerous” additional targets to develop drugs to treat neurological diseases, Ionis said in its Form 10-Q filing for the second quarter, filed August 9.

On July 17, Ionis disclosed that it had received nearly $650 million from Biogen since the start of the collaboration. Since then, Ionis has announced receiving a $40 million regulatory milestone payment from Biogen tied to pricing approval of Spinraza in Japan, in addition to the $10 million milestone payment for IONIS-MAPTRx.


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