Tracking drugs deep into the brain

To meet these challenges, Biogen scientists have been collaborating with Ionis Pharmaceuticals to develop ASOs (antisense oligonucleotides) that may provide hope to patients in need.

ASOs are the same types of building blocks that make up DNA and RNA, the protein-making machinery in the cell.^1,2 ASOs bind and alter the cell’s RNA and as a consequence, modify, reduce or restore important proteins.³

“When we looked at the [ASO] data, I literally got chills,” says Toby Ferguson, M.D., Ph.D., Vice President of Biogen’s Neuromuscular Development Unit, a former practicing neurologist who saw every day the incredible need for a breakthrough. “I realized that what we’re developing could possibly change the future for patients with neurological diseases.”

Toby Ferguson, M.D., Ph.D.
Vice President, head of Neuromuscular Development Unit at Biogen

Perhaps the biggest hurdle was finding drugs that could reach the brain despite the blood-brain barrier, a divide that blocks approximately 95 percent of both oral and intravenous treatments.⁴

“Without being able to cross the barrier and get to the right place in the brain, there is no hope of impacting a disease, regardless of how effective the treatment may be,” says Toby. “That’s why a tool that gets a drug to the brain is such an important part of treatment of neurological diseases.”

Administered with a needle into the cerebral spinal fluid, ASOs travel directly into the brain and can be highly targeted, which is necessary in order to address the underlying genetic disease.⁵

“Like oncologists who treat various mutations in cancer, we are going after disease caused by mutations in multiple genes, like SMA and ALS,” Toby explains. “We couldn’t be more excited about the potential for treating diseases like ALS, which we’ve been working on for years.”

The effectiveness of ASOs in reaching the brain led the Biogen team to ask another important question: How can we measure the way ASOs are absorbed, distributed and cleared within the body? By answering this question, it was hoped that physicians could optimize dose delivery and better understand how ASOs work.

Biogen found a solution by imaging radiolabeled ASOs, “so we monitor drug candidates’ distribution in the body, to confirm that they reach the tissues affected by the disease/pathology, leading to clinical benefits to patients,” says Laurent Martarello, Ph.D., Head of Biogen’s Research and Early Development Imaging group.

Laurent Martarello, Ph.D.
Head of Biogen’s Research and Early Development Imaging group

“For the first time, we are tagging and tracking this class of drugs as they travel to the brain, providing insights like never before in humans,” he adds. “As a result, we believe physicians can have the confidence, and the evidence, that medicines in the brain are doing what they should, and patients are getting the right care within the fewest number of intrathecal injections possible.”

For its groundbreaking work in 2019, the Biogen-Ionis team received the annual Healey Center International Prize for Innovation in ALS, a global award celebrating excellence in research that catalyzes exceptional discoveries leading to a transformative advance in the development of ALS therapy.

Building on their knowledge and expertise, the team is now preparing for the next frontier and is working with Invicro, a leading Imaging Contract Research Organization, with plans to use “EXPLORER,” the world’s first total-body PET Scanner. Designed by UC Davis, the two-meter long scanner provides greater sensitivity, better images and total body kinetic data.

“The scanner’s increased sensitivity will give us a more accurate view of the ASO’s pharmacokinetics. For the first time we will be able to image the entire body as the ASO travels through the spinal fluid, without the individual being repositioned. The significance of this new technology is that it also allows us to minimize the radiation dose to subjects while recording clear images of the distribution of the asset we are tracing,” says Roger Gunn, Ph.D., Executive Vice President, Quantitative Data Sciences at Invicro and Professor and Visiting Professor at Imperial College London and University of Oxford, respectively.

For Biogen, scientific pursuit for patient benefit is unrelenting and the team continues to push new boundaries looking for answers and innovation.