Crossing Barriers to Deliver New Medicines

[Photo] Colocalization of BTK (purple) and a B cell marker (CD20, brown) in an MS lesion 
Credit: Nilesh Pande (immunohistochemistry) and Bruce Trapp/Cleveland Clinic

More than 2.3 million people around the world are living with Multiple Sclerosis (MS), a chronic, inflammatory, autoimmune, neurodegenerative disease that typically results in accumulation of disability over time.

In MS, the myelin, an insulating layer (sheath) that protects the nerve cells are gradually destroyed. As a result, the nervous system no longer functions properly, and people living with MS eventually develop difficulty with muscle control, movement, speech and vision. As disability increases in MS patients, health status, quality of life, and personal daily activities deteriorate. This can result in loss of ability to work, impair cognition, decrease life expectancy, and increase cost of care.

Despite numerous treatment options for people living with MS, each patient experiences the disease differently and disease progression remains an unaddressed reality for most patients. Throughout the disease, inflammation is present in the brain and spinal cord as well as in the body, leading to a worsening of long-term disability along with accelerated brain volume loss.

Today there are limited ways to effectively address ongoing disease progression in MS. This gap has captured the focus of researchers who are seeking alternate ways to control immune system dysfunction that are thought to be at work in MS disease progression.

As a company that’s been committed to bringing innovative treatments to this community for more than 20 years, Sanofi researchers are among those who continue to explore new mechanisms and approaches to address the challenges that patients continue to confront.

“MS is a very dynamic and unpredictable disease, which makes it challenging to treat and manage,” said Rita Balice-Gordon, Sanofi’s Head of Rare and Neurologic Diseases Research.

The immune system’s role in MS

Over the past decade, scientists have learned more about the immune system’s role in the progression of MS.

The MS Treatment Landscape

By Timothy J. Turner, Ph.D., Clinical Research Director MS/Neurology at Sanofi

It is established that T as well as B-cells play a role in MS. The B-cell is one of several types of cells that make up the immune system’s complex network. B-cells are essential to a healthy, functioning immune system, but when B-cells go awry, they also are believed to play a major role in activating the cells that attack nerve sheaths in MS patients. That has led researchers to look for ways to control the activity of B-cells.

As part of their effort to identify new approaches to treating this disease, Sanofi scientists are exploring ways to inhibit the activity of an enzyme known as Bruton’s tyrosine kinase (BTK). The enzyme plays an important role in B-cell maturation and function. BTK is an essential component of the B-cell receptor (BCR) signaling pathway, where it regulates B-cell activation and propagation.

Controlling BTK can enable variation of B-cell function, yet without destroying the body’s B-cells entirely. Researchers hope that by inhibiting BTK they may be able to selectively interfere with the activity of B-cells and their effect on microglia (type of neuronal support cell responsible for clearing dead neurons in the central nervous system - CNS), while preserving their beneficial activity. In turn, this could potentially mitigate the neuroinflammation and neurodegeneration in the peripheral nervous system and the CNS.

Addressing disease effects in the brain

While the damage associated with MS occurs in the brain and spinal cord as well as throughout the body, in all forms of MS, and particularly in progressive forms, more damage occurs to nerve sheaths and other cells in the CNS. To truly advance care for patients, scientists knew they would have to target the way B-cells affect microglia in the brain that contribute to neuronal tissue damage and neuroinflammation in MS leading to ongoing disease progressions. 

“When we saw the effect that modulating B-cells had in the peripheral immune system, it led us to think that we needed to develop something that would modulate B-cells, but not destroy them, in the brain and beyond,” said Erik Wallstrom, Sanofi’s Therapeutic Area Head for Multiple Sclerosis, Neurology and Gene Therapy Development.

Reaching the brain, however, is a major challenge for research scientists. Humans have evolved a blood-brain barrier that protects the brain by blocking the movement of many harmful substances that may be present in the bloodstream. Unfortunately, the barrier also treats many medicines the same way, thus preventing numerous treatments that work in the rest of the body from getting into the brain. Finding something that has both the potential to be effective and cross into the brain is extremely difficult.

Sanofi’s scientists, in partnership with Principia Biopharma, are now exploring the development of a BTK inhibitor they hope may be able to successfully cross the blood-brain barrier. They hypothesize that, if the substance reaches the brain, it might be possible to modulate B-cells and microglia in the brain and cancel out their damaging effects.

Sanofi has started a clinical trial intended to gather more data on the workings of this BTK inhibitor, one of several areas of research the company is pursuing as part of its commitment to address the tremendous need for a solution for people living with MS.

“Just 25 years ago, there was nothing we could offer patients with MS,” Wallstrom said. “Now the outlook is getting much better.”

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