Sanofi Researchers Turn a Hunch into a Clinical Study for Rare Diseases

Image of tissue sample from brain of a mouse with Sandhoff disease shows abnormal accumulation of gangliosides characteristic of GM2 diseases 
Photo credit: Dinesh Bangari, Distinguished Scientist, Group Head, Global Discovery Pathology, Sanofi

People with rare diseases typically go undiagnosed or misdiagnosed until their condition has already progressed for years. Even with a correct diagnosis, they still may not have access to specific treatment options.  

One reason for this is that rare diseases pose a conundrum for researchers. “By the very token that they are rare, there is insufficient information to establish measurable endpoints on disease progression,” explains Alaa Hamed, Sanofi Global Head, Medical. “Such endpoints are required by regulators and without them, it is difficult to design an effective clinical trial or get financial backing to pursue development of promising treatment candidates.”

Dr. Hamed is one of a small group of researchers at Sanofi who refuses to be deterred by these obstacles. Instead, these scientists keep their focus on the critical need to find treatment solutions for a specific class of rare diseases called GM2 gangliosidosis (see Understanding GM2 sidebar).

What if? 

Like most scientific pursuits, the researchers started with a hypothesis. They believed that a novel compound, under investigation at the time for another disease at Sanofi, might be beneficial against GM2 diseases, because it targets the same biological pathway—series of actions among molecules in a cell—implicated in GM2 gangliosidosis. 

“We also had a reason to take our research forward based on preclinical data which showed this compound could cross the blood-brain barrier,” adds Samantha Walbillic, Global Project Manager for GM2 research at Sanofi. “Which means, it might offer therapeutic potential for diseases impacting the brain and other parts of the central nervous system like the GM2 diseases.”

The blood brain barrier is a matrix of vessels that form both a structural and chemical barrier between the brain and blood stream. This barrier is meant to prevent toxins and other substances from crossing over into the brain or other parts of the central nervous system (CNS). However, it also makes it difficult for scientists to develop medicines that can effectively treat CNS disorders. 

The researchers set out to identify measurable markers of disease progression that could be used to evaluate the therapeutic effect of an investigational compound in clinical trials. Their goal was to build a strong enough case to establish a clinical development program targeting GM2 gangliosidosis. 

‘Walking’ in patients’ shoes

In order to gain a deeper understanding of the natural course of these diseases, they turned to the patient advocacy groups—grass roots organizations led by people whose lives have been affected by a GM2 and related condition.

Information on the natural history of Tay Sachs in the literature is very sparse. Until you meet people who have been affected by these diseases and listen to their stories, you cannot really know what it is like for them.

Julie Kissell, Sanofi Field Science Director and a Genetic Counselor

The next obstacle was the development of a research tool capable of measuring impact on disease progression. To develop this tool, the team collaborated with physicians from renowned institutions, benefiting from their collective experience working with Tay-Sachs and Sandhoff diseases (see Understanding GM2 sidebar).

They also adapted existing neurological measurement tools to GM2 patients to collect data for a clinical trial endpoint. These bespoke tools were used for the first time at the National Tay-Sachs & Allied Diseases (NTSAD) Annual Family 2015 conference. 

“We set up stations in a ballroom at the meeting to test some basic functions, like getting up, walking, putting pegs into a board,” recalled Dr. Hamed. “We also did interviews and focus groups with people affected by GM2 diseases, including their caregivers to gain insights into possible disease progression endpoints.”

After three years, the scientists finally had enough data to establish measurable endpoints.

Hoping to win big

The team succeeded in getting a green light to initiate a clinical trial in GM2 later this year. 

The researchers hope that the trial will show the potential to stabilize the disease by preventing additional accumulation of lipids and slow worsening damage to the central nervous system. 

“Even if the effects of the disease can’t be reversed, if the investigational treatment slows its progress, that would be a big win,” says Samantha Walbillic.

The effects of a system out of balance

The GM2 gangliosidosis family of diseases is caused by an inherited defect in a gene called GM2A that oversees production of the GM2 activator protein. This protein is required for the normal function of an enzyme called beta-hexosaminidase whose job is to break down a type of fatty acid derivative known as gangliosides1. Without enough enzyme, these gangliosides accumulate in the brain and spinal cord, eventually leading to loss of muscle strength, vision, hearing and motor coordination, including the ability to swallow and speak. 

Common pathway leads to three potentially fatal diseases

Three GM2 gangliosidosis conditions were discovered and named separately: Tay–Sachs disease, AB variant, and Sandhoff disease. People inherit a GM2 condition when both parents carry a genetic mutation that causes a deficiency of the beta-hexosaminidase A enzyme. Onset of these diseases can occur in infancy and adolescence, as well as later in life. While it may start earlier, the late-onset form of the disease is first diagnosed when people are already in their late teens or early 20s.

“It is a devastating diagnosis for people who are in their teens or early adulthood that often leads to problems with social isolation and employment even in earlier stages of the illness,” recounts Julie Kissell, Sanofi Field Science Director and a Genetic Counselor.

Currently, there is no specific treatment for GM2 gangliosidosis diseases2.


1. Mahuran DJ (1999-10-08). "Biochemical consequences of mutations causing the GM2 gangliosidoses". Biochimica et Biophysica Acta. 1455 (2–3): 105–138. doi:10.1016/S0925-4439(99)00074-5. PMID 10571007.
2. Patterson, Marc C. (2013-01-01), Dulac, Olivier; Lassonde, Maryse; Sarnat, Harvey B. (eds.), "Chapter 174 - Gangliosidoses", Handbook of Clinical Neurology, Pediatric Neurology Part III, Elsevier, 113, pp. 1707–1708, retrieved 2019-08-01

SAGLB.R&D.20.02.0143a – 02/2020

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