7:50 PM
Nov 01, 2018
 |  BC Innovations  |  Targets & Mechanisms

Rethinking definitions of autoimmune disease

Why autoimmune diseases should be redefined by molecular pathway

The autoimmune field is dialing up its search for better biomarkers as it seeks to make the next step change from the targeted therapies that overtook blanket immunosuppressants. The question is whether autoimmunity might follow the lead of oncology and classify indications by molecular drivers rather than the symptoms or tissues involved.

While TNF-α inhibitors and other therapies targeting specific immune pathways have provided better outcomes for many patients than generalized immunosuppressants such as steroids, there is still no good way to match therapies to patients or disease stage.

For patients, this often means cycling through treatments in a trial-and-error fashion before finding one that works.

For drug developers, it raises the risk of failure as companies have little to guide their patient selection or clinical strategy to optimize outcomes.

“Rheumatoid arthritis is the classic example of the problem across autoimmune disease,” said Christoph Lengauer, president of precision autoimmune start-up Celsius Therapeutics. “Anti-TNF-α is a great drug, but 40% of patients don’t respond. We don’t know how to predict who will respond, when to give it during the course of the disease, or who will have side effects.”

Celsius and Scipher Medicine announced series A rounds this year, and aim to develop autoimmune precision therapeutics and diagnostics based on patients’ underlying disease biology.

Pharmas have started incorporating exploratory biomarker studies in their clinical development programs to tackle the problem.

And a cadre of smaller diagnostics companies, including DxTerity Diagnostics Inc., Exagen Diagnostics Inc. and Inova Diagnostics Inc., is developing genetic biomarkers or antibodies to stratify patients.

“It has become clear that conditions like rheumatoid arthritis are actually not one disease, but a syndrome defined by the presence of similar symptoms with varying root causes.”

Paul-Peter Tak, Sitryx Therapeutics

If successful, such biomarkers could enrich future trials for responders and lead to new targets.

The impact could eventually support a departure from the traditional way autoimmune diseases are defined, to characterize indications by the molecular targets involved or the pathways in which they act.

In this scenario, a drug could be indicated for diseases involving a cytokine such as IL-17, for example. That would mimic oncology, where Keytruda pembrolizumab became the first drug approved for a cancer defined by molecular target regardless of the tumor’s tissue of origin. Merck & Co. Inc.’s drug was approved in 2017 to treat advanced microsatellite instability-high (MSI-H) or mismatch repair...

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