PIM kinase inhibition: a Swiss startup’s unique approach to tackling complex autoimmune disorders

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Mysthera Therapeutics

A healthy immune system is supposed to defend the body against disease and infection, but in autoimmune diseases, the immune system malfunctions, and instead attacks the body’s healthy cells, tissues, and organs. Despite recent progress in therapeutic options for autoimmune disorders, a significant unmet need remains, which is why Mysthera Therapeutics is aiming to take on these diseases using a very unique approach: PIM kinase inhibition.

There are more than 100 known autoimmune diseases, with some of the most common ones being rheumatoid arthritis (a long-term condition causing pain, swelling and stiffness in the joints), systemic lupus erythematosus (a condition that causes widespread inflammation and tissue damage in affected organs), and type 1 diabetes. 

The unmet need for new approaches to treat autoimmune disorders comes from the fact that there are still certain issues with currently available treatment options, including insufficient response rates, drug resistance, and an unfavorable therapeutic index.

On top of that, there has been a rise in the incidence of certain autoimmune disorders; a recent population-based study of 22 million people, investigating 19 of the most common autoimmune diseases, showed that, taken together, these 19 disorders now affect about 10% of the population. This statistic is higher than previous estimates, which ranged from 3% to 9%. 

With all of this in mind, Swiss startup Mysthera Therapeutics – created by founding investor Forty51 Ventures – is now looking to transform the lives of patients suffering with complex autoimmune disorders through an approach known as PIM kinase inhibition. 

Launched just last month in the bubbling biotech hub of Basel, the company is uniquely positioned as the only ones to be developing PIM kinase inhibitors as therapeutics specifically for autoimmune disorders. 

What exactly are PIM kinases?

PIM kinases are essentially gateway kinases in multiple cell lineages, driving excessive inflammation. They belong to a family of serine/threonine kinases that have three members with greatly similar sequence and function: PIM-1, PIM-2, and PIM-3. 

Although PIM expression is generally low in healthy tissue, high expression is specifically induced during immune cell inflammation, and, at the site of persistent inflammation, PIM is involved in the pathogenic T and B cell effector responses and immune escalation.

In recent times, PIM kinase inhibition has emerged as a possible treatment for cancer, as PIM kinase is known to play an important role in cancer biology, whereby PIM-1, PIM-2, and PIM-3 act as a weak oncogene and, whenever expressed in exacerbating forms, are responsible for different types of human cancer. 

But, despite largely being developed as cancer therapies, Mysthera Therapeutics has decided instead to develop PIM kinase inhibitors for the treatment of autoimmune diseases. 

So, why did the company decide to take this unique approach, and how can PIM kinase inhibition be used to treat autoimmune disorders?

Mysthera Therapeutics‘ unique approach to tackling autoimmune disorders

Tertiary lymphoid structures (TLS) are ectopic, vascularized hubs of lymphocyte interaction and activation that arise in tissues during chronic inflammation. The interaction of activated T and B cells via CD40L-CD40 and STAT3 signaling cytokines are central elements in the initiation of these structures, frequently found in autoimmune diseases, and their presence is typically associated with disease severity and progression.

It is believed that the disruption of TLS can curtail autoimmune disease progression, and because elevated PIM kinase may further contribute to the formation and maintenance of TLS, PIM kinase inhibition offers a novel approach to potentially address complex autoimmune diseases, including lupus nephritis, rheumatoid arthritis, and inflammatory bowel disease (IBD). 

“Our intention was to specifically tackle what we call complex autoimmune disease with particular high unmet medical need. In those diseases we are faced by pathology which is not driven by only one bottle neck molecule or cell type but multiple independent elements. This means a therapeutic approach needs to be broad enough to meet this complexity, but narrow and specific enough to not cause toxicity and be sustainable for long-term treatment,” commented Mysthera Therapeutics.

With this aim in mind, PIM emerged as a potential therapeutic target. According to the company, this is because PIM has a low expression level and high functional redundance at a steady state in healthy tissue, but is drastically upregulated in activated T and B cells in the context of severe and persistent inflammation.

“In this inflammatory context PIM carries critical, non-redundant functions in the differentiation and function of effector T and B cells. Specifically, PIM have been shown to be involved in plasma cell differentiation, which is the effector type producing destructive auto-antibodies in many autoimmune diseases. On the T cell side, PIM drives pathogenic effector types, like Th1 and Th17, while at the same time suppressing tolerogenic regulatory T cells,” Mysthera Therapeutics continued to explain.

And, the company said, the fact that PIM is induced preferentially at the site of inflammation, and that it is modulating rather than shutting down the immune system, means that, as a therapy, it should be safer and better tolerated than current approaches. 

Although Mysthera Therapeutics is the only company developing PIM kinase inhibitors for autoimmune diseases, there is previous safety evidence available that the company can take into consideration. 

“While a highly innovative approach, the company can leverage the fact that earlier generation 3rd party PIM kinase inhibitors have been shown to be safe in early trials, albeit all cancer trials,” commented the company. 

Furthermore, the company expects that, as a small molecule used to target PIM kinase, it is positioned to offer a convenient oral and cost-effective solution compared to other therapeutic approaches.

A pre-clinical stage portfolio

Mysthera Therapeutics’ PIM kinase program was in-licensed from Inflection Biosciences, a leading PIM kinase company that was co-founded by Mysthera Therapeutics’ chief executive officer (CEO), Darren Cunningham, who has more than 10 years of insights into the PIM kinase field and has executed several licensing transactions involving PIM kinase. 

The molecules in the company’s pre-clinical stage PIM kinase portfolio have been rationally designed to offer favorable drug like properties, high potency, and best-in-class selectivity.

When asked why Mysthera Therapeutics wanted to launch with a pre-clinical stage portfolio, the company answered: “The company is innovating a new way to treat complex autoimmune diseases, and as with any highly innovative approaches, this is typically earlier stage. To start up with a clinical stage therapeutic, the company would no doubt have had to make sacrifices on the level of innovation applicable and the impact that could be made.” 

Meanwhile, the $3.5 million seed investment from Forty51 Ventures will be used to confirm a PIM kinase inhibitor clinical candidate for development within nine to 12 months. According to the company, a lead has already been identified, and is currently being further assessed. Once it is confirmed as a clinical candidate, IND enabling studies can be commenced. 

Next steps for Mysthera Therapeutics

Having only just launched last month, Mysthera Therapeutics has a busy time ahead; as mentioned, it is assessing a lead clinical candidate to take forward into IND enabling studies. It will then be seeking to rapidly advance it through IND studies and into the clinic. 

These are the near term goals that the company is currently focused on, but, once in the clinic, it will be aiming to execute well-designed clinical trials to prove the benefits of its first-in-class approach over existing therapies, and pave the way for better oral treatments for patients suffering with complex autoimmune disorders. 

The company said it sees high potential for its program in the treatment of lupus nephritis, but it also wants to pursue it for other orphan indications and larger complex autoimmune conditions, such as rheumatoid arthritis. 

In order to support this activity, it is planning a Series A fundraising, once it delivers on the objectives of its seed capital round.

“The company is writing the next chapter in autoimmune disease therapeutics…Despite recent progress in therapeutic options in autoimmune diseases, millions remain underserved. It is the company’s mission to innovate new therapeutic options to transform the lives of patients suffering with complex autoimmune disease globally,” stressed Mysthera Therapeutics.

Explore other topics: Autoimmune diseasebiotech startup

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