Eli Lilly to Codevelop Inhibitors for Neurodegenerative Diseases

Eli Lilly and Company and Rigel Pharmaceuticals recently announced an agreement and strategic collaboration to codevelop and commercialize inhibitors for immunological and neurodegenerative diseases. 

The companies will develop and commercialize Rigel’s R552, a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor. The inhibitor is intended for all indications, including autoimmune and inflammatory diseases. 

As part of the collaboration, Eli Lilly and Company will also lead all clinical development of brain penetrating RIPK1 inhibitors in central nervous system (CNS) diseases.

"At Lilly, our immunology strategy is focused on the pursuit of novel targets that have the potential to develop into best-in-class medicines for patients with autoimmune conditions," Ajay Nirula, MD, PhD, vice president of immunology at Eli Lilly and Company, said in the announcement. 

"RIPK1 inhibitors are a promising approach, and R552 is an exciting addition to our immunology pipeline. We look forward to working with Rigel to advance its clinical development,” Nirula continued. 

RIPK1 is a signaling protein implicated in a range of key inflammatory cellular processes, including necroptosis and cytokine production, an Eli Lilly and Company spokesperson explained.  

In necroptosis, cells rupture and lead to the diffusion of cell contents that may elicit an immune response and increase inflammation. 

In pre-clinical studies, Rigel’s lead RIPK1 inhibitor, R552, demonstrated prevention of joint and skin inflammation in a RIPK1-mediated murine model of inflammation and tissue damage.

R552 has already completed Phase 1 clinical trials and will begin Phase 2 clinical trials later this year as part of the collaboration. Additionally, Rigel  has ongoing pre-clinical activities with its lead CNS penetrant RIPK1 inhibitor candidates. 

Under the terms of agreement, Eli Lilly and Company will pay an upfront cash payment to Rigel of $125 million and will be responsible for all costs of global commercialization for R552. 

Rigel will be eligible to receive up to $835 million in potential development, regulatory, and commercial milestone payments and will also have the right to co-commercialize R552 in the US. 

"We are very excited to form this strategic partnership with Lilly. This collaboration will provide significant resources and expertise to support a broad investigation in multiple disease indications with our RIPK1 inhibitors," said Raul Rodriguez, Rigel's president and CEO. 

"With Lilly's extensive knowledge in immune and CNS diseases, they are our ideal partner to ensure the clinical and commercial success of our RIPK1 inhibitor program,” Rodriguez continued. 

Closing of the transaction is subject to conditions, including clearance under the Hart-Scott-Rodino (HSR) Antitrust Improvements Act of 1976.

RIPK1 kinase has emerged as a promising therapeutic target for the treatment of various neurodegenerative, autoimmune, and inflammatory diseases. 

Recently, RIPK1 was used in studies examining the role of this kinase in ALS, a progressive neurodegenerative disease that affects motor neurons in the brain and the spinal cord.

A study mentioned in a June 2020 Nature article stated that the activation of RIPK1 has been seen in post-mortem spinal cord samples from patients with ALS.

An ex vivo human co-culture system of astrocytes and motor neurons from patients with a specific ALS mutation showed necroptotic death of motor neurons, which could be helped with Necrostatin-1s (Nec-1s).

Nec-1s was the first small-molecule inhibitor of RIPK1 kinase to be developed and has been used to investigate the role of RIPK1 in various studies and animal models of human diseases.

Additionally, a mouse model of ALS treated orally with Nec-1s showed improvements in survival, motor activity and axonal pathology. The observations suggested a potential approach to “genetic stratification” of patients in a disease where 90 percent of patients exhibit idiopathic disease without known genetic identifiers.