Dogs help Eli Lilly scientists identify new osteoarthritis target

Running Dog
In a study of pet dogs, Eli Lilly researchers showed an mPGES-1 inhibitor called LYA could reduce osteoarthritis symptoms and signs of clinical pain. (Pixabay/oscarhenao)

Existing anti-inflammatory drugs for osteoarthritis have their limitations, including gastrointestinal side effects and increased risk of cardiovascular events. With the help of pet dogs, scientists at Eli Lilly have identified a potential new treatment for osteoarthritis that could offer an alternative for both animals and people.

The drug, dubbed LYA, inhibits an enzyme called microsomal PGE synthase-1 (mPGES-1). According to results published in Science Translational Medicine, it reduced symptoms and signs of clinical pain in companion dogs with spontaneous osteoarthritis but didn’t induce side effects that are typically seen with nonsteroidal anti-inflammatory drugs (NSAIDs).

Most currently available NSAIDs target PGE2, a lipid mediator of inflammation. PGE2 is formed by mPGES-1, which is found to be upregulated in inflamed tissues. Therefore, inhibiting mPGES-1 has emerged as a potential alternative mechanism for treating arthritis.

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The Lilly study enrolled 163 dogs with spontaneous osteoarthritis and treated them with one of four different compounds: LYA, an approved veterinary NSAID called carprofen, another investigational drug called LYB that inhibits PGE2’s inflammatory receptor EP4 or placebo. They used an index called the Canine Brief Pain Inventory (CBPI) to assess pain severity, mobility and other measures in the animals two weeks after treatment.

The dogs that received LYA showed improvements in CBPI measures compared to those that received the placebo, and the benefits of LYA were comparable to carprofen. Even though the probability of superiority to placebo on the CBPI pain interference score for LYA (80%) didn’t meet the predefined threshold of 95%—the study’s primary endpoint—the compound still provided pain relief and produced improvements in all other secondary efficacy measures.

The proportion of dogs that experienced an adverse event was not significantly different between the placebo and either LYA or carprofen. However, the carprofen-treated dogs were significantly more likely to experience increased cholesterol.

The EP4 antagonist LYB didn’t perform better than the placebo; it fell behind LYA in the primary endpoint, and dogs receiving it experienced adverse events more often. But the researchers believe EP4 is still an important mechanism for pain relief and deserves further investigation.

RELATED: Improving osteoarthritis treatment with a cartilage-penetrating 'nanocarrier'

Other research groups have recognized the potential of targeting mPGES-1 in the treatment of osteoarthritis. In fact, Glenmark Pharmaceuticals already has an mPGES-1 inhibitor, GRC 27864, in phase 2b development in Indian patients with moderate osteoarthritic pain.

And some companies and academic researchers are looking for therapies that treat more than just pain and inflammation. A research team at the Massachusetts Institute of Technology designed a nanoparticle to help deliver an experimental tissue-regenerative drug deep into cartilage to achieve better results. And San Diego-based biotech Samumed is targeting the Wnt pathway to help fix joint damage. Its lead program, lorecivivint, is already in phase 3 for knee osteoarthritis.

Because the progression of osteoarthritis is similar in dogs and humans, the Lilly researchers argue their LYA canine clinical study “suggests a proof-of-concept pain efficacy signal” and that LYA could be a promising drug to treat the painful disorder in both pets and people, they said in the study.

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