New Drug Family Targets Dupuytren's, Frozen Shoulder | Orthopedics This Week
Biologics

New Drug Family Targets Dupuytren’s, Frozen Shoulder

Dr. Jim Woody / Source: 180 Life Sciences

Can an anti-TNF drug be used to fight Dupuytren's and frozen shoulder? One company is betting so…

In 2020, three companies merged to form 180 Life Sciences. The founding dream team includes innovative physician/researchers from Oxford, Stanford and Hebrew Universities, James Woody, M.D., and Professor Sir Marc Feldmann, A.C., F.A.A., F.R.C.P., F.R.C.Path, F.Med.Sci., (inventors of the rheumatoid arthritis drug Remicade®), Lawrence Steinman, M.D., inventor of the multiple sclerosis drug Tysabri®, drug researcher Jonathan Rothbard, Ph.D., and discoverer of numerous endocannabinoids Raphael Mechoulam.

This team have come together to develop “new therapeutics for one of the world's largest drivers of disease: inflammation.”

The research team at 180 Life Sciences is currently working to develop a number of novel drugs to address unmet patient needs and market opportunities in inflammation—and thus fibrosis and pain.

OTW recently interviewed 180 Life Sciences Chief Executive Officer, Dr. James “Jim” Woody. Dr. Woody has decades of experience in pharmaceutical research and currently also serves as Chairman of Oncomed Pharmaceuticals, where he was previously founder and CEO. Dr. Woody holds an M.D. from Loma Linda University, trained in pediatric immunology at Duke University and Boston Children’s Hospital (Harvard) and holds a Ph.D. in Immunology from the University of London. He has co-authored over 140 published articles.

With over 25 years of pharmaceutical research and management experience, Dr. Woody was part of the research team at Centocor that discovered arthritis drug Remicade, today one of the best-selling pharmaceuticals globally.

Dr. Jim Woody and 180 Life Sciences

Sir Marc Feldmann, AC FAA FRS FRCP FRCPath FMedSci professor at the University of Oxford and a Senior Research Fellow at Somerville College, Oxford

Dr. Woody told OTW about the remarkable memory of watching patients experience such decreased pain during the Remicade trials that they stood and no longer needed wheelchairs from disabling arthritic pain—some even danced. This marked a pivotal development in pharmacology, the first anti-TNF drug. Anti-TNF medication consists of antibodies which block inflammatory hormone tumor necrosis factor (TNF). TNF is made by white blood cells and causes inflammation.

Today anti-TNF drug treatment has eliminated wheelchair use for rheumatoid arthritis and the anti-TNF field is a $40 billion/year market.

At his new company 180 Life Sciences, Dr. Woody and his colleagues aim to address painful conditions stemming from inflammation. “In terms of orthopedics, what our scientists have done is tried to figure out…what other pathways are operating that anti-TNF would be helpful in.” With roughly 125 million Americans alone suffering chronic illness, much of which is inflammation-driven, this makes for a massive potential target market.

Potential Treatment for Early Dupuytren's Contracture

Jonathan Rothbard, Founder and Chief Scientific Officer, 180 Life Sciences

Despite groundbreaking developments in drug treatments for some chronic inflammatory conditions, others are still largely painful and untreatable. Dupuytren's contracture is one of these conditions.

Team researchers Jagdeep Nanchahal, M.D., a Fellow of the Royal College of Surgeons and Feldmann have discovered that certain fibrotic diseases, such as Dupuytren's contracture, also stem from TNF.

Dupuytren's disease begins as a small nodule in the hand, with fibrous cords that form and eventually contract the hand into a claw position, Dr. Woody explained. Effective drug treatment is limited and often the patient requires surgery as well as several months of subsequent physical therapy.

Around 15 million Americans over 35 have Dupuytren’s. As the disease develops, it makes everyday activities like food preparation or writing impossible, affecting patient quality of life. “The goal of our whole program was to try to prevent this altogether,” Dr. Woody reported.

Dr. Nanchahal examined patient nodules post-surgery and was able to determine the metabolic pathways that were the fibrosis. “He found that TNF was driving alpha smooth muscle action, which was the thing that forms the cords,” Dr. Woody told OTW, “and he found out the dose of anti-TNF that you would have to use to block this.” Unlike lung and liver fibrosis, Dupuytren’s can be diagnosed early. This means early intervention is possible.

Researchers have previously used animal or late stage cells to study such fibrosis, yet neither accurately reflect human disease. Researchers at 180 Life Sciences have instead used human tissue for more accurate clinical outcomes.

Dr. Nanchahal and his research team set up the largest clinical trial ever, made up of 180 patients, offering half with drug injection and half with placebo injection, four times over the course of one year. The study completion was delayed due to the COVID-19 pandemic but is expected to be released by the end of Q4 2021, Dr. Woody states, with press releases and medical conference presentations to come.

Frozen Shoulder

Raphael Mechoulam, professor of Medicinal Chemistry at the Hebrew University of Jerusalem

The company is also anticipating approval to begin a similar clinical trial on the use of anti-TNF drug treatment for frozen shoulder (adhesive capsulitis). Frozen shoulder, Dr. Woody explained, is an extremely trying condition that eventually leads to complete immobility of the shoulder and most often ultimately requires surgery. The affliction affects roughly 11 million people in the U.S.

“This starts out as very, very painful,” explained Dr. Woody, “and then it goes on to be fibrotic and eventually you can’t move your shoulder at all.” Dr. Woody also explained that the condition is much more common in diabetics.

The researchers believe it may also be possible to prevent this disability through early intervention with anti-TNF treatment. Dr. Woody noted that up to half of frozen shoulder patients also have Dupuytren’s disease. “We think the fibrosis is similar to what was going on in the palm of the hand,” Dr. Woody reported.

Dr. Woody said the 40 to 50 patient clinical trial will, pending regulatory approval, begin in September 2021. “We will be injecting anti-TNF into the shoulder joint as soon as the pain is evident…and maybe we can prevent the pain and also the formation of the fibrosis going forward.”

If approved, it will be the first treatment providing long-term benefits for frozen shoulder. The 180 Life Sciences team is excited to share both study outcomes. “We think this is quite exciting. If you can prevent the disability, patients would find that favorable,” said Dr. Woody.

Looking Ahead: Postoperative Cognitive Dementia and TNF Receptor Research

Dr. Lawrence Steinman, professor of Neurology and Neurological Sciences and Pediatrics at Stanford University.

A third research trial, unrelated to fibrosis, is also in the works at 180 Life Sciences. For many years, people have talked about elderly family members who seem to have never been the same after a major surgery. In more recent years evidence-based research has explored this reality.

Dr. Woody explained that elderly patients are at increased risk for postoperative cognitive dementia (POCD) after emergency surgeries such as hip replacements. “We now know this is because tissue damage can release TNF which can travel to the brain and incite inflammation. Some of these patients unfortunately never recover and require nursing home care.”

The researchers at 180 Life Sciences hypothesize that injecting anti-TNF at the time of surgery may prevent post cognitive damage and hope to start clinical trials exploring this treatment around the turn of the year.

Looking ahead, Dr. Woody also reported that 180 Life Sciences is interested in developing more specific anti-TNF drug treatments as understanding of the biology of inflammation becomes more developed. “It turns out that there are two kinds of TNF receptors, and if you block them with say Humira or Remicade you block both of them—but one of them is an inflammatory type one and the other is anti-inflammatory. So, the next generation of anti-TNF inhibitors will probably be trying to block the inflammatory one and let the anti-inflammation one work,” Dr. Woody told OTW.

“That’s a whole new generation of drugs coming along in the next five years,” Dr. Woody explained. “It will, I think, avoid all the infectious disease complications or oncology risks of anti-TNF. For orthopedics this would be quite interesting as well.”

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