Before it became a big-name company that was bought by J&J, Centocor was a biotech struggling to stay alive following the devastating failure of its promising sepsis treatment Centoxin. Then, Sir Marc Feldmann, an immunologist, and Dr. James Woody, the company’s chief scientific officer, conceived a trial that would change the company’s fortunes.
Feldmann found evidence that an immune system protein called tumor necrosis factor (TNF) was driving the damage to the tissue and joints in patients with rheumatoid arthritis. Separately, Centocor had developed and shelved a TNF-blocking antibody after it also flopped in sepsis patients.
“He and I worked out a way that we could do a 20-patient trial of the anti-TNF treatment in patients with rheumatoid arthritis,” Woody said. “I sent him the antibody and they set up the first 10 patients.”
All the patients in that initial test group were wheelchair-bound, like many back then with the chronic autoimmune disease who had few options to halt its destructive march.
“We administered the drug for the first time,” Woody said.
Within hours, the patients were feeling better.
“The next day, several of them got out of their wheelchairs, and to be honest, we were astonished. We never expected anything like that,” Woody recalled.
The triumph of that experiment foretold the success of what became the blockbuster drug Remicade, the first TNF inhibitor, which won FDA approval in 1998. Johnson & Johnson then bought Centocor for $4.9 billion the following year, and the investment paid off. Remicade has generated more than $50 billion in sales worldwide and laid the groundwork for a host of successful TNF inhibitors, which now make up a booming $40 billion-a-year drug class, led by AbbVie’s Humira, the best-selling drug of all time. These drugs have also changed the trajectory of many autoimmune diseases, including Crohn’s disease, psoriasis, Ankylosing Spondylitis, ulcerative colitis and psoriatic arthritis.
Now, through a clinical-stage venture called 180 Life Sciences, Woody and Feldmann are putting anti-TNF drugs to a new test.
New frontiers for anti-TNF
While anti-TNF drugs have been a boon for many patients, Woody said they haven’t exhausted their potential. Today, Woody leads 180 Life Sciences as CEO and director, alongside Feldmann, co-founder and executive co-chairman, and other pioneers in the field who are finding other conditions that might benefit from anti-TNF treatments while developing new drugs to cool damaging inflammation.
The California company’s most advanced anti-TNF program is for Dupuytren’s contracture, a progressive hand condition. Its anti-TNF treatment, a repurposed version of Humira, saw good results in a phase 2b trial, and the company is now pursuing marketing approval in the U.K. while starting talks with the FDA, Woody said.
Dr. Jagdeep Nanchahal, co-founder and chairman of 180 Life Sciences’ clinical advisory board, was the first to identify the role of TNF in Dupuytren’s, which affects more than 12 million people in the U.S. It starts with one or more hard, painful nodules in the center of the palm, sometimes followed by the formation of thick cords under the skin that tighten, pulling a finger, or fingers inward.
“We’ve been successful before and in creating drugs and agents. We’re pleased to be where we are.”
Dr. James Woody
CEO, 180 Life Sciences
“You can’t button your clothes anymore, you can’t play instruments, you can’t type. It’s a real disability,” Woody said. “There are no therapies for patients until they actually have the bent fingers.”
At that point, patients may opt for a needle aponeurotomy, a surgery that includes needle pricks to loosen the tight bands, or collagenase injections, which can help improve finger mobility by releasing the fibrous bands. But afterwards, the condition could recur. Woody said they hope to prevent this progression entirely with a series of anti-TNF injections, which proved effective at softening, shrinking or eliminating the nodules in a phase 2b trial.
The company is also testing an anti-TNF treatment drug for post-surgical cognitive decline, confusion and memory problems that arise in people, most often elderly, following aggressive surgery, such as a hip replacement or open-heart procedure. For 15% to 20% of patients, this surgical fog never lifts.
“A fair number of those patients have short-term dementia following the surgery,” Woody said. “They end up in nursing homes because their dementia is persistent.”
Doctors once assumed that the condition was a side effect of anesthesia, but Nanchahal’s research shows it may be TNF-driven inflammation sneaking into the brain’s cognitive centers. To test the theory, Woody said they’re launching a phase 2 trial that will give patients anti-TNF treatment just before surgery to see whether it can prevent the condition. The trial is expected to begin in the fourth quarter of 2023.
“It’ll be quite a large trial, several hundred patients, some will get saline and some will get the anti-TNF treatment and we’ll see if it actually benefits patients,” Woody said. “If it does it can become the standard of care for all kinds of aggressive surgeries.”
A third candidate in the anti-TNF program targets frozen shoulder, a condition that immobilizes the shoulder joint with a stiff capsule of fibrous tissue. The condition, which affects around 9% of people between the ages of 25 and 64, shares significant overlap with Dupuytren’s contracture; patients with one often have the other, Woody said. The condition can improve on its own or with the help of pain relievers, physical therapy or less commonly, surgery. But this process takes time — sometimes up to three years.
“We’ll be treating patients by injecting anti-TNF into the shoulder joint as soon as the pain become apparent to see if we can block the formation of the fibrosis and the frozen shoulder part of it,” Woody said. The company recently halted a feasibility clinical trial for frozen shoulder started in the UK due to low enrollment, but hopes to shift the trial location to the U.S. with better results.
The company is also doing early-stage work to determine whether TNF is involved in liver fibrosis, nonalcoholic steatohepatitis (NASH), the most severe form of nonalcoholic fatty liver disease. If the company were to develop a successful treatment for this condition, which currently has none, it could be tapping into a market estimated at more than $20 billion by Allied Market Research. But Woody said it’s not clear if TNF is involved in NASH or how a treatment might target the condition.
“NASH is an interesting area, but it’s a long ways off because it’s very, very preliminary research right now,” he said.
From TNF to CBD
Anti-TNF drugs aren’t the only way to halt inflammation, so the company is also exploring synthetic cannabidiol analogs, made from CBD derivatives.
“We’ve been able to show that certain CBDs are anti-inflammatory and analgesic, so they’re anti-pain medicines as well,” Woody said.
CBD has seen a surge in popularity in recent years as users try it for everything from pain and anxiety to insomnia, but plant-derived treatments have some drawbacks, including challenges with oral delivery, standardizing doses, ensuring purity and determining how much of the drug is absorbed, Woody said. The company is starting pharmacokinetic studies of its oral CBD formulation to see whether it can achieve the steady doses needed to control inflammation and treat pain.
“We’ll then move from there into a trial using these as an anti-inflammatory and anti-pain agent,” he said. “Those will be coming along in the next year.”
Also in the early stages of exploration is a potential mechanism to target an additional pain receptor in the body that they hope might boost the effectiveness of anti-TNF drugs and mitigate some of the side effects, including the heightened susceptibility to infections, Woody said. Given the track record of the company’s team, he’s hopeful they will achieve their aims.
“We’ve been successful before and in creating drugs and agents,” he said. “We’re pleased to be where we are.”
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