In an interview with PharmaShots, Dr. Jim Woody, MD, Ph.D., Chief Executive Officer at 180 Life Sciences shared his insights on the Phase 2b study of anti-TNF for the treatment of the early Dupuytren's disease.

Shots:

• 180 Life Sciences used anti-TNF to treat early Dupuytren’s disease and the Phase 2b study is complete.
• Additional programs using anti-TNF soon to be in the clinic include frozen shoulder and post-operative cognitive deficit.
• 180 Life Sciences also has a preclinical cannabinoid program exploring synthetic CBD compounds that will be pure and orally absorbable.

Tuba: 180 Life Sciences recently completed a Phase 2b study on Dupuytren's disease. Tell us about the condition. What are the epidemiology, the incidence, and the prognosis?

Jim Woody: Dupuytren's trial was managed by Dr. Jagdeep Nanchahal in the U.K. and was focused on treating people very early in their disease so as to prevent the finger contractions that eventually occur. All other current therapies begin treatment after the disability has occurred. Patients cannot button their clothes, cannot type or send a text message. They treated 181 patients very early, as soon as the small nodule in their hand appeared. The nodule gradually creates small cords inside your palm that pull the fingers together.

In our trial, there were three to four injections per patient, and the study’s primary and secondary endpoints, relating to the nodule and contracture of the hand, were both met and were statistically significant. The data were submitted to a major journal for publication and we will hopefully hear back in the next month or so whether it's been accepted. Then we can release the entire data set to the public.

Tuba: What is the incidence of Dupuytren’s disease and what is typically the prognosis without the 180 Life Sciences drug candidate?

Jim Woody: There are about 16 million patients in the U.S. with Dupuytren’s, and a similar number in the European Union. It starts out as a small nodule in the palm of the hand and then gradually, over a year or maybe several years, it becomes disabling as it pulls fingers together. Typically, doctors try to treat this with steroid injections, needle disruption of the cords, or collagenase injections, but the treatments are only modestly effective. Eventually, patients have to have surgery, and even then, it recurs in about 5 or 6% of the patients after that.

Interestingly, in our trial, almost all the patients came back for all the injections, which especially during COVID was a substantial achievement, and it indicates that they actually knew what was going to happen to them. Patients can go on the internet and see what's going to happen to their hands over time, and decide what they want to do: prevent it or wait and see if they have the disability. Most chose not to wait.

Tuba: Could you give us some insights into the Phase 2b trial design? A treatment regimen, enrollment metrics, and any of the data that has been disclosed to date.

Jim Woody: This all began with Dr. Jagdeep Nanchahal’s research work at Oxford University in the U.K. He was able to collect specimens from patients who were undergoing surgery for their Dupuytren’s. The nodule was removed during surgery. Dr. Nanchahal studied these nodules and learned that the cord formation process was driven by a substance called smooth muscle actin. He also found out that the biologic drug anti-TNF would block this production of smooth muscle actin. The team also determined what dose was needed to do this. Based on those research findings, he was able to design the Phase 2b trial to go ahead. They determined what dose was necessary and estimated how frequently it needed to be given to patients. It is three to four shots over about a year—every three months or so—as the basis of the trial.

The team put together an analytical plan, which is customary for randomized controlled trials, in which half of the patients got saline injected in their nodule and the others got anti-TNF — specifically, we used adalimumab (Humira) from AbbVie for this particular trial, because it has a concentrated formula, and seemed to be the best for this purpose. Then the clinicians measured all of these aspects that had to do with the nodule (size, whether it’s soft or hard, etc.), whether it changed or whether the fingers were contracted, whether there was any other therapy that they had to have and a whole range of other endpoints that we were able to achieve. The details beyond that haven't been released yet, but we will share them when the paper is in press.

Tuba: What are your company's plans for frozen shoulder?

Jim Woody: The frozen shoulder trial has been approved and funded by a grant in the U.K. The sites are lined up and ready to go. Interestingly enough, frozen shoulder is more common in diabetics, and about half of these patients also have Dupuytren’s. We think that the fibrosis process that drives Dupuytren’s is similar to the process behind the frozen shoulder. Frozen shoulder starts out as a very painful shoulder joint that goes on for some time, and then it gets frozen, such that you really can't move your shoulder at all. Surgery can correct the fibrosis but has a lengthy rehabilitation process. We expect the first patient to enroll in late January or February 2022. Again, the issue of COVID in the U.K. has delayed this and could delay it again.

Tuba: 180 Life Sciences has shown a role for TNF in post-operative cognitive deficit. Tell us more about POCD and your plans for a clinical trial there.

Jim Woody: We have learned that in major surgeries such as a hip fracture or CABG, or any extensive surgical procedure, the damage to the tissue releases TNF. We have been able to measure that in patients and in animal models. During surgery, we think that the TNF opens the blood-brain barrier and causes inflammatory substances and cytokines to go to the area of the brain that deals with dementia, and in in the current literature it is reported that somewhere around 20% or more of patients with major surgeries experience dementia after surgery. This may persist for a whole year or longer, and eventually, some patients end up in nursing homes, which is a very unfavorable outcome after having major surgery.

Our therapy is to give a small amount of anti-TNF right at the time of surgery and block this process with a single dose, and then we'll follow them for a whole year to see whether it had an impact on their dementia. There's a whole range of instruments you can use for determining dementia. Most come from the Alzheimer’s world, and we’ll follow patients along to see whether we're having an impact on it. This trial will probably start in the third or fourth quarter of 2022.

Tuba: 180 Life Sciences is also working in the cannabis space. Tell us in brief about your lead synthetic CBD analog, HUM-217 — its mechanism of action and formulation, among other details.

Jim Woody: The cannabis program is being done in Israel with Dr. Raphael Mechoulam. He discovered the endocannabinoid system and has been researching cannabinoids for the past 30-to-40 years. We know that if you take the regular cannabis that you buy in the local dispensary, it has more than 100 different compounds in it, so it has some issues, not just the euphoria, but also side effects that might occur. We are making a single totally synthetic compound. We have been looking at different compounds and we want them to be orally absorbable.

We do not want them to have psychoactive properties, to not be addictive, and we want them to be able to prevent pain and reduce inflammation. Our scientists have been able to discover some that have those properties. We've tested HUM-217 in animal models with inflammation and pain, and we can show that it seems to be effective. We are in the process of beginning to consider IND-enabling studies, to determine the required dosage if there is any toxicity, etc. — the usual things that go into submitting an IND to either the FDA or the U.K. or Israeli regulatory bodies.

Tuba: Which other drugs are being developed in your pipeline?

Jim Woody: We just licensed in a new compound called HMGB1, which Dr. Nanchahal had been working on for some time, and which has a very unique property: HMGB1 can help tissues that are damaged, either from inflammation or some other injury like liver fibrosis, regrow and regenerate. In the case of liver fibrosis, we think it will stimulate the liver stem cells to regrow and be able to function. We know it does this, and there are several other organs where it might work. For example, after heart attacks, it could possibly stimulate the heart muscle to regrow. For this program, we're just starting the IND-enabling studies for that compound, and that will be going on for the next year. Trials could start in a year or a year and a half.

Tuba: Tell us a little bit about 180 Life Sciences’ third preclinical nicotinic acetylcholine receptor program.

Jim Woody: We've known for some time that nicotine is a modest anti-inflammatory agent. We know that some people develop ulcerative colitis or similar conditions when they stop smoking. We're making a specific compound to bind to this nicotinic receptor so that we can get all the effects of nicotine in a larger amount with a single substance. We're still trying to find the best compound to use, so it will be quite a while before we get that one very far off the ground.

Tuba: Is there anything else you’d like to add?

Jim Woody: With the Dupuytren’s trial we're confident enough about what we think the data will show that we've hired regulatory teams to help us, and they're taking the study to both the U.K. regulators, the MHRA, and to the FDA. Currently, there is a backlog of things going on with COVID and vaccines and medicines and you can't get an appointment with either of the regulatory bodies until about March. Stay tuned for Q2 when we have time to talk with them and we will be able to discuss the path forward as to getting this therapy approved and on the market for Dupuytren's.

Image Source: Sharecare

About James:

James N. Woody, M.D., Ph.D. has more than 25 years of pharmaceutical research and management expertise. He has served as our Chief Executive Officer and as a director since the closing of the business combination in November 2020. Dr. Woody has served as the CEO of 180 since July 2020, and as a director of 180 Life Sciences since September 2020.

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