Following Positive IIb Study Data, Can 180 Life Sciences Clear The Next Regulatory Hurdle?

The UK Medicines and Healthcare products Regulatory Agency and the US Food and Drug Administration have both asked California-based biotech 180 Life Sciences for extra information about the use of adalimumab to treat early-stage Dupuytren’s disease following the company’s Phase IIb study results. (Also see "180 Life Sciences Adalimumab Study Publishes Positive IIb Dupuytren’s Disease Data" - Generics Bulletin, 3 Jun, 2022.)

Both organizations have requested additional information on how the primary and secondary endpoints of the study – nodule hardness and size – correlate to disease progression.

Patients with Dupuytren’s disease gradually experience the formation of a hard nodule in the fascia underneath the skin of the palm, which immobilizes the fingers at it forces them to curl inwards. The condition cannot currently be treated without collagenase enzymes or surgery.

180 Life Sciences CEO Jim Woody told Generics Bulletin: “The existing therapies are all done after you have the contracture – after you can’t button your clothes anymore, after you can’t type. We’re arguing that we can prevent all of that. Anyone with a nodule in their hand certainly is a subject that might want to have this therapy and shut the disease down before they develop the finger contraction.”

As part of the firm’s repurposing initiative, researchers carried out a randomized, double-blind, placebo-controlled trial of 140 participants, administering four injections of either 40mg adalimumab in 0.4ml or placebo saline over the course of nine months. The primary endpoint of the study was nodule hardness at 12 months, as measured with a durometer. The secondary endpoint of nodule size was measured using an ultrasound at 12 and 18 months.

Nodule hardness was found to be lower in the adalimumab treatment arm compared to the placebo at 12 months and had decreased further at 18 months, nine months after the last injection. The same was true for nodule size, which was also lower at both 12 and 18 months in the treatment arm.

Also noteworthy is that fewer patients in the treatment group were found to be awaiting surgery at the 18-month mark compared to the placebo group, although the researchers accepted that longer-term follow up would be needed to assess the impact of adalimumab treatment on eventual surgery.

Regulators Seek Further Clarification

Following a scientific advice meeting, the MHRA has told 180 Life Sciences that it sees no need for additional non-clinical studies for the planned use of adalimumab to treat early-stage Dupuytren’s disease. It has however asked for additional evidence to validate the endpoints of the IIb study as clinically meaningful, expressing that without this it is unlikely the research would be considered acceptable as a single pivotal study to support a marketing authorization application.

Meanwhile, the FDA has indicated that the outcome measures used by 180 Life Sciences “are not clinical outcome measures that measure how a patient feels, functions or survives,” which would be required to support a demonstration of efficacy in registrational studies. It has recommended requesting a pre-investigational new drug meeting to receive additional regulatory guidance, which 180 Life Sciences says it plans to request.

“The MHRA pretty much accepted all of the studies we had done and didn’t think we needed another clinical trial,” Woody said. “The data we collected was very solid and the results were highly statistically significant. Their questions were about the endpoints we used, which were the size of the nodule and the hardness of the nodule. Did they actually represent surrogate markers that would tell us that we can also prevent the eventual contracture? That was a reasonable question, and we knew that was going to come up.”

"There are hundreds of patients who have already contacted us asking where they can get this therapy for the nodule in their hands. It will probably be hundreds more by next week."

Woody explained that 180 Life Sciences would be going back to the MHRA and FDA armed with longitudinal research published by researchers at the University of Groningen which correlate nodule size with eventual finger contraction in Dupuytren’s disease, alongside “a couple of other publications.”

The big question now is whether this is information the regulators will be willing to accept. The difficulty with treating Dupuytren’s in this way, Woody explained, is that the condition progresses differently in each patient, meaning those in the early stage of the disease have no way of knowing whether they will eventually progress to the stage of surgical intervention – making the efficacy of the adalimumab therapy more difficult to establish. Roughly 75% of patients eventually progress to advanced stages of disease, with between 20% to 33% experiencing regression after surgery.

He elaborated: “Some patients it progresses very quickly over a couple of years. Some patents that goes slower over four or five years and some patients for a very long time and some it never does turn into the finger contractions. The difficulty is you don’t know that, there’s no way to know upfront. But since these injections are pretty harmless and not very painful, most people say ‘let’s see if we can prevent this’.”

He added: “We might be willing to set up a registry to follow patients for a long time, but I must say there are hundreds of patients who have already contacted us asking where they can get this therapy for the nodule in their hands. It will probably be hundreds more by next week. People are tuned in to not wanting to go through the finger contraction problem.”

Treating Frozen Shoulder And Post-Operative Dementia

Alongside Dupuytren’s disease, 180 Life Sciences is investigating the use of anti-tumor necrosis factors in treating frozen shoulder and post-operative cognitive dysfunction (see sidebar.) It expects to begin phase II trials into these indications this year.

Frozen shoulder causes pain and stiffness in the shoulder joint due to fibrosis, with a treatment list that includes painkillers, anti-inflammatories, physiotherapy, steroid injections and in some cases surgery. The condition is more common in patients with Dupuytren’s than the general population, leading 180 Life Sciences to believe that if adalimumab injections can prevent progression of fibrosis of the hand, then they may well have the same effect in the shoulder.

Meanwhile, POCD is defined as a decline in cognitive function, particularly memory and executive functions, which occurs following surgery, most commonly in those over 65 years of age. This typically does not persist beyond six to 12 months following the procedure, but in some patients can have a long-term effect.

“A fair percentage never recover and end up in nursing homes, which isn’t a great outcome for a major surgery,” Woody remarked.

While POCD was once thought to be caused by anesthesia, researchers now believe that TNF released during tissue damage in surgery may be able to cross the blood-brain barrier and allow inflammatory cytokines to enter the brain and affect cognition. 180 Life Sciences plans to give a single infusion of anti-TNF to patients right before surgical procedures, which they hope will lead to a reduction in cases of POCD.

These indications, the company hopes, should also be easier to pass by regulators, due to a larger pre-existing body of research to measure disease progression.

“The Dupuytren’s trial was complicated because nobody had ever done a similar trial in early-stage Dupuytren’s, so trying to decide what the endpoints would be for a trial we could complete in a couple of years was difficult,” explained Woody. “With frozen shoulder and post-operative dementia, there’s lots of instruments out there to measure how the disease is progressing. Those are well-known and well accepted.”

The firm is also conducting pre-clinical research into the use of anti-TNF for non-alcoholic steatohepatitis, and hopes to begin doing the same for HMGB1 during Q2 2022.

Picking Partners For Commercialization

During the Dupuytren’s trial 180 Life Sciences used adalimumab products supplied by Celltrion, announcing their collaboration toward the end of 2021. (Also see "Celltrion Allies With 180 Life Sciences On Repurposing Biosimilars" - Generics Bulletin, 21 Sep, 2021.) At the time “both companies anticipate[d] entering into detailed discussions for a potential worldwide development and commercialization license agreement to be completed within the next year.”

Woody explained that 180 Life Sciences will seek to partner with a firm which makes a high-concentration citrate-free adalimumab biosimilar for commercialization. This could be Celltrion, but if a partnership with Korean biotech doesn’t come to pass then firms such as Alvotech, Amgen or Sandoz could all be contenders. (Also see "Alvotech Reveals Action Date For Interchangeable Adalimumab BLA" - Generics Bulletin, 7 Mar, 2022.) (Also see "Amgen: Humira Interchangeability ‘A Nice To Have, Not A Need To Have’" - Generics Bulletin, 17 Feb, 2022.) (Also see "Sandoz Lines Up Higher-Strength Adalimumab In Europe" - Generics Bulletin, 20 Jun, 2022.)

The company also plans to develop a specialized syringe and injection kit just for administering adalimumab in Dupuytren’s disease. The conventional needles used by companies such as originator AbbVie to inject the biologic are not strong enough, since the nodules in patients’ palms can be so dense, so a tougher needle is used. The kit will also need to be able to inject just the right amount of adalimumab – 0.4ml – to prevent the compound from leaking out into the tissues of the hand.

Woody said that a similar specialized medical device would likely need to be developed for frozen shoulder patients too. He added that 180 Life Sciences had “filed patents over all of this so that we’re well protected.”

The market size for Dupuytren’s is fairly large, with a worldwide prevalence of around 8.2% and few treatment options to prevent the progression of the disease. If 180 Life Sciences can convince regulators that adalimumab can be suitably repurposed for this indication, the market opportunities both for the biotech and its collaborators could be hugely significant.