Summary: 180 Life Sciences is an under the radar stock worthy of a closer look. We sat down with CEO Dr. James Woody to dig deeper into ATNF to learn if the stock merits being added to your portfolio.

Image Source: 180lifesciences.com

180 Life Sciences (ATNF) is a small company focusing on inflammatory diseases. With a market cap of just $37mn and a low volume of trading, ATNF stays firmly under the radar. However, the company is doing interesting science, so Avisol Capital Partners, through TalkMarkets, reached out to ATNF CEO, Dr, Jim Woody, to discuss his company.

The company's lead candidate is a well-known anti-TNF agent adalimumab or Humira, which they are repurposing for Dupuytren’s Disease, or DD, a debilitating disease where one or more fingers of your hand may bend after knots form in the underlying tissues. While needling, certain enzymes and invasive surgery may be used to treat the disease, there’s a major unmet need because none of these options offer a perfect solution and are only used after the disability is present. 

The question that immediately comes to a potential investor’s mind is - isn’t Humira owned by AbbVie (ABBV)? What is the sort of intellectual property protection ATNF is going to get here, given that Humira’s major patents expire next year? What will be the competitive hurdle which ATNF can put up for other companies trying to piggyback on its research? How strong are these methods of use patents the company has, and what sort of competition do they think they will face here?
 

So we asked ATNF’s CEO Dr. Jim Woody about this, and here’s what he told us:
 

Although Humira is owned by AbbVie, it is not indicated for DD. To understand our rationale for using Humira, we need some historical context. In a published preclinical study, Dr. Nanchahal, head of the 180 Life Sciences Clinical Advisory Committee, utilized anti-TNF biologic preparations from many vendors to determine which seemed most effective in blocking the mediators that drive Dupuytren’s collagen cord formation. In a later published Phase 2a study with Dupuytren’s patients, Dr. Nanchahal determined the critical dose to arrest the disease progress. At the time (2017-2018), AbbVie was the only producer of high concentration anti-TNF, with their 100mg/mL citrate-free Humira preparation. Because citrate causes pain on injection and the team needed to inject 0.4mL or 40mg to arrest the disease, the AbbVie product was the best choice to use for our randomized, placebo-controlled, 140-patient Phase 2b trial. 

ATNF owns/has exclusive rights to a portfolio of Method of Use/Treatment IP for DD. The challenges for any competitor hoping to piggyback on our research are twofold: 1) because of the IP, a competitor cannot actively promote the product for use (off-label promotion) and 2) the Company has pending IP surrounding a kit, with a particular needle size to deliver the 0.4mL of drug, that we intend to develop to facilitate the administration of adalimumab. The kit offers some important advantages, including the convenience of an easy administration in a prefilled syringe (0.4mL is a small amount and to do this outside of a prefilled kit will be challenging) as well as the accompanying time-saving advantage for the administering physician. We are engaged in discussions with potential partners developing adalimumab biosimilars who will supply the adalimumab as well as commercialize the end product. There are now three producers of the high concentration citrate-free Humira biosimilars, with several more expected next year. In our discussions with regulatory agencies, they do not seem to be concerned that a switch from Humira to an adalimumab biosimilar would be problematic. We believe the patent portfolio for DD is robust, with 9 Method of Use/Treatment patents granted in anti-TNF and many others pending. Aside from the current treatment options available to patients with DD, all of which are suboptimal with high recurrence rates and are focused on late-stage disease, ATNF is the only company working to address early-stage DD. Hence, we do not anticipate any competition over the near-term horizon. 

We now come to the other critical aspect of ATNF’s present history - the MHRA’s and the FDA’s refusal to accept ATNF’s phase 2b trial as adequate for a Marketing Authorization Application (in the UK) and an NDA (in US). The company did a 174-patient phase 2b trial of adalimumab in DD with the primary endpoint of nodule hardness and secondary endpoint of nodule size, both of which were met with statistical significance in December 2021. What both regulatory agencies objected to was that they did not believe that these surrogate endpoints were clinically meaningful, which means, in plain language, that the agencies do not think just because adalimumab reduces nodule hardness and size, that it will be able to treat the disease. 

So we asked the CEO, Dr Jim Woody the following questions:
 

1. What does the literature say about appropriate clinical endpoints for a DD trial? 
   Woody: The typical clinical endpoints for DD revolves around improvements in hand functions. There is only one approved therapeutics for DD and that is Xiaflex, a collagenase injection marketed by Endo (ENDP). Xiaflex focuses on late-stage DD and carries a recurrence rate of 47% at 5 year.
    
2. Why were these two surrogate endpoints chosen by ATNF? 
   Woody: These surrogate endpoints were chosen by ATNF because a study to directly measure improvements in hand functions would not be feasible, understanding that it can take 10-15 years for the condition to progress. Given the long period of disease progression, the company hypothesized, based on extensive preclinical studies of the biologic process driving collagen cord formation in Dupuytren’s, that reducing nodule hardness and nodule size would interrupt the cord formation process that leads to finger contraction and hence, be logical surrogates that we can measure over a much shorter time horizon. Moreover, there is literature out there that have shown progression to the finger disability is directly correlated with increase in nodule size. Hence, we expect that a reduction in nodule size, as observed in the Phase 2b trial, would decrease or eliminate that progression. While these are very small numbers in the Phase 2b trial, 10 patients who received the placebo injection went on to have surgery while only 3 in the adalimumab-treated group required surgery.
    
3. What is the company planning to do now - a new trial, or efforts to convince the regulators that these surrogate endpoints are indicative of clinical efficacy?
   Woody: We are working with Kinexum, our regulatory consultants, to address the concerns raised by the regulatory authorities. We have produced a white paper to include as part of our follow-up discussion with the MHRA. We anticipate having another meeting with them in October, but the timing is entirely dependent on them.
    
4. How does the company plan to fund a clinical trial, if one is needed? 
   Woody: We do not plan on having another clinical trial. Given the extremely favorable p value published in the The Lancet Rheumatology April 2022, another clinical study would not provide deeper insights into the statistical significance of the data nor provide further safety information on adalimumab, a product that has been marketed for years. However, should the need arise, we are entertaining several avenues, including having a partner take that on or raising additional capital to conduct such a study.

Besides anti-TNF therapy, the company has two other foci. These are:

1. SCAs platform: focusing on drugs which are synthetic cannabidiol (“CBD”) or cannabigerol (“CBG”) analogues (“SCAs”); and 
2. α7nAChR platform: focusing on alpha 7 nicotinic acetylcholine receptor (“α7nAChR”).

These are in preclinical stages, so we asked the CEO for more details on the research they are doing here. Dr. Woody's response to us is below:
 

These programs are temporarily on hold while we focus our attention to the clinical programs under the anti-TNF family. Outside of DD, we expect to initiate a Phase 2 exploratory study in Frozen Shoulder, another localized fibrotic disease where 50% of the patients have Dupuytren’s, in 2H 2022. We surmise that the pathologic process is similar, and patients would benefit from anti-TNF injections. The study is organized to determine how to best conduct a Phase 3 pivotal study. A Phase 2 study in Post Operative Cognitive Delirium (POCD) is scheduled to begin in 1H 2023. From our preclinical studies, we hypothesize that anti-TNF injections at the time of surgery may reduce or prevent POCD. These programs will be funded by non-dilutive grants. For SCAs, our research focuses on developing synthetic CBD analogs for pain and inflammation, analogs which are safe, non-psychoactive and real alternatives to unregulated consumption of medical cannabis or OTC CBD. For a7nAChR, our research focuses on repurposing it for inflammation, specifically ulcerative colitis, as it is a known immune suppressive. 

The company has a highly regarded team of founders and other scientists. This is something of a novelty for such a small company, so we asked the CEO about the involvement of leading scientists like Professors Marc Feldman and Lawrence Steinman. How did they come to be involved? Who brought the team together? What was the early history of the company?
 

Dr. Feldmann is recognized as a central pioneer in the inflammation therapy field and has won numerous international prizes for his contributions. His discovery that TNF was driving the joint destruction in rheumatoid arthritis (RA), which could be prevented with anti-TNF injection, revolutionized RA care and allowed patients today to live a normal life. Dr. Steinman, another entrepreneur, discovered that blocking integrins could reduce inflammation, leading to the development of Tysabri, the first major drug to reduce progress in multiple sclerosis. These professors and I have known and collaborated with one another over many years. The Company came about from an aggregation of three separate entities and became publicly-traded via a SPAC. Please refer to our latest 10K SEC filing for further information.

Finally, we asked Dr Woody a question we ask every company: 
Give us 3 reasons retail investors would be interested in buying ATNF. 

His responses:

1. Robust IP-protected product pipeline with large market potential & no known competitors
   1. Fibrosis & Anti-TNF
   2. Orally Available Synthetic CBD Analogs (SCAs)
   3. A7nAChr
   4. 18 granted patents; 28 filed patent applications
2. Numerous near-term inflection points
   1. Anti-TNF programs: 2 Phase 2 trials in 2H 2022 in frozen shoulder and POCD, respectively
   2. SCA programs: chronic pain Phase 1 trial in 1H 2023
3. Scientific pioneers backed by experienced operators and Board
   1. Founders: 100+ cumulative years of discovery and clinical experience; successes include Remicade and Tysabri
   2. Board: seasoned and diverse executives with broad skillsets that complement the Company’s needs
   3. Senior Management: operators with decades of experience at large & small life sciences companies

Thanks for reading. Have a great day.

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