Targeting Rare, Immunologic Disorders

Aristea Therapeutics was spun out of AstraZeneca to develop medicines for rare, immunologic disorders. Its lead program in development is an experimental therapy for a rare skin condition that causes repeated outbreaks of painful pustules on the hands and feet and is being looked at for other neutrophil-mediated diseases. We spoke to James Mackay, president and CEO of Aristea, about the decision to form the company, its lead therapy in development, and its collaboration and development deal with Arena Pharmaceuticals that gives its partner an option to acquire it outright.

Daniel Levine: James, thanks for joining us.

James Mackay: It’s a pleasure, Danny. Thank you for having me.

Daniel Levine: We’re going to talk about Aristea Therapeutics, it’s focus on rare immunological disorders, and its lead candidate for a rare skin condition. Let’s start with the formation of the company. Aristea was spun out of AstraZeneca in 2018. What was the vision for the company?

James Mackay: Aristea Therapeutics is an immunology focused clinical stage biotech. I was a long term AstraZeneca executive. I’d been with the company for nearly 30 years and decided it was time, after a fantastic career at AstraZeneca, to start up my own biotech. So, I started up Aristea Therapeutics in August 2018. We raised $15 million from Novo Ventures. They were the sole investor in the series A, and we licensed a CXCR2 antagonist called RIST4721 from AstraZeneca. That molecule was a molecule I’d been very familiar with at my time at AstraZeneca. It had been being developed for respiratory indications before that program had been terminated a number of years ago for portfolio prioritization reasons. And I’d always liked the molecule, always felt that it did what it was meant to do from a mechanism of action perspective, and really felt that it was a drug in search of a disease. So we decided to license that. We wanted to have Aristea Therapeutics focus on developing therapeutics for serious inflammatory conditions, and we felt that RIST4721 was the perfect basis for that.

Daniel Levine: And is the sense that this is a pipeline in a product, or is there the expectation that you’re going to build other immunological therapies behind it?

James Mackay: Yeah, actually both. It is a pipeline in a product and I’m sure we’ll get into that in a little bit more detail as we as we go through the discussion. We’re planning to develop RIST4721 in multiple different diseases, but we are also very active as a company in looking to bring additional immunology based assets into the company that we can repurpose and focus on rare inflammatory conditions—so really, both a pipeline and a product, and also developing a pipeline within the company.

Daniel Levine: Your lead candidate is an experimental therapy in development for palmoplantar pustulosis, or PPP. What is PPP?

James Mackay: It’s a rare inflammatory skin condition. It’s characterized by sterile neutrophil filled pustules, like blisters on the palms of the hands and the soles of the feet, nowhere else in the body, and it’s a flaring disease, so patients will have a flare, the pustules will appear, the skin becomes very inflamed. The pustules then start to dry out, the skin cracks open, the inflammation continues, and even before the patients have a chance to completely resolve the flare, they’ll actually get another flare. They often get six to eight flares a year. So, they’ll get another flare before they get resolution of the previous one and you get this sort of vicious flare upon flare upon flare situation where the skin becomes more inflamed, becomes very cracked and extremely painful because these pustules are very close to the nerve endings in the skin on the hands and the feet. And clearly, being on the hands and the feet is very debilitating for these patients—obviously a stigma associated with it. If it’s on the hands it actually prevents people from using their hands to work. If it’s on the feet, it prevents people from walking—so an incredibly debilitating condition.

Daniel Levine: Well, go a little deeper on that. I think in the world of rare disease, we’re often talking about fatal conditions, conditions that are progressive and degenerative. People can be dismissive of conditions that are not the deadly. From a quality of life point of view, what is it like to live with PPP?

James Mackay: Yeah. If you talk to these patients, they’ll tell you that their lives are really miserable because the disease is there all the time and they suffer constant pain from the disease. I understand your comment, as you said, in the world of rare diseases, often we’re talking about fatal conditions and clearly that’s terrible as well, but these patients really are suffering terribly, you know, with constant pain, constant cracking open of the skin, the inability to do normal daily activities. So, it has a really major impact on their lives. And just to give you one example, in the first clinical trial that we did in Canada, we actually had one patient who was prepared to drive five hours to the clinic and five hours back on the same day just to participate in the trial, and they did that every week that we ran the trial. So, I think that gives you an indication of how much patients like that are desperate for new therapies that will give them at least some relief from this pretty recalcitrant disease that’s very difficult to treat.

Daniel Levine: Do patients have treatment options today? Are existing immunological therapies repurposed to treat PPP?

James Mackay: Yeah. What happens is that when a patient first has an outbreak of these pustules, they’ll normally go to the PCP. PCPs don’t tend to diagnose this correctly. They’ll feel it’s some form of psoriasis rather than palmoplantar pustulosis that’s a specific and unique condition. They’ll normally treat the patient with topical corticosteroids, a fairly standard treatment initially for a PCP to prescribe. In most cases that really won’t have much impact on the disease. The PCP will then refer the patient to a dermatologist. Dermatologists tend to start with oral treatment. So they’ll start with oral retinoids—maybe cyclosporin maybe methotrexate—again no consistent response in these patients. Some of those medications will help some of the patients some of the time but not really a consistent response. And about 50 percent of dermatologists will actually start their patients on off label psoriasis approved biologics. Many of the injectable biologics are approved for general psoriasis and the physicians will use those off label. And it’s a bit like inflammatory bowel disease where physicians will often cycle through various different therapies, trying to get some relief for patients. They’ll do the same with PPP. They’ll cycle through the off-label psoriasis approved biologics, trying to find something that will provide some relief for the patients. But again, the response tends not to be consistent in these patients, so there’s definitely a significant unmet medical need.

Daniel Levine: Earlier you mentioned that this is a neutrophil mediated disease. What role do neutrophils play in the immune system?

James Mackay: Yeah, neutrophils are part of the white blood cells that are part of the innate immune system. And they really perform a role in fighting infection and also inflammation. So, neutrophils are two important types of what are called cytokines that are responsible for the migration and activation of neutrophils. So, the first one is CXCR2, which is what our molecule blocks. CXCR2 is primarily responsible for migrating neutrophils from the bone marrow to the site of infection or inflammation in the first case. And then CXCR1—a different cytokine that our molecule does not impact—is responsible for activating the neutrophils. It’s responsible for the oxidative burst that’s required for those neutrophils to actually fight the infection and which they do by phagocytosis. Basically, they engulf the infection or the foreign body in the body. So, neutrophils are very important, and it’s important when we are developing a molecule like RIST4721, which is a CXCR2 antagonist and stops the migration of the neutrophils from the bone marrow, it’s important that we are able to titrate the dose level correctly so that we can reduce the movement of the neutrophils to the site of inflammation, but we must retain a certain proportion of the neutrophils in the circulating bloodstream so that they’re there and ready to be activated should there need to be an infection because the last thing that we want to do is to have patients become what is called neutropenic, where they have low levels of neutrophils and they’re not capable of fighting an infection. This is a clearly understood potential side effect of a treatment like RIST4721, which is a CXCR2 antagonist, so something that we’re watching very, very closely.

Daniel Levine: Well, what exactly is RIST4721 and how does it work?

James Mackay: It’s a CXCR2 antagonist so it blocks the CXCR2 receptor on the neutrophils, and in the immune system there are molecules called cytokines that will activate CXCR2 by linking to the receptor. And I think in the case of CXCR2, there are seven different cytokines that will activate that. Our molecule actually blocks all seven of those cytokines so we’ll actually stop the neutrophils from leaving the bone marrow and going to the site of inflammation. And we believe that for diseases where the neutrophils are playing a key role in that disease, that this is a potentially promising therapeutic approach to take.

Daniel Levine: What’s known about the safety and efficacy of the molecule from studies that have been done to date?

James Mackay: So far, when we licensed the molecule, AstraZeneca had already completed the phase 1 studies, so single ascending dose, multiple ascending dose. They’ve seen in those studies that the drug was well tolerated, that it did cause a dose related reduction in the level of peripheral neutrophils in the peripheral blood. Subsequent to that, we’ve conducted a phase 2 study in PPP patients. We saw nice activity of the molecule in those patients and saw a good reduction in the disease severity, particularly in patients who were actively flaring as they came into that trial. So, the data that we’ve generated from that is very promising in terms of what we’ll see from an efficacy perspective in longer term studies and then from a safety perspective. We did see some side effects, mostly in the gastrointestinal and musculoskeletal systems, but all what are called “treatment emergent adverse events” were mild in nature. We did have two examples of patients who had an adverse event of neutropenia, as I talked about earlier, but both those patients continued to take drug throughout the trial and did not get to the level of neutropenia where physicians start to become concerned. So, they were able to continue taking the drug, and then when with the trial completed and the drug was stopped, they actually went back to normal within a few days. Then apart from the effect that we see on the neutrophils there’s really no other notable changes in the hematological parameters or any effect on liver function, renal function—overall a very tolerable drug and good signs of efficacy and in these initial studies.

Daniel Levine: What’s the development path forward?. When might you be in a position to file for approval if all goes well?

James Mackay: Yeah. We were successful in the middle of last year in closing a $63 million series B funding around, which was led by Fidelity, participation from Novo Ventures, our existing investor, and then new investors Tekla Capital and Arena Pharmaceuticals. That’s allowed us to move forward into a large three month phase 2b study that actually started screening patients last month. We expect to see data from that study about the middle of next year, in about 18 months’ time. That’s a dose ranging study. It’s a placebo controlled blind dose ranging, so we’re looking at three arms, a placebo arm, a 200 milligram RIST4721 arm, and a 400 milligram RIST 4721 arm. That’s going to give us good data about two different dose levels of RIST 4721 with a treatment period of three months, which will equip us then to have further discussions with the regulatory authorities, including the FDA and the European authorities, and then move into a phase 3 program with the potential to have this molecule available probably in the 2026-27 timeframe.

Daniel Levine: You mentioned Arena’s participation in your series B round. Arena also entered into a collaboration with Aristea around RIST 4721. It provided $60 million in the upfront payment and it took an equity stake as well. It does have an option to acquire Aristea. Why did you do the deal?

James Mackay: Yeah, so we had been talking to Arena for really quite a long time. We founded the company in August 2018. I think our first discussion with Arena was around about January 2019, so less than six months after we started the company. At that time, they were really just developing their dermatology franchise. We continued to talk with them and they continued to familiarize themselves with the molecule and what we were doing with the program. I think what attracted us to Arena was that they really understood what we were doing. So, if we think about RIST 4721, it’s mechanism of action, and how it impacts neutrophils, it’s very similar in a way to Arena’s lead molecule, etrasimod, and the effect that it has on lymphocytes. So, from a mechanism of action perspective and how we were using that mechanism of action to target neutrophil mediated diseases, Arena understood completely what we were trying to do, and we saw that there was good synergy there in terms of the scientific capabilities of the Arena team and the Aristea team. Obviously, by striking the deal, we brought in a significant amount of non-dilutive cash into the company, which we’re now using to look for and acquire additional assets. In addition to that, it also brought in some $10 million of non-dilutive R&D cash that allowed us to extend the number of diseases that we are investigating from three to five. Currently at Aristea, we were planning to continue the PPP program, and then look at two other neutrophil mediated diseases, familial Mediterranean fever, and Bechet’s disease, which are both rheumatology conditions, but with the Arena money, we’re now expanding that to five different diseases, so we’ll do a phase 2 proof of concept study in hidradenitis suppurativa, which is another inflammatory skin condition, and then Arena themselves are going to do an inflammatory bowel disease study with RIST4721. So, we’re going to have five indications running in parallel through this year and into the middle of next year. And as we talked about, definitely a portfolio and a product approach and so that’s why we did the deal with Arena, which has resulted in the company being well capitalized at a time when public markets are [tight] and money is somewhat challenging to access.

Daniel Levine: How are the two companies dividing responsibilities, and how closely are you working together? Is there a point of a clear handoff or is there kind of a joint development now going on?

James Mackay: So, Aristea Therapeutics remains accountable for the development of RIST4721. We’re still acting independently in that respect.  In addition to the three indications or diseases that we were studying, the two new diseases, hidradenitis suppurativa—Aristea Therapeutics is running that study; and Arena is running the inflammatory bowel disease study. In addition, Arena is also doing some manufacturing work for us in terms of how to best manufacture the active pharmaceutical ingredient and the ultimate tablets that we give patients. The two companies work very closely together. We have weekly meetings so it’s truly a collaboration we share with each other, our plans for each of the particular studies, we review key documents that each of us has produced and are going to submit to regulatory authorities. So, it’s a very close collaboration, but with Aristea retaining ultimate accountability for the development of RIST 4721.

Daniel Levine: And in addition to pursuing additional indications, are you bringing any other molecules in behind?

James Mackay: Yeah, this is an area where we’re very active right now. As I said at the beginning of our discussion, we are an immunology focused company so we are spending quite a bit of time looking for other immunology molecules that we can bring into the company, either small molecules or biologics. We’re very active right now. We agreed to a term sheet with another biotech at the end of December. We’re currently in an exclusive due diligence phase. We have two other term sheets that are currently under negotiation and a couple of other molecules that we’re just starting due diligence on. Now, I would said overall at any point in time, we’ve got 15 to 20 different molecules at various different stages that we’re looking at. And we’ll work our way through evaluating whether we believe that those molecules are molecules that we think can be developed into successful drugs. And then based on the mechanism of action, which diseases should we focus on, particularly given our focus is rare inflammatory diseases. So, often we’ll repurpose the molecule into one of those diseases just in the same way as we did with RIST 4721 when we licensed that.

Daniel Levine: Are there formal decision points under the collaboration at what point will Arena need to decide about marketing RIST 4721 or acquiring Aristea?

James Mackay: Yeah. Arena has an exclusive option to acquire Aristea Therapeutics, as you indicated, that option is triggered by the delivery of the data from the phase 2b PPP study. As soon as we’ve delivered that data package, then Arena has a 60 day period to review that data and make a decision about whether to exercise the option. Arena can, however, if they so wish at their discretion, they can also exercise the option at any other time prior to that. But the delivery of the phase 2b PPP data is the thing that really triggers the review of the option by Arena.

Daniel Levine: James McKay, president and CEO of Aristea Therapeutics. James, thanks so much for your time today.

James Mackay: Thanks very much for having me on Danny. It’s been great to talk with you.

This transcript has been edited for clarity and readability.