James Mackay, PhD, Aristea Therapeutics president and CEO

Aristea carries a few meanings in Greek, from the excellence of a hero in battle, to a broader sense of excellence or the best, which explains its definition by the Urban Dictionary as perfection and ultimate coolness. Living up to these lofty ideals is the challenge for a namesake, immunology-focused developer of drugs for serious inflammatory orphan diseases that was spun out of AstraZeneca in 2018.

Aristea Therapeutics declares the passionate pursuit of excellence as its major priority, along with the harnessing of synergistic partnerships and a combination of “focus, agility, and diligence—with compassion.” Aristea’s logo, an abstract feline figure—perhaps a leopard or a puma—signifies the company’s focus on its end goal, and the speed of execution needed to accomplish it.

Recently, Aristea showed focus and execution by attracting a combined $123 million in investment tied to further clinical development of its lead pipeline candidate RIST4721, an oral CXC chemokine receptor 2 (CXCR2) antagonist being developed as a treatment for palmoplantar pustulosis (PPP), and possibly other neutrophil-mediated diseases.

Aristea inked an up-to-$70 million strategic collaboration with Arena Pharmaceuticals to advance RIST4721, through which Arena agreed to pay Aristea $60 million upfront and invest $10 million equity toward a $63 million Series B financing also completed by the San Diego biotech.

In return, Aristea granted Arena an exclusive option to acquire Aristea, including rights to all CXCR2 programs, upon completion of a Phase IIb trial assessing RIST4721 in PPP. During the option period, Arena and Aristea agreed to jointly explore development of additional neutrophil-mediated diseases, including hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD).

Arena will conduct the IBD study since it has greater expertise in that therapy area than Aristea, which will oversee the HS study.

Arena was one of several biopharmas with which Aristea had engaged in talks to partner on development of RIST4721, Aristea president and CEO James M. Mackay, PhD, told GEN Edge.

“We talked to numerous pharmas over the last couple of years,” Mackay said. “Arena’s interest in the molecule and the way that they were interested in developing it was very much aligned with the way that we were thinking from an Aristea Therapeutics perspective. Their whole drug development philosophy is very much aligned to ours. And we felt that there was a there was a good fit here between the two companies where we could do something together and move this molecule forward into the next stage of development.”

Initial talks, Phase IIa results

Aristea had an initial discussion with Arena, which is also based in San Diego, early in 2019, about six months after spinning out from AstraZeneca.

“They were interested in what we were doing. But at that time, their dermatology focus was relatively new. They were just starting up their dermatology franchise, so I think at that point, it was a little bit early for the discussion,” Mackay recalled.

“We remained in contact. And then about a year ago, they came back and started to look more closely. They did a very thorough due diligence on RIST4721 and our company,” Mackay continued. “The nice thing about the relationship is that we’ve known each other for two and a half years, and over that period of time, the teams have actually got to know each other pretty well. I think that sets us up nicely for the collaboration going forward.”

RIST4721 has completed the Phase IIa RIST4721-201 trial (NCT03988335), reporting results last year at the virtual 29th Congress of the European Academy of Dermatology and Venereology (EADV 2020). The study was designed to assess RIST4721 300mg daily vs placebo in palmoplantar pustulosis, with the primary endpoint being change from baseline in fresh pustules and total pustules at week 4.

At EADV 2020, researchers acknowledged that their primary endpoint data “was not significant”—but added that a post-hoc analysis in a subgroup with progressing disease “showed statistically significant results” that included:

  • A 50% reduction in PPPASI achieved by five of seven (71%) RIST4721 patients, vs two of 13 (15%) placebo patients.
  • A target palm or sole pustule count of -29.0 in the seven RIST patients vs. -3.5 in the 13 placebo patients.
  • Significant pharmacodynamic results in the RIST arm, which included a decrease in circulating neutrophils, a decrease in T-cell activation markers, and an increase in IL-8 levels.
  • Treatment emergent adverse events were seen in 86.7% of RIST patients vs 36.8% of placebo patients—though most of the AEs were mild (“mainly gastrointestinal or musculoskeletal”), with no severe AEs or deaths.

“RIST is a potent small molecule CXCR2 antagonist with potential as novel oral treatment for neutrophil diseases; further studies are needed to assess its potential efficacy,” the researchers concluded.

Aristea said it remains on track to advance RIST4721 to the study’s Phase IIb dose-ranging portion later this year, as well as expand the development of RIST4721 into two additional orphan indications, familial Mediterranean fever (FMF) and Behcet’s disease.

“We’re currently doing the feasibility for that trial with the CRO that we’ve selected. We anticipate that the data from that trial will be available in Q2 2023,” Mackay said.

Successful results from that trial could trigger Arena to exercise its option to acquire Aristea, he added.

A lucrative venture

Joseph P. Schwartz, managing director, rare diseases and a senior research analyst with SVB Leerink, wrote in a research note that the deal with Aristea made sense for Arena.

“Given ARNA’s expertise in both dermatology and gastroenterology, we view this collaboration (and option) not only as a de-risked move for the company, but also as a potentially lucrative venture, given the broad clinical application of RIST4721.”

He added that the deal “helps to bolster ARNA’s early-stage pipeline, while remaining fiscally prudent.”

SVB reiterated its “outperform” rating on Arena stock and its price target of $112 a share set on May 7, 126% above its closing share price Thursday of $49.63 [SVB does not rate shares of Aristea as it is privately held]. Arena shares rose 4% the day after the Aristea agreement was announced, to $63.82, before dipping after Arena pushed back the anticipated timeframes for reading out data from several studies of its lead pipeline candidate etrasimod, under development in several gastroenterology and dermatology indications.

Arena was one of two new investors Aristea attracted in its $63 million Series B; the other was funds managed by Tekla Capital Management. Arena and the Tekla funds joined lead investor Fidelity Management & Research Company and Novo Holdings. In conjunction with the Series B financing, Loretta Tse, PhD, vice president at Tekla Capital Management, will join Aristea’s Board of Directors, and Maurice Mezzino, senior vice president corporate development at Arena, will join as a Board Observer.

Aristea’s logo, an abstract feline figure that could be a leopard or a puma, signifies the company’s focus on its end goal, and the speed of execution needed to accomplish it.

Novo Holdings invested $15 million in Series A funding to launch Aristea in December 2018. The startup obtained exclusive global rights to RIST4721 (terms not disclosed) from AstraZeneca, which four years earlier terminated development of the drug for COPD while it was in Phase I.

Mackay was a longtime AstraZeneca executive who held several VP-level clinical and product positions with the pharma giant, where he led the development and commercialization of drugs across a range of therapy areas and managed significant global functional departments. He later oversaw development of AstraZeneca’s gout franchise as president and COO and then CEO of Ardea Biosciences, which remained an independent business unit following its acquisition in 2012 by AstraZeneca.

From COPD to PPP

RIST4721 was originally developed under the name AZD4721 as a respiratory drug, part of a portfolio of CXCR2 antagonists built by AstraZeneca.

“From its mechanism of action, we knew exactly how [RIST4721] worked: It stops neutrophils trafficking from the bone marrow to the site of inflammation, wherever that’s located in the body,” Mackay said.

“Based on the fact that we knew that mechanism of action worked, we basically went searching for a disease that would fit that mechanism of action. We looked for neutrophils mediated diseases and we identified neutrophilic dermatoses originally as a group of diseases, and then we narrowed that down to PPP for an initial clinical trial.”

PPP is a debilitating condition that is characterized by repeated flares of sterile neutrophil-filled pustules that lead to redness and thickening on the palms of the hands and/or the soles of the feet and associated pain, itching, and burning sensations. Aristea reasons that CXCR2 represents a promising therapeutic target for the treatment of neutrophil-mediated inflammatory diseases since the chemokine receptor has been shown to play key roles in neutrophil recruitment to inflammatory sites.

What prompted Aristea to build its drug development effort around RIST4721?

“It was very clear from the early data that this was a very selective CXCR2 antagonist,” Mackay said. “The early clinical data showed that the drug did exactly what was expected, so it stopped neutrophils trafficking out of the bone marrow to the site of inflammation. We could see a nice reduction in peripheral blood neutrophils levels.”

Two other attractions of RIST4721, he added, included its half-life of between 21 and 23 hours in humans—making the drug amenable to once-a-day dosing and a longer patent life than other CXCR2 antagonists under consideration.

Gradual workforce growth

Aristea’s plans to launch a Phase IIb trial of RIST4721 will not lead to a large expansion of its workforce. The company has seven staffers and has hired an eighth, a chief financial officer that the company plans to announce in coming weeks.

Earlier this year, Aristea brought on board Stacy Anthony as senior director, clinical operations. She joined the company from Arena, where she was senior director, clinical operations, dermatology. Also hired this year was Sean Premeau as senior director of chemistry manufacturing and control (CMC). He was previously director, CMC, for Amplyx, now a subsidiary of Pfizer.

“We plan to grow the company up to 10 during this year by adding an additional physician and an additional clinical operations person,” Mackay said. “But we’re a small organization by design, in order to ensure that we can remain flexible.”

He said Aristea’s future plans will benefit from drawing upon the resources within the San Diego region—which is ranked No. 5 in GEN’s most recent A-List of Top 10 U.S. Biopharma Clusters.

Mackay is a board member of Biocom California, the life-sci industry group that has evolved in recent years from a San Diego to a statewide focus; and chairs the board of CONNECT-San Diego, a nonprofit focused on incubating and accelerating regional startups. Mackay is also a member of the San Diego regional network of Tech Coast Angels, the largest angel investor group in the United States, and a former board member for the San Diego Regional Economic Development Corp.

“When I arrived here, I quickly began to realize that both from a life science and tech perspective, there’s an incredible innovation ecosystem here with hundreds of life science companies, and a lot of academic organizations that are doing basic research that support that innovation ecosystem, and then many life science and tech entrepreneurs that have created multiple companies over time, sold those, and often basically recycled themselves back into that innovation ecosystem,” Mackay said. “So I got heavily involved.”