Drug development based on Janus kinase (JAK) inhibitors hasn’t progressed as far as other biopharma specialties since the first such treatment won approval more than a decade ago.

Ajax Therapeutics, a drug developer created to develop JAK inhibitors for people with rare blood cancers called myeloproliferative neoplasms (MPNs), hopes to change that through its recent financing and clinical development plans.

Earlier this month Ajax completed an oversubscribed $95 million Series C financing, with proceeds set to advance clinical development of Ajax’s lead candidate AJ1‑11095—a first-in-class Type II JAK2 inhibitor—as a treatment for myelofibrosis, as well as further develop the company’s pipeline.

The FDA on May 13 cleared Ajax’s investigational new drug (IND) application for a Phase I dose escalation study (NCT06343805) of AJ1-11095. The study is expected to begin in the second half of this year. When that happens, AJ1-11095 will become the first Type II JAK2 inhibitor to enter the clinic.

Ajax aims to disrupt the JAK inhibitor space long dominated by the first such drug to reach the market, ruxolitinib, marketed in the U.S. as Jakafi® by Incyte and outside the U.S. as Jakavi® by Novartis. Jakafi/Jakavi is a selective inhibitor of JAK1 and JAK2 indicated for forms of myelofibrosis, polycythemia vera, and graft-versus-host disease.

Last year Jakafi generated $2.594 billion in U.S. net product revenues (up 8% year-over-year) and another $1.72 billion in rest-of-world net sales (up 10%). During the first quarter, however, Jakafi racked up $571.839 million in U.S. sales—down 1%, with a 5% rise in total paid patients being offset by an inventory drawdown for Jakafi and pricing—while Jakavi garnered $478 million in ex-U.S. sales (up 15%).

“There’s a vulnerable incumbent out there in Jakafi,” Martin Vogelbaum, Ajax’s co-founder and CEO, told GEN Edge. “Since ruxolitinib was approved in 2011, there haven’t been a lot of novel single agents that have moved into the clinic, certainly in the JAK2 class of compounds. So, there’s a lot of investigator enthusiasm to get their hands on this and get it into patients.”

Attack mode

Ajax is not named for the Trojan War hero of Greek mythology, or present-day kitchen cleaning products, but for a contraction of the phrase, “ATTACK JAK”—the stated goal of the research consortium from which the company originated.

Martin Vogelbaum, Ajax Therapeutics co-founder and CEO

“The idea of this consortium was to come together and come up with a different way to attack JAK and drug JAK, and that way was through the Type II inactive conformation of the protein itself, which they had found both in vitro and in vivo,” Vogelbaum recalled.

Using a tool compound obtained from Novartis, the consortium validated that inhibiting Type II of the JAK2 protein not only provided better efficacy than the existing drugs, all of them Type I active conformation JAK2 inhibitors, but could overcome the resistance and persistence seen in MPN cells that were exposed to chronic Type I inhibition.

“Probably most importantly, we were able to provide disease modification in the form of reversing fibrosis and reducing the mutant clone that facilitates the onset of the disease,” Vogelbaum said.

The consortium was founded about seven years ago by investigators specializing in JAK pathway biology. As the researchers pursued JAK2 inhibition, they realized they needed additional capital and management help to build a company around their work—a need they addressed by launching Ajax in June 2019.

“We reasoned that developing a drug that bound the inactive or Type II mechanism of action based on preclinical data from my lab and the lab of our co-founder David Weinstock, MD, that that 1) worked better and 2) worked after Type I inhibitor failure,” a scientific co-founder of Ajax, Ross Levine, MD, of Memorial Sloan Kettering Cancer Center (MSK), told GEN Edge.

Levine is senior vice president for translational research at MSK’s Memorial Hospital and Weinstock is vice president of discovery oncology at Merck & Co. and was previously a professor at Dana-Farber Cancer Institute and Harvard Medical School.

Consortium members quickly set out to translate their exciting early science to actual clinical impact. Drawing on Vogelbaum’s previous working relationship with Schrödinger, the computational platform developer focused on molecular discovery and design helped co-found Ajax and worked with the consortium-turned-startup.

Doing “justice”

“Our understanding here was in order to do this justice, and to really create a highly selective, highly potent JAK2 inhibitor, we needed to employ computational methods at scale, and best-of-breed structural based drug design.”

Schrödinger’s drug design and computational methods assisted Ajax in designing AJ1-11095 to selectively bind the Type II conformation of the JAK2 kinase. Ajax reasons that will help AJ1-11095 offer greater efficacy with disease modification compared to all currently approved JAK2 inhibitors, which are designed to bind the Type I conformation of JAK2.

Head shot of Ross Levine, MD, of Memorial Sloan Kettering Cancer Center (MSK), a scientific co-founder of Ajax Therapeutics
Ross Levine, MD, of Memorial Sloan Kettering Cancer Center (MSK), a scientific co-founder of Ajax Therapeutics

“It was really Martin bringing us together with what was the Ajax team we created and Schrodinger—because that brought chemistry and structures with people that really know them,” Levine said. “Since then, we’ve moved incredibly fast. And we’ve been just so focused. And to go from incorporation to an IND, and a drug that’s going to go into patients this year and to have the support and investors aligned to do it, we couldn’t be more thrilled.”

The Phase I study, called AJX-101, is designed to investigate the safety, tolerability, pharmacokinetics (PK), clinical activity, and biomarker changes in AJ1-11095 in people with primary or secondary myelofibrosis who were previously treated with at least one Type I JAK2 inhibitor.

AJX-101 will use a 3+3 sequential dose escalation design followed by a dose expansion phase. Investigators plan to establish a maximally tolerated dose and/or inform the establishment of a recommended Phase II dose for AJ1-11095. The first-in-human, non-randomized, multi-center, open-label clinical trial is designed to enroll an estimated 76 participants.

Ajax is targeting the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, to be held in December, as its potential timeframe for releasing data from the study, Vogelbaum said.

“If there’s an opportunity to enrich a cohort or two in polycythemia vera, or essential thrombocythemia—the other two most common MPNs—those would be two additional cohorts that we would enroll,” Vogelbaum said “The idea would be to get out of the dose escalation phase in 12 to 14 months, and have a dose or two that we could take into an expansion phase in second-line [myelofibrosis] and potentially into the first line.”

Growing need

Ajax says its initial focus on myelofibrosis reflects growing medical need. An estimated 16 million to 18.5 million Americans live with the rare blood cancer, according to the Incyte-developed education and awareness initiative Voices of MPN, up from an estimated 13,000 in 2010. The market for myelofibrosis treatments is expected to grow over the next decade at a compound annual growth rate of 5.5%, from the $749.05 million reported for 2023 to a projected $1.28 billion in 2033, according to Future Market Insights.

While current JAK inhibitors indicated for myelofibrosis have shown significant clinical benefit by reducing symptoms and shrinking enlarged spleens, they have not shown ultimate disease modifying activity, and most patients are off the drugs within a year or two.

Despite those limitations, four JAK inhibitors have won FDA approval to treat myelofibrosis, all in adults. In addition to Jakafi, the other three:

  • Bristol Myers Squibb’s Inrebic® (fedratinib)—indicated for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. FDA approved in 2019.
  • CTI BioPharma (Sobi)’s Vonjo® (pacritinib)—intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10 /L. FDA accelerated approval granted in 2022.
  • GlaxoSmithKline (GSK)’s Ojjaara® (momelotinib)—intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)] with anemia. FDA approval granted in September 2023.

None of the three drugs approaches Jakafi in annual sales. Inrebic finished 2023 with $110 million in product revenues (up 29% from a year ago) and did not disclose first quarter sales, instead lumping Inrebic with three other drugs plus royalty revenues.

Vonjo generated SEK 706 million ($65.89 million) in 2023 and SEK 320 million (about $30 million) in Q1 2024; year-ago comparisons were not applicable. Ojjaara made £29 million (about $37 million) in revenue last year, its first year on the market, and £52 million ($66.05 million) in the first quarter.

The four myelofibrosis-indicated drugs are among 10 JAK inhibitor therapies that have gained FDA approval.

“There’s a long track record of the current JAK inhibitors providing some, but not enough value. Therefore, first and foremost, that means that you’ve got a lot of people that have already taken and not gotten enough, or no longer get benefit from a JAK inhibitor. We think that’s a perfect population to try a different, distinct, and what we believe better JAK2 inhibitor,” Levine asserted.

“Be better”

“There is such a medical need still in that area initially, for when patients no longer benefit from those drugs. But in general, our goal is just to be better than the current drugs in that space. We think that’s an important clinical opportunity. And we’re going to go hard after that.

While Ajax’s long-term goal is to develop best-in-class JAK2 inhibitors for all myelofibrosis patients, Levine said: “There are others with dysregulated JAK2 signaling. We’re excited about those opportunities, and other disease states where JAKs are important.”

Ajax isn’t disclosing details of its pipeline, though Vogelbaum said: “We’re using the same methodologies, the same team, the same knowhow to approach other ways to drug JAK2. There are complementary potential combination opportunities with some of the other pipeline programs we’re working on right now.”

Added Levine: “We have two areas of really deep expertise that set us apart. One is that we have incredible expertise in JAK2 and JAK/STAT [signal transducer and activator of transcription] signaling writ large. And the second is, we know a lot about not just myeloproliferative neoplasms, but blood cancers in general. We’re not saying there aren’t opportunities to explore outside those, but our mission is going to be to stick to the areas where we believe we have deep, collaborative, and unique expertise.

“We’re going to look and work currently on and look for additional opportunities to take advantage of those areas of expertise and not try to bring in or develop things that don’t meet or aren’t in our wheelhouses,” Levine added.

Levine is among scientific co-founders and advisors of Ajax, along with Weinstock and:

  • Eric Fischer, PhD, an independent investigator and director of the chemical biology program at Dana Farber Cancer Institute, and an associate professor at Harvard Medical School.
  • Stevan Hubbard, PhD, a professor at the New York University (NYU) Grossman School of Medicine and a member of NYU’s Skirball Institute of Biomolecular Medicine.
  • Olli Silvennoinen, MD, PhD, director of Biocenter Finland, a professor at Tampere University, chief physician at Fimlab Laboratories, and research director at the Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE) at the University of Helsinki.
  • Radek Skoda, MD, a professor and research group leader at the University of Basel and the University Hospital Basel.
  • Srdan “Serge” Verstovsek, MD, PhD, chief medical officer of Kartos Therapeutics, and previously a professor at University of Texas MD Anderson Cancer Center.

$145M in total capital

Based in Cambridge, MA, and New York, Ajax has raised about $145 million in total capital since its launch, including a $40 million financing completed in 2021. Over time, Ajax plans to add to its staff of six, though Vogelbaum and Levine say it’s hard to quantify how much the company’s workforce will grow.

“We’ll add to areas we need to complement based on where we are as a clinical-stage company,” Levine said. “Our chief medical officer [David P. Steensma, MD] is amazing. But he’s one person, and we’re going to want to grow the clinical operations. We also have a great CRO [contract research organization] we’re working with, so we’re going to continue to always be nimble and ask how we can bring those capabilities in.”

“As we grow the biology and work both on [AJ1-11095] and other pipeline candidates,” Levine added, “we’ll let the science tell us what we need.”

Goldman Sachs Alternatives led Ajax’s Series C financing with participation by new investors Eli Lilly, Vivo Capital, RA Capital Management, Point72; and four existing investors: EcoR1 Capital, Boxer Capital, Schrödinger, and Inning One Ventures.

What sold them on investing in Ajax?

“All of the preclinical studies have achieved what we had hypothesized they would achieve, and we’ve been able to develop a drug that has the product profile we expected,” Levine said. “But I also think that the medical need and the clear path to something delivering really differential clinical impact is easy to understand.”

Concurrent with the financing, Amit Sinha, head of life sciences investing and Ming Cheah, PhD, vice president, within life sciences investing at Goldman Sachs Alternatives, joined Ajax’s board of directors.

“Despite significant advances brought by the introduction of JAK inhibitors, patients with MPNs continue to have major unmet needs as current therapies, including Type I JAK2 inhibitors, often fail to provide adequate symptomatic relief and have little effect on the underlying disease,” Amit Sinha, head of life sciences investing at Goldman Sachs Alternatives, said in a statement. “We look forward to working with Ajax’s management team to bring novel therapies, such as AJ1-11095, to patients with myelofibrosis.”

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