In gout, the drug selections for sufferers stay restricted. The historical past of this area consists of many molecules that fell quick within the clinic or in the marketplace for security causes. James Mackay is aware of firsthand having led an organization that developed two of these withdrawn merchandise.
Mackay is again to strive once more. He’s now CEO of Crystalys Therapeutics, whose primary asset is an in-licensed gout drug candidate with validation from its approval in a number of Asian international locations and extra security information from real-world use in these areas. On Tuesday, Crystalys revealed $205 million raised for Part 3 checks that would help plans to ultimately convey this small molecule to sufferers within the U.S. and different markets.
Gout, a typical type of inflammatory arthritis, stems from excessive uric acid ranges within the blood that kinds crystals in joints and surrounding tissue, inflicting irritation and ache. The dysfunction is characterised by sudden assaults of ache and swelling within the joints known as gout flares. Sufferers with uncontrolled gout for a protracted time period develop deposits of uric acid within the joints, which known as gout tophus. These tophi might not be painful, however they will impair joint motion and seem disfiguring.
The usual drug therapy for gout is allopurinol, a 60-year-old medicine that inhibits an enzyme key to producing uric acid. This capsule helps solely about 40% of gout sufferers, Mackay stated. San Diego-based Crystalys takes a distinct method with its drug, dotinurad. The oral small molecule is designed to dam URAT1, a protein chargeable for the reabsorption of uric acid within the kidney. Usually, folks excrete extra uric acid of their urine. Dotinurad is meant to assist gout sufferers try this.
“Should you block the transporter [protein], you mainly urinate out extra uric acid,” Mackay stated. “What’s good about its mechanism of motion is it immediately impacts the primary reason for gout, which is the shortcoming to excrete sufficient uric acid. Principally, it is going to trigger you to excrete extra and subsequently scale back the extent of uric acid within the physique.”
Mackay is conversant in URAT1 inhibitors as a result of he developed them at a earlier firm, Ardea Biosciences. Ardea’s lead drug candidate, lesinurad, reached Part 3 growth in gout when the biotech was acquired by AstraZeneca in 2012 for about $1 billion. In 2015, the FDA accepted the drug, which reached the market beneath the model identify Zurampic. That drug and the mix of lesinurad and allopurinol, branded as Duzallo, have been later withdrawn from the marketplace for enterprise causes. Mackay stated renal toxicity dangers made commercializing these medication difficult. He doesn’t anticipate these issues for dotinurad, which has a security and efficacy profile outlined by its use in additional than 1.2 million gout sufferers in Japan.
Dotinurad was found and developed by Japanese firm Fuji Yakuhin, which steered the molecule to a regulatory approval in its residence nation in 2020. Eisai holds rights to the drug in a number of different Asian international locations. In 2021, Fortress Bio subsidiary Urica Therapeutics acquired U.S. and European rights to dotinurad; the next 12 months, the license settlement was expanded to the Center East and North Africa. Urica superior dotinurad so far as Part 1 testing in wholesome volunteers and gout sufferers.
Mackay stated Novo Ventures, which had invested in one other firm he had led, approached him with curiosity in coming into the gout area. Given Mackay’s expertise in gout, they needed his expertise and experience.
“We mainly went out and did a panorama search of all of the molecules beneath growth,” he stated. “We recognized dotinurad because the one which we felt had the perfect security and efficacy profile. And we approached Urica Therapeutics and in the end persuaded them that we must always do an asset buy of the license from Fuji.”
In July 2024, Urica bought rights to dotinurad to Crystalys for 35% of the younger biotech’s excellent fairness, in line with Fortress regulatory filings. The settlement additionally places Urica in line for a 3% royalty on future internet gross sales of the drug.
Dotinurad may assist fill the hole in second-line gout therapy, the place therapy choices are dwindling. Apart from the market withdrawal of Ardea’s medication, Takeda Pharmaceutical’s febuxostat, model identify Uloric, is exiting the market. This drug, which affords a mechanism of motion just like allopurinol, gained FDA approval in 2009. A decade later, the FDA added a black field warning to Uloric’s label flagging the larger threat of cardiovascular issues, together with loss of life. Takeda has determined to discontinue the product, which at present faces generic competitors. Based on FDA information, Takeda will stop Uloric distribution in March 2026.
Amgen drug Krystexxa is on the market as a third-line gout therapy. This drugs is an engineered model of the enzyme that breaks down uric acid. However Krystexxa have to be administered intravenously. One other limitation is that sufferers’ immune techniques can produce antibodies that ultimately render the biologic drug ineffective.
There are different corporations creating URAT1 inhibitors that would doubtlessly compete with Crystalys’s dotinurad. San Diego-based Arthrosi Therapeutics’ contender is AR882; China-based Atom Therapeutics is creating ABP-671. Each are in Part 3 growth. If these medication are based mostly on the identical molecular spine as Adrea’s withdrawn Zurampic, they may probably have the identical renal toxicity points, Mackay stated. Higher security for dotinurad is a part of the design of the molecule.
Analysis in URAT1 inhibition to deal with gout dates to the Nineteen Seventies, with the event of a molecule known as benzbromarone. This drug gained regulatory approvals in some international locations, however by no means the U.S. Benzbromarone was hampered by studies of liver toxicity. Mackay stated Fuji Yakuhin’s chemists designed dotinurad to take away the renal toxicity points seen with earlier URAT1 inhibitors. Their work additionally eliminated the hepatotoxicity noticed with benzbromarone.
Dotinurad is extremely particular to the URAT1 protein, leaving different renal transporters unaffected, Mackay stated. Consequently, there’s a extra managed launch of uric acid over 24 hours. Different URAT1 inhibitors have proven a spike in uric acid excretion, Mackay stated. Pushing out an excessive amount of uric acid via the kidney in a brief time period ends in crystallization of uric acid that damages the kidney, he defined.
“We imagine [dotinurad] doesn’t have that legal responsibility and there’s no requirement within the Japanese or the Chinese language label for renal monitoring,” Mackay stated. “And clearly the Japanese have given it to over 1,000,000 sufferers since launch and no renal poisonous sign has been recognized.”
Crystalys’s financing, a Sequence A spherical, was co-led by Novo Holdings, SR One, and Catalys Pacific. Different individuals embody Perceptive Xontogeny Enterprise Funds, Lightstone VC, AN Enterprise Companions, funds managed by abrdn Inc., KB Investments, Pontifax, Longwood Fund, Alexandria Enterprise Investments, Wedbush Healthcare Companions, and Prebys Ventures Fund.
With the brand new capital, Crystalys will advance dotinurad straight to 2 Part 3 research, one assessing the drug’s impact on gout flares and the opposite testing tophus decision. Given the intensive medical trial and real-world information for the drug in Asia, the FDA is allowing Crystalys to skip Part 2 testing, Mackay stated. The one stipulation is that the FDA needs to see some stage of dose ranging within the Part 3 program, so one of many research will consider a 2 mg dose and a 4 mg dose. The research have a focused enrollment of about 750 sufferers whole. Mackay expects information from these trials in late 2027.
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