A 12-week Open-label, Single-arm, Phase 2 Study to Evaluate the Safety and Efficacy of RIST4721 in Subjects with Familial Mediterranean Fever followed by an additional Open-label Extension Phase.

Start Date13 Sep 2022

Sponsor / Collaborator

Aristea Therapeutics, Inc.Startup

NCT05348681 / TerminatedPhase 2

A Randomized, Double-blinded, Placebo-controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects With Hidradenitis Suppurativa

A Randomized, Double-blinded, Placebo-controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Hidradenitis Suppurativa

Start Date18 Jul 2022

Sponsor / Collaborator

Aristea Therapeutics, Inc.Startup

EUCTR2021-003029-31-DE / Unknown statusPhase 2

A Randomized, Double-blind, Placebo-controlled, Dose Ranging Phase 2 Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis - RIST4721 in Subjects with Palmoplantar Pustulosis

Start Date27 Apr 2022

Sponsor / Collaborator

Aristea Therapeutics, Inc.Startup

100 Clinical Results associated with AZD-4721

100 Translational Medicine associated with AZD-4721

100 Patents (Medical) associated with AZD-4721

Literatures (Medical) associated with AZD-4721

01 Mar 2022·Journal of pharmaceutical sciencesQ3 · MEDICINE

Possible Extraction of Drugs from Lung Tissue During Broncho-alveolar Lavage Suggest Uncertainty in the Procedure's Utility for Quantitative Assessment of Airway Drug Exposure

Q3 · MEDICINE

Article

Author: Bäckström, E ; Grime, K ; Lindberg, W ; Fihn, B-M ; Erngren, T ; Fridén, M ; Sadiq, M W

Following inhaled dosing, broncho-alveolar lavage (BAL) is often used for sampling epithelial lining fluid (ELF) to determine drug concentration in the lungs. This study aimed to explore the technique's suitability. Urea is typically used to estimate the dilution factor between the BAL fluid and physiological ELF, since it readily permeates through all fluids in the body. As representatives of permeable small molecule drugs with high, medium and low tissue distribution properties, propranolol, diazepam, indomethacin and AZD4721 were infused intravenously to steady state to ensure equal unbound drug concentrations throughout the body. The results showed that propranolol had higher unbound concentrations in the ELF compared to the plasma whilst this was not the case for the other compounds. Experiments with different BAL volumes and repeated lavaging indicated that the amount of drug extracted is very sensitive to experimental procedure. In addition, the results show that the unbound concentrations in ELF compared to plasma differs dependent on molecule class and tissue distribution properties. Overall data suggests that lavaging can remove drug from lung tissue in addition to ELF and highlights significant uncertainty in the robustness of the procedure for determining ELF drug concentrations.

01 Dec 2021·Dermatology and therapyQ4 · MEDICINE

A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis

Q4 · MEDICINE

ArticleOA

Author: Reid, DeAnne ; Maari, Catherine ; Baumgartner, Scott ; Bissonnette, Robert ; Mackay, James ; Tsianakas, Athanasios ; Bhakta, Nihar ; McCutchan, Sara

INTRODUCTION:

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition with neutrophilic infiltration of the epidermis. RIST4721 antagonizes CXC chemokine receptor type 2, which is important in neutrophil recruitment and migration. In this study, the efficacy and safety of RIST4721 versus placebo were assessed in adult subjects with moderate to severe PPP.

METHODS:

This phase 2a, multicenter, randomized, double-blind, placebo-controlled study investigated RIST4721 versus placebo in subjects with moderate to severe PPP. Key eligibility criteria included: Palmoplantar Pustulosis Area and Severity Index (PPPASI) ≥ 8 and Palmoplantar Pustulosis Physician Global Assessment ≥ 3. Subjects were randomized 1:1 to RIST4721 300 mg or placebo once daily for 28 days. The primary efficacy endpoints were relative change from baseline in fresh and total pustule count at day 28.

RESULTS:

Fifteen subjects received RIST4721 and 19 subjects received placebo. Treatment with RIST4721 was found to be generally well tolerated. At day 28, the mean ± standard deviation (SD) relative change from baseline in fresh pustule count was 0.86 ± 0.692 and 0.53 ± 0.561 (P = 0.240) and in total pustule count was 0.99 ± 0.667 and 0.96 ± 0.672 (P = 0.804) for RIST4721 and placebo groups, respectively. Subgroup analysis of subjects with progressing disease demonstrated that subjects with a PPPASI-50 at day 28 was significantly higher for subjects treated with RIST4721 (71%) than placebo (15%) (P = 0.022).

CONCLUSION:

Preliminary data suggest RIST4721 is well tolerated and may be a potential therapy for patients with PPP.

TRIAL REGISTRATION:

RIST4721-201 was registered in June 2019 at clinicaltrials.gov: NCT03988335.

01 Aug 2019·Drug metabolism and disposition: the biological fate of chemicalsQ2 · MEDICINE

Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs

Q2 · MEDICINE

Article

Author: Cox, Rhona J ; Gardiner, Philip ; Grime, Ken

The low volume of distribution associated with acidic molecules means that clearance (CL) must also be very low to achieve an effective half-life commensurate with once or twice daily dosing. Plasma protein binding (PPB) should not usually be considered a parameter for optimization, but in the particular case of acidic molecules, raising the PPB above a certain level can result in distribution volume becoming a constant low value equal to the distribution volume of albumin while acting to reduce CL through restricting hepatic and renal access of unbound drug. Thus effective half-life can be increased. Here we detail the approaches and lessons learned at AstraZeneca during the optimization of acidic CXC chemokine receptor 2 (CXCR2) antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(2R,3S)-3,4-dihydroxybutan-2-yl]oxypyrimidin-4-yl]azetidine-1-sulfonamide (AZD5069) and AZD4721, orally bioavailable acidic molecules with PPB of <1%, human hepatocyte intrinsic clearance values <5 µl/min per 10⁶ cells and predicted human volume of distribution at steady state (V _ss) <0.3 l/kg, resulting in effective half-lives in humans of 4 and 17 hours, respectively. SIGNIFICANCE STATEMENT: Provided that the pharmacologic potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimize the effective half-life of drug candidates in humans.

News (Medical) associated with AZD-4721

03 May 2023

·www.biospace.com

Pfizer Cuts Mid-Stage Candidates Amid Declining Revenues

Pictured: Blue and white Pfizer sign on building/cbies/Adobe Stock Fresh off its $43 billion acquisition of Seagen, Pfizer is making deep cuts to its Phase II pipeline in cardiology and inflammatory diseases, the company revealed Tuesday during its first-quarter financial report. On Pfizer’s chopping block is temanogrel, an inverse agonist of the serotonin 2A receptor being trialed for microvascular obstruction and Raynaud’s phenomenon related to systemic sclerosis. Pfizer is also dumping its cardio candidate APD418, an antagonist of the beta-3 adrenergic receptor in Phase II studies for acute heart failure. Pfizer obtained access to temanogrel and APD418 from its $6.7 billion buy of Arena Pharmaceuticals in December 2021. Tuesday’s pipeline cuts leave etrasimod, an orally available selective sphingosine 1-phospate receptor modulator, as the only mature Arena molecule on Pfizer’s pipeline. In May 2022, Pfizer posted data from two pivotal trials from the Phase III ELEVATE UC registrational program, showing that etrasimod significantly improved remission rates in patients with moderate-to-severely active ulcerative colitis. In December 2022, the FDA accepted etrasimod’s New Drug Application in this indication, with a decision set for the second half of 2023. Etrasimod is also being trialed in other immuno-inflammatory conditions such as Crohn’s disease and alopecia areata. Pfizer’s pipeline clean-out also included the biologic blocker of the TNFSF15 protein for ulcerative colitis and the CXCR2 antagonist RIST4721, which was in Phase II studies for hidradenitis suppurativa and palmoplantar pustulosis. RIST4721, initially developed by Aristea Therapeutics, works by suppressing inflammation. In July 2021, concurrent with a $63 million Series B funding round, Aristea inked a strategic partnership with Arena to advance the candidate through the clinic. However, in February 2023, Aristea announced that it was discontinuing the development of RIST4721 due to safety concerns, forcing the company to shutter its operations. Business Beyond COVID-19 For the first quarter of 2023, Pfizer posted nearly $18.3 billion in revenue, down 29% from the same period during the prior year. Much of this downtrend could be attributed to the drop in coronavirus-related sales, said Pfizer CEO Anthony Bourla during an investor call Tuesday. Revenues in non-COVID-19 products grew 5%, driven mainly by its anticoagulant Eliquis (apixaban), migraine drug Nurtec ODT (rimegepant) and sickle-cell disease therapy Oxbryta (voxelotor). Pfizer still expects to hit its target of 7% to 9% operational growth for its non-COVID-19 revenues in 2023, which will be due mostly to product launches in the second half of the year. Among these is Zavzpret (zavegepant), a nasal spray for acute migraine in adults that Pfizer won from its $11.6 billion buyout of Biohaven. Two Phase III trials showed that compared with placebo, Zavzpret led to significantly better pain freedom and freedom from the most bothersome migraine symptom within two hours of dosing. The FDA gave Zavzpret its approval in March 2023. Pfizer is also pinning its 2023 hopes on its respiratory syncytial virus (RSV) vaccine candidate, which won the backing of the FDA’s Vaccines and Related Biological Products Advisory Committee in March 2023 for its favorable risk-benefit pro older adults. A final verdict is expected this month. Similarly, the company is anticipating expanded approval for its prostate cancer drug Xtandi (enzalutamide), allowing its use in non-metastatic castration-sensitive prostate cancer. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Phase 2Drug ApprovalPhase 3VaccineClinical Result

13 Feb 2023

·www.biospace.com

AstraZeneca Spin-off Aristea Folds After Safety Issues End Lead Program

Aristea Team/Courtesy Photo Due to safety concerns, Aristea Therapeutics announced Friday it is discontinuing the development of its Phase II lead program RIST4721. As a result, the San Diego-based biotech is also dissolving its business. After careful and extensive consideration and “exploring a range of strategic alternatives,” Aristea’s board decided that ending the company and its operations was a sound business decision, said James Mackay, Ph.D., president and CEO, Aristea, in a statement. Aristea launched in December 2018 as an AstraZeneca spin-out. The company dove into the biopharma space with $15 million in Series A backing to rehome molecules to develop novel treatments against severe inflammatory conditions. “Our aim here is to take molecules that have been discarded by big pharma for a variety of reasons, or from other biotechs who have taken them through preclinical development but are not equipped to take them into clinical,” Mackay told BioSpace in a January 2022 interview. Novo Holdings, the private limited liability company under the Novo Nordisk group, backed the startup. Aristea gained exclusive global rights to RIST4721, its lead asset, from AstraZeneca. The candidate is an antagonist of the CXCR2 protein and was set to enter Phase II assessments in palmoplantar pustulosis when the company launched. The company completed enrollment into this study in October 2019. Palmoplantar pustulosis is a recurrent inflammatory disorder characterized by flares of neutrophil-filled pustules on the palms and feet, causing pain, itching and burning sensations at these sites. RIST4721 intended to treat this condition by suppressing CXCR2, which is chiefly responsible for recruiting neutrophils at the site of inflammation. In July 2021, RIST4721’s potential attracted $63 million in Series B financing, which helped Aristea further advance the candidate through the clinic, build its leadership team and form new strategic partnerships. The Series B was again led by Novo Holdings, with new investors Arena Pharmaceuticals and Tekla Capital Management joining. Concurrent with the funding round, Aristea entered into a strategic collaboration with Arena Pharmaceuticals, a Pfizer unit, giving the latter the exclusive option to acquire Aristea and all its CXCR2 programs post-Phase II in exchange for $60 million upfront and $10 million in equity investments. However, in Friday’s announcement, Aristea revealed that safety concerns had snuffed out RIST4721’s promise. In an email to BioSpace, a company representative said they did not have additional information to provide regarding the safety concerns. By the time Aristea folded, RIST4721 was also being trialed for hidradenitis suppurativa, familial Mediterranean fever and Behcet’s disease. The company also developed RIST5122 and RIST8309, both CXCR2 antagonists, for undisclosed indications.

Phase 2AcquisitionPhase 1PROTACsLicense out/in

10 Feb 2023

·www.fiercebiotech.com

Faced with safety issues over inflammation drug, AstraZeneca spinout Aristea closes shop

February alone has seen Magenta Therapeutics and Vyant Bio announce they are closing down. Confronted with safety findings, Aristea Therapeutics is not only canning work on its mid-stage inflammatory program but has decided to dissolve the business entirely. Things seemed to be going well for Aristea as recently as last November, with the biotech taking on board a crop of clinical experts as it looked to expand its pipeline. The company’s lead asset, a CXCR2 antagonist dubbed RIST4721, was undergoing phase 2 trials for four neutrophil-mediated diseases: a rare inflammatory disorder called palmoplantar pustulosis (PPP), a painful skin condition called hidradenitis suppurativa, a genetic disorder called familial Mediterranean fever and Behcet's disease, which causes inflammation of the blood vessels. But safety findings from the phase 2 trials have blown up those plans, the company revealed in a bombshell announcement this morning. Aristea didn’t go into details of the specific safety signals or which trials they had been observed in. Whatever they were, the findings were significant enough that the San Diego-based biotech “has discontinued the RIST4721 development program in order to protect patient safety.” With that decision goes any hopes of keeping the business up and running. "Although the decision to discontinue the RIST4721 development program is disappointing for the Aristea Therapeutics team and patients in need of new treatment options, we believe it is absolutely the right decision to protect patient safety, which must always be paramount in drug development," CEO James Mackay, Ph.D., said in the release. "The board's decision to dissolve Aristea Therapeutics was reached after exploring a range of strategic alternatives and is a sound business decision." The news may be felt all the way up at Pfizer’s headquarters. The Big Pharma had acquired the option to take over the biotech after it bought Arena Pharmaceuticals at the tail end of December 2021. That deal came six months after Arena had stumped up funding for Aristea as part of a collaboration to push RIST4721 through the clinic. Once the therapy completed the phase 2 trial in PPP, Arena—and later Pfizer—had the option to buy Aristea outright. At the time, analysts also saw potential in RIST4721 as a PPP treatment. There are no treatments specifically for the condition—which causes blisterlike sores to form on the palms of the hands and soles of the feet. Patients use topical steroids, moisturizers or ultraviolet light therapy to ease symptoms. Aristea’s drug was designed to tackle PPP at the source by dialing down CXCR2, a receptor that plays a role in recruiting neutrophils, or white blood cells, to areas of inflammation. Aristea is only the latest in a string of biotech closures in the opening weeks of this year, a reflection of the tough climate that the industry still faces. February alone has already seen Magenta Therapeutics wind down in the wake of a patient death as well as Vyant Bio announce that it's reached the end of the road.

Phase 2Acquisition

100 Deals associated with AZD-4721

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Familial Mediterranean Fever	Phase 2	US	Aristea Therapeutics, Inc.Startup	30 Jul 2022
Hidradenitis Suppurativa	Phase 2	US	Aristea Therapeutics, Inc.Startup	18 Jul 2022
Hidradenitis Suppurativa	Phase 2	CA	Aristea Therapeutics, Inc.Startup	18 Jul 2022
Pustular psoriasis	Phase 2	CA	Aristea Therapeutics, Inc.Startup	13 Feb 2019
Pustular psoriasis	Phase 2	DE	Aristea Therapeutics, Inc.Startup	13 Feb 2019
Inflammation	Phase 1	GB	Aristea Therapeutics, Inc.Startup	25 Jul 2019
Pulmonary Disease, Chronic Obstructive	Phase 1	GB	AstraZeneca PLC	-
Inflammatory Bowel Diseases	Preclinical	US	Arena Pharmaceuticals, Inc.	24 Nov 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05194839 (CTgov)	Phase 2	Pustular psoriasis	79	RIST4721 (RIST4721 400 mg)	zwyeqybnsf(dvidrphahl) = amtilhjzre szdqdeaenu (ihgsyxzgxq, soetktwojv - zrhegtmomh) View more	-	29 Jun 2023
				Placebo+RIST4721 (RIST4721 200 mg)	zwyeqybnsf(dvidrphahl) = paytnebwld szdqdeaenu (ihgsyxzgxq, lporyblaxt - ndnsbdjdjk) View more
NCT05348681 (CTgov)	Phase 2	Hidradenitis Suppurativa	25	RIST4721 (RIST4721 400 mg)	wszkaqwbyt(gqbrphutko) = bfimfroyif aakknxvfnt (yludgtmcxw, wlepzmxxdx - ndmzxyaycj) View more	-	13 Jun 2023
				Placebo (Placebo)	wszkaqwbyt(gqbrphutko) = hoxanginil aakknxvfnt (yludgtmcxw, zhuwmmpfzg - jnqhoogvcu) View more
NCT03988335 (RIST4721-201, CTgov)	Phase 2	Pustular psoriasis	35	Placebo	kkrzccupgn(onrybhfepu) = bdejojepda zohskpwqji (yrztpmntzl, pihlyumhvg - bzpcikuaur) View more	-	03 Mar 2022
NCT03988335 (RIST4721-201, Pubmed \| Dermatol Ther (Heidelb))	Phase 2	Psoriasis	35	RIST4721 300 mg	ugbsetyece(tgxdkpmmfk) = czxnfzvuey tfeymvtkfu (kpuuqbbbhu )	Positive	30 Oct 2021
				Placebo	ugbsetyece(tgxdkpmmfk) = unqmptugpi tfeymvtkfu (kpuuqbbbhu )

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