A Multicenter Phase 2, 12-week Double-blind, Placebo-controlled, Randomized, Parallel-group Study of JZP150 for the Treatment of Posttraumatic Stress Disorder

This is a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the safety and efficacy of JZP150 in the treatment of adult participants with post-traumatic stress disorder (PTSD).

Start Date29 Dec 2021

Sponsor / Collaborator

Jazz Pharmaceuticals, Inc.

NCT03386487 / CompletedPhase 2IIT

A Phase 2B, 8-week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults With DSM5 Current Cannabis Use Disorder (CUD)

A Phase 2B, 8-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults with DSM-5 Current Cannabis Use Disorder (CUD)

Start Date14 Jan 2019

Sponsor / Collaborator

Yale University

[+4]

EUCTR2016-005013-47-SE / Unknown statusPhase 2IIT

Effects of the FAAH inhibitor PF-04457845 on fear extinction in healthy volunteers - PF-04457845 and fear extinction

Start Date28 Feb 2017

Sponsor / Collaborator

University of Linköping

100 Clinical Results associated with Redafamdastat

100 Translational Medicine associated with Redafamdastat

100 Patents (Medical) associated with Redafamdastat

Literatures (Medical) associated with Redafamdastat

01 Apr 2023·Molecular pharmacology

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Article

Author: Chen, Chaoling ; Gewirtz, David A ; Ahmadinejad, Fereshteh ; Raymond, Marissa ; Lichtman, Aron H ; Poklis, Justin L ; Em, Brandon ; Wang, Weili ; Li, Ningjun

Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah^-/- mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah^-/- mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1β, as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity. SIGNIFICANCE STATEMENT: Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.

01 Jan 2023·Cell death and differentiation

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system

Article

Author: Meng, Guangxun ; Hao, Xiaohan ; Huang, Yubing ; Wang, Meimei ; Yao, Han ; Zhang, Yunjiao ; Zhu, Yangyang ; Zhong, Suqin ; Huang, Xiaowan ; Xu, Youcui ; Yan, Kai ; Chen, Sirong ; Ye, Zhiming ; Qin, Xiaohua ; Shen, Jiani ; Mao, Huawei ; Wang, Liansheng ; Yang, Zhenyu ; Wen, Longping ; Li, Juan ; Zhang, Yue ; Zhang, Hao ; Song, Yang ; Zhang, Wenbin ; Zhao, Zhibin

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

01 Jan 2023·FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Inhibition ofFAAHsuppressesRANKL‐induced osteoclastogenesis and attenuates ovariectomy‐induced bone loss partially through repressing theIL17pathway

Article

Author: Wang, Sibo ; Zhao, Hongjian ; Guo, Qian ; Wang, Pengju ; Chen, Liangxi ; Xu, Shimeng ; Peng, Renpeng ; Kang, Honglei ; Zhang, Yayun ; Zhu, Meipeng ; Dong, Yimin ; Liu, Haiyang ; Dong, Zijian ; Song, Kehan ; Liu, Jian ; Li, Feng

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.

News (Medical) associated with Redafamdastat

12 Mar 2024

·www.biospace.com

Alkermes and Jazz: Two Different Approaches to Neuroscience, Oncology Portfolios

Pictured: A fork in a dirt road/iStock, by-studio Dublin-based Alkermes is one of the industry’s most recent examples of a global biopharma spinning off a business as part of its strategy to generate profitability and cash flow. Alkermes entered 2024 as a pure-play neuroscience company focused on difficult-to-treat psychiatric and neurological disorders, having completed the separation of its oncology business into a new company, Mural Oncology, in November 2023. Founded in 1987, Alkermes decided a couple of years ago to “clean up and clarify” the company’s business for investors, CEO Richard Pops told BioSpace. “Alkermes has always been so multivalent, so complicated. We had a legacy drug delivery royalty business—with large cash flows coming from that. We had a neuroscience business, a commercial business. We had an oncology business. And we didn’t fit in a particular category,” Pops said. The CEO compared Alkermes’ evolution over the years to a tree with two trunks: neuroscience and oncology. “When you plant the tree and it’s growing, for a while it’s no problem. But pretty soon they get big, and you’ve got to decide how you’re going to support both of them,” Pops said. Spinning off Alkermes’ oncology business by creating Mural Oncology, a public company, was a big undertaking given the IRS and SEC regulations, Pops said, but the cancer business deserved its own capital, instead of sharing with the neuroscience arm of the business. Moreover, Alkermes now has “a really clear story,” Pops said. “It’s a pure-play neuroscience company that has a billion dollars of revenue and growing.” It’s important to have that division for oncology-focused investors and analysts and those following the neuroscience market, he said. Jazz Pharmaceuticals, on the other hand, has opted not to divorce its neuroscience and oncology pipelines. Bruce Cozadd, co-founder and CEO, told BioSpace that the Dublin-based company has been in the neuroscience space since its founding in 2003, only beginning to target oncology nine years later. Today, about half of Jazz’s revenues currently come from its oncology portfolio. “Both of those businesses are growing and have robust pipelines,” Cozadd said. He added that while he’s aware of companies like Alkermes that have separated their neuroscience and oncology businesses, Jazz was not considering such a move. Cozadd pointed to his company’s financial strength as one reason for that decision. Jazz reported late last month that its oncology revenue surpassed $1 billion in 2023, while total neuroscience revenue came in at $2.8 billion. By comparison, Alkermes last month announced total 2023 revenues of $1.66 billion. As of Dec. 31, 2023, Jazz had $1.6 billion in cash, cash equivalents and investments, while Alkermes reported about half that. “We’re in the fortunate position that we can fund our key growth drivers commercially . . . while at the same time making pipeline investments,” Cozadd said. To expand its early-stage oncology pipeline, Jazz last month bought Redx Pharma’s KRAS inhibitor program in a potential $880 million deal, including preclinical-stage drug candidates, with the companies working to advance assets through IND-enabling studies. However, it hasn’t been smooth sailing for Jazz’s neuroscience business. In December 2023, Jazz reported top-line Phase II results for JZP150—a small molecule being studied in patients with post-traumatic stress disorder—showing that the investigational candidate fell short of its primary efficacy endpoint and failed to meet key secondary endpoints. “We’re not in both oncology and neuroscience because of some mechanistic scientific medical reason,” Cozadd said. “We’re in these two areas because we look for areas where there’s significant unmet medical need and we can offer a differentiated product that really benefits patients in a unique way.” While Jazz’s neuroscience portfolio currently generates more revenue than its oncology business, the nearer term “larger” potential opportunities are in the oncology pipeline, according to Cozadd. “We don’t have a particular goal of a ratio,” he added. “I’d like both of them to be as big as possible.” Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

AcquisitionPhase 2Clinical Result

22 Dec 2023

·www.fiercebiotech.com

Jazz drops PTSD drug over phase 2 trial failure

Jazz’s latest clinical setback comes less than a month after the biotech paused a phase 1 trial of its sleep disorder med JZP441. Jazz Pharmaceuticals is planning to drop its post-traumatic stress disorder (PTSD) therapy after the small molecule selective fatty acid amide hydrolase (FAAH) inhibitor failed to beat placebo in a phase 2 study. The biotech had been testing the drug, dubbed JZP150, in a trial of 282 patients diagnosed with PTSD aged 18 to 70 years who were randomized to receive either 0.3 mg or 4 mg doses of the therapy or placebo. At 12 weeks, JZP150 was unable to show a statistically significant decrease in the severity of PTSD symptoms over placebo, missing the trial’s primary endpoint. No new safety signals were observed, the biotech noted. The most common treatment-emergent adverse events were headache, nausea and urinary tract infection, although the company pointed out that these also occurred in placebo-treated participants. "We plan to fully evaluate these data; however, based on topline results we do not anticipate moving forward with additional JZP150 development in PTSD,” Rob Iannone, M.D., Jazz’s global head of R&D, said in the post-market release Thursday. “We recognize the significant unmet need for PTSD patients and plan to share the findings from this trial with the medical community at a future date," Iannone added. Jazz had high hopes for JZP150, having previously pointed out that it had a chance of becoming the first new drug approved in 20 years for patients with the disorder. PTSD has been in the headlines recently as the Multidisciplinary Association for Psychedelic Studies' submitted a new drug submission for MDMA to treat the condition, marking the first time ever that the agency will consider approving a psychedelic-assisted therapy. Jazz’s latest clinical setback comes less than a month after the biotech paused a phase 1 trial of its sleep disorder med JZP441 in the wake of reports of “visual disturbances” and cardiovascular effects. Executives wouldn’t go as far as to fully terminate the orexin-2 receptor agonist, which was licensed from Sumitomo Pharma, instead saying at the time that they were looking to further investigate the side effects and how to potentially mitigate them. Discussing those JZP441 results on a Nov. 28 conference call, executives made sure to swiftly transition from bad news to good, announcing that Jazz planned to initiate rolling submission of its bispecific antibody zanidatamab before the end of the year. The company is seeking accelerated approval as a second-line treatment for patients with biliary tract cancer, with the application set to be completed by the first half of 2024.

Phase 2Phase 1

22 Dec 2023

·www.biospace.com

Jazz’s Future in PTSD Left Uncertain Following Mid-Stage Trial Failure

Pictured: Man crouched on a bed with his head on his knees/iStock, pcess609 Jazz Pharmaceuticals on Thursday announced top-line Phase II results for JZP150, showing that the investigational fatty acid amide hydrolase inhibitor fell short of its primary efficacy endpoint in a mid-stage study of post-traumatic stress disorder. The Irish biopharma company did not provide specific data in Thursday’s announcement but said that compared with placebo “there was not a statistically significant decrease” in post-traumatic stress disorder (PTSD) symptoms in patients treated with JZP150. The investigational drug also failed key secondary endpoints, including clinician- and patient-assessed disease severity. Jazz’s stock price dropped 2.6% in response to the readout, according to Seeking Alpha. Rob Iannone, executive vice president and global head of research and development at Jazz, said in a statement that the company is still conducting a full evaluation of the study’s findings and will share their analyses in the future. However, Iannone added that “based on top-line results, we do not anticipate moving forward with additional JZP150 development in PTSD.” Designed to be orally available, JZP150 is a selective small molecule inhibitor of the fatty acid amide hydrolase enzyme, the activity of which has previously been associated with arousability and the extinction of negative memories—both key markers of PTSD. This mechanism of action allows JZP150 to potentially target the underlying causes of PTSD. In assessing JZP150 for PTSD, Jazz ran the Phase II randomized, double-blinded and placebo-controlled trial with 282 adult patients enrolled. JZP150 was given at either 4-mg or 0.3-mg doses and its primary endpoint was the 12-week change in symptom severity, as quantified using the Clinician Administered PTSD Scale. Key secondary endpoints were also measured using the Clinical Global Impression of Severity and the Patient Global Impression of Severity scales. Beyond efficacy, the mid-stage study looked at JZP150’s safety and found no new safety signals of concern. The most common treatment-emergent side effects were nausea, urinary tract infection and headache, most of which were mild or moderate in severity. Thursday’s Phase II failure for Jazz breaks the industry’s winning streak in PTSD in recent months. On Wednesday, Compass Pathways released Phase II data showing that its investigational psilocybin therapy COMP360 was well-tolerated for the treatment of PTSD. In September 2023, Bionomics announced that its ion channel modulator BNC210 aced the Phase IIb ATTUNE trial, eliciting significant symptom reduction in PTSD patients. A few days earlier, Alto Neuroscience likewise reported a Phase IIb victory for its BDNF-targeted ALTO-100 and its AI-enabled precision psychiatry platform. 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 2Clinical Result

100 Deals associated with Redafamdastat

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Stress Disorders, Post-Traumatic	Phase 2	US	Pfizer Inc.	01 Oct 2014
Osteoarthritis, Knee	Phase 2	US	Pfizer Inc.	01 Nov 2009
Osteoarthritis, Knee	Phase 2	CA	Pfizer Inc.	01 Nov 2009
Osteoarthritis, Knee	Phase 2	SE	Pfizer Inc.	01 Nov 2009
Pain	Phase 2	US	Pfizer Inc.	01 Nov 2009
Pain	Phase 2	CA	Pfizer Inc.	01 Nov 2009
Pain	Phase 2	SE	Pfizer Inc.	01 Nov 2009
Sleep	Phase 1	US	Pfizer Inc.	01 Nov 2009
Acute Pain	Phase 1	SG	Pfizer Inc.	01 Feb 2009
Chronic Pain	Phase 1	SG	Pfizer Inc.	01 Feb 2009

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03386487 (CTgov)	Phase 2	Marijuana Use	228	PF 04457845 (PF-04457845)	lkorktvrlp(efydfcxhwp) = dcdfpbwsbc uvzuujirji (jqionabsfb, lgkaxlfjfq - mrmuszumtz) View more	-	14 Feb 2024
				Placebo Oral Tablet (Placebo)	lkorktvrlp(efydfcxhwp) = xdimlabbqu uvzuujirji (jqionabsfb, tduaywivik - fgrlbabubq) View more
NCT05178316 (Corporate Publications) Manual	Phase 2	Stress Disorders, Post-Traumatic	282	JZP150	lxqrikyhdq(kuhlfqkufd) = not a statistically significant decrease in total PTSD symptom severity between JZP150 (4mg or 0.3mg) compared to placebo from baseline waexhyiraz (helyeuxtki ) Not Met View more	Positive	21 Dec 2023
				Placebo
NCT01618656 (Pubmed) Manual	Phase 2	Cannabis withdrawal	70	PF-04457845	xqvklnocoe(uarbrmjjjx) = zwsyllubkr vzkagqupti (dqpiwgmoie, 7.78 ~ 15.57) View more	Positive	01 Jan 2019
				Placebo	xqvklnocoe(uarbrmjjjx) = zqwllgdavo vzkagqupti (dqpiwgmoie, 4.43 ~ 8.24) View more
NCT02216097 (CTgov)	Phase 2	Stress Disorders, Post-Traumatic	14	Placebo	lajdlbjayx(vtjxiwqlee) = xazoodbxkb plqzzsfpwr (qaofekehed, frgvceevcx - zlciosclpm) View more	-	08 Apr 2016

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