作者: Altintas, Mehmet O ; Ozpinar, Aysenur ; Kilic, Ertugrul ; Beker, Mustafa C. ; Bayraktaroglu, Cigdem ; Beker, Mustafa C ; Sengun, Nursena ; Altintas, Mehmet O. ; Dogan, Enes ; Balaban, Buse ; Altunay, Serdar

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.

2024-11-05·ANESTHESIOLOGY

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice

Article

作者: Kallenborn-Gerhardt, Wiebke ; Gerninghaus, Hannah ; Hernandez-Olmos, Victor ; Petersen, Jonas ; Schmidtko, Achim ; Feil, Susanne ; Sinderwald, Rekia ; Stehle, Daniel ; Proschak, Ewgenij ; Feil, Robert ; Duman, Emre ; Lu, Ruirui ; Nagel, Chantal ; Metzner, Katharina ; Gross, Tilman ; Zhou, Fangyuan

Background:

Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy.

Methods:

In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.

Results:

PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund’s adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.

Conclusion:

Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

2024-08-01·SCHIZOPHRENIA RESEARCH

Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial

Article

作者: Mukai, Yuki ; Egan, Michael F ; Voss, Tiffini ; Lupinacci, Robert ; Smith, Sean M ; Snow-Adami, Linda ; Marder, Stephen

BACKGROUND:

PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia.

METHODS:

Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks.

RESULTS:

The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight.

CONCLUSIONS:

These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted.

TRIAL REGISTRATION:

Clinicaltrials.gov identifier: NCT03055338.

项与 PDE10A inhibitors(Janssen) 相关的新闻（医药）

2024-10-17

·GlobeNewswire-Health Care

Noema Pharma Announces NOE-105 (gemlapodect) Phase 2a Study in Tourette Syndrome met Primary and all Key Secondary Endpoints

– Topline results from Phase 2a study – Nearly 60% of all patients treated with gemlapodect and 88% of patients completing the study at the target clinical dose range were responders based on the primary efficacy assessment The Yale Global Tics Severity Scale Total Tic Score (YGTSS-TTS) showed a statistically significant improvement of -7.8 points for all patients, and -12.8 points for patients completing the study at the target clinical dose No weight gain, events of metabolic marker increase, or serious adverse events were reported BASEL, Switzerland, Oct. 17, 2024 (GLOBE NEWSWIRE) -- Noema Pharma AG, a clinical-stage neuroscience-based company, today announced the Phase 2a ALLEVIA-1 study with NOE-105 (gemlapodect) in patients with Tourette syndrome (TS) met its primary and all key secondary endpoints. Gemlapodect is a novel and first-in-class PDE10A inhibitor currently being studied to assess its potential to reduce vocal and motor tics in people with TS with an improved tolerability profile over current treatment options. The Phase 2a study, ALLEVIA-1 (NOE-TTS-211), was a multicenter, 12-week, open-label, single-arm monotherapy study which enrolled a total of 15 patients with TS with a mean age of 26.2 (+/- 8.7) years. Patients were treated with ascending doses of gemlapodect ranging from 2.5 to 15 mg once daily, with a target dose range of 10 to 15 mg per day. The ALLEVIA-1 study achieved its primary and secondary objectives. Key findings included: 57% of patients showed tic improvement compared to baseline, with the remaining patients having no change and no patients worsening on the independently adjudicated TS Clinical Global Impression of Change (TS-CGI-C; primary endpoint) (n=14 patients taking at least one dose of study medication and having at least one post-baseline efficacy assessment).For patients who completed the study within the target clinical dose range, 87.5% showed improvement and 75% were rated as much or very much improved on the TS-CGI-C (n=8).YGTSS Total Tic Score showed a mean improvement of -7.8 points (p=0.009) from baseline to endpoint for all patients taking at least one dose and having at least one post-baseline assessment.YGTSS Total Tic Score showed a mean improvement of -12.8 points (p=0.003) from baseline to endpoint for all patients completing the study within the target clinical dose range.Adverse events were consistent with the known profile of gemlapodect, and no serious adverse events were reported during the trial.No weight gain and no clinically significant changes in laboratories (including metabolic measures such as blood glucose or lipids) were reported. “Based on these promising data, we believe gemlapodect has the potential to offer a meaningful advancement in the treatment of Tourette syndrome,” said Ilise Lombardo M.D., CEO of Noema Pharma. “I would like to thank the investigators and patients for their important contributions to the ALLEVIA-1 study.” “Tourette syndrome is a devastating disease that impacts patients and their families. Recurrent and severe tics interfere with the patient’s ability to learn, work and interact with others.” said Prof. Kirsten Mueller-Vahl, Principal Investigator, MHH, Hannover, Germany. “Current treatments, essentially antipsychotics, are associated with side effects such as significant weight gain and insulin resistance, as well as stigma. Our findings with gemlapodect are very encouraging, given that the need for new treatments and novel mechanisms in Tourette syndrome remains notably high.” Initial study data were presented at the MDS 2024 Congress, September 28, 2024. About Noema Pharma Noema Pharma is a clinical-stage biotech company advancing a portfolio of transformative therapeutics utilizing first-in-disease approaches targeting neuroscience-based conditions with high unmet need. Noema has four programs currently in active Phase 2 clinical trials evaluating pain in Trigeminal Neuralgia, seizures in Tuberous Sclerosis Complex, Tourette syndrome and vasomotor symptoms plus associated symptoms of menopause with readouts expected in 2025. Noema was founded by leading venture capital firm Sofinnova Partners and is supported by current investors including Forbion, Gilde Healthcare, Invus, Jeito Capital, Polaris Partners and UPMC Enterprises. Learn more at www.noemapharma.com. About NOE-105/gemlapodect NOE-105/gemlapodect is a potential first-in-class phosphodiesterase-10A (PDE10A) inhibitor in mid-stage clinical development as a dopamine modulator for Tourette syndrome. NOE-105 has been well-tolerated in studies with healthy volunteers and in patients with Tourette syndrome with no evidence of metabolic side effects including weight gain, hyperlipidemia and type 2 diabetes. NOE-105 has the potential to achieve a more targeted effect by modulating dopamine signaling exclusively in the medium spiny neurons of the striatum in the brain, while limiting off-target effects compared to other dopamine antagonists. About Tourette Syndrome Tourette syndrome is a neurodevelopmental disorder in the wider spectrum of tic disorders, consisting of motor and vocal abrupt and brief movement or sound which is preceded by a local or generalized urge/premonitory sensation. TS impacts over a half-million individuals and families in the US alone, as well as millions of individuals worldwide. Investors Contact and Media Contact Precision AQAlex Lobo212-698-8802alex.lobo@precisionaq.com

临床2期临床结果

2024-07-09

·GlobeNewswire-Health Care

Strong Proof-of-Concept Data from Phase 2 Trial of PDE10A Inhibitor (CPL’36), a Novel Oral Antipsychotic

-Statistically significant benefit demonstrated in primary endpoint of positive subscale of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) at Week 4- -Dose-response was demonstrated, consistent with higher efficacy in the 40 mg dose- -Favorable tolerability profile demonstrated relative to standard-of-care atypical antipsychotics- -Investor call to be held 10th of July at 3 PM CEST with details provided below: MS Teams: https://teams.microsoft.com/l/meetup-join/19%3ameeting_NTA4ZDg0NzEtYjU2ZS00N2NjLWI4MjAtYzAwMzQxMDBhNDlj%40thread.v2/0?context=%7b%22Tid%22%3a%22dc816c94-0313-4f34-8ed1-1bff167d7003%22%2c%22Oid%22%3a%22640e4061-4b30-4b4f-ab73-ea6aee635b80%22%7dTelephone: +48 22 161 67 63, 522919119# Poland, Warsaw. 522 919 119# WARSAW, Poland, July 09, 2024 (GLOBE NEWSWIRE) -- Celon Pharma S.A. (CLN.WA) announces today robust and positive Phase 2 clinical trial results for its PDE10A inhibitor (CPL’36), a novel, oral, once-daily antipsychotic. Statistically significant and clinically meaningful improvements in the primary endpoint of positive subscale of the PANSS were seen in both tested doses of CPL’36, with a dose-response effect. Management plans to discuss these highly encouraging results with regulatory agencies to advance CPL’36 towards registrational trials and global marketing approvals. Additionally, CPL’36 is being investigated as a potential treatment for levodopa-induced dyskinesia in Parkinson’s disease, with Phase 2 results expected to be reported in 4Q 2024. “The results from this Phase 2 trial suggest a beneficial effect of CPL’36 across multiple aspects of schizophrenia pathophysiology. Clinical efficacy was deemed strong, and moreover, the drug tolerability was quite favorable,” confirmed Maciej Wieczorek, Ph.D., CEO of Celon Pharma S.A. “We believe that these results could herald a breakthrough in the treatment of this disease that impacts over 24 million patients world-wide, by identifying an innovative drug class with a new mechanism of action that may be used to replace or complement the current standard of care. These results represent a lengthy and satisfying journey for Celon as we have been closely analyzing the competitive environment in schizophrenia and the clinical trial designs of major international companies working on PDE10A inhibitors. We are therefore proud to have developed a drug characterized by unprecedented efficacy, with global potential to help underserved patients,” he concluded. Trial description The CPL’36 Phase 2 study was an international, multicenter, randomized, placebo-controlled clinical trial conducted on a group of 189 adult patients hospitalized due to acute schizophrenia. CPL’36 was administered for 4 weeks in two doses of 20 and 40 mg once daily and was placebo-controlled at a ratio of 1:1:1. Patient baseline severity was moderate-severe to severe, as characterized by a PANSS total score of approximately 106. Patients were screened for up to 10 days and then randomized and treated over a four-week period, at which time the primary endpoint assessment was conducted at Day 28. At Week 4 of treatment, the reduction in positive PANSS subscale score which was the primary endpoint in the trial was 3.7 units from baseline in the 20 mg dose (LS mean difference from placebo, p<0.001, Cohen’s d: 0.73), and 6.3 units in the 40 mg dose (LS Mean difference from placebo, p<0.001, Cohen’s d: 1.38). For total PANSS score at week 4 of treatment (a key secondary endpoint), the 20 mg dose of CPL’36 demonstrated a 9.7 unit reduction from baseline compared to placebo (LS mean difference from placebo, p<0.001, Cohen’s d: 0.77), and 16.4 units in the 40 mg dose (LS mean difference from placebo, p<0.001, Cohen’s d: 1.47). Other secondary endpoints in the trial included the effects of CPL’36 on overall clinical improvement cognitive performance and functioning such as Clinical Global Impression Scale Improvement (CGI-I), Brief Assessment of Cognition in Schizophrenia (BACS), and number of participants who withdraw due to adverse events (AEs). Results across all of these endpoints were also positive. Drug tolerability was favorable with most treatment emergent adverse events characterized as mild. Exacerbations of schizophrenia represented the most common severe adverse events that were potentially related to the drug (1.5% in the placebo group, 1.8% in the 20 mg group and 3.1% in the 40 mg group). Treatment discontinuation due to adverse events likely related to the drug occurred in 3.1% patients in the placebo group, 0% patients in the 20 mg group and 7.7% patients in the 40 mg group. Investor Call Information: Małgorzata Siewierskainwestorzy@celonpharma.com+48519066531 ABOUT CELON PHARMA Celon Pharma is an integrated biopharmaceutical company which designs, develops, manufactures and distributes pharmaceutical products. It was founded in 2002 by Maciej Wieczorek, PhD. The Company currently has approx. 500 employees. It employs approx. 160 scientists responsible for research and development, half of whom either have a PhD or are in the process of acquiring their PhD. The Company's pipeline includes more than a dozen projects for the development of innovative drugs with therapeutic groups such as oncology, neuro-psychiatry, autoimmunity and metabolism. The Company has its own research and development laboratories, which allow it to develop its own pharmaceutical technologies by using extensive laboratory equipment resources, as well as the experience and expertise of its staff. It also has a modern manufacturing facility where dry pharmaceutical forms are manufactured. Over the last few years, the Company has introduced products into the market in the following therapeutic areas: oncology, central nervous system diseases, cardiology, respiratory diseases. The Company has been developing the technology for manufacturing inhalation drugs and several projects of innovative drugs since 2007. It has been listed on the Warsaw Stock Exchange since 2016. www.celonpharma.com DisclaimerThis press release (“Press release”) has been prepared by Celon Pharma S.A. (the “Company”). By reading the Press release, you agree to be bound by the following limitations. This Press release is strictly confidential to the recipient. Neither this Press release or any part hereof nor the information contained herein may be reproduced or redistributed, passed on, or the contents otherwise divulged, directly or indirectly, to any other person or published, in whole or in part. If you gain access to this Press release by mistake, or you are not an addressee of this Press release or a person authorized to use this Press release, please bear in mind the confidential nature of this Press release and immediately contact the Company in order to return it to the Company. The Press release does not constitute an offer to sell or subscribe for or a solicitation of an offer to purchase or subscribe for securities. This Press release is provided for informational purposes only. This Press release does not constitute or form part of and should not be construed as an offer, solicitation or invitation to sell or issue, or an offer, solicitation or invitation to, subscribe for, underwrite, buy or otherwise acquire, securities of the Company or any of its subsidiaries in any jurisdiction, or an inducement/recommendation to enter into investment activity in any jurisdiction. Neither this Press release nor any part hereof, nor the fact of its distribution or issuance, shall form the basis of, or be relied on in connection with, any contract, commitment or investment decision whatsoever. The information contained herein is only preliminary and indicative and does not purport to contain the information that would be required to evaluate the Company, its financial position and/or any investment decision. This Press release is not intended to provide, and should not be relied upon for, accounting, legal or tax advice nor does it constitute an investment recommendation. This Press release is given in conjunction with an oral press release and should not be taken out of context. No information included in this Press release may be considered as investment advice or investment recommendation. The information contained in the Press release has not been independently verified. No repress release, warranty or undertaking, expressed or implied, is made as to, and no reliance should be placed on, the fairness, accuracy, completeness or correctness of the information or the opinions contained herein. Matters discussed in this Press release may constitute forward-looking statements. Forward-looking statements constitute statements that are other than statements of historical fact. Statements which include the words “expects”, “intends”, “plans”, “believes”, “projects”, “anticipates”, “will”, “targets”, “aims”, “may”, “would”, “could”, “continue” and similar statements of a future or forward-looking nature identify such forward-looking statements. Forward-looking statements include in particular statements regarding the financial performance, business strategy, plans and objectives of the Company for future operations (including growth potential). All forward-looking statements included in this Press release address matters that involve known and unknown risks, uncertainties and other factors which could cause the Company’s actual results, performance or achievements to differ materially from those indicated in such forward-looking statements and from past results, performance or achievements of the Company. Such forward-looking statements are based upon various assumptions and estimates regarding future events, including numerous assumptions regarding the Company’s present and future business strategies and future operating environment. Although the Company believes that these estimates and assumptions are reasonable, they may prove to be incorrect. The information, opinions and forward-looking statements contained in this Press release speak only as at the date of this Press release and are subject to change without notice. The Company, its directors, agents, employees and advisors do not intend to, and expressly disclaim any duty, undertaking or obligation to, make or disseminate any supplement, amendment, update or revision to any of the information, opinions or forward-looking statements contained in this Press release to reflect any change in events, conditions or circumstances. To the extent permitted under the applicable provisions of law, neither the Company nor any of their affiliates, advisers or representatives shall have any liability whatsoever (in negligence or otherwise) for any loss however arising from any use of this Press release or its contents or otherwise arising in connection with this Press release. This Press release is not for distribution or use by any person or entity in any jurisdiction where such distribution or use would be contrary to local law or regulation or which would subject the Company or any of its affiliates to authorization, notification, licensing or other registration requirements under applicable laws. Any failure to comply with this restriction may constitute a violation of United States securities laws. Persons into whose possession this Press release comes should observe all such restrictions. Obtain more information by contacting:Małgorzata Siewierskamedia@celonpharma.com

临床结果临床2期

2023-03-16

·Outsourcing Pharma

Noema Pharma raises $112M in Series B financing for nervous system disorders

The funding will be put towards development of its diversified pipeline focused on central nervous system disorders. The round was co-led by European healthcare focused investment firms, Forbion and Jeito Capital. UPMC Enterprises and an additional new investor joined existing investors Sofinnova Partners, Polaris Partners, Gilde Healthcare and Invus to complete the round. The proceeds of the financing will be used to advance the company’s lead compound basimglurant (NOE-101), an mGluR5 inhibitor which is being evaluated in phase 2b clinical trials for severe pain in trigeminal neuralgia (TN) and seizures in tuberous sclerosis complex (TSC). Noema is also developing gemlapodect (NOE-105), a PDE10a inhibitor being evaluated in phase 2b clinical trials for Tourette syndrome and childhood onset fluency disorder (COFD) or stuttering; and NOE-115, a phase 2 ready, triple reuptake inhibitor for atypical depression and binge eating disorder. “We are excited to announce the successful completion of this oversubscribed Series B financing round and very pleased to have a world-class group of investors supporting our vision of bringing much-needed treatments to those living with debilitating central nervous system disorders," said Luigi Costa, Chief Executive Officer of Noema Pharma. “We welcome our new investors who bring extensive expertise and knowledge of drug development and company building and add further strength to our robust investor base. This financing comes at a key time for Noema Pharma as we look forward to extensive news flow over the next 24 months.” googletag.cmd.push(function () { googletag.display('text-ad1'); }); Following the close of the financing, Nanna Lüneborg from Forbion and Rachel Mears from Jeito Capital will join the Board of Directors of Noema Pharma. Lüneborg, general partner at Forbion, said: “We have been following Noema since inception and have been impressed by the quality and progress of Noema Pharma’s clinical pipeline. We believe this is the right time to invest as the company has started to generate very encouraging clinical data in indications of high unmet need and particularly with its lead asset basimglurant.” Mears, a partner at Jeito added: “One of the pillars of our investment strategy is to deploy capital in truly differentiated and innovative therapies with high unmet medical need. The research and clinical work being undertaken by Noema Pharma fit these criteria exactly. The dedication of the Noema team and the quality of their work is clear to see and positions the company as the upcoming global leader in its field.” The series B financing follows a $60 million series A financing concluded in December 2020, led by Sofinnova Partners and Polaris Partners. Noema Pharma was founded in 2019 with a seed investment from Sofinnova Partners and four clinical stage assets in-licensed from Roche. Antoine Papiernik, chairman and managing partner of Sofinnova Partners “As co-founders and initial investors of Noema Pharma, we are incredibly proud of what the company has accomplished since its inception,” said. “Raising an oversubscribed funding round of this magnitude is a significant achievement that further reinforces our conviction that Noema can make a meaningful difference in the lives of patients suffering from debilitating CNS disorders.”

临床2期

100 项与 PDE10A inhibitors(Janssen) 相关的药物交易

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