FAAH

Company advancing innovative, small molecule for treatment of refractory chronic cough where there are currently no FDA-approved therapies Lead program, EX937, initially targeting a $11B global market with potential to expand into multiple high-value indications Differentiated approach with demonstrated preclinical efficacy and safety Rapidly advancing towards the clinic with potential value driving milestones in 2024 AURORA, CO / ACCESSWIRE / January 25, 2024 / Exxel Pharma ("Exxel" or the "Company"), an early-stage pharma company working to develop EX937 as a safe and effective treatment for patients suffering from refractory chronic cough, today provided a business overview and outlined its expected upcoming milestones. Exxel is leveraging innovative science and research to reduce neuronal hypersensitivity and address a number of chronic conditions, including refractory chronic cough. The Company uses a differentiated approach and EX937 works by specifically inhibiting the fatty acid amide hydrolase (FAAH) enzyme, thereby increasing the levels of anandamide, a naturally occurring signaling molecule. Anandamide plays a number of roles throughout the body, including sensory and pain modulation, and increased levels are expected to desensitize overactive sensory neurons in the upper airways of chronic cough patients, limiting the urge to cough. Soren Mogelsvang, PhD, President and Chief Executive Officer of Exxel commented, "Chronic cough is a persistent condition that has a significant negative impact on overall quality of life for adults. With no currently FDA-approved therapies available, treatment options are limited and often marginally effective, with some side-effects. Our lead program, EX937 has demonstrated profound effects in a variety of animal models of cough, neuropathic pain, hyperactive bladder and migraine headache. We are dedicated to advancing this important and much-needed therapy and believe it has the potential for broad clinical application and commercial opportunities." The Company's lead program, EX937, is a first-in-class, proprietary small molecule being developed for refractory chronic cough, a large underserved market with no current FDA-approved therapies, that affects approximately 10% of the global population. Key Program Highlights Once-a-day oral dosing Potential for Fast Track Designation Demonstrated efficacy and favorable safety by being entirely excluded from the central nervous system and brain Expected Upcoming Milestones Q1 2024 Drug product prototype test results Q3 2024 Completion of drug product development Availability of drug product specification Launch enrollment and dose first patient in the first-in-human Phase 1/1b study Q1 2025 Completion of SAD study Report topline data from SAD Q3 2025 Completion of MAD study Completion of cough challenge cohort Q4 2025 Report topline data from MAD Report topline data from cough challenge cohort For more information about the Company's development program, please visit exxelpharma.com and connect with the Company on LinkedIn , X and Facebook . About Exxel Pharma Exxel Pharma is a privately held company focused on developing novel therapeutics for the treatment of neuronal hypersensitivity disorders. The Company's lead program, EX937, is a first-in-class, proprietary small molecule being developed for refractory chronic cough, a large underserved market with no current FDA-approved therapies, that affects approximately 10% of the global population. Leveraging a differentiated approach by inhibiting the FAAH enzyme, EX937 has demonstrated efficacy and favorable safety in its ability to modulate chronic cough in preclinical models. The Company is rapidly advancing the development of EX937 towards a first-in-human Phase 1/1b study. EX937 also has the potential to be utilized across a number of blockbuster indications, including hyperactive bladder, peripheral neuropathic pain and migraine headaches. For more information, please visit exxelpharma.com . Investor Contact: Jenene Thomas Chief Executive Officer JTC Team, LLC T: 833.475.8247 E: exxel@jtcir.com SOURCE: Exxel Pharma, Inc. View the original press release on accesswire.com

近日（12月21日），爵士制药（Jazz Pharmaceuticals）宣布了该公司的PTSD（创伤后应激障碍）药物JZP150的II期临床数据，该实验未达所有主要终点和次要终点，这也宣告了这项曾被两度转手的产品最终停止了在PTSD这一唯一适应症的开发。从药品本身来看，JZP150（又名PF-04457845）是一款脂肪酸酰胺水解酶（FAAH）抑制剂，用于潜在治疗PTSD及相关症状。这款产品最初由辉瑞开发，后来又在2017年被辉瑞许可给了SpringWorks Therapeutics，而爵士制药最终又在2020年向SpringWorks购得该产品的独家全球权利。那么FAAH抑制剂本身靠谱吗？还确实有点不靠谱。爵士制药是一家大麻素科学相关的制药企业，许多产品和管线都与大麻素相关，而此次FAAH抑制剂的作用机理确实和大麻素相关。一例FAAH抑制剂致人脑死亡脂肪酸酰胺水解酶是一种完整的膜酶，它可以水解脂质递质的脂肪酰胺家族，包括研究最彻底的内源性大麻素，但也有很多其他受体也参与这一路径如PPARs，TRPV1，GPR55。从机制上来看，FAAH抑制剂/灭活剂能够增加内源性大麻素的浓度。而内源性大麻素是膜磷脂前体按需释放的脂质介质。内源性大麻素的增加相对于外源性激动剂来说会减少大麻素样的副作用。而从FAAH抑制剂的普遍性疗效来看，其实相对于那些外源性大麻素的效果还是相当不错的。在对于那些FAAH抑制剂，如JZP150（PF-04457845）、JNJ-42165279、SSR-411298、V-158866和URB597，来说，虽然长期结果尚且未知，但普遍观察结果是FAAH抑制剂并没有明显诱发通常与外源性大麻素相关的副作用，如认知障碍、运动协调和精神病。已完成的临床试验的可用数据还表明，FAAH抑制剂耐受性良好。JZP150（当时还是辉瑞在推动临床）的一项I期研究表明，与安慰剂相比，嗜睡的增加只是轻微的，对认知功能没有影响。相应的II期研究表明，该药物的安全性与安慰剂没有区别，其主要治疗相关副作用为头晕。但就在大家都以为副作用似乎不是很严重的时候，法国Biotrial Pharmacology Center开发的同类竞品BIA 10-2474在一项临床研究中出现了一例严重不良事件（SAE），一位志愿者之前服用较低剂量(20 mg)时未报告SAE。最严重的症状具有中枢神经系统特征的，可之后却出现迅速导致脑死亡的单一昏迷病例相关的症状。在其他5名住院参与者中，2名有严重的神经损伤(几天内临床症状明显改善)。由于这些事件，BIA 10-2474的临床立即终止。在Biotrial事故宣布后，作为预防措施，JNJ-42165279的两个试验也被暂停。辉瑞也在临床没什么成效（当时开发的是骨关节镇痛）后转手了给了SpringWorks。不明来源的发病机制法国国家药品和保健品安全局（ANSM）后续对于BIA 10-2474的报告还揭露了一些令人不安的事实：他们的简报提到了与大脑功能严格相关的症状，核磁共振成像观察显示存在“不同严重程度的微脑组织损伤和不同寻常的扫描断层”，而且这种损伤似乎还是因人而异的，有着“突然就出现”的特征。但是这种现象为什么会出现？这个问题并没有答案，也没人愿意或者再敢去回答，有些人认为可能是由与其他药理学靶点的相互作用引起的，或者是仅在超过特定浓度阈值时才变得重要，还有些人认为因为阻断了FAAH触发了人体内未知的替代补偿途径，但是也不知道人体内到底有什么触发的替代补偿途径。ANSM至少排除了制造相关问题，在临床前研究似乎也没什么问题，FAAH缺陷型小鼠(基因敲除)生长健壮，没有表现出异常行为症状，这支持了BIA 10-2474本身或其代谢产物而不是FAAH的抑制是不良反应原因的假设。总结很显然，因为人体机制可能存在的未接明机制使得HAAP复杂化，也没有太多人愿意冒着生命风险试探不可预知的风险，因此JZP150这一类的FAAH抑制剂的开发未来可能仍然存在许多问题，还需要很多基础研究。参考来源：Mallet C, Dubray C, Dualé C. FAAH inhibitors in the limelight, but regrettably. Int J Clin Pharmacol Ther. 2016 Jul;54(7):498-501. doi: 10.5414/CP202687. PMID: 27191771; PMCID: PMC4941643.https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-provides-update-phase-2-trial

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.