ACT-709478

Ad hoc announcement pursuant to Art. 53 LR Allschwil, Switzerland – October 29, 2024 Idorsia Ltd (SIX: IDIA) today announced its financial results for the first nine months of 2024. Highlights Net revenue 9M 2024 at CHF 53 million.US GAAP operating loss 9M 2024 of CHF 154 million and Non-GAAP operating loss of CHF 248 million.Improved Guidance for 2024, driven by diligent cost control.QUVIVIQ™ (daridorexant) total net sales of CHF 39 million in 9M 2024.Commercial partnership for QUVIVIQ with Menarini France.QUVIVIQ approved for the treatment of insomnia in Japan.TRYVIO™ (aprocitentan) commercially available in the US since October 2024.JERAYGO™ (aprocitentan) approved by the European Commission in June 2024 and marketing authorization applications submitted in the UK, Canada, and Switzerland.Collaboration with Neurocrine Biosciences comes to an end. André C. Muller, Chief Executive Officer of Idorsia, commented:“The one thing everyone wants to hear about – both internally and externally – is the status of a deal with aprocitentan. I’m pleased to share that our efforts on this front are advancing well. Our improved financial guidance includes our cost-conscious attitude across the whole organization, without compromising advancements, such as making progress in ramping up sales of QUVIVIQ, making TRYVIO available in the US, and expanding marketing authorization for JERAYGO.” Financial results US GAAP resultsNine MonthsThird Quarterin CHF millions, except EPS (CHF) and number of shares (millions)2024202320242023Net revenues531312680Operating expenses(211)(275)(118)150Operating income (loss)(154)(144)(90)231Net income (loss)(180)(181)(101)224Basic EPS(1.00)(1.02)(0.55)1.26Basic weighted average number of shares180.5178.2182.4178.4Diluted EPS(1.00)(1.02)(0.55)0.96Diluted weighted average number of shares180.5178.2182.4232.5 Net revenue of CHF 53 million in the first nine months of 2024 is the result of QUVIVIQ product sales (CHF 39 million), product sales to partners in the Asia-Pacific-Region (CHF 9 million) and contract revenue recognized in connection with Owkin (CHF 3 million). This compares to CHF 131 million in the first nine months of 2023, which included CHF 34 million sales of PIVLAZ in Japan (assigned in the meantime to Nxera Pharma as part of a transaction, more details can be found in the dedicated press release) and CHF 68 million one-off impact of the Nxera deal as well as CHF 4 million revenue share from Johnson & Johnson related to ponesimod sales (revenue-sharing agreement now eliminated as part of the reacquisition of aprocitentan, more details can be found in the dedicated press release). US GAAP operating expenses in the first nine months of 2024 benefited from extraordinary income of CHF 125 million from the Viatris deal resulting in an expense of CHF 211 million (CHF 275 million in the first nine months of 2023), of which CHF 16 million related to cost of sales (CHF 7 million in the first nine months of 2023), CHF 111 million to R&D expenses (CHF 235 million in the first nine months of 2023), and CHF 209 million to SG&A expenses (CHF 318 million in the first nine months of 2023). US GAAP net loss in the first nine months of 2024 amounted to CHF 180 million (CHF 181 million net loss in the first nine months of 2023). The net loss was favorably impacted by a one-off income related to the Viatris deal of CHF 125 million (CHF 302 million one-off income related to the Nxera deal in the first nine months of 2023) and lower operating expenses throughout all functions. The US GAAP net loss resulted in a basic net loss per share of CHF 1.00 (basic and diluted) in the first nine months of 2024, compared to a net loss per share of CHF 1.02 (basic and diluted) in the first nine months of 2023. Non-GAAP* measuresNine MonthsThird Quarterin CHF millions, except EPS (CHF) and number of shares (millions)2024202320242023Net revenues531312680Operating expenses(305)(517)(106)(124)Operating income (loss)(248)(386)(78)(44)Net income (loss)(258)(420)(75)(51)Basic EPS(1.43)(2.36)(0.41)(0.29)Basic weighted average number of shares180.5178.2182.4178.4Diluted EPS(1.43)(2.36)(0.41)(0.29)Diluted weighted average number of shares180.5178.2182.4178.4 * Idorsia measures, reports, and issues guidance on non-GAAP operating performance. Idorsia believes that these non-GAAP financial measurements more accurately reflect the underlying business performance and therefore provide useful supplementary information to investors. These non-GAAP measures are reported in addition to, not as a substitute for, US GAAP financial performance. Non-GAAP net loss in the first nine months of 2024 amounted to CHF 258 million: the CHF 78 million difference versus US GAAP net loss was mainly due to the one-off effect of the Viatris deal (CHF 125 million income), depreciation and amortization (CHF 14 million), share-based compensation (CHF 17 million) and a consent fee paid in shares to the bondholders resulting from amended terms of the 2024 convertible bonds (CHF 14 million). The non-GAAP net loss resulted in a net loss per share of CHF 1.43 (basic and diluted) in the first nine months of 2024, compared to a net loss per share of CHF 2.36 (basic and diluted) in the first nine months of 2023. Viatris collaborationIn March 2024, Idorsia closed agreements with Viatris Inc. (NASDAQ: VTRS), a global healthcare company, for collaboration on the global development and commercialization of two Phase 3 assets – selatogrel and cenerimod – with Idorsia receiving an upfront payment of USD 350 million, and the right to potential development and regulatory milestone payments of up to USD 300 million, potential sales milestone payments of up to USD 2.1 billion, and potential contingent tiered royalties from mid-single- to low-double-digit percentage on annual net sales. A joint development committee is overseeing the development of the ongoing Phase 3 programs for selatogrel and cenerimod up to regulatory approval. Idorsia will contribute up to USD 200 million in the next 3 years and transferred the dedicated personnel for both programs to Viatris. Viatris has worldwide commercialization rights for both selatogrel and cenerimod (excluding, for cenerimod only, Japan, South Korea, and certain countries in the Asia-Pacific region). Idorsia has also granted Viatris a right of first refusal and first negotiation for certain other pipeline assets. Convertible bonds 2024In July 2018, the Group issued CHF 200 million of senior unsecured convertible bonds (ISIN: CH0426820350), which were due to mature on July 17, 2024. On May 6, 2024, a bondholder meeting was held, where 83.5% of the total outstanding bondholders voted in favor of amendments to the terms of the bonds. The approved bond terms include an amended conversion price of CHF 6.00, extended maturity date of January 17, 2025, and the option to call the bonds at par, in full or in part, at any time upon giving ten trading days' notice. A consent fee of 8,000 shares per Bond was paid to bondholders on September 5, 2024. Financial outlook 2024For 2024 – excluding unforeseen events – the company expects QUVIVIQ net sales of around CHF 55 million; SG&A expenses of around CHF 265 million; R&D expense of around CHF 130 million for Idorsia-led pipeline assets; non-GAAP operating expenses around CHF 400 million. This performance would result in a non-GAAP operating loss of around CHF 350 million (excluding contract revenues and the one-off benefit from the Viatris deal). The company expects US GAAP operating loss for 2024 to reach CHF 260 million which includes a one-off benefit of CHF 125 million from the Viatris deal. Arno Groenewoud, Chief Financial Officer, commented:“While closing a deal for TRYVIO is a key focal point, we have also sharpened our cost-conscious approach, which we will increase going forward. Hence, we have been able to stretch the cash runway out to about year-end 2024, which allows us to appropriately plan and execute the next steps of our financial strategy. Furthermore, as a result of lower than expected spending we can upgrade our US GAAP and non-GAAP operating loss guidance by around 60 million Swiss francs each, taking them to 260 million and 350 million Swiss francs, respectively.” Liquidity and indebtednessAt the end of the first nine months of 2024, Idorsia’s liquidity amounted to CHF 92 million. (in CHF millions)Sep 30, 2024Jun 30, 2024Dec 31, 2023Liquidity Cash and cash equivalents92237145Total liquidity*92237145 Indebtedness Convertible loan335335335Convertible bond797797796Other financial debt162162162Total indebtedness1,2941,2941,293 *rounding differences may occur Commercial operationsIn the first nine months of 2024, QUVIVIQ™ (daridorexant) in the US, Germany, Italy, Switzerland, Spain, UK, Canada, Austria, and France generated total product sales of CHF 39 million. United States ProductMechanism of actionIndicationCommercially available sinceDual orexin receptor antagonistTreatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenanceMay 2022 In the US, net sales of QUVIVIQ® (daridorexant) in the first nine months of 2024 reached CHF 21 million, an increase of +41% versus the first nine months of 2023. As of the end of the third quarter 2024, more than 165,000 patients have been treated with QUVIVIQ since launch in the US, over 500,000 prescriptions have been dispensed, and the product has been prescribed by almost 50,000 healthcare professionals. Tosh Butt, President, and General Manager of Idorsia US, commented:“Due to budget constraints we have recently reduced our field force for QUVIVIQ. Despite the reduction, the sales are holding-up for now. Importantly, the citizen petition requesting a review of the evidence from available data, which will hopefully lead to the descheduling of the DORA class of chronic insomnia medications, continues to make progress.” For more information about QUVIVIQ in the US, see the Full Prescribing Information (PI and Medication Guide). ProductMechanism of actionIndicationCommercially available sinceDual endothelin receptor antagonistTreatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugsOctober 2024 On March 19, 2024, the US Food and Drug Administration (FDA) approved TRYVIO™ (aprocitentan) for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. The recommended dosage of TRYVIO is 12.5 mg orally once daily, with or without food. Tosh Butt concluded:“Idorsia is making robust progress with the preparation of everything required for a full commercial launch of TRYVIO by the end of the first quarter of 2025. Both the REMS program and specialty distribution channel are fully up and running, we have begun engaging with hypertension experts through our presence at major cardiovascular and nephrology congresses. The initial discussions with payors are also encouraging. TRYVIO is now available to prescribe to the millions of patients in the US whose high blood pressure is not adequately controlled by other drugs. We have everything in place except a field-force and funding for promotional activities, which is dependent on a partnership deal.” Further details on the approval, together with commentary from company management can be found in the dedicated press release and investor webcast available from the company corporate website. For more information see the Full Prescribing Information including BOXED Warning (PI and Medication Guide). Europe and Canada ProductMechanism of actionIndicationCommercially availableDual orexin receptor antagonistTreatment of adult patients with insomnia characterised by symptoms present for at least three months and considerable impact on daytime functioningSweden: Sept. 2024France: Mar. 2024Austria: Feb. 2024UK: Oct. 2023Spain: Sept. 2023Switzerland: Jun. 2023Germany: Nov. 2022Italy: Nov. 2022 Management of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenanceCanada: Nov. 2023 QUVIVIQ (daridorexant) net sales in the first nine months of 2024 reached CHF 18 million in the EUCAN region. In the third quarter of 2024, net sales have increased by 46% compared to the second quarter of 2024. In Germany, QUVIVIQ was launched in November 2022. By law, sleep medications were then subject to a 4-week prescribing limitation (Anlage III BtMG). Following a review by the Federal Joint Committee (G-BA) this limitation was lifted for QUVIVIQ in November 2023. This makes it the only sleep medication in Germany that can be prescribed for long-term treatment of chronic insomnia. In December 2023, the price negotiated for QUVIVIQ under the AMNOG process became effective. Following the lifting of the prescribing limitation, the company submitted a second AMNOG dossier for the long-term treatment of chronic insomnia disorder (beyond 4 weeks), reflecting the indication approved by the EMA in 2022. The second AMNOG process is expected to end in March 2025. The progress made in Germany is reflected by the performance of QUVIVIQ on the market, with sales doubling in the first nine months of 2024 compared to the first nine months of 2023. In Italy, QUVIVIQ was launched in November 2022. Currently, QUVIVIQ can only be prescribed by neurologists, psychiatrists, and specialists from sleep centers, and no sleep therapy is reimbursed. The company submitted a reimbursement dossier in June 2023 and requested the expansion of the prescriber base. The submission – detailing the efficacy and safety profile of QUVIVIQ and its estimated budget impact and cost-effectiveness in Italy – is under review, with a hearing expected to take place before the end of the year. In Switzerland, QUVIVIQ was launched to the self-pay market in June 2023. Following the launch of QUVIVIQ, awareness and sales have increased solidly. Reimbursement discussions are ongoing and remain a priority for Switzerland. In Spain, QUVIVIQ was launched to the self-pay market in September 2023. Spain represents the largest insomnia market in Europe, as was apparent in the first months of this product’s availability, despite it only being launched to the self-pay market. The company submitted a reimbursement dossier to the Spanish authorities in July 2024, in order to allow equal access for all patients with chronic insomnia. In the UK, QUVIVIQ is recommended as first-line pharmaceutical treatment for patients with chronic insomnia, after, or as an alternative to, cognitive behavioral therapy for insomnia (CBT-I). QUVIVIQ was launched in October 2023 and the team has achieved full reimbursement throughout the UK. The priority in the UK is to secure regional access, which currently stands at around 80%, as well as raising awareness of QUVIVIQ among general practitioners. In Austria, QUVIVIQ was made available in February 2024. A reimbursement dossier was submitted in October 2024, with a conclusion expected in the second half of 2025. In France, QUVIVIQ was included in both the hospital and the retail formulary list of reimbursed pharmaceutical specialties in January 2024 and launched in March 2024 as the first and only pharmacotherapy recommended for the treatment of chronic insomnia disorder. There was a very strong uptake at launch largely due to the excellent market preparation work with psychiatrists. This can be seen by the fact that the majority of prescriptions are being made by the specialists, despite the French market being composed of 55’000 general practitioners who between them represent 75% of the insomnia prescriptions. As a result, the priority becomes expanding awareness to the primary care market to secure strong long-term growth. To address this, Idorsia is expanding its commercial reach from specialist prescribers to general practitioners (GPs) through a new commercial partnership with Menarini in France. In Sweden, QUVIVIQ was made available in September 2024. A reimbursement dossier was submitted in May 2024. As a result, a decision on reimbursement is expected by the end of 2024. In Canada, after being approved in April 2023, QUVIVIQ was launched in November 2023 to the private market, representing 55% of the Canadian insomnia market. The reimbursement dossier was submitted to private market payers in the third quarter of 2023 and currently stands at 80% coverage. The focus is now on public payers with the submission confirmation in Quebec received in October 2024 and submissions in all other provinces ongoing and to be completed by year end. Benjamin Limal, President of Europe and Canada region, commented:“Securing public access to Europe’s only dual orexin receptor antagonist remains our number one priority throughout the EUCAN region – this is the pathway to unlocking the true value of QUVIVIQ. Until then, the performance is satisfactory with a great adoption from specialists and a strong quarterly growth in demand and sales. As one of the newest launches, I have to mention France – QUVIVIQ is really off to a flying start and we are quickly reinforcing the launch momentum through a commercial partnership with Menarini, experts with established relationships in primary care, to handle the promotion of QUVIVIQ to GPs.” For more information about QUVIVIQ in the EU, see the Summary of Product Characteristics. For more information about QUVIVIQ in Switzerland, see the Patient Information and Information for Healthcare Professionals. For more information on the marketing authorization of QUVIVIQ in Canada, see the Product Monograph. ProductMechanism of actionIndicationCommercially available sinceDual endothelin receptor antagonistTreatment of resistant hypertension in adult patients in combination with at least three antihypertensive medicinal productsApproved Jun. 2024 On June 27, 2024, the European Commission (EC) approved JERAYGO™ (aprocitentan) for the treatment of resistant hypertension in adult patients in combination with at least three antihypertensive medicinal products. The recommended dose is 12.5 mg orally once daily. The dose can be increased to 25 mg once daily for patients tolerating the 12.5 mg dose and in need of tighter blood pressure (BP) control. Further details on the approval, together with commentary from company management can be found in the dedicated press release available from the company corporate website. For more information about JERAYGO in the EU, see the Summary of Product Characteristics. Research & DevelopmentIdorsia has a diversified and balanced portfolio, comprising assets developed and/or marketed by Idorsia and assets that are partner-led to maximize the value we have created. Our drug discovery engine has produced innovative drugs with the potential to transform the treatment paradigm in multiple therapeutic areas, including CNS, cardiovascular, and immunological disorders, as well as orphan diseases. The company also has a vaccine platform for the discovery and development of glycoconjugate vaccines containing synthetic antigenic glycan molecules, with or without a carrier protein, to prevent infection. Idorsia-led portfolio CompoundMechanism of actionTarget indicationStatusQUVIVIQ™ (daridorexant)Dual orexin receptor antagonistInsomniaCommercially available in the US, Germany, Italy, Switzerland, Spain, the UK, Canada, Austria, France, and Sweden; approved throughout the EUTRYVIO™ (aprocitentan) Dual endothelin receptor antagonistSystemic hypertension in combination with other antihypertensivesCommercially available in the USJERAYGO™ (aprocitentan)Dual endothelin receptor antagonistResistant hypertension in combination with other antihypertensivesApproved in the EU; Marketing authorization applications submitted in the UK, Canada, and SwitzerlandLucerastatGlucosylceramide synthase inhibitorFabry diseasePhase 3 primary endpoint not met; open-label extension study ongoingPhase 3 focused on renal function in preparationDaridorexantDual orexin receptor antagonistPediatric insomniaPhase 2 in pediatric insomnia ongoingACT-1004-1239ACKR3/CXCR7 antagonistDemyelinating diseases including multiple sclerosis Phase 2 in preparationACT-777991CXCR3 antagonistVitiligoPhase 2 in preparationSinbaglustatGBA2/GCS inhibitorRare lysosomal storage disordersPhase 1 completeIDOR-1117-2520UndisclosedImmune-mediated disordersPhase 1 ongoingIDOR-1134-2831Synthetic glycan vaccineClostridium difficile infectionPhase 1 ongoing Further details including the current status of each project in our portfolio can be found in our innovation fact sheet. Idorsia partner-led portfolioFor Idorsia, sophisticated partnerships are a way of gaining strategic access to technologies or products and fully exploiting our discovery engine and clinical pipeline. We seek suitable external project partners to maximize the value of internal innovation. CompoundMechanism of actionTarget indicationPartner/statusQUVIVIQ™ (daridorexant)Dual orexin receptor antagonistInsomniaSimcere: Approved for the treatment of insomnia in Hong-KongQUVIVIQ™ (daridorexant)Dual orexin receptor antagonistInsomniaNxera Pharma: license to develop and commercialize for Asia-Pacific region (excluding China)Approved for the treatment of insomnia in JapanDaridorexantDual orexin receptor antagonistInsomniaSimcere: license to develop and commercialize for Greater China regionNDA submitted in Greater ChinaSelatogrelP2Y12 inhibitorAcute myocardial infarctionViatris: worldwide development and commercialization rightsPhase 3 “SOS-AMI” program ongoingCenerimodS1P1 receptor modulatorSystemic lupus erythematosusViatris: worldwide development and commercialization rights (excluding Japan, South Korea, and certain countries in the Asia-Pacific region)Phase 3 “OPUS” program ongoingDaridorexantDual orexin receptor antagonistPosttraumatic stress disorder (PTSD)US Department of Defense (DOD): Idorsia is supporting a clinical study sponsored by the US DOD to develop new therapies to treat PTSDACT-1002-4391EP2/EP4 receptor antagonistImmuno-oncologyOwkin: global license to develop and commercializePhase 1 in preparation On October 1, 2024, Nxera Pharma announced that it had entered a commercial partnership agreement with Shionogi & Co., Ltd regarding the distribution and sales for QUVIVIQ in Japan. At the same time, the previous commercialization agreement between Nxera and Mochida Pharmaceutical Co., Ltd. was terminated. After negotiation among Nxera, Shionogi and Mochida regarding the optimal sales scheme, Shionogi is solely responsible for distribution and sales activities in Japan. Idorsia and Neurocrine Biosciences had a collaboration for ACT-709478, Idorsia’s novel T-type calcium channel blocker. The compound was investigated as a treatment of pediatric patients with epileptic encephalopathy with continuous spike-and-wave during sleep (CSCW), a rare form of pediatric epilepsy. The Phase 2 study did not meet the primary endpoint in June 2022, and further analysis from an open-label extension study resulted in the decision to stop further development. As a result, the development agreement has come to an end. Further details including the current status of each project in our partner-led portfolio can be found in our innovation fact sheet. Results Day CenterInvestor community: To make your job easier, we provide all relevant documentation via the Results Day Center on our corporate website: www.idorsia.com/results-day-center. Upcoming Financial Updates Full Year 2024 Financial Reporting together with the publication of the Annual Report 2024 on February 27, 2025 Notes to the editor About IdorsiaIdorsia Ltd is reaching out for more – We have more ideas, we see more opportunities and we want to help more patients. In order to achieve this, we will develop Idorsia into a leading biopharmaceutical company, with a strong scientific core. Headquartered near Basel, Switzerland – a European biotech-hub – Idorsia is specialized in the discovery, development, and commercialization of small molecules to transform the horizon of therapeutic options. Idorsia has a 25-year heritage of drug discovery, a broad portfolio of innovative drugs in the pipeline, an experienced team of professionals covering all disciplines from bench to bedside, and commercial operations in Europe and North America – the ideal constellation for bringing innovative medicines to patients. Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June 2017 and has over 750 highly qualified specialists dedicated to realizing our ambitious targets. For further information, please contactAndrew C. WeissSenior Vice President, Head of Investor Relations & Corporate CommunicationsIdorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil+41 58 844 10 10investor.relations@idorsia.com media.relations@idorsia.com www.idorsia.com The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Attachment Press Release PDF

▲10月26-27日成都中国临床试验产业发展大会点击免费报名 注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。 这一系列综述的主要焦点是突出离子通道临床药物开发中所取得的进展，这是靶点选择（Target selection）的关键性验证参数（Key Validation Parameter--KVP），当然我们还需要同时考虑其他因素，如人类遗传数据、药物设计中的冷冻电镜结构、相关动物和iPSC模型的可用性，以及每个适应症中医学和商业驱动因素：未被满足的临床需求一定是药物研发的底层驱动力和变现的力量。 爱思益普电生理团队希望这些讨论有助于克服一个根深蒂固的执念：离子通道是“难以攻克”的药物研发靶点以及将历史失败归咎于靶点类别而非发现过程本身的倾向。我们都知道，无论靶点或开发方式如何，药物发现都是一段曲折且昂贵的旅程，因此重要的是要认识到离子通道调节剂进入临床试验的成功经验并从陷阱中吸取教训。 让我们一起试试吧：大家的阅读以此带来的价值，是我们坚持这件事情的动力和源泉！！！ 在2024年的第二季度对于离子通道药物研发而言是具有突破性的。我们看到了国内外令人激动的进展。同样一些失败的案例也是颇具启发性质的。我们的综述，将围绕外周系统疾病（Peripheral disease indication）和中枢神经系统疾病（CNS disease indication） 展开。这一部分主要集中在CNS疾病。 PART2. 中枢神经系统疾病（CNS disease indication） a 癫痫类疾病 这个季度，癫痫这个领域出现了一些新的竞争者的消息，同时，一些长期从事抗癫痫离子通道药物研发项目的现有玩家也发布了正面和负面的临床数据。 在这疾病领域中，出现了一个值得我们关注的玩家ES Therapeutics。他们在药物抵抗性癫痫患者的IIa期试验中发表了积极的疗效。ES 481是一种AMPA GluR TARPγ8辅助亚基抑制剂，但它并不是一种化学分子。它有着复杂的历史；最初由Cerecor（CERC 611）发现，并于与Eli Lilly合作研究其在癫痫中的临床前疗效（结果在2016年发表），之后公司更名为Avalo Therapeutics，然后在2020年将该资产出售给澳大利亚的ES Therapeutics，后者进行了IIa期试验（NCT04714996）。与接受安慰剂治疗的患者相比，该药物将每周发作次数减少了68-80%，而安慰剂组为38-49%，在75 mg BID的最高剂量下达到了边际统计显著性。这种复杂的故事在药物发现中相当有代表性。所以很高兴看到那些对有价值的化合物及其作用机制有信心的研究者们在经历了几次公司更迭后，最终为需要的患者取得了有希望的结果。 另一个新加入的竞争者，也在研究AMPA GluR TARPγ8辅助亚基抑制剂，是Rapport Therapeutics，他们在5月EILAT XXVII会议上的摘要中公开了他们的第一个离子通道抗癫痫配体RAP-219（见https://www.eilatxvii.com/program-outline），在Rapport Therapeutics的官网中我们可以看到这个化合物设计到多个疾病管线。这也提示了这个靶点的潜在价值。 （https://www.rapportrx.com/pipeline/） EILAT XXVII会议中同时披露的还有GRIN Therapeutics（Radiprodil NMDA 2B负向变构调节剂）、Praxis Precision Medicine的PRAX-628 Nav1.x阻断剂、Encoded和Stoke Therapeutics的Nav1.1基因疗法ETX101和STK-001、UniQure的AMT-260 GluR kainate miRNA沉默剂、Xenon的XEN1101和Biohaven的BHV-7000 Kv7.x开放剂、Autifony的Kv3.x正性调节剂，以及上述的ES Therapeutics ES-481 AMPA-R Tarp g8配体的介绍。RAP-219起源于Janssen在圣地亚哥的神经科学项目，并带有I期安全性数据；关于Rapport起源的更多细节可以在第3节找到。 2024年第二季度，癫痫领域的知名公司也发布了一些更新。首先是Xenon Pharmaceuticals，他们在全美神经学会会议上展示了他们完成的IIb期X-TOLE试验和Kv7.x开放剂XEN1101在局灶性癫痫患者中的开放标签扩展的数据。这些演讲的链接可以在这里访问，显示XEN1101通过在8周给药期间产生剂量依赖性和统计学上显著的发作频率降低，达到了其主要疗效终点，并且不良事件率低，没有心血管安全警示（这一点很重要，因为Kv7.1亚型在心脏中表达，并且是LQT1综合症的基础）。鉴于这种有希望且显著的疗效，几乎所有的初始参与者都参加了开放标签扩展，其中药物剂量为20 mg，继续在30个月内显著降低发作频率，但到分析期末只有一半的人仍然在使用，因为缺乏疗效（13.8%）、不良事件（12.0%）或患者撤回（12.0%）而中断。事后分析显示，在发作频率较低和/或服用较少抗癫痫药物的患者中，响应率更高（>50%），这可能解释了为什么有些人退出了。XEN1101现在正在进行3项III期试验，针对局灶性和强直-阵挛性发作。 近日，Encoded Therapeutics在EILAT XXVII会议上就他们针对Dravet癫痫的Nav1.1基因疗法ETX101进行了演讲，并在2024年5月举行的美国基因与细胞治疗学会第27届年会上也进行了演讲，他们在那里专注于扩大AAV生产和表达以适应FIH临床剂量的挑战。该公司已经计划了一个复杂的全球I/II期试验项目，针对年轻的Dravet癫痫患者，目的是建立适当的剂量递增程序，并最终形成一种长期治疗方案，随着患者的成长，这种方案可能会有所调整。基于AAV的基因疗法最初的承诺现在已经达到了人类患者反应和安全问题的现实，例如抗原免疫反应，这可能会限制这些疗法只能一次性使用，因此确定正确的剂量方案（和AAV血清型）现在是迫切需要解决的问题，需要在不同的患者群体和治疗指征中进行解决。 最后，我们从这个系列中的一个知名公司听到了一些负面消息：Marinus Pharmaceuticals一直在测试GABA-A PAM Ganaxolone作为难治性癫痫的静脉注射配方，但在4月份遇到了一个重大障碍，当时他们正在进行的III期试验的中期分析显示，这种药物在与主要终点相比时未能达到统计学意义。然而，它也未能跌破预先确定的“停止”点，因此公司决定继续进行试验，但不招募任何新患者，并等待2024年夏季之后完成试验的分析结果。这种药物已经作为Ztalmy上市，因为它在去年被批准用于治疗Cdkl5癫痫，所以并非一切都失去了，但显然一个负面结果将限制他们的患者群体和总收入。然而，5月份的更新显示，该公司正在进行削减，并已暂停任何进一步的Ganaxolone癫痫试验，等待完成的III期试验结果和随后的分析。 b 抑郁类疾病 Xenon对他们的Kv7.x PAM/开放剂XEN1101（现在已经更名为Azetukalner）有宏伟的计划，除了在第1节提到的正在进行的癫痫试验之外，他们还在重度抑郁症（MDD）中推进这种配体。这种药物候选在抑郁症患者的II期概念验证试验中表现不佳，未能与安慰剂相比达到统计学意义，但明显的剂量依赖性和在20 mg最高剂量下看到的“临床意义”的改善足以让公司宣布他们将继续推进，现在公司网站上有更多关于计划在2024年下半年开始的III期试验的细节。该公司还与西奈山医院的伊坎医学院合作，进行一项由研究者发起的II期概念验证平行臂安慰剂对照多中心研究，研究对象为60名MDD患者。 在为重度抑郁症（MDD）开发临床离子通道药物方面也取得进展的是Neurocrine Biosciences，他们在2024年第二季度公布了有关GluR相关化合物并行临床项目的消息。首先是NBI-1065845（TAK-653），一种AMPA GluR PAM，在剂量范围的II期研究中显示出积极的疗效数据。这种首创药物候选的高剂量在第28天和第56天分别显著减少了标准抑郁评分量表测量的症状，达到了主要和次要终点，而低剂量则显示出相似但非显著的趋势。这种药物是通过与Takeda的一项交易（2020年预先支付1.2亿美元）独家获得的，用于开发后者的七个早期和中期精神病学配体，并且是在GPR139配体NBI-1065846在2023年第四季度的II期MDD试验失败后，第一个发布积极结果的药物。 Neurocrine Biosciences 在第二季度还宣布，他们的GluR NMDA NR2B选择性亚基NAM NBI-1070770已在重度抑郁症的II期试验中对首位患者进行了剂量给药，使用的是与他们AMPA MDD试验相同的抑郁症状评分调查。这种小分子化合物是2020年从Takeda授权的程序之一，因此Neurocrine似乎在这个交易上做得很好。 还有一些其他公司正在研究用于治疗抑郁症的NMDA受体调的小分子化合物。从积极的方面来看，Gilgamesh Pharma宣布他们已经将他们的NMDA拮抗剂GM-1020推进到MDD的IIa期试验中，预计在2024年下半年会有中期结果。GM-1020包含了一种氯胺酮的重新配方，氯胺酮是一种竞争性NMDA受体拮抗剂，已被证明可以比传统的单胺类化合物更快地缓解抑郁症状，并且在治疗抵抗性患者中显示出显著的疗效，但它也展示了传统神经化学配体和最近对迷幻剂兴趣之间的交叉，Gilgamesh也在追求这一点。 最后，有消息说NRx公司的NMDA的化合物在双相抑郁症的II/III期试验中失败了。NRX-101在6周治疗后未能达到上述提到的相同抑郁评分系统的主要终点，尽管该试验缺乏安慰剂组，而是将疗效与他们的药物替代品（用于精神分裂症患者的鲁拉西酮）进行了比较，这是由于他们的患者群体自杀风险高。然而，NRX-101在主要抑郁评分上取得了一些显著的降低，与对照组相似，并且还减少了自杀意念，因此公司决定进入一个更大规模的III期试验，重点是自杀终点。 c 精分类疾病 Newron的抗精神病药物Evenamide（NW-3509）在精神分裂症患者中的Ib期和IIa期积极数据；在2023年第四季度和2024年第一季度对2023年开始的II/III期试验进行了更新。现在结果已经公布，这些结果支持并改进了这些早期研究，满足了主要和次要终点。这种药物被定位为一种附加疗法，与现有的治疗如氯氮平联合使用，并显示出在4周的给药期间显著改善正面和负面症状并降低整体疾病严重程度，与安慰剂相比具有极佳的安全性和副作用概况。Evenamide是一种状态依赖性的电压门控Nav1.x通道阻断剂，在临床前试验中减少了谷氨酸突触传递和神经元兴奋性，并且声称与其他调节其他神经递质、5-羟色胺能和多巴胺能GPCRs的抗精神病药物协同作用。之前的开放标签试验显示，药物效果在6-12个月内维持甚至增加，症状减少了30-50%，因此现在正在计划一项为期1年的III期后续试验，希望这种新的抗精神病药物候选物能为治疗不足的患者群体带来显著的改善。 d 神经退行性疾病 Cerevance公司正在为肌萎缩侧索硬化症（ALS）和阿尔茨海默病开发的THIK1 K2P通道抑制剂CVN293，但现在它已正式成为临床候选药物，因为公司网站现在列出了一个正在进行的I期安全性试验，预计将在2024年第二季度公布结果（尽管在clinicaltrials.gov网站上还没有发现这一试验安排）。该公司还在2024年4月发表了一篇论文，描述了从高通量Ti influx assay测定中发现并优化CVN293的过程, 这一研究产生了一种强效且亚型选择性良好的抑制剂，专门针对小胶质细胞上的这种特定的K2P通道，能够减少中枢神经系统中NLRP3炎症体的激活和细胞因子的释放，这被认为是治疗各种神经退行性和神经炎症性疾病的一个非常有用的作用机制。 相比之下，Sage Therapeutics采用一种更传统且长期运行的神经化学方法来治疗神经退行性疾病的尝试在2024年第二季度彻底崩溃了：GluR NMDA PAM SAGE-718（dalzanemdor）在帕金森病和亨廷顿病的II期临床试验中连续失败。公司原本计划在帕金森病、亨廷顿病和阿尔茨海默病中进行一系列中期临床试验，这些试验都计划在2024年公布结果，但在前两项试验中都遭遇了失败。首先报告的是帕金森病试验，与安慰剂相比，未能改善认知的主要终点或探索性的次要终点。这导致公司决定取消SAGE-718在帕金森病项目中的开发，但保持了对亨廷顿病的主要兴趣。然而，两个月后，他们透露亨廷顿病的II期试验也未能显示出与安慰剂相比在各种认知能力度量上的显著改善，尽管试验样本量较小，只有40名亨廷顿病患者和29名健康对照组。2024年7月的公司对第二季度的审查表明，他们仍在继续进行SAGE-718在AD和HD患者中增强认知的II期试验，这两项试验都应在2024年底报告结果，但已调整了第二项HD试验的主要终点，使用了一个特定的认知测试，这可能是在失败的试验中显示出最佳反应的测试。 e 特发性震颤 2024年第二季度，针对本态性震颤进行测试的临床候选药物有进展也有挫折，6月份宣布，Jazz Pharmaceuticals的T型Cav3.x阻断剂Suvecaltamide在一个最初于2021年开始的高级IIb期试验中失败。它未能达到主要和次要终点，但公司当时对30毫克最高剂量看到的一些非显著性改善持乐观态度，并正在等待一个于2022年开始的、针对帕金森病震颤患者的平行研究结果，该研究预计将在2025年第一季度报告，然后公司将决定这种药物的未来。Suvecaltamide（JZP385）是一种强效且状态依赖性但相对非选择性的Cav3.x家族成员阻断剂，就像第2节开头提到的ES Therapeutics的ES-481一样，它有着漫长而复杂的历史；最初由Merck在2010年代开发（作为MK-8998），并进行了针对与精神分裂症相关精神病的不成功临床试验，然后被授权给Cavion Therapeutics（作为CX-8998），并在Cavion被Jazz在2019年收购（预付款5250万美元）之前进一步测试用于本态性震颤，并被带入了这个IIb期试验。 这是一种我们不熟悉的疾病类型。直到最近几年，由于Praxis Precision Medicines（PRAX-944）和Neurocrine Biosciences（NBI-827104）在他们的Cav3.x阻断剂方面的工作，才让我们对本态性震颤（Essential Tremor）作为离子通道治疗领域有所了解。Neurocrine的药物候选在2022年第四季度的II期试验中失败，但在也在罕见的儿童癫痫的小型II期试验中失败后才被取消。Praxis在2023年第一季度也遭遇了挫折，他们的II期本态性震颤试验未能达到主要终点，但该公司仍在继续推进Ulixacaltamide在2024年的III期试验。不幸的是，不好的消息还在继续，我们也关注到Sage Therapeutics和Biogen正在开发的GABA-A PAM SAGE-324在2024年第三季度的II期试验中未能实现疗效后已被放弃的最新消息。 小结 这一系列综述的主要焦点是突出离子通道临床药物开发中所取得的进展。这是爱思益普电生理团队做的一次尝试，希望可以对国内离子通道靶点的药物研发提供一些启发和帮助。由于数据的可得性，目前我们主要聚焦了国外的研发进展，后续我们也会不多的增加和汇总来自国内企业的进展和突破。 版权声明：本文转自爱思益普，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 【关于药融圈】 药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。