LDL膽固醇升高的患者進行的Inclisiran的兩項3期試驗

StephenW

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
We found that a regimen of inclisiran every 6 months was feasible and significantly reduced LDL cholesterol levels by approximately 50%. More injection-site adverse events occurred with inclisiran than with placebo.
In our trials, a regimen of subcutaneous inclisiran injections on day 1, day 90, and then every 6 months reduced LDL cholesterol levels by 49.9% to 52.2% at month 17 and lowered time-adjusted LDL cholesterol levels between months 3 and 18 by 49.2% to 53.8% as compared with placebo in two separate populations at high risk for cardiovascular disease. These reductions were achieved on top of maximum tolerated, guideline-recommended statin treatment. The results for the percentage change in LDL cholesterol levels at month 17 were consistent across subgroups. Among patients given placebo, PCSK9 levels generally increased, whereas PCSK9 levels decreased in nearly all the patients given inclisiran.
The use of stable doses of statin treatment was high (89.2% in the ORION-10 trial and 94.7% in the ORION-11 trial), with the majority of patients receiving high-intensity statins (68.0% and 78.6%, respectively). Use of ezetimibe either alone or in combination with statins was low (9.9% in the ORION-10 trial and 7.1% in the ORION-11 trial). The mean (±SD) LDL cholesterol level at baseline was 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter) in the respective trials (Table 1).
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.
Peak plasma levels of inclisiran occur approximately 4 hours after dosing, and most is excreted through the kidney.8 Triantennary N-acetylgalactosamine (GalNAc) modification of the double-stranded inclisiran molecule ensures rapid hepatic uptake through the asialoglycoprotein receptors expressed exclusively on liver cells; after uptake, inclisiran is bound to the RNA-induced silencing complex in liver-cell cytoplasm.9,10 Inclisiran is no longer detectable in plasma within 24 to 48 hours after dosing.9,10 A theoretical concern for therapies with a long duration of action is the potential for irreversible adverse events. Without further injections, the LDL cholesterol–lowering effects of inclisiran are reversed at the rate of approximately 2% per month,3,4 which means that these effects can persist for up to approximately 2 years. It is therefore reassuring that in the present trials with 6075 injections of inclisiran and 2166 person-years of exposure, the adverse-event profile of inclisiran was similar to that of placebo. Injection-site adverse events were more frequent with inclisiran than with placebo, but most were mild or moderate, did not require intervention, and were not persistent. Ongoing open-label extension studies will provide additional longer-term safety follow-up information.8

Novartis receives complete response letter from U.S. FDA for inclisiran

https://www.novartis.com/news/me ... m-us-fda-inclisiran
Dec 18, 2020

    The U.S. Food and Drug Administration (FDA) has not raised any concerns related to the efficacy or safety of inclisiran. The complete response letter is due to unresolved facility inspection-related conditions

    No onsite inspection was conducted of the single third-party facility in question. If a facility inspection is needed, FDA will define an approach once safe travel may resume based on public health need and other factors

    Novartis will work with FDA and the third-party manufacturing facility in Europe to complete the inclisiran review, to bring this potential first-in-class siRNA to patients in the U.S. as quickly as possible

Basel, December 18, 2020 — The U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for inclisiran, a potential treatment for hyperlipidemia in adults who have elevated low-density lipoprotein cholesterol (LDL-C) while being on a maximum tolerated dose of a statin therapy. The FDA stated that the agency cannot approve the NDA by the Prescription Drug User Fee Act (PDUFA) action date of December 23, 2020, due to unresolved facility inspection-related conditions. The conditions will be conveyed to the European manufacturing facility within 10 business days. The third-party facility is responsible for drug product manufacturing. Satisfactory resolution of the unresolved facility inspection-related conditions is required before the Novartis NDA may be approved. No onsite inspection was conducted. If it is determined that a facility inspection is needed to approve the application, the FDA will define an approach for scheduling once safe travel may resume based on public health need and other factors.

“Novartis is confident in the quality of the regulatory submission for inclisiran, which includes a robust body of evidence related to efficacy and safety. We look forward to meeting with the FDA and our third-party manufacturing partner to discuss the feedback received and next steps,” said John Tsai, Head Global Drug Development and Chief Medical Officer, Novartis. “We are committed to bringing this potential first-in-class small interfering RNA cholesterol-lowering treatment to patients as soon as possible.”

The European Commission (EC) recently granted Novartis marketing authorization for Leqvio® (inclisiran) in Europe on December 11, 2020.

About inclisiran
Inclisiran (KJX839) is the first and only small interfering RNA (siRNA) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels via an RNA interference (RNAi) mechanism of action and could help improve outcomes for patients with atherosclerotic cardiovascular disease (ASCVD), a deadly form of cardiovascular disease1-3. With two doses a year and effective and sustained LDL-C reduction, inclisiran works as a complement to statins. Inclisiran works differently from other therapies by preventing the production of the target protein in the liver, increasing hepatic uptake of LDL-C and clearing it from the bloodstream3. Inclisiran is dosed initially, again at 3 months, and then once every 6 months. In three clinical trials, patients taking inclisiran maintained LDL-C reduction throughout each 6-month dosing interval1,2. Administered in-office as a subcutaneous injection, inclisiran is expected to integrate seamlessly into a patient’s healthcare routine1,2.

In the Phase III trials, inclisiran was well-tolerated1,2. The most common adverse events reported (≥3% of patients treated with inclisiran and occurring more frequently than placebo) were injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity and dyspnea1,2. Among those, injection site reactions were the most frequent ones. Those were generally mild and none were severe or persistent1,2.

Novartis has obtained global rights to develop, manufacture and commercialize inclisiran under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.

About Novartis in Cardiovascular-Renal-Metabolism
Bending the curve of life requires addressing some of society’s biggest public health concerns. Novartis has an established and expanding presence in diseases covering the heart, kidney and metabolic system. In addition to essential treatment Entresto® (sacubitril/valsartan), Novartis has a growing pipeline of potentially first-in-class molecules addressing cardiovascular, metabolic and renal diseases.

StephenW

LDL膽固醇升高的患者進行的Inclisiran的兩項3期試驗
我們發現每6個月使用inclisiran方案是可行的，並且可以將LDL膽固醇水平降低約50％。與安慰劑相比，inclisiran發生的注射部位不良事件更多。
在我們的試驗中，在第1天，第90天，然後每6個月皮下注射inclisiran的方案在第17個月將LDL膽固醇水平降低了49.9％至52.2％，在第3到18個月之間將經過時間調整的LDL膽固醇水平降低了49.2與安慰劑相比，在兩個罹患心血管疾病的高風險人群中，這一比例達到了53.8％。這些減少是在最大耐受，指南推薦的他汀類藥物治療的基礎上實現的。各亞組在第17個月時LDL膽固醇水平變化百分比的結果是一致的。在接受安慰劑的患者中，PCSK9水平通常升高，而幾乎所有接受inclisiran的患者中PCSK9水平均下降。
穩定劑量的他汀類藥物的使用率很高（ORION-10試驗中為89.2％，ORION-11試驗中為94.7％），大多數患者接受高強度他汀類藥物（分別為68.0％和78.6％）。單獨或與他汀類藥物聯合使用依澤替米貝的使用率較低（ORION-10試驗為9.9％，ORION-11試驗為7.1％）。在各自的試驗中，基線時的平均（±SD）LDL膽固醇水平為104.7±38.3 mg /分升（2.71±0.99 mmol /升）和105.5±39.1 mg /分升（2.73±1.01 mmol /升）（表1）。
分別在ORION-10和ORION-11試驗中分別對1561名和1617名患者進行了隨機分組。基線時的平均（±SD）LDL膽固醇水平分別為104.7±38.3 mg /分升（2.71±0.99 mmol /升）和105.5±39.1 mg /分升（2.73±1.01 mmol /升）。在第510天，在ORION-10試驗中，inclisiran將LDL膽固醇水平降低了52.3％（95％置信區間[CI]，從48.8至55.7），在ORION-11試驗中降低了49.9％（95％CI，從46.6至53.1）。 ，相應的時間調整後減少量分別為53.8％（95％CI，51.3至56.2）和49.2％（95％CI，46.8至51.6）（對於所有比較，與安慰劑相比，P <0.001）。在每項試驗中，inclisiran和安慰劑組的不良事件通常相似，儘管inclisiran的注射部位不良事件比安慰劑更為頻繁（ORION-10試驗為2.6％vs. 0.9％，在ORION-10試驗中為4.7％vs. 0.5％ ORION-11試驗）；這種反應通常是輕微的，沒有一個是嚴重的或持續的。
劑量後約4小時，血漿inclisiran的水平達到峰值，並且大部分通過腎臟排泄。8雙鏈inclisiran分子的三天線N-乙酰半乳糖胺（GalNAc）修飾可確保通過肝臟細胞上專門表達的去唾液酸糖蛋白受體迅速吸收肝臟；攝取後，inclisiran與肝細胞質中RNA誘導的沉默複合物結合。9,10在給藥後24至48小時內，血漿中不再檢測到Inclisiran。9,10對於長期持續治療的理論問題採取行動是可能發生不可逆的不良事件。如果不進一步注射，Inclisiran降低LDL膽固醇的作用將以每月約2％的速度逆轉[3,4]，這意味著這些作用可以持續長達約2年。因此，可以放心的是，在本次試驗中，使用6075次inclisiran注射液和2166人年的暴露量，inclisiran的不良事件特徵與安慰劑相似。與安慰劑相比，inclisiran注射部位的不良事件更為頻繁，但多數為輕度或中度，不需要干預且並非持續存在。正在進行的開放標籤擴展研究將提供更多的長期安全隨訪信息。8

諾華收到美國FDA關於inclisiran的完整答复信

https://www.novartis.com/news/me ... m-us-fda-inclisiran
2020年12月18日

    美國食品和藥物管理局（FDA）並未提出與inclisiran的功效或安全性相關的任何擔憂。完整的回复信是由於未解決的設施檢查相關條件造成的

    沒有對單個第三方設施進行現場檢查。如果需要進行設施檢查，則一旦基於公共衛生需要和其他因素，安全出行可能恢復，FDA將定義一種方法

    諾華將與FDA和歐洲的第三方製造工廠合作完成inclisiran審查，以將這種潛在的一流siRNA盡快帶給美國患者。
2020年12月18日，巴塞爾-美國食品藥品監督管理局（FDA）已發布有關inclisiran的新藥申請（NDA）的完整答复函（CRL），inclisiran是一種低脂蛋白水平升高的成年人高脂血症的潛在治療方法接受最大耐受劑量的他汀類藥物治療時的膽固醇（LDL-C）。 FDA表示，由於與設施檢查相關的條件尚未解決，FDA無法通過2020年12月23日的《處方藥使用者費用法》（PDUFA）批准NDA。這些條件將在10個工作日內傳送到歐洲製造工廠。第三方機構負責藥品生產。在批准諾華NDA之前，需要對未解決的設施檢查相關條件做出令人滿意的解決。沒有進行現場檢查。如果確定需要對設施進行檢查以批准該申請，則FDA將基於公共衛生需要和其他因素，確定一旦安全出行可以恢復的時間表。

“諾華公司對inclisiran法規提交的質量充滿信心，其中包括與功效和安全性相關的大量證據。我們期待與FDA和我們的第三方製造合作夥伴舉行會議，討論收到的反饋意見和下一步措施。”諾華全球藥物研發主管兼首席醫學官John Tsai說道。 “我們致力於盡快將這種潛在的一流的小分子乾擾RNA降低膽固醇的療法帶給患者。”

歐盟委員會（EC）最近於2020年12月11日授予諾華針對Leqvio®（inclisiran）在歐洲的營銷許可。

關於inclisiran
Inclisiran（KJX839）是第一個也是唯一的小分子乾擾RNA（siRNA）治療，可通過RNA干擾（RNAi）作用機制降低低密度脂蛋白膽固醇（LDL-C）水平，並有助於改善患有動脈粥樣硬化性心血管疾病的患者的預後（ASCVD），這是心血管疾病的致命形式1-3。 inclisiran每年兩次服用，有效且持續地降低LDL-C，可作為他汀類藥物的補充。 Inclisiran通過阻止肝臟中靶蛋白的產生，增加肝臟對LDL-C的吸收並將其從血流中清除，從而與其他療法有所不同3。最初使用Inclisiran，每3個月一次，然後每6個月一次。在三項臨床試驗中，服用inclisiran的患者在每個6個月的給藥間隔1,2中均保持LDL-C降低。 inclisiran可以通過辦公室內皮下注射的方式無縫整合到患者的醫療程序中1,2。

在III期試驗中，inclisiran的耐受性良好1,2。據報導，最常見的不良事件（≥3％的inclisiran治療患者，發生率高於安慰劑）是注射部位反應，關節痛，尿路感染，腹瀉，支氣管炎，四肢疼痛和呼吸困難1,2。其中，注射部位反應是最常見的。這些通常是輕度的，沒有嚴重或持續的1,2。

根據與RNAi治療領域的領導者Alnylam Pharmaceuticals的許可和合作協議，諾華已獲得了開發，生產和商業化inclisiran的全球權利。

關於諾華在心血管-腎臟-新陳代謝中的作用
改變生活曲線，需要解決社會上一些最大的公共衛生問題。諾華在涉及心臟，腎臟和新陳代謝系統的疾病中已經建立並不斷擴展。除了基本療法Entresto®（屈比特爾/纈沙坦）外，諾華還擁有不斷增長的潛在一流分子，這些分子致力於解決心血管，代謝和腎臟疾病。