歐盟委員會批准首個每年兩次注射使用的 HIV 藥物

目前，僅批准用於多重耐藥 HIV 患者

資料來源：Liz Highleyman / 2022 年 8 月 25 日 /aidsmap財團法人台灣紅絲帶基金會編譯

圖片：Peter Stanic/Pixabay

本週，歐盟委員會成為第一個批准 Gilead Sciences 的長效 HIV 衣殼抑製劑來那卡帕韋( lenacapavir) 的監管機構，該藥物將作為 Sunlenca 上市銷售。每年兩次的抗反轉錄病毒藥物適用於接受過治療的多重耐藥 HIV 患者，他們無法以其他方式構建完全抑制方案。 Lenacapavir 也顯示出一線治療和暴露前預防 (PrEP) 的前景，但本週的批准僅涵蓋以前接受過治療的人。

「Lenacapavir 有助於滿足那些有復雜既往治療史的人的關鍵未滿足需求，並為這些更有可能發展為 AIDS 的患者提供期待已久的每年兩次的選擇」，巴黎 Cité 大學的 Jean-Michel Molina 教授在吉利德的新聞稿中說。「Lenacapavir 提供了一種創新的長效 HIV 治療選擇，有可能改變臨床格局」。

Lenacapavir（以前稱為 GS-6207）破壞 HIV 衣殼，即圍繞病毒遺傳物質和必需酶的錐形外殼。實驗室研究顯示，它會干擾 HIV 生命週期的多個階段。由於它與現有藥物的作用不同，lenacapavir 對已經對其他抗反轉錄病毒藥物產生耐藥性的 HIV 仍然具有活性。

lenacapavir在體內的半衰期很長，可以每六個月通過皮下注射一次。它需要與其他抗反轉錄病毒藥物聯合服用，這些藥物目前是每天服用的口服藥物。開始使用 lenacapavir 時，首先使用錠劑製劑進行為期兩週的「加載期」，以便在開始長效注射之前建立足夠的藥物水平。

CAPELLA 試驗之II/III 期正在評估 lenacapavir 用於治療經驗豐富的人，這些人的病毒已經發生突變，從而對幾種較舊的抗反轉錄病毒藥物產生耐藥性。這些人可能使用了早期次優的 HIV 藥物，必須依賴複雜的治療方案，其中包含多種藥物，但仍可能無法完全抑制病毒。參與者目前正在接受抗反轉錄病毒治療，但無法維持病毒抑制。中位年齡為 52 歲，他們平均感染 HIV 24 年，使用中位數為 11 種藥物。近三分之二的人患有晚期免疫抑制，CD4 計數低於 200。

第一批 36 名參與者被隨機分配到他們失敗的治療方案中添加口服 lenacapavir 或安慰劑藥片，為期 14 天，這意味著 lenacapavir 基本上起到單一療法的作用。那時，向每個人提供每六個月一次的lenacapavir注射液，以及根據耐藥性測試選擇的優化背景方案。非隨機世代中的另外 36 人從一開始就接受了 lenacapavir 和優化的背景方案，從第一次注射前的兩周口服負荷期開始。

在 2021 年反轉錄病毒和伺機性感染會議 (CROI) 上，研究人員報告說，在最初的 14 天期間結束時，隨機 lenacapavir 組中 88% 的參與者的病毒載量至少下降了 0.5 log，而安慰劑組僅為 17%。在去年夏天的國際愛滋病學會 HIV 科學會議上，研究人員展示了隨機世代的後續結果，顯示 81% 的 lenacapavir 接受者在 26 週時病毒載量低於 50 拷貝/ml。

在今年的 CROI 上，研究人員報告了隨機世代在 52 週時的更新結果。經過一年的治療，即兩次來那卡韋注射後，83% 的病毒載量低於 50。但反應率因背景治療方案中活性藥物的數量而異：94% 使用兩種或兩種以上活性藥物的患者達到無法檢測到的病毒負載，相比之下，只有一種活性劑的人和沒有活性劑的人分別為 79% 和 67%。

在 52 週時，隨機世代的平均 CD4 增加為 83 個細胞/mm3。更重要的是，隨著時間的推移，CD4 計數非常低（低於 50）的人的比例從 22% 下降到 3%，而計數為 200 或更高的人的比例——低於該水平的人有患機會性疾病的風險—— – 從 25% 上升到 60%。

lenacapavir總體安全且耐受性良好，沒有與藥物相關的嚴重不良事件。最常見的副作用是注射部位反應，例如疼痛、發紅或腫脹。這些大多是輕度至中度，儘管一些參與者有長時間的硬結（硬度）或結節。

這項研究的結果以及評估 lenacapavir 首次治療的 CALIBRATE 試驗（也在 CROI 2021 上展示）顯示，lenacapavir 可用作長效治療的一個組成部分。然而，目前還沒有其他抗反轉錄病毒藥物可以在如此長的時間間隔內給藥以形成完整的每年兩次的治療方案。一個潛在的合作夥伴，默克公司的長效核苷反轉錄酶易位抑製劑 islatravir，由於無法解釋的 T 細胞下降，於去年年底被擱置。現有持續時間最長的完整方案是 ViiV Healthcare 的可注射 cabotegravir (Vocabria) 和 rilpivirine (Rekambys)，由醫療保健提供者每月或每隔一個月給藥一次。

本週的營銷授權適用於歐盟所有 27 個成員國，以及挪威、冰島和列支敦士登。英國藥品和保健品監管機構於 8 月 25 日批准了 lenacapavir。美國食品和藥物管理局 (FDA) 可能會在意外延遲之後成為下一個。由於擔心用於注射製劑的玻璃小瓶類型，FDA 對 lenacapavir 進行了臨床試驗並拒絕批准。但在 5 月，FDA 取消了暫停，吉利德在公司改用不同類型的玻璃後重新提交了新藥申請；預計將在今年年底作出批准決定。

參考文獻

吉利德科學。 吉利德宣布 Sunlenca (Lenacapavir) 首次獲得全球監管批准，這是唯一一年兩次的 HIV 治療選擇，新聞稿，2022 年 8 月 22 日。

更新：本文於 2022 年 8 月 30 日進行了修訂，以提及英國監管機構的批准。

European Commission approves first twice-yearly HIV medication

For the moment, only approved for people with multidrug-resistant HIV

Liz Highleyman / 25 August 2022 / aidsmap

Peter Stanic/Pixabay

This week the European Commission became the first regulatory agency to approve Gilead Sciences’ long-acting HIV capsid inhibitor lenacapavir, to be marketed as Sunlenca. The twice-yearly antiretroviral is indicated for treatment-experienced people with multidrug-resistant HIV who cannot otherwise construct a fully suppressive regimen. Lenacapavir has also shown promise for first-line treatment and pre-exposure prophylaxis (PrEP), but this week’s approval only covers previously treated people.

“Lenacapavir helps to fill a critical unmet need for people with complex prior treatment histories and offers physicians a long-awaited twice-yearly option for these patients who are at greater risk of progressing to AIDS,” Professor Jean-Michel Molina of Université Paris Cité said in a Gilead press release. “Lenacapavir provides an innovative long-acting HIV therapy option with the potential to transform the clinical landscape.”

Lenacapavir (formerly known as GS-6207) disrupts the HIV capsid, the cone-shaped shell that surrounds the viral genetic material and essential enzymes. Laboratory studies have shown that it interferes with multiple stages of the HIV lifecycle. Because it works differently to existing drugs, lenacapavir remains active against HIV that has developed resistance to other antiretrovirals.

Lenacapavir has a long half-life in the body, allowing it to be administered by subcutaneous injection once every six months. It needs to be taken in combination with other antiretrovirals, which are currently oral medications taken daily. When starting lenacapavir, a tablet formulation is used first for a two-week ‘loading period’ to establish an adequate drug level before starting the long-acting injections.

The phase II/III CAPELLA trial is evaluating lenacapavir for treatment-experienced people whose virus has developed mutations that confer resistance to several older antiretrovirals. Such individuals, who may have used early suboptimal HIV medications, must rely on complex regimens with multiple drugs that still may not be fully suppressive. The participants were currently on antiretroviral therapy but unable to maintain viral suppression. The median age was 52 years, they had been living with HIV for 24 years on average and they had used a median of 11 drugs. Nearly two thirds had advanced immune suppression with a CD4 count below 200.

The first cohort of 36 participants were randomly assigned to add either oral lenacapavir or placebo pills to their failing regimen for 14 days, meaning lenacapavir was essentially functioning as monotherapy. At that point, everyone was offered lenacapavir injections administered every six months plus an optimised background regimen selected based on resistance testing. Another 36 people in a nonrandomised cohort received lenacapavir plus an optimised background regimen from the outset, starting with a two-week oral loading period before the first injection.

At the 2021 Conference on Retroviruses and Opportunistic Infections (CROI), researchers reported that at the end of the initial 14-day period, 88% of participants in the randomised lenacapavir group experienced at least a 0.5 log drop in viral load, compared with just 17% in the placebo group. At last summer’s International AIDS Society Conference on HIV Science, researchers presented follow-up results from the randomised cohort showing that 81% of lenacapavir recipients had a viral load below 50 copies/ml at 26 weeks.

At this year’s CROI, researchers reported updated results for the randomised cohort at 52 weeks. After a year of treatment, meaning two lenacapavir injections, 83% had a viral load below 50. But response rates differed according to the number of active agents in the background regimen: 94% of those with two or more active agents reached an undetectable viral load, compared with 79% of those with only one active agent and 67% of those with none.

The mean CD4 increase in the randomised cohort was 83 cells/mm3 at 52 weeks. What’s more, the proportion of people with a very low CD4 count (below 50) fell from 22% to 3% over time, while the proportion with a count of 200 or higher – the level below which people are at risk for opportunistic illnesses — rose from 25% to 60%.

Lenacapavir was generally safe and well tolerated with no drug-related serious adverse events. The most common side effect was injection site reactions such as pain, redness or swelling. These were mostly mild to moderate, though some participants had prolonged induration (hardness) or nodules.

Results from this study, along with the CALIBRATE trial evaluating lenacapavir for first-time treatment (also presented at CROI 2021), show that lenacapavir can be used as a component of long-acting therapy. However, there are currently no other antiretrovirals that can be given at such a long interval to create a complete twice-yearly regimen. A potential partner, Merck’s long-acting nucleoside reverse transcriptase translocation inhibitor islatravir, was placed on hold late last year due to unexplained T-cell declines. The existing complete regimen with the longest duration is ViiV Healthcare’s injectable cabotegravir (Vocabria) and rilpivirine (Rekambys ), which is administered by a healthcare provider once a month or every other month.

This week’s marketing authorisation applies to all 27 member states of the European Union, as well as Norway, Iceland and Liechtenstein. The UK’s Medicines and Healthcare products Regulatory Agency approved lenacapavir on 25 August. The US Food and Drug Administration (FDA) may be next after an unexpected delay. The FDA put a clinical hold on lenacapavir and declined to approve it due to concerns about the type of glass vial used for the injectable formulation. But in May, the FDA lifted the hold and Gilead resubmitted a new drug application after the company switch to a different type of glass; an approval decision is expected by the end of the year.

References

Gilead Sciences. Gilead Announces First Global Regulatory Approval of Sunlenca (Lenacapavir), the Only Twice-Yearly HIV Treatment Option, press release, 22 August 2022.

Update: this article was amended on 30 August 2022 to mention approval by the regulatory authority in the UK.