Efruxifermin

好像自从GLP-1成为医药界顶流以来，但凡被它“临幸”过的领域就要寸草不生，其中NASH就是很多人说是下一个“被GLP-1打没了的市场”。恰逢今年的EASL，几个重要的NASH在研管线都首次公布了病理数据，我们可以横向比较一下，在这个领域GLP-1是否还是万能的？ 1 THR-β 在Madrigal的Resmetirom带头大哥，成为首个获批的NASH治疗药物后，THR-β自然而然成为这个适应症绝对的显学，而继续光大门楣的任务就落到新贵Viking身上。 本次会议Viking公布了VK-2809的2b期临床VOYAGE研究的52周病理结果，在每日一次10mg/5mg/2.5mg/1mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为75.0%/63.0%/65.4%/71.4%/29.3%、最高剂量组相比安慰剂组高45.7%，纤维化改善且NASH不恶化的患者比例为56.8%/51.9%/44.2%/57.1%/34.1%，最高剂量组相比安慰剂高22.7%。安全性方面也相对可接受，虽然不良反应发生率偏高，但最高剂量组因不良反应而停药的比例不到10%、且与安慰剂组相差不大。 https://ir.vikingtherapeutics.com/2024-06-04-Viking-Therapeutics-Announces-Positive-52-Week-Histologic-Data-from-Phase-2b-VOYAGE-Study-of-VK2809-in-Patients-with-Biopsy-Confirmed-Non-Alcoholic-Steatohepatitis-NASH 与之相比，本门大师兄Resmetirom就有点黯然失色了，最高剂量组在两个终点的安慰剂修正比例分别为20.2%和11.7%，都远低于VK-2809。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2028395 VK-2809这次的临床数据其实可以说是超预期的，不仅显著优于同靶点已获批的Resmetirom，而且从两个终点的绝对值来看也处于整个NASH在研药物的领先位置。不过蹊跷之处在于逆天的安慰剂效应（两个终点安慰剂组响应率为29%和34%），导致相对来看有效性没有那么惊艳，而且剂量依赖性也不明显，可能都成为数据发布后股价大跌的一些解释。 2 GLP-1 在GLP-1的封神之路上，NASH应该是除减重以外最大的适应症机会之一，Semaglutide已经一马当先（尽管结果也不算很理想，见后文），紧随其后的是两个双靶点Tirzepatide和Survodutide。 本次会议Eli Lilly公布了Tirzepatide的2期临床SYNERGY-NASH研究的52周病理结果，在每周一次15mg/10mg/5mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为73.3%/62.8%/51.8%/13.2%、最高剂量组相比安慰剂组高60.1%，纤维化改善且NASH不恶化的患者比例为51.0%/51.3%/54.9%/29.7%、最高剂量组相比安慰剂高21.3%。虽然安全性尚未具体披露，但入组190例患者到最后只有157例完成治疗接受肝穿，脱落率还是有点偏高了。 https://events-distribution.easl.eu/from.storage?image=mIoM6rsplpmkPbT9D4cRMhCdB962jqqPLI0ekg3BGloLb0klBbYoN9dNVhvU-7Oz0 本次会议BI也公布了Survodutide的2期临床48周病理结果，在每周一次6.0mg/4.8mg/2.4mg和安慰剂组中，NASH缓解且纤维化不恶化的患者比例为43%/62%/47%/14%、最优剂量组相比安慰剂组高48%，纤维化改善且NASH不恶化的患者比例为32.4%/36.1%/34.2%/17.6%、最优剂量组相比安慰剂高18.5%。安全性就有点堪忧，不仅不良反应发生率高达93-97%，而且因不良反应而停药的比例也在16-23%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2401755 与新一代的这两个双靶点GLP-1相比，Semaglutide此前公布的数据同样也都是明显处于下风，最高剂量组在两个终点的安慰剂修正比例分别为42%和10%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/10.1056/NEJMoa2028395 从GLP-1这几个药物的NASH临床结果中，可以读出一些共性的问题：1）首先看起来GLP-1药物对于纤维化的改善不太在行，相对而言在NASH缓解上表现要好不少；2）其次GLP-1药物有效性的剂量依赖程度很低，三个药物都出现了随着剂量升高而效果增加不明显、甚至倒挂的情况，可能说明其作用机制与想象中存在较大差异；3）这三个临床，在NASH缓解且纤维化不恶化终点的安慰剂效应都控制到比较低（13-17%），但在另一边纤维化改善且NASH不恶化终点的安慰剂组都响应率偏高（S药和T药分别33%和30%），这对于统计学显著性与否产生了很关键的作用。 3 FGF-21 Akero在今年三月公布了Efruxifermin的2b期临床HARMONY试验的96周病理结果，在每日一次50mg/28mg和安慰剂组中，纤维化改善且NASH不恶化的患者比例为75%/46%/24%、最高剂量组相比安慰剂高达51%，NASH缓解且纤维化不恶化的患者比例为57%/62%/24%、最高剂量组相比安慰剂组高达33%。安全性方面略有点尴尬，SAE和因不良反应而停药的比例都超过10%。 https://ir.akerotx.com/static-files/c76e5581-39ab-4d46-a6c7-b5893f7a2210 另一家企业89Bio在今年五月公布了Pegozafermin的2b期临床ENLIVEN试验的24周病理结果（又在本次会议公布了48周非病理结果），在每两周一次44mg、每周一次30mg/15mg和安慰剂组中，纤维化改善且NASH不恶化的患者比例为27%/26%/22%/7%、最高剂量组相比安慰剂高20%，NASH缓解且纤维化不恶化的患者比例为26%/23%/37%/2%、最高剂量组相比安慰剂组高24%。安全性方面则相当优秀，特别是每两周一次的剂量组，不良反应发生率67%、停药比例仅2%。 https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2304286 FGF-21的有效性在两个终点之间相对均衡，而Efruxifermin很明显更加突出，其改善纤维化能力是目前的全场最佳；然而除了同样存在剂量依赖性不足的问题外，Efruxifermin最大的蹊跷在于24周和96周在NASH终点的倒挂，以及安全性的隐忧。 4 横向对比 在纤维化改善且NASH不恶化终点上，Efruxifermin处在一骑绝尘的位置（哪怕是结合96周和24周的数据），VK-2809和Tirzepatide看绝对值本来也有希望、但在奇高的安慰剂效应抵消之下显得较为平庸，另有Denifanstat也值得关注，至少目前这几个后来者都优于已获批的Resmetirom。 在NASH缓解且纤维化不恶化终点上，GLP-1们就比较优秀，VK-2809也很能打，Efruxifermin则呈现吊诡的“长短倒挂”，同样地也都优于Resmetirom。 综上所述，NASH目前仍处于群雄逐鹿的蛮荒状态，既没有因为首个获批的药物而定鼎大局，也没有看出会被GLP-1扫穴犁庭之势，这几家正在推进的三期临床都还有充分的竞争机会。 往期NASH药物相关文章： 【药海听涛】最后的烛火能否燃到黎明：NASH领域再现希望 【药海听涛】弦歌不辍还是功败垂成：NASH药物近期主要进展 【药海听涛】Madrigal鼙鼓动地来，惊破NASH羽衣曲 【药海听涛】以往不谏，来者可追：NASH研发方向的新旧交替

SOUTH SAN FRANCISCO, Calif., June 08, 2024 (GLOBE NEWSWIRE) -- Akero Therapeutics, Inc. (Nasdaq: AKRO), a clinical-stage biotechnology company developing transformational treatments for patients with serious metabolic disorders marked by high unmet medical need, today announced two presentations featuring its lead product candidate efruxifermin (EFX) at the European Association for the Study of the Liver (EASL) Congress 2024, in Milan, Italy. The presentations will also be available on Akero’s website following the meeting. A late-breaking oral presentation will feature 96-week data from HARMONY, a Phase 2b study evaluating the efficacy and safety of EFX in patients with metabolic dysfunction-associated steatohepatitis (MASH), fibrosis stage 2 or 3 (F2–F3). The study met its primary endpoint of ≥1-stage improvement in fibrosis with no worsening of MASH after 24 weeks of treatment for both the 50 mg EFX (41%, p<0.05) and 28 mg EFX (39%, p<0.05) dose groups, compared to 20% for the placebo group. At Week 96, response rates for this endpoint increased to 75% (p<0.001) for 50 mg EFX and 46% (p=0.07) for 28 mg EFX, vs 24% for placebo. The study also met additional histology endpoints at week 96. Notably 36% (p<0.01) and 31% (p<0.01) of patients treated with 50 mg EFX and 28 mg EFX, respectively, had a 2-stage improvement in fibrosis without worsening of MASH, more than 10-fold the placebo rate of 3%. A comparison of week 96 with week 24 results showed that treatment response among EFX-treated patients was both sustained and expanded with longer treatment, particularly among the 50 mg EFX group. More than 80% of all EFX-treated patients with improved fibrosis at week 24 experienced sustained improvement through week 96, reflecting maintained reductions in markers of liver injury and fibrosis, whereas more than half of placebo responders at week 24 failed to maintain their response. In addition, 63% of patients treated with EFX 50 mg who were non-responders at week 24 experienced an improvement in fibrosis and no worsening of MASH with the benefit of treatment for 96 weeks, three times the placebo rate of 21%. In a subset of patients with baseline F3, treatment with EFX was associated with response on fibrosis improvement similar to the overall study population of F2 and F3 patients treated with EFX, showing the potential for treating more-advanced fibrosis, associated with increased risk of progression to cirrhosis. Results from the HARMONY study indicate EFX was generally well tolerated, with no liver injury or decompensation events, and no deaths. The most frequent adverse events (AEs) were transient Grade 1 or 2 gastrointestinal events, with an overall event profile similar to what was observed during the first 24 weeks. A poster presentation will present results from a post-hoc analysis of key biomarkers associated with collagen synthesis and degradation. These data improve our understanding of EFX pharmacology and its effects on extracellular matrix (ECM) remodeling in the liver and fibrosis improvement. EFX treatment was associated with significant changes in the ECM toward a potentially beneficial phenotype, with decreased interstitial collagens (fibrils) and regeneration of structural collagens (basement membrane). The observed remodeling of ECM biomarkers after 24 weeks was associated with reductions in markers of liver injury over the same period and with improvements in liver fibrosis after longer treatment. Together, the data to be presented at EASL suggest that EFX modulates markers of pathological fibrosis consistent with improvements in metabolic health, liver health, and suppression of fibrogenesis. “We’re looking forward to sharing our Week 96 data from the Phase 2b HARMONY study in patients with pre-cirrhotic MASH (F2–F3) with the scientific community at EASL Congress,” said Andrew Cheng, M.D., Ph.D., president and chief executive officer of Akero. “We are highly encouraged by these results, which are the first reports of histological improvement after more than 48 weeks. We believe the unprecedented response rates of EFX-treated patients who experienced not only 1-, but 2-stage improvement in fibrosis without worsening of MASH observed in the HARMONY study, sustained over 96 weeks, is a key differentiator of EFX from other treatments in the MASH therapeutic landscape.” Details of the presentations are as follows: Oral Presentation Title: Efruxifermin significantly reduced liver fibrosis in MASH patients with F2–F3 fibrosis, with sustained improvement in liver injury and resolution of steatohepatitis over 96 weeks (HARMONY phase 2b study) Presenter: Vlad Ratziu, M.D., Ph.D. Professor of Hepatology, Sorbonne Université and the Hôpital Pitié-Salpêtrière Medical SchoolLate Breaker Abstract Number: LBO-002Session Title: Late BreakerSession Date and Time: Saturday, June 8, 2024, 2:00 PM – 3:30 PM CESTPresentation Time: 2:15 PM CESTLocation: Gold Room Poster Presentation Title: Efruxifermin treatment improved collagen biomarkers consistent with remodeling of the extracellular matrix in patients with F2-F3 fibrosis due to MASH Presenter: Erik Tillman, Ph.D., Associate Director, Translational Biology & PharmacologyLate Breaker Abstract Number: SAT-220-YISession Title: MASLD: TherapySession Date and Time: Saturday, June 8, 8:30 AM – 5:00 PM CESTLocation: Poster Area About the HARMONY Study The Phase 2b HARMONY study was a multicenter, randomized, double-blind, placebo-controlled trial in biopsy-confirmed adult MASH patients with fibrosis stage 2 or 3. The study enrolled a total of 128 patients who were randomized to receive once-weekly subcutaneous dosing of 28 mg or 50 mg EFX, or placebo for 24 weeks, 126 of whom received at least one study dose. The primary efficacy endpoint for the study was the proportion of subjects who experienced ≥1-stage fibrosis improvement without worsening of MASH. The study continued for up to 96 weeks. Secondary endpoints at Week 96 included proportion of patients with ≥1-stage fibrosis improvement and no worsening of MASH, proportion of patients with 2-stage fibrosis improvement without worsening of MASH, and proportion of patients with ≥1-stage fibrosis improvement and MASH resolution, as well as changes from baseline in noninvasive markers of liver injury and fibrosis, glycemic control, lipoproteins, and change in body weight as well as safety and tolerability measures. About EfruxiferminEfruxifermin (EFX), Akero’s lead product candidate for MASH, is a long-acting, bivalent Fc-FGF21 fusion protein that has been engineered to mimic the balanced biological activity profile of native FGF21, an endogenous hormone that alleviates cellular stress and regulates metabolism throughout the body. EFX appears to reduce liver fat and inflammation, reverse fibrosis, increase insulin sensitivity and improve lipid and lipoprotein profile. This pleiotropic mechanism offers the potential to address the complex, multi-system disease state of MASH, including improvements in risk factors linked to cardiovascular disease – the leading cause of death in patients with pre-cirrhotic MASH. EFX is designed to offer convenient once-weekly dosing and has been generally well tolerated in clinical trials to date. About MASHMASH is a serious form of metabolic dysfunction-associated steatotic liver disease (MASLD) that is estimated to affect more than 17 million Americans. MASH is characterized by an excessive accumulation of fat in the liver that causes stress and injury to liver cells, leading to inflammation and fibrosis, which can progress to cirrhosis, liver failure, cancer and eventually death. MASH is the fastest-growing cause of liver transplants and liver cancer in the US and Europe. About Akero TherapeuticsAkero Therapeutics is a clinical-stage company developing transformational treatments for patients with serious metabolic diseases marked by high unmet medical need, including MASH. Akero's lead product candidate, EFX, is currently being evaluated in the ongoing SYMMETRY study, a 96-week Phase 2b clinical trial in patients with compensated cirrhosis due to MASH (F4 fibrosis), as well as two ongoing Phase 3 clinical trials: the SYNCHRONY Histology study in patients with pre-cirrhotic MASH (F2-F3 fibrosis) and the SYNCHRONY Real-World study in patients with MASH (F1-F3 fibrosis) or MASLD. A third clinical trial, the SYNCHRONY Outcomes study in patients with compensated cirrhosis due to MASH (F4 fibrosis), is expected to be initiated in the second quarter of 2024. The Phase 3 SYNCHRONY program builds on the results of two Phase 2b clinical trials, the HARMONY study in patients with pre-cirrhotic MASH (F2-F3) and the SYMMETRY study in patients with compensated cirrhosis due to MASH (F4). Akero is headquartered in South San Francisco. Visit us at akerotx.com and follow us on LinkedIn and Twitter for more information. Forward Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements, including, but not limited to, statements regarding Akero’s business plans and objectives, including future plans or expectations for EFX; the therapeutic effects of EFX; the timing and initiation of Akero’s Phase 3 SYNCHRONY program and upcoming milestones. Any forward-looking statements in this press release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost, and timing of Akero’s product candidate development activities and planned clinical trials; Akero’s ability to execute on its strategy; positive results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies; regulatory developments in the United States and foreign countries; Akero’s ability to fund operations; as well as those risks and uncertainties set forth more fully under the caption "Risk Factors" in Akero’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q, as filed with the Securities and Exchange Commission (SEC) as well as discussions of potential risks, uncertainties and other important factors in Akero’s other filings and reports with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Akero undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Investor Contact:Christina Tartaglia212.362.1200IR@akerotx.com Media Contact:Peg Rusconi617.910.6217peg.rusconi@vergescientific.com