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Research Brief Released in Preventing Chronic Disease WASHINGTON, Feb. 2, 2023 /PRNewswire/ -- A new study by the Centers for Disease Control and Prevention, Office on Smoking and Health shows a majority of Americans support phasing out the sale of all tobacco products. Read the Research Brief here> Data from a 2021 web panel survey of adults in the US aged 18 years or older (N = 6,455) showed: 62.3% of adults supported a policy prohibiting the sale of menthol cigarettes. The CDC Research Brief adds, "Approximately two-thirds of respondents who did not currently use tobacco products and more than one-third who currently used tobacco products, including menthol cigarettes, supported this policy." 57.3% of adults supported a policy prohibiting the sale of all tobacco products. The Research Brief clarifies, "More than 61% of respondents who did not currently use tobacco products and about one-fourth of respondents who currently used tobacco products supported this policy." "ASH welcomes this strong support from Americans who recognize the deadly and unnecessary toll tobacco products bear on our families, communities, and country," said Laurent Huber, Executive Director of Action on Smoking and Health, a global non-profit leading the effort to advance tobacco endgame policies worldwide. Cigarettes are the only consumer good that kills when used exactly as their manufacturer intends – they don't require misuse or overuse to cause extensive harm and death. There is no benefit to our society for allowing the sale of tobacco products, and more jurisdictions are now acting to remove them from store shelves. Policies to phase out tobacco sales – often called "tobacco endgame" can take several forms, including: A reduction in nicotine in cigarettes to non-addictive levels, as New Zealand is doing and the US FDA is exploring. Prohibiting the sale of tobacco to anyone born after a specific date, effectively raising the age to purchase tobacco products by one year every year, as New Zealand and Brookline, MA have done (often called Tobacco or Smoke Free Generation). Phase out tobacco retail licenses. Ban filters in cigarettes, as ASH and partners are working to do through the UN Plastic Pollution Treaty being negotiated this year. "Political will is often what delays tobacco endgame policies from being implemented," said Laurent Huber of ASH. "We have the science on our side and now the CDC has demonstrated that public support is strong as well." ASH encourages more jurisdictions to follow the lead of Beverly Hills and Manhattan Beach, CA in prioritizing the health of their citizens by phasing out the sale of tobacco products. ACTION ON SMOKING AND HEALTH Founded in 1967, Action on Smoking and Health (ASH) is America's oldest anti-tobacco organization, dedicated to a world with ZERO tobacco deaths. Because tobacco is the leading cause of preventable death worldwide, ASH supports bold solutions proportionate to the magnitude of the problem. ash.org Media Contact: Megan Arendt-Manning (202) 390 – 9513 SOURCE Action on Smoking and Health

1维奈克拉之后，国产Bcl-2i崛起 维奈克拉（Venclexta）是目前全球唯一获批Bcl-2抑制剂，其作为艾伯维在血液瘤领域重要布局，其2021年销售额达18.2亿美元。虽维奈克拉不及伊布替尼近百亿美元销售亮眼，根据前3季度销售表现也基本确定今年将迈入20亿美元重磅药物队列。 图1 维奈克拉上市后的销售情况（来源：艾伯维、FDA，丰硕创投整理） 维奈克拉在2019年5月获批1L CLL后一直未有新的适应获批（FDA批准），近几年销售增长渐显乏力。根据艾伯维年初的管线计划，预计维奈克拉将在今年新增1L CLL/SLL（+伊布替尼）、高风险MDS，以及2023年新增r/r MCL（+伊布替尼）、3L+ MM w/t(11;14)合计4项适应症获批，而这几项新适应的批准也将给维奈克拉的销售注入新的动力。 在刚刚过去的ASH会议上，国内亚盛APG-2575、百济BGB-11417两款Bcl-2i有多项研究公布，同时CLL/SLL治疗临床研究也都被纳入口头报告。BcL-2领域药物开发进展缓慢，维奈克拉上市7年一直未有新药获批，两款国产Bcl-2抑制剂都在ASH上表现不俗，下面我们具体看看产品的研发进展，尝试分析两款产品的应用潜力与未来的前景。 2有效性，不光只看ORR 我们主要回顾CLL/SLL适应症本次ASH会议上两款产品临床研究数据： APG-2575：一项评估APG-2575单药与联合阿卡替尼或利妥昔单抗用于初治或复发/难治CLL/SLL患者的全球性II期临床研究。在r/r CLL/SLL患者中单药、联合阿卡替尼、联合利妥昔单抗ORR分别为67%、98%、79%，对于初治患者APG-2575联合阿卡替尼ORR为100%。（这里顺带一提，阿卡替尼在r/r CLL中单药ORR=81%、一线与奥妥珠单抗联用ORR=94%、CR=13%，一线单药ORR=86%。） 图2 APG-2575治疗CLL/SLL有效性数据（来源：亚盛医药官方、资料1） 该II期研究共纳入146例患者，且各个亚组都有一定数量可评估患者（图2），APG-2575临床疗效得到初步有效验证，其中与BTKi阿卡替尼联用的疗效较为突出。 BGB-11417：一项在CLL/SLL中展开的BGB-11417单药或与泽布替尼联合的I期研究。在百济官网最期更新的ASH口头报告数据回顾文件中（资料2），在接受BGB-11417治疗且疗效可评估的患者中，单药、联用组在r/r CLL中ORR分别为67%、95%，CR分别为 33%、30%；对于初治患者联合治疗ORR为100%，CR为18%。 图3 APG-2575治疗CLL/SLL有效性数据（来源：百济神州官网、资料2） 总的来看BGB-11417初步疗同样具有潜力，尤其是在治疗r/r患者中获得较高的CR率，不过注意到该研究目前可评估患者数较少，需要进一步看II期研究的结果。 小结 这里我们将维奈克拉、APG-2575、BGB-11417在CLL/SLL中数据做了简单汇总整理。APG-2575、BGB-11417单药在r/r患者中疗效不算出色，但在联合用药探索中，都获得了富有潜力ORR或CR数据。 图4 三款Bcl-2抑制剂用于CLL/SLL的有效性数据（来源：ASH、FDA label，丰硕创投整理） 但需要注意的是，CLL/SLL这类长病程的癌种，对于药物的临床获益评估，早期响应率是只是第一关，而患者长期获益的考量更为重要。一项汇总研究显示维奈克拉单药在r/r CLL/SLL治疗中估计中位进展时间为36.9个月，mPFS为30.6个月（资料3）。在ASH官网的摘要披露中，APG-2575单药组在中位暴露16.5个周期（每周期28天）内有42%患者（18/43）因PD而终止治疗，中位暴露时间7~9个周期内APG-2575联用组仅1例复发（资料4），APG2575单药复发人数较高。BGB-11417单药组在中位随访11个月（范围 8.5-18.3）间，接受治疗的6例患者仍在治疗中，联合用药组在5.8个月中位随访期间有1例PD（1/44）（资料5）。 3每日递增比每周递增更安全吗？ 由于患者需要长期治疗，因此药物的安全性显得尤为重要，临床上为避免TLS，维奈克拉用药初期需要通过剂量递增的方式用药。APG-2575为每日剂量递增的方案（预计6日达目标剂量），BGB-11417是更为保守的每周剂量递增方案（5周达最高剂量，如图5）。此外还所区别的是，BGB-11417联用组先用泽布替尼治疗8~12周再给予BGB-11417治疗，APG-2575联用组则为两药同时服用。 图5 BGB-11417临床研究给药方案设计（来源：资料2） 临床研究中维奈托克单药与联合用药分别有有2%、13%患者发生TLS。APG-2575在141例受试者中发现4例TLS（2例临床TLS，2例实验室TLS），BGB-11417在50例受试者中发现1例实验室TLS。根据两款产品公布数据来看，≥3级的中性粒细胞减少、血小板减少、发热率BGB-11417单药治疗高于APG-2575，而≥3级COVID-19 感染与肺炎率APG-2575单药高于BGB-11417；而在联用组中，≥3级AE事件与发生率BGB-11417均少于APG-2575。此外，随访期间两药都没有患者因AE导致终止治疗。 图6 BGB-11417、APG-2575临床不良反应汇总（来源：ASH、官网，丰硕创投整理） 值得肯定的是，BGB-11417联用组通过更保守的每周剂量递增降低TLS发生，同时早期先使用泽布替尼降低患者肿瘤负担，减轻了后续BGB-11417治疗的相关不良反应（如中性粒细胞减少、血小板减少等）。由此，若对临床治疗没有产生显著影响的前提下，能够降低临床不良反应，又何必纠结给药方案呢？ 小结 临床上维奈克拉因AE导致的“停药\剂量减少\剂量中断”发生率为单药9%\13%\36%、联用利妥昔单抗16%\15%\71%、联用奥比妥珠单抗16%\21%\74%。在两款国产Bcl-2i的临床研究中，随访期间两药均未发生AE导致终止治疗，同时≥3级AE、TLS发生率较低，显示出优于维奈克拉的安全性潜力。尤其是BGB-11417联用泽布替中先后服药方案的设计，整体≥3级AE率明显降低。 4临床布局与进度 目前APG-2575、BGB-11417适应症布局，基本都参考了维奈克拉覆盖的适应症。APG-2575更早进入临床，活跃状态下的临床研究达11项，其中r/r CLL/SLL为注册性临床。BGB-11417共登记了6项临床，其中包含r/r CLL/SLL、r/r MCL两项II期临床（潜在注册性研究）。 图7 APG-2575、BGB-11417临床布局与进展（来源：clinicaltrials、公司官网，丰硕创投整理） 从研发进度上看，已进入关键性临床的APG-2575在r/r CLL/SLL的临床数据更成熟具有领先优势，但在其他适应症临床开发上并未占优。而BGB-11417在血液瘤领域的数据披露更全面，今年ASH会议上披露了4项摘要，涉及CLL/SLL、NHL、WM、AML、MCL多个适应症初步临床研究结果（资料5-8），是BioPharm的临床速度的体现。此外，百济将r/r CLL/SLL，MCL两项有望通过单臂上市适应症推向II期临床，已有迎头赶上之势。 5结语 目前两款国产Bcl-2i在临床上显示出良好安全性，以及富有潜力的联合治疗前景，均有望超越FIC品种维奈克拉。亚盛深耕细胞凋亡领域，围绕Bcl-2为主线外延至多个靶点领域，APG-2575领衔5项FDA孤儿药资格，涉及多个适应症布局，目前在核心适应症CLL/SLL中占领先地位。百济凭借BTKi开发之后在血液瘤的临床中积累的经验以及自身资源优势，BGB-11417临床开发速度更快，在多个适应症都已验证初步疗效。同时BGB-11417能与泽布替尼在血液瘤领域联动，巩固企业产品矩阵。 两款药物尚处于开发早期，未来要将产品推向更多适应症，有钱又有资源的Biopharm优势将会愈发明显。Biotech资金有限，寻求外部合作相对赢面更大。Bcl-2i联合用是临床开发的重要趋势，尤其在CLL/SLL中与BTKi的联用，恰恰BTKi领域不缺大买家，最终还是要回归药物本身。 参考资料 资料1、【直击2022 ASH】ORR达98%！亚盛医药口头报告APG-2575联合BTK抑制剂治疗R/R CLL/SLL患者数据亮眼 资料2、https://sseir.beigene.com/news-events/events-and-presentations/(ASH数据回顾会议辅助材料） 资料3、Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables 资料4、https://ash.confex.com/ash/2022/webprogram/Paper160386.html 资料5、https://ash.confex.com/ash/2022/webprogram/Paper169662.html资料6、https://ash.confex.com/ash/2022/webprogram/Paper169664.html 资料7、https://ash.confex.com/ash/2022/webprogram/Paper169666.html 资料8、https://ash.confex.com/ash/2022/webprogram/Paper171046.html 内容来源于网络，如有侵权，请联系删除。

Courtesy of Getty Images BioCryst Pharmaceuticals is discontinuing the development of its twice-daily Factor D inhibitor BCX9930 after determining it is not likely to be commercially competitive in the paroxysmal nocturnal hemoglobinuria (PNH) market. The company will shift its focus to the earlier-stage asset, BCX10013. North Carolina-based BioCryst discussed the potential of BCX9930 at the American Society of Hematology meeting held this week. BCX9930 was in development for the treatment of complement-mediated diseases, including PNH, C3 glomerulopathy, immunoglobulin A nephropathy and primary membranous nephropathy. Safety data hamstrung BioCryst’s BCX9930, preventing higher dosing levels. In April, the FDA placed a partial clinical hold on three clinical trials involving BCX9930 due to reports of elevated serum creatinine levels in PNH patients participating in the REDEEM trial. Those patients received twice-per-day 500 mg doses of BCX9930. The FDA lifted the hold in August after BioCryst researchers determined a lower dose and adequate hydration would dilute the concentration of BCX9930 in the urine. The dilution would mitigate the formation of crystals associated with elevated serum creatinine levels, the company announced at the time. Chief Executive Officer Jon Stonehouse said Thursday that an inability to increase the dosing levels of BCX9930 would likely hinder its competitive chances. Chief Medical Officer Ryan Arnold echoed Stonehouse’s statements. He said conversations at the conference helped inform the company’s decision to discontinue BCX9930 in favor of BCX10013, a once-per-day Factor D inhibitor with best-in-class potential. Investigators and researchers at ASH suggested a once-per-day oral drug would be the best option for patients, Arnold said. BioCryst anticipates BCX10013 will be assessed in multiple disease indications. Stonehouse said that the relationships built with clinical testing sites during the development of BCX9930 will expedite future clinical plans for BCX10013. He added that some patients who participated in the BCX9930 trials could switch to BCX10013, which could speed up enrollment. Investors reacted negatively to the decision. Shares of BioCryst fell nearly 6% in premarket trading Wednesday to $10.60. The stock closed at $11.17 at the end of the day. A Competitive Space During ASH, several significant advancements in PNH were announced, including vital Phase III data from Novartis. The Swiss pharma giant reported its experimental drug, iptacopan, met the primary goal of achieving meaningful hemoglobin levels without transfusion. That announcement, built on data announced in October, showed iptacopan demonstrated superiority against two AstraZeneca's PNH drugs, Soliris and Ultomiris. In September, AstraZeneca posted positive interim results from a Phase III trial assessing danicopan, a complementary drug for Soliris and Ultomiris. The interim data showed danicopan significantly improved hemoglobin levels.