CHIESI Farmaceutici SpA

Pictured: FDA Headquarters/iStock, JHVEPhoto The FDA’s schedule is picking up speed, with six target action dates over the next two weeks, including one for a blockbuster cancer treatment and another for a highly anticipated therapy for a rare pediatric disorder. Merck Looks to Add Perioperative NSCLC to Keytruda’s Label The FDA has until October 16 to decide whether or not to approve Merck’s Keytruda (pembrolizumab) for the treatment of resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC) before and after surgery. Merck is backing its supplemental Biologics License Application (sBLA) with interim results from the Phase III KEYNOTE-671 study, which last week showed that Keytruda significantly improved overall survival (OS), one of its two primary endpoints, in this patient population. Though details were sparse, these findings make Keytruda the first anti-PD-1 therapy to demonstrate significant OS benefit as a neoadjuvant and adjuvant treatment versus pre-operative chemotherapy in NSCLC, the company said in its announcement. At the American Society of Clinical Oncology (ASCO) annual meeting in June, Merck revealed data from KEYNOTE-671 showing that Keytruda aced a second primary endpoint of event-free survival. Patients treated with the blockbuster therapy saw a 42% drop in the risk of recurrence, progression or death. Keytruda is already approved for the treatment of NSCLC, though its current label only authorizes its use in metastatic or unresectable stage III disease and as an adjuvant treatment after resection and platinum-based chemotherapy. Ardelyx Tries Again with CKD Drug After an initial rejection in 2021, Ardelyx is trying again for approval of tenapanor to control serum phosphate levels in adults with chronic kidney disease (CKD) on dialysis who have shown either poor response or intolerance to phosphate binder therapy. The FDA’s target action date is October 17. Ardelyx resubmitted its New Drug Application (NDA) in April 2023, providing data from a large development program with more than 1,200 patients enrolled across three Phase III trials: PHREEDOM, BLOCK and AMPLIFY. All studies met their primary and key secondary endpoints, pointing to the efficacy and safety of tenapanor for this indication. The company also included data from two Phase IV open-label studies: OPTIMIZE and NORMALIZE. In the FDA’s rejection letter in October 2021, the regulator said that while Ardelyx had provided “substantial evidence” of tenapanor’s effects on serum phosphorous levels, the candidate’s overall efficacy was “small and of unclear clinical significance.” More than a year later, in November 2022, tenapanor faced the FDA’s Cardiovascular and Renal Drugs Advisory Committee, which voted 9–4 that the benefits of Ardelyx’s candidate outweighed its risks. Bausch Awaits Regulatory Ruling on Acne Gel By October 20, the FDA is expected to release its decision on Bausch Health’s NDA proposing its investigational gel IDP-126 (clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide 3.1%) for the treatment of acne vulgaris. Affecting some 50 million Americans, acne is the most common skin problem in the U.S. and can often leave scars on the skin and cause emotional distress. Typically, physicians prescribe a combination of treatments to address the many different underlying factors contributing to the development of acne. Bausch takes a similar approach with IDP-126, which combines the retinol adapalene, the anti-microbial benzoyl peroxide, and the topical antibiotic clindamycin. All three agents, alone or in various combinations, have shown promising dermatologic activity. To back its regulatory application, Bausch presented data from two Phase III randomized and placebo-controlled trials, with over 360 patients enrolled. Results from both studies showed that IDP-126 could significantly reduce inflammatory and non-inflammatory lesions and achieve significantly greater treatment success. Bausch is developing IDP-126 through its dermatology unit Ortho Dermatologics. BioMarin Proposes Voxzogo for Younger Children One of the fall’s most highly anticipated FDA decisions involves BioMarin’s Voxzogo (vosoritide), which was initially approved in November 2021 for the treatment of achondroplasia in children aged five years and above. On or before October 21, the FDA will decide whether or not to approve Voxzogo to treat children under the age of five with achondroplasia—a rare genetic disorder that causes the most common form of dwarfism. Designed as a once-daily injection, Voxzogo is a C-type natriuretic peptide analog that works by positively regulating the signaling cascade downstream of the FGFR3 protein. In achondroplasia, FGFR3 is mutated, and Voxzogo’s mechanism of action helps override this dysfunction to promote endochondral bone growth. BioMarin supported its supplemental NDA, which the FDA accepted in March, with data from a Phase II randomized, double-blinded and placebo-controlled study. Results showed that the safety and efficacy profiles of Voxzogo were similar between children older and younger than five years of age. The European Medicines Agency is also reviewing Voxzogo in this younger patient population and if approved in both markets, the label expansion could make the treatment available as early as birth for over 1,000 more patients. Regeneron, Sanofi Seek Additional Indication for Dupixent By October 22, the FDA is due to release its decision on Sanofi and Regeneron’s sBLA proposing their blockbuster Dupixent (dupilumab) as a treatment for chronic spontaneous urticaria (CSU) in adults and in adolescents 12 years and above. Dupixent, a fully human monoclonal antibody that blocks the IL-4 and IL-13 signaling pathways, is approved for a variety of indications, including atopic dermatitis, asthma, eosinophilic esophagitis, prurigo nodularis and chronic rhinosinusitis with nasal polyposis. This would be Dupixent’s first approval in CSU. Data from two Phase III studies in the LIBERTY-CUPID development program—A and B—formed the evidence base supporting Sanofi’s and Regeneron’s sBLA. Results of Study A, posted in July 2021, showed that Dupixent aced its primary and key secondary endpoints, with treatment leading to a significant drop in itch and hives, as compared with standard-of-care antihistamine medication, in biologic-naïve patients. In contrast, an interim analysis of Study B showed that Dupixent treatment did not significantly improve these symptoms in CSU patients refractory to omalizumab treatment. Next Week: Santhera, Catalyst Await DMD Verdict for Vamorolone Joining BioMarin’s Voxzogo among the year’s most highly anticipated rare disease decisions is Santhera’s investigational anti-inflammatory drug vamorolone, which the company is proposing as a treatment for Duchenne muscular dystrophy (DMD). The FDA’s verdict is due on or before October 26. One of the most frequently documented rare diseases, DMD is caused by mutations in the dystrophin gene and often manifests as progressive muscle weakness and degeneration. In its most severe forms, DMD can also afflict the heart and respiratory muscles, typically leading to the failure of these organ systems. A common treatment regimen for DMD involves the use of glucocorticoids, which have been shown to slow muscle weakness and prolong life expectancy. However, this approach bears substantial side effects. Vamrolone, a dissociative anti-inflammatory drug candidate, acts on the same receptor as glucocorticoids but elicits different downstream activity. According to Santhera, this mechanism has the potential to “dissociate” efficacy from typical steroid safety concerns. In June 2023, Catalyst Pharmaceuticals bet up to $231 million in upfront and milestone payments, plus royalties, to gain exclusive North American license to vamrolone. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

2023年，生物制药圈的并购交易不算多，也不算大。百时美施贵宝（BMS）以48亿美元收购Mirati Therapeuticsi的交易，是最近生物制药市场M&A（Mergers and Acquisitions）领域内的热门话题。这笔交易也折射出了2023年生物医药领域融资与M&A方面的现状。 以BMS如此体量的生物制药公司48亿美元的价格收购Mirati的交易来看，反映出了2023年大型公司对较小“补强”型收购（Bolt-on）的普遍兴趣 （Bolt-on 表示一家公司通过小规模的收购或合并，将新获得的业务或资产无缝地整合到其现有运营中，以实现战略增长和扩张。这种策略有助于最大限度地利用已有的资源和能力）。BMS将向 Mirati 支付每股 58美元(总计约48亿美元)，如果合并后七年内 Krazati（Mirati现有产品） 的两项申请之一得到了批准，则将另外支付每股 12 美元 (总计约10 亿美元)。随着备受关注的 XBI 生物技术指数今年下跌 13%，每笔生物制药领域内的并购交易都有助于提振市场情绪。但BMI的这次收购却仍然投资者意兴阑珊，这个小型补强收购的价格并不令人满意。 图1. 2023年上半年生物制药收购的交易总额与数量与往年比较图。（图片来源：Evaluate Pharma）2019 年，生物制药行业的收购交易创造了纪录，在那一年百时美施贵宝斥资 740 亿美元收购了Celgene，艾伯维630 亿美元收购了Allergan。2019年的前十大收购总额超过了 2000 亿美元。但随着新冠疫情的爆发，这一数字到 2021 年骤降至 530 亿美元。2022 年寒意依然犹在，高额并购活动更加稀缺，直到 12 月安进拟议以 278 亿美元收购 Horizon，才将年度总额推向了650 亿美元。经过 2022 年的低迷之后，生物制药领域内的并购活动在 2023 年有所回升（图1）。但几位大型制药公司的CEO一致表示，在当今环境下，大型交易是他们敬而远之的项目，有可能会对公司的核心目标和战略方向产生干扰甚至破坏。但到 2023 年中期，为了缓解专利悬崖和填补收入缺口，以及大型公司对于已上市或者后期资产的渴望，仍然推动了十几笔价值超过 10 亿美元的交易。包括辉瑞430亿美元收购Seagen（尚未完成，涉及四种已上市的癌症药物和众多临床阶段的后续项目）、默沙东108亿美元收购Promtheus（溃疡性结肠炎和克罗恩病的 III 期抗体，以及另一种临床抗体项目）、Astellas 59亿美元收购Iveric Bio（当时已经提交申请的补体C5抑制剂，治疗罕见的视网膜疾病地图样萎缩）、诺华32亿美元收购 Chinook Therapeutics（两种治疗罕见慢性肾病的晚期临床候选药物）等。但这些交易相对于2019年百时美施贵宝豪掷740亿美元收购Celgene的大手笔来说，从体量上看无不相形见绌。然而值得警醒的是，正是被收购的Celgene，其2023年在BMS内部资产销售额已经缩水到了只有7%的水平。虽然2023年也存在辉瑞收购Seagen的大手笔，但从整体来看，规模较小的补强交易是 2023 年并购领域的基调。除了商业风险较低之外，还可能避免被FTC（美国联邦贸易委员会） 盯上的麻烦（反垄断法）。GlaxoSmithKline 20 亿美元收购 Bellus Health （3 期慢性咳嗽药物camlipixant） ，以及 Chiesi 在 2023 年初12.5 亿美元收购罕见疾病公司 Amyrt Pharma 的交易都符合这一模式。未来影响生物制药企业M&A的掣肘因素，除了市场本身的力量之外，还在于FCT对于反垄断法的监督和IRA（降低通胀法案）的影响。有两笔大型交易目前仍在 FTC 审查之下：辉瑞在 2023 年初以 430 亿美元收购 Seagen，以及安进去年年底宣布拟以 280 亿美元收购 Horizon。FTC对于超级并购案的高度关注，可能会对生物制药企业进行大宗交易的热情产生抑制作用。这在一定程度上也推动了补强型交易在今年的盛行。美国药品价格立法的影响是另一个潜在的抑制因素。一些行业观察人士表示，新法律将导致生物制剂比小分子产品更受青睐，并使多适应症产品（包括孤儿药）的吸引力降低。例如在今年完成了32亿美元收购Chinook Therapeutics交易的诺华，其CEO  Vas Narasimhan 表示，诺华试图降低或者避免 IRA对其收购的不利影响。至于收购Chinook的交易，也是在考虑到适应症因素的基础上谨慎做出的，因为针对罕见慢性肾病的交易就IRA来说基本是可控的。在医药资本的寒潮下，在各种政策的掣肘下，生物制药的融资并购交易未来走向如何？您怎么看？附表：2023年生物制药企业并购交易 (截止2023年10月8日)Ref.Bristol Myers Squibb Strengthens and Diversifies Oncology Portfolio With Acquisition of Mirati Therapeutics. BMS. 08. 10. 2023.Swift, R. Astellas Pharma buys Iveric Bio for $5.9 billion. Reuters. 01. 05. 2023.Waldron, J. 'That's certainly on our minds': Novartis, GSK mull impact of IRA on R&D, M&A strategies. FierceBiotech. 26. 07. 2023.Feuerstein, A. Bristol ‘take-under’ of Mirati is not so great for biotech, but company’s new cancer target has potential. STAT. 09. 10. 2023.Dunleavy, K. Patent cliffs, divestitures and maturing biotechs all point to more pharma M&A: analysts. FiercePharma. 07. 09. 2023.Armstrong, A. et al. Fierce Biotech M&A Tracker 2023: Applied Molecular Transport finds a buyer; Atriva, Biocure ink reverse takeover. FierceBiotech. 05. 10. 2023.Biopharma Company Acquisition. Evaluate Pharma. Aug. 2023.

Swiss biotech Santhera has secured a positive opinion for vamorolone from the EU’s CHMP for patients with Duchenne muscular dystrophy (DMD), sparking plans for a staggered launch in the continent starting next year with an initial focus on the big five markets. EU approval is still pending a European Commission decision, which is expected in December, but commercial preparations are already underway at the Swiss company. “We will launch in Germany in mid-January,” CEO Dario Eklund told Endpoints News in an interview. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.