更新于：2024-09-07
Octreotide oral film(Connexios Life Sciences Pvt Ltd.)
更新于：2024-09-07
概要
基本信息
非在研机构- |
最高研发阶段临床1期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
结构
分子式C49H66N10O10S2 |
InChIKeyDEQANNDTNATYII-OULOTJBUSA-N |
CAS号83150-76-9 |
序列信息
Sequence Code 19721
关联
4
项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的临床试验Octreotide treatment to improve nutritional recovery after surgery for patients with esophageal or gastric cancer, a prospective randomized open label phase II study - OTIS
开始日期2022-12-20 |
The Effect of Preoperative Long Period Octreotide Combined With Postoperative Short Period Octreotide on the Complications After Pancreatectomy. A Prospective, Multicenter Clinical Trial
The Effect of Preoperative Long Period Octreotide Combined With Postoperative Short Period Octreotide on the Complications After Pancreatectomy. A Prospective, Multicenter Clinical Trial
开始日期2018-02-01 |
申办/合作机构 |
Changes in Pancreatic Texture After Single-shot Administration of 500 µg Octreotide in the Gastroduodenal Artery During Pancreatoduodenectomy - a Double-Blinded Randomized Controlled Trial
The aim of the study is to test the hypothesis that intraarterial bolus application of 500 µg Octreotide in the gastroduodenal artery during the resectional phase of pancreatoduodenectomy in patients with soft pancreatic tissue hardens the texture of the pancreatic remnant.
A primary end-point of the study is a change in pancreatic texture.
A secondary end-point is the rate of postoperative pancreatic fistula.
A primary end-point of the study is a change in pancreatic texture.
A secondary end-point is the rate of postoperative pancreatic fistula.
开始日期2011-08-01 |
100 项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的临床结果
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100 项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的转化医学
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100 项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的专利（医药）
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2,637
项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的文献（医药）2106-07-05·Oncotarget
The impact of 177Lu-octreotide therapy on 99mTc-MAG3 clearance is not predictive for late nephropathy
Article
作者: Lapa, Constantin ; Hänscheid, Heribert ; Bluemel, Christina ; Lassmann, Michael ; Beykan, Seval ; Herrmann, Ken ; Lückerath, Katharina ; Werner, Rudolf A. ; Weich, Alexander ; Buck, Andreas K. ; Higuchi, Takahiro ; Scheurlen, Michael
Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of 99mTc-mercaptoacetyltriglycine (99mTc--MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq 177Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by 99mTc-MAG3-clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.
2024-03-01·Indian journal of pediatrics
Nano Carbon Tracer in the Repairing of Congenital Abdominal Chylorus Leakage
Article
作者: Su, Pengjun ; Zhang, Zhibo
Congenital chylous ascites (CCA) is a rare cause of ascites in newborn infants. The main causes include congenital lymphatic obstruction due to atresia or stenosis of the major lacteals, mesenteric cysts and lymphangiomatosis. The mainstay of treatment for CCA is conservative management including medium-chain triglycerides (MCT)-based diet or total parenteral nutrition (TPN), and the addition of octreotide. Surgical exploration is reserved for those cases in whom conservative management has failed. The core problem of chylous abdominal surgery is to find the leakage; once the exact chylous leakage is found, the problem will be solved. The authors used a new carbon nanopartides material to accurately locate the location of chylous leakage. The operation is simple and fast, easy to use, and the effect is remarkable.
2024-01-01·Journal of pain and symptom management
Palliative Management of Inoperable Malignant Bowel Obstruction: Prospective, Open Label, Phase 2 Study at an NCI Comprehensive Cancer Center
Article
作者: Walter, Michelle ; George, Anthony ; Carozza, Desi ; Attwood, Kristopher ; Mann, Gary ; Case, Amy ; Hansen, Eric ; Hamid, Showkat ; Roche, Charles
CONTEXT:
Malignant bowel obstruction (MBO) is a common complication of intra-abdominal cancer, frequently seen in advanced gastrointestinal and gynecologic cancer. Management of MBO can be challenging, particularly if the patient is not a surgical candidate. No consensus exists on how best to manage these patients medically. Retrospective studies suggest that the combination of dexamethasone, octreotide and metoclopramide may lead to relief of obstruction and improvement in symptoms associated with the obstruction.
OBJECTIVES:
This study seeks to prospectively evaluate the combination of drug "triple therapy" dexamethasone 4 mg BID, metoclopramide 10 mg Q6 and octreotide 300 mcg TID to assess tolerability, safety, and effect on symptoms and deobstruction.
METHODS:
Adults admitted at Roswell Park Comprehensive Cancer Center with malignant bowel obstruction were eligible. Eligible patients who constented to the study were started on the triple therapy with close monitoring of symptoms and for adverse effects.
RESULTS:
A total of 15 patients enrolled in the study. Two patients experienced bradycardia as adverse effect and there was no incidence of bowel perforation. All patients who completed the study had complete resolution of their nausea, and improvement in other symptoms including pain, constipation, tolerance of oral intake and resumption of bowel movements. Only two of the 15 patients were alive to complete the six-month post study follow up.
CONCLUSION:
"Triple therapy" with dexamethasone, metoclopramide, and octreotide for management of nonsurgical MBO in this small sample size appears safe and well tolerated however a diagnosis of inoperable MBO remains associated with poor prognosis and death within months.
35
项与 Octreotide oral film(Connexios Life Sciences Pvt Ltd.) 相关的新闻（医药）2023-11-07
Crinetics Pharmaceuticals Reports Third Quarter 2023 Financial Results and Provides Corporate Update
Phase 3 PATHFNDR-1 Study Met Primary and All Secondary Endpoints as Reported in September
Phase 3 PATHFNDR-2 Study Topline Data Expected in 1Q 2024
Initial Data from Phase 2 Study of Paltusotine in Carcinoid Syndrome Expected in December 2023 SAN DIEGO, Nov. 07, 2023 (GLOBE NEWSWIRE) -- Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) today reported financial results for the third quarter ended September 30, 2023. “The resounding success of paltusotine in our PATHFNDR-1 Phase 3 study for acromegaly is a significant step toward fulfilling our strategic vision of building a premier, fully integrated endocrine company that can consistently create pioneering therapies for people around the world,” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “We intend to build additional momentum around our investigational compound paltusotine in the next few months. In December, we plan to analyze initial data from approximately half of the study participants in our ongoing Phase 2 study in carcinoid syndrome that should provide a preliminary indication of pharmacokinetic exposure, safety, and efficacy in this important second indication. We anticipate the full Phase 2 dataset from carcinoid to be available in the first half of 2024, and we remain on track to announce Phase 3 data from the PATHFNDR-2 study in the first quarter of 2024. We are enthusiastic about these upcoming key milestones for the paltusotine franchise.”
Third Quarter 2023 and Operating Highlights:
Phase 3 PATHFNDR-1 study met primary and all secondary endpoints. In September 2023, Crinetics reported positive topline results from its placebo-controlled Phase 3 clinical study of paltusotine in participants with acromegaly switching from standard-of-care injected depot somatostatin analogs which is designed to support an indication for the maintenance of acromegaly treatment. The study met statistical significance (p<0.0001) on the primary endpoint, based on the proportion of participants taking paltusotine (83%) who maintained an insulin-like growth factor 1 (IGF-1) level ≤ 1.0 times the upper limit of normal (xULN) compared to those taking placebo (4%). All secondary endpoints also met statistical significance as compared to placebo: change from baseline in IGF-level (p<0.0001), change from baseline in acromegaly symptoms diary (ASD) total score (p=0.02), and proportion of participants who maintained growth hormone level of <1.0 ng/mL (p=0.0003).Completed enrollment in paltusotine’s Phase 3 PATHFNDR-2 study. PATHFNDR-2 is a placebo-controlled Phase 3 clinical study of oral paltusotine in participants with acromegaly who are treatment-naïve or not currently receiving medical therapy which is designed to support an indication for the treatment of acromegaly. The study completed enrollment of 112 participants with acromegaly who were either treatment-naïve or untreated for at least four months (Stratum 1: n=82), or who washed out of prior octreotide or lanreotide monotherapy (Stratum 2: n=30). Topline data from the study is expected in the first quarter of 2024.Hosted Key Opinion Leader (KOL) webinar discussing acromegaly unmet need. In August 2023, Crinetics hosted a webinar featuring presentations by KOLs Beverly MK Biller, M.D. and Karen JP Liebert, R.N., BSN, both of Massachusetts General Hospital, who discussed the current landscape and unmet medical need in acromegaly, as well as the treatment burden associated with standard-of-care injectable somatostatin receptor ligands (SRLs). A replay of the webinar can be accessed here.Paltusotine NDA submission anticipated in 2024. Pending successful data from the PATHFNDR-2 study, Crinetics plans to submit a new drug application (NDA) to the Food and Drug Administration seeking regulatory approval for both the treatment of acromegaly and maintenance of acromegaly treatment indications.Initial data from Phase 2 study of paltusotine in carcinoid syndrome expected December 2023. The Phase 2 open-label study of paltusotine in carcinoid syndrome associated with neuroendocrine tumors is completing enrollment. A preliminary analysis from a subset of approximately half of the expected 30 participants is anticipated in December 2023. The study is designed primarily to assess the pharmacokinetic exposure and safety profile of paltusotine in participants with carcinoid syndrome. In addition, the study should provide descriptive efficacy information on the frequency of bowel movements and flushing episodes. CRN04894 studies for Cushing’s disease and congenital adrenal hyperplasia (CAH). Based on successful Phase 1 studies demonstrating pharmacologic proof-of-concept, Crinetics is advancing clinical studies of CRN04894 in both Cushing’s disease and congenital adrenal hyperplasia. Data from the ongoing studies are expected in the second half of 2024.Strengthened balance sheet with $350 million public offering. In September 2023, Crinetics announced the pricing of an upsized underwritten public offering of 11,441,648 shares of its common stock at $30.59 per share. Gross proceeds from the offering were $350.0 million. Third Quarter 2023 Financial Results Research and development expenses were $43.8 million for the three months ended September 30, 2023, compared to $32.0 million for the same period in 2022. The change was primarily due to an increase in personnel costs of $8.3 million, increased net spending on manufacturing and development activities of $1.8 million associated with our clinical and nonclinical programs, and increased outside services of $1.2 million.General and administrative expenses were $15.5 million for the three months ended September 30, 2023, compared to $11.9 million for the same period in 2022. The change was primarily due to an increase in personnel costs of $3.2 million.Net loss for the three months ended September 30, 2023, was $57.5 million, compared to a net loss of $41.9 million for the same period in 2022.Revenues were $0.3 million for the three months ended September 30, 2023, compared to $0.5 million for the same period in 2022. Revenues in both periods were primarily derived from the paltusotine licensing arrangement with Sanwa Kagaku Kenkyusho Co., Ltd.Unrestricted cash, cash equivalents, and investments totaled $554.7 million as of September 30, 2023, compared to $334.4 million as of December 31, 2022. Based on its current projections, the company now expects that its cash, cash equivalents and short-term investments will be sufficient to fund its current operating plan into 2026.The company had 66,799,257 common shares outstanding as of October 31, 2023. About Crinetics Pharmaceuticals Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors. Paltusotine, an investigational, first-in-class, oral somatostatin receptor type 2 (SST2) agonist, is in Phase 3 clinical development for acromegaly and Phase 2 clinical development for carcinoid syndrome associated with neuroendocrine tumors. Crinetics has demonstrated pharmacologic proof-of-concept in a Phase 1 clinical study for CRN04894 a first-in-class, investigational, oral ACTH antagonist, that is currently in Phase 2 clinical studies for the treatment of Cushing’s disease and congenital adrenal hyperplasia. All of the Company’s drug candidates are orally delivered, small molecule new chemical entities resulting from in-house drug discovery efforts, including additional discovery programs addressing a variety of endocrine conditions such as hyperparathyroidism, polycystic kidney disease, Graves’ disease, thyroid eye disease, hyperinsulinism, diabetes and obesity. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward-looking statements, including statements regarding the plans and timelines for the clinical development of paltusotine and CRN04894, including the therapeutic potential and clinical benefits or safety profile thereof; the expected timing of topline data from the ongoing Phase 3 clinical studies of paltusotine in acromegaly and Phase 2 study of paltusotine in carcinoid syndrome; plans to submit data from the ongoing Phase 3 clinical studies of paltusotine in acromegaly to regulators in support of applications seeking approval for the use of paltusotine in acromegaly patients and the expected timing of an NDA submission for paltusotine for the treatment or maintenance of treatment of acromegaly in the United States; the expected timing of data from studies of CRN04894 in Cushing’s disease and congenital adrenal hyperplasia; and the expected timing through which our cash, cash equivalents, and short-term investments will fund our operating plans. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including, without limitation, topline data that we report may change following a more comprehensive review of the data related to the clinical studies and such data may not accurately reflect the complete results of a clinical study, and the FDA and other regulatory authorities may not agree with our interpretation of such results; we may not be able to obtain, maintain and enforce our patents and other intellectual property rights, and it may be prohibitively difficult or costly to protect such rights; the COVID-19 pandemic and other geopolitical events may disrupt Crinetics’ business and that of the third parties on which it depends, including delaying or otherwise disrupting its clinical studies and preclinical studies, manufacturing and supply chain, or impairing employee productivity; unexpected adverse side effects or inadequate efficacy of the company’s product candidates that may limit their development, regulatory approval and/or commercialization; the company’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the success of Crinetics’ clinical studies and nonclinical studies; regulatory developments in the United States and foreign countries; clinical studies and preclinical studies may not proceed at the time or in the manner expected, or at all; the timing and outcome of research, development and regulatory review is uncertain, and Crinetics’ drug candidates may not advance in development or be approved for marketing; Crinetics may use its capital resources sooner than expected; any future impacts to our business resulting from geopolitical developments outside our control; and the other risks and uncertainties described in the company’s periodic filings with the SEC. The events and circumstances reflected in the company’s forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Additional information on risks facing Crinetics can be found under the heading “Risk Factors” in Crinetics’ periodic reports, including its annual report on Form 10-K for the year ended December 31, 2022. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by applicable law, Crinetics does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
CRINETICS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED FINANCIAL STATEMENT DATA(In thousands, except per share data)(Unaudited) Three months endedSeptember 30, Nine months endedSeptember 30, STATEMENTS OF OPERATIONS DATA: 2023 2022 2023 2022
Revenues $346 $458 $4,013 $4,028 Operating expenses:
Research and development 43,839 31,987 122,947
93,234 General and administrative 15,484 11,925 41,016
31,120 Total operating expenses 59,323 43,912 163,963
124,354 Loss from operations (58,977) (43,454) (159,950) (120,326)Total other income, net 2,516 1,529 6,515
2,409 Loss before equity method investment (56,461) (41,925) (153,435) (117,917)Loss on equity method investment (997) — (997) (1,010)Net loss $(57,458) $(41,925) $(154,432) $(118,927)Net loss per share - basic and diluted $(1.01) $(0.78) $(2.81) $(2.32)Weighted-average shares - basic and diluted 56,808 53,768 55,003
51,356
BALANCE SHEET DATA: September 30,2023 December 31,2022
Cash, cash equivalents and investments $554,653 $334,425 Working capital $535,297 $317,461 Total assets $641,537 $352,176 Total liabilities $93,789 $35,848 Accumulated deficit $(593,605) $(439,173)Total stockholders’ equity $547,748 $316,328
Contact: Chas SchultzVP, IR & Corporate Communicationscschultz@crinetics.com(858) 450-6464 Investors / Media: Corey Davis LifeSci Advisors, LLC cdavis@lifesciadvisors.com (212) 915-2577 Jenn GordonSpectrum Sciencejgordon@spectrumscience.com (202) 957-7795
临床2期临床3期临床结果临床1期财报
2023-10-24
Ad hoc announcement pursuant to Art. 53 LR
Transformation into a “pure-play” innovative medicines business is complete, with the spin-off of Sandoz; commentary below is on continuing operations2Q3 sales grew +12% (cc, +12% USD) with core operating income growing +21% (cc, +17% USD) Growth driven by continued strong performance from Kesimpta (+124% cc), Entresto (+31% cc), Kisqali (+76% cc), Pluvicto (+217% cc) and Scemblix (+157% cc) Q3 operating income grew +13% (cc, -4% USD) driven by higher sales and lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects Q3 net income grew +37% (cc, +14% USD) mainly due to higher operating incomeQ3 free cash flow3 was USD 5.0 billion (+24% USD) driven by higher net cash flows from operating activitiesQ3 core EPS grew +29% (cc, +24% USD) to USD 1.74Strong nine months performance with sales growing +10% (cc, +8% USD) and core operating income growing +19% (cc, +13% USD)Q3 key innovation milestones, including positive Ph3 data for multiple pipeline assets with blockbuster potential: Cosentyx – FDA approval for intravenous formulation in three indications (PsA, AS, nr-axSpA)Demonstrated clinically meaningful and statistically significant Ph3 data for: 1) Pluvicto (mCRPC pre-taxane), 2) iptacopan (IgAN), 3) remibrutinib (CSU), 4) Lutathera (GEP-NETs) Kisqali – Ph3 NATALEE iDFS 500 event analysis complete; file submitted in EU, US submission planned for Q4 2023 Initiated previously announced, up-to USD 15 billion share buyback to be completed by year-end 2025Full-year 2023 guidance raised for core operating income based on strong momentum4
Net sales expected to grow high single digitCore operating income expected to grow mid to high teens (from low double digit to mid teens)
Basel, October 24, 2023 – commenting on the quarter, Vas Narasimhan MD, CEO of Novartis, said: “Novartis delivered a very strong quarter, with double-digit sales and core operating income growth leading to a further upgrade to 2023 guidance. We have successfully executed the spin-off of Sandoz, allowing us to fully focus on high-value innovative medicines. Our growth drivers, including Kesimpta, Entresto, Kisqali and Pluvicto, continue to perform well in the market. Our robust pipeline also continues to deliver, and we have achieved important innovation milestones for Pluvicto, iptacopan, remibrutinib and Lutathera. We are confident in our mid-term growth outlook and remain committed to creating value for our shareholders.”
Key figures1
Continuing operations2
Q3 2023 Q3 2022 % change 9M 2023 9M 2022 % change
USD m
USD m USD cc
USD m
USD m USD cc Net sales 11 782 10 492 12 12
34 017 31 630 8 10 Operating income 1 762 1 826 -4 13
7 187 6 191 16 31 Net income 1 513 1 330 14 37
5 934 4 734 25 41 EPS (USD) 0.73 0.61 20 45
2.84 2.16 31 49 Free cash flow 5 043 4 054 24
11 019 8 661 27
Core operating income 4 405 3 772 17 21
12 551 11 149 13 19 Core net income 3 585 3 035 18 23
10 320 8 983 15 22 Core EPS (USD) 1.74 1.40 24 29
4.95 4.09 21 28
1 Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year. 2 As defined on page 37 of the Condensed Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division and the continuing Corporate activities and Discontinued operations include operational results from the Sandoz business. 3 Effective January 1, 2023, Novartis revised its definition of free cash flow, to define free cash flow as net cash flows from operating activities less purchases of property, plant and equipment. To aid in comparability, the prior year free cash flow amounts have been revised to conform with the new free cash flow definition. See page 48 of the Condensed Interim Financial Report. 4 Please see detailed guidance assumptions on page 8.
Strategy update
Our focus
Novartis has completed its transformation into a “pure-play” innovative medicines business, with the successful spin-off of Sandoz. Our focus is now centered on four core therapeutic areas (cardiovascular, renal and metabolic; immunology; neuroscience, and oncology). In each of these areas, we have multiple significant in-market and pipeline assets, all of which address diseases with a high burden and have substantial growth potential. In addition to two established technology platforms (chemistry and biotherapeutics), three emerging platforms (gene & cell therapy, radioligand therapy, and xRNA) are being prioritized for continued investment into new R&D capabilities and manufacturing scale. Geographically, we are focused on growing in our priority geographies – the US, China, Germany and Japan.
Financials
Following the September 15, 2023, shareholders’ approval of the spin-off of the Sandoz business the Company reported its consolidated financial statements for the current and prior years as “continuing operations” and “discontinued operations.”
Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division and the continuing corporate activities. Discontinued operations include the Sandoz Division and selected portions of corporate activities attributable to Sandoz’s business, as well as certain expenses related to the spin-off.
With the spin-off of the Sandoz business, Novartis operates as a single global operating segment, being a focused innovative medicines company.
The commentary below focuses on continuing operations. We also provide information on discontinued operations, which mainly includes Sandoz and allocated corporate activities.
Continuing operations
Third quarter
Net sales were USD 11.8 billion (+12%, +12% cc) driven by volume growth of 17 percentage points. Pricing had a negative impact of 1 percentage point and generic competition had a negative impact of 4 percentage points.
Operating income was USD 1.8 billion (-4%, +13% cc), mainly driven by higher sales and lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects.
Net income was USD 1.5 billion (+14%, +37% cc), mainly due to higher operating income and lower tax rate driven by non-recurring items. EPS was USD 0.73 (+20%, +45% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding.
Core operating income was USD 4.4 billion (+17%, +21% cc), mainly driven by higher sales. Core operating income margin was 37.4% of net sales, increasing by 1.4 percentage points (+2.7 percentage points cc).
Core net income was USD 3.6 billion (+18%, +23% cc), mainly due to higher core operating income. Core EPS was USD 1.74 (+24%, +29% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding.
Free cash flow amounted to USD 5.0 billion (+24% USD), compared with USD 4.1 billion in the prior year quarter driven by higher net cash flows from operating activities.
Nine months
Net sales were USD 34.0 billion (+8%, +10% cc) driven by volume growth of 16 percentage points. Pricing had a negative impact of 2 percentage points and generic competition had a negative impact of 4 percentage points.
Operating income was USD 7.2 billion (+16%, +31% cc), mainly driven by higher sales, other income from legal matters, lower restructuring charges, partly offset by higher impairments through discontinuation of early stage development projects.
Net income was USD 5.9 billion (+25%, +41% cc), mainly due to higher operating income. EPS was USD 2.84 (+31%, +49% cc), growing faster than net income, benefiting from lower weighted average number of shares outstanding.
Core operating income was USD 12.6 billion (+13%, +19% cc), mainly driven by higher sales. Core operating income margin was 36.9% of net sales, increasing by 1.7 percentage points (+2.9 percentage points cc).
Core net income was USD 10.3 billion (+15%, +22% cc), mainly due to higher core operating income. Core EPS was USD 4.95 (+21%, +28% cc), growing faster than core net income, benefiting from lower weighted average number of shares outstanding.
Free cash flow amounted to USD 11.0 billion (+27% USD), compared with USD 8.7 billion in the prior year period driven by higher net cash flows from operating activities.
Discontinued operations
Results for discontinued operations in the third quarter and nine-months 2023 include the results of the Sandoz Division and selected portions of corporate activities attributable to Sandoz business, as well as certain expenses related to the spin-off.
In connection with the Sandoz spin-off on October 4, 2023, the Company will report as part of its Q4 discontinued operations results a one-time non-cash non-taxable IFRS gain of approximately USD 5.9 billion. This IFRS gain represents mainly the excess amount of the IFRS distribution liability, which is the estimated fair value of the Sandoz business distributed to Novartis AG shareholders, over the then carrying value of Sandoz business net assets.
Third quarter
Discontinued operations net sales were USD 2.5 billion (+8%, +6% cc), mainly driven by ex-US growth.
Operating loss amounted to USD 86 million, compared to an operating income of USD 342 million in the previous year. The operating loss in third quarter was driven by the discontinued corporate transaction cost related to spin-off of the Sandoz business, which were core adjustments.
Core operating income was USD 250 million (-51%, -38% cc), mainly driven by lower gross margin and higher SG&A expenses.
Net income from discontinued operations amounted to USD 250 million, compared to USD 245 million in the previous year.
Nine months
Discontinued operations net sales were USD 7.4 billion (+6%, +8% cc), mainly driven by ex-US growth.
Operating income amounted to USD 265 million, compared to USD 1.1 billion in the previous year. The current year period includes the discontinued corporate transaction cost related to spin-off of the Sandoz business, which were core adjustments.
Core operating income was USD 1.2 billion (-20%, -11% cc), mainly driven by higher SG&A expenses and R&D investments.
Net income from discontinued operations amounted to USD 440 million, compared to USD 755 million in the previous year.
Total company
Third quarter
Total company net income was USD 1.8 billion, mainly due to higher operating income and lower tax rate driven by non-recurring items compared to USD 1.6 billion in the prior year. EPS increased to USD 0.85 from USD 0.73 in prior year.
Cash flows from operating activities amounted to USD 5.4 billion compared to USD 4.7 billion in the prior year. Free cash flow amounted to USD 5.0 billion compared to USD 4.4 billion in the prior year.
Nine months
Total company net income was USD 6.4 billion, mainly due to higher operating income compared to USD 5.5 billion in the prior year. EPS increased to USD 3.05 from USD 2.50 in prior year.
Cash flows from operating activities amounted to USD 11.9 billion compared to USD 10.1 billion in the prior year. Free cash flow amounted to USD 11.0 billion compared to USD 9.3 billion in the prior year.
Q3 key growth drivers
Underpinning our financial results in the quarter is a continued focus on key growth drivers including:
Kesimpta (USD 657 million, +124% cc) sales growth was driven by increased demand, strong access and benefitting from a one-time revenue deduction adjustment in Europe
Entresto (USD 1 485 million, +31% cc) sustained robust demand-led growth, benefitting from the adoption of guideline-directed medical therapy across regions
Kisqali (USD 562 million, +76% cc) sales grew strongly across all regions, based on increasing recognition of consistent overall survival and quality of life benefits Pluvicto (USD 256 million, +217% cc) continued sales growth in the US. Supply now unconstrained, focusing on initiating new patients Ilaris (USD 335 million, +24% cc) sales grew across all regions Scemblix (USD 106 million, +157% cc) sales grew across all regions, demonstrating the high unmet need in CML Leqvio (USD 90 million, +165% cc) launch in the US and other markets ongoing, with focus on patient on-boarding, removing access hurdles and enhancing medical education Cosentyx (USD 1 329 million, +4% cc) continued demand growth across key regions, partly offset by US revenue deduction fluctuations across periods. Ex-US sales grew +15% (cc) Promacta/Revolade (USD 576 million, +10% cc) grew across all regions, driven by increased use in chronic ITP and severe aplastic anemia Xolair (USD 369 million, +13% cc) sales grew across most regions Jakavi (USD 427 million, +9% cc) sales grew in Emerging Growth Markets, Europe and Japan, driven by strong demand in both myelofibrosis and polycythemia vera Tafinlar + Mekinist (USD 482 million, +8% cc) sales grew in the US and Emerging Growth Markets, driven by demand in BRAF+ adjuvant melanoma and NSCLC indications Lutathera (USD 159 million, +19% cc) sales grew mainly in the US, Japan and Europe due to increased demand
Emerging Growth Markets* Overall, grew +17% (cc). Growth in China (+14% cc, USD 848 million) *All markets except the US, Canada, Western Europe, Japan, Australia, and New Zealand
Net sales of the top 20 products in 2023
Q3 2023 % change 9M 2023 % change
USD m USD cc USD m USD cc Entresto 1 485 31 31 4 400 31 33 Cosentyx 1 329 4 4 3 677 -1 1 Promacta/Revolade
576 10 10 1 706 10 12 Kesimpta- excl. revenue deduction adjust.*
657 12787
124 86
1 530
112
95
112
96
Kisqali
562 72 76 1 470 68 74 Tafinlar + Mekinist
482 7 8 1 436 10 13 Tasigna
464 -5 -5 1 402 -3 -1 Jakavi
427 11 9 1 276 9 11 Lucentis
363 -20 -22 1 174 -20 -19 Xolair
369 15 13 1 085 4 6 Sandostatin
338 15 15
998 7 8 Ilaris
335 23 24
979 18 20 Zolgensma
308 -3 -2
928 -13 -11 Gilenya
270 -47 -48
771 -54 -53 Pluvicto
256 220 217
707 nm nm Exforge Group
187 1 3
557 -5 -1 Galvus Group
181 -15 -4
539 -17 -10 Diovan Group
153 -4 -1
466 -9 -4 Lutathera
159 20 19
458 34 34 Gleevec/Glivec
144 -19 -17
433 -24 -21 Top 20 brands total 9 045 13 13 25 992 9 11
nm= not meaningful* Sales growth benefiting from a one-time revenue deduction adjustment in Europe
R&D update - key developments from the third quarter
New approvals
Leqvio Approved in China and Japan as the first and only small interfering RNA (siRNA) therapy for LDL-C reduction Cosentyx In October, FDA approved the intravenous formulation in three indications: Psoriatic Arthritis, Ankylosing Spondylitis, and non-radiographic axial SpA
Regulatory updates
Kisqali
EU file submission in adjuvant early breast cancer setting; US submission planned for Q4 2023 Adakveo EC adopts decision endorsing CHMP recommendation to revoke conditional marketing authorization
Results from ongoing trials and other highlights
iptacopan In October, Ph3 APPLAUSE-IgAN study interim analysis demonstrated clinically meaningful and highly statistically significant proteinuria reduction in patients with IgA nephropathy. The trial met its pre-specified interim analysis (9 months) primary endpoint, demonstrating superiority vs. placebo in proteinuria reduction, with safety consistent with previously reported data. Novartis plans to review interim data with regulatory authorities for accelerated approval; study continues with final readout at 24 months
remibrutinib
Ph3 REMIX-1 and REMIX-2 studies met all primary and secondary endpoints, showing fast, clinically meaningful improvements across urticaria disease activity scores. Remibrutinib demonstrated a favorable safety profile with rates of adverse events comparable to placebo and balanced liver function tests across both studies.Final (52 weeks) readout and submissions to health authorities are expected in 2024. Full data will be presented at upcoming medical meetings
Pluvicto Ph3 PSMAfore study demonstrated clinically meaningful and statistically significant rPFS benefit in patients with PSMA+ mCRPC in the pre-taxane setting. Per updated analysis presented at ESMO, median rPFS more than doubled compared to ARPI switch. Patients on Pluvicto showed improved quality of life compared to daily oral ARPI, along with improvements in other clinically meaningful efficacy endpoints including PSA response, ORR, DOR and time to symptomatic skeletal event, with favorable safety. Pre-specified crossover-adjusted OS analysis demonstrated a HR of 0.80 (0.48, 1.33); the unadjusted ITT OS analysis was confounded by a high rate of crossover. Novartis is continuing to collect OS data, regulatory filings are anticipated in 2024
Lutathera Ph3 NETTER-2 study demonstrated clinically meaningful and statistically significant improvement in PFS (primary endpoint) in patients with newly diagnosed somatostatin receptor (SSTR)-positive, Grade 2 and 3, advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) vs. high-dose long-acting octreotide alone. The trial also met its key secondary endpoint of ORR. No new or unexpected safety findings were observed and data are consistent with the already well-established safety profile of Lutathera.Data to be presented at an upcoming medical meeting and discussed with regulatory authorities, with submissions to follow
Kisqali
Ph3 NATALEE iDFS 500 event analysis complete. Updated data is consistent with the interim analysis results announced in March 2023 and will be communicated at an upcoming medical meeting.Health-related quality of life (HRQoL) analyses from Ph3 NATALEE trial demonstrated that patients with early breast cancer receiving adjuvant Kisqali plus ET for up to 3 years maintained physical and social functioning; psychological well-being; and overall health scores, compared to baseline. Data was presented at the ESMO Virtual Plenary 2023
Leqvio Long-term data from Ph3 ORION-8 demonstrated that Leqvio, in addition to statin therapy, provides consistent low-density lipoprotein cholesterol (LDL-C) reduction beyond six years of treatment in patients with atherosclerotic cardiovascular disease (ASCVD), increased risk of ASCVD or heterozygous familial hypercholesterolemia. Efficacy and safety were consistent with previously reported Ph3 results. Data was presented at ESC 2023 GT005 (PPY988)
Development in Geographic Atrophy secondary to dry-Age-related Macular Degeneration discontinued based on benefit-risk assessment. No new safety signals identified. Patients treated will be provided with long term safety follow up Tislelizumab Novartis and BeiGene mutually agreed to terminate the collaboration and license agreement for tislelizumab for certain markets. With the termination, BeiGene will re-assume all development and commercialization rights for tislelizumab, and Novartis will manufacture tislelizumab for certain markets. BeiGene will also provide Novartis with ongoing clinical supply of tislelizumab to support its clinical trials ‘Front of Eye’ Assets
Divestment completed of ‘front of eye’ ophthalmology assets to Bausch + Lomb
Capital structure and net debt
Retaining a good balance between investment in the business, a strong capital structure and attractive shareholder returns remains a priority.
During the first nine months of 2023, Novartis repurchased a total of 74.9 million shares for USD 7.2 billion on the SIX Swiss Exchange second trading line. These repurchases included 52.8 million shares (USD 4.9 billion) under the USD 15 billion share buyback (announced in December 2021 and completed in June 2023) and 10.4 million shares (USD 1.1 billion) under the new up-to USD 15 billion share buyback announced in July 2023. In addition, 11.7 million shares (USD 1.2 billion) were repurchased to mitigate dilution related to participation plans of associates. Furthermore, 1.4 million shares (for an equity value of USD 0.1 billion) were repurchased from associates. In the same period, 12.2 million shares (for an equity value of USD 0.8 billion) were delivered as a result of options exercised and share deliveries related to participation plans of associates. Consequently, the total number of shares outstanding decreased by 64.1 million versus December 31, 2022. These treasury share transactions resulted in an equity decrease of USD 6.5 billion and a net cash outflow of USD 7.3 billion.
As of September 30, 2023, net debt excluding net debt related to discontinued operations increased to USD 10.8 billion compared to USD 7.2 billion total net debt at December 31, 2022. The increase was mainly due to the USD 7.3 billion annual dividend payment, net cash outflow for treasury share transactions of USD 7.3 billion and net M&A / intangible assets transactions of USD 2.9 billion. This increase in net debt was partially offset by USD 11.0 billion free cash flow.
As part of the spin-off, Sandoz incurred total bank debt of approximately USD 3.7 billion and paid approximately USD 3.0 billion in cash, including payment in satisfaction of certain intercompany indebtedness owed by Sandoz and its subsidiaries to Novartis and its affiliates as of September 30, 2023. This reduced the net debt position of Novartis by USD 3.0 billion.
As of Q3 2023, the long-term credit rating for the company is A1 with Moody’s Investors Service and AA- with S&P Global Ratings.
2023 outlook raised due to strong momentum
Barring unforeseen events; growth vs prior year in cc
Previous Guidance Net sales Expected to grow high single digit Unchanged
Core operating income Expected to grow mid to high teens
(from low double digit to mid teens)
Key assumptions:
No US Entresto Gx at risk launch in 2023No Sandostatin LAR generics enter in the US in 2023
Entresto patent update
Novartis has appealed to reverse the negative US District Court decision and to uphold the validity of its combination patent covering Entresto and other combinations of sacubitril and valsartan, which expires in 2025 (with pediatric exclusivity). No generics have tentative or final approval in the US. Any US commercial launch of a generic Entresto product prior to the final outcome of Novartis combination patent appeal, or ongoing litigations involving other patents, may be at risk of later litigation developments.
Foreign exchange impactIf late-October exchange rates prevail for the remainder of 2023, the foreign exchange impact for the year would be negative 2 percentage point on net sales and negative 6 percentage points on core operating income. The estimated impact of exchange rates on our results is provided monthly on our website.
Key figures1
Continuing operations2 Q3 2023 Q3 2022 % change
9M 2023 9M 2022 % change
USD m
USD m USD cc
USD m
USD m USD cc Net sales 11 782 10 492 12 12
Net sales 34 017 31 630 8 10 Operating income 1 762 1 826 -4 13
Operating income 7 187 6 191 16 31 As a % of sales 15.0 17.4
As a % of sales 21.1 19.6
Net income 1 513 1 330 14 37
Net income 5 934 4 734 25 41 EPS (USD) 0.73 0.61 20 45
EPS (USD) 2.84 2.16 31 49 Cash flows from operating activities 5 304 4 275 24
Cash flows from operating activities 11 673 9 271 26
Non-IFRS measures
Non-IFRS measures
Free cash flow
5 043 4 054 24
Free cash flow
11 019 8 661 27
Core operating income 4 405 3 772 17 21
Core operating income 12 551 11 149 13 19 As a % of sales 37.4 36.0
As a % of sales 36.9 35.2
Core net income 3 585 3 035 18 23
Core net income 10 320 8 983 15 22 Core EPS (USD) 1.74 1.40 24 29
Core EPS (USD) 4.95 4.09 21 28
Discontinued operations2 Q3 2023 Q3 2022 % change
9M 2023 9M 2022 % change
USD m
USD m USD cc
USD m
USD m USD cc Net sales 2 476 2 286 8 6
Net sales 7 428 6 998 6 8 Operating (loss)/income -86 342 nm nm
Operating income 265 1 057 -75 -60 As a % of sales nm 15.0
As a % of sales 3.6 15.1
Net income 250 245 2 79
Net income 440 755 -42 -18 Non-IFRS measures
Non-IFRS measures
Core operating income 250 510 -51 -38
Core operating income 1 185 1 486 -20 -11 As a % of sales 10.1 22.3
As a % of sales 16.0 21.2
Total company
Q3 2023 Q3 2022 % change
9M 2023 9M 2022 % change
USD m
USD m USD cc
USD m
USD m USD cc Net income 1 763 1 575 12 44
Net income 6 374 5 489 16 33 EPS (USD) 0.85 0.73 16 51
EPS (USD) 3.05 2.50 22 40 Cash flows from operating activities 5 378 4 721 14
Cash flows from operating activities 11 911 10 125 18
Non-IFRS measures
Non-IFRS measures
Free cash flow
5 043 4 435 14
Free cash flow
11 038 9 325 18
Core net income 3 784 3 419 11 16
Core net income 11 209 10 101 11 18 Core EPS (USD) 1.83 1.58 16 22
Core EPS (USD) 5.37 4.60 17 24
nm= not meaningful
1 Constant currencies (cc), core results and free cash flow are non-IFRS measures. An explanation of non-IFRS measures can be found on page 48 of the Condensed Interim Financial Report. Unless otherwise noted, all growth rates in this Release refer to same period in prior year.2 As defined on page 37 of the Condensed Interim Financial Report, Continuing operations include the retained business activities of Novartis, comprising the Innovative Medicines Division and the continuing Corporate activities and Discontinued operations include operational results from the Sandoz business.
Detailed financial results accompanying this press release are included in the Condensed Interim Financial Report at the link below:https://ml-eu.globenewswire.com/resource/download/1a97fd38-edbc-49ea-9350-8042dc006c1c/
Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995, that can generally be identified by words such as “guidance,” “expected,” “momentum,” “continue,” “drivers,” “confident,” “outlook,” “remain,” “committed,” “prioritized,” “prioritizing,” “continued,” “growing,” “growth,” “plans,” “on-track,” “continuing,” “anticipated,” “to follow,” “will,” “outlook,” “may,” “upcoming,” “ongoing,” “focus,” “pipeline,” “potential,” “estimated,” “launch,” “to deliver,” “transformation,” “transformative,” “address,” “planned,” “focusing,” “accelerated,” “long-term,” “innovation,” “priority,” “can,” “awaiting,” or similar expressions, or by express or implied discussions regarding potential new products, potential new indications for existing products, potential product launches, or regarding potential future revenues from any such products; or regarding potential future, pending or announced transactions; or regarding potential future sales or earnings of Novartis; or regarding discussions of strategy, priorities, plans, expectations or intentions, including our transformation into a “pure-play” innovative medicines business; or regarding our liquidity or cash flow positions and our ability to meet our ongoing financial obligations and operational needs; or regarding our USD 15 billion share buyback; or regarding our appeal of the negative decision of the US District Court for the District of Delaware on the validity of our patent covering Entresto and combinations of sacubitril and valsartan. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. You should not place undue reliance on these statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. Neither can there be any guarantee expected benefits or synergies from the transactions described in this press release will be achieved in the expected timeframe, or at all. In particular, our expectations could be affected by, among other things: liquidity or cash flow disruptions affecting our ability to meet our ongoing financial obligations and to support our ongoing business activities; the impact of a partial or complete failure of the return to normal global healthcare systems including prescription dynamics; global trends toward healthcare cost containment, including ongoing government, payer and general public pricing and reimbursement pressures and requirements for increased pricing transparency; uncertainties regarding potential significant breaches of data security or data privacy, or disruptions of our information technology systems; regulatory actions or delays or government regulation generally, including potential regulatory actions or delays with respect to the development of the products described in this press release; the potential that the benefits and opportunities expected from our planned spin-off of Sandoz may not be realized or may be more difficult or take longer to realize than expected; the uncertainties in the research and development of new healthcare products, including clinical trial results and additional analysis of existing clinical data; our ability to obtain or maintain proprietary intellectual property protection, including the ultimate extent of the impact on Novartis of the loss of patent protection and exclusivity on key products; safety, quality, data integrity, or manufacturing issues; uncertainties involved in the development or adoption of potentially transformational technologies and business models; uncertainties regarding actual or potential legal proceedings, investigations or disputes; our performance on environmental, social and governance measures; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise.
All product names appearing in italics are trademarks owned by or licensed to Novartis AG and its subsidiaries. BAUSCH + LOMB is a registered trademark of Bausch & Lomb Incorporated.
About Novartis
Novartis is a focused innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide.
Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram.
Novartis will conduct a conference call with investors to discuss this news release today at 14:00 Central European time and 8:00 Eastern Time. A simultaneous webcast of the call for investors and other interested parties may be accessed by visiting the Novartis website. A replay will be available after the live webcast by visiting https://www.novartis.com/investors/event-calendar.
Detailed financial results accompanying this press release are included in the condensed interim financial report at the link below. Additional information is provided on Novartis divisions and pipeline of selected compounds in late stage development and a copy of today's earnings call presentation can be found at https://www.novartis.com/investors/event-calendar.
Important dates
November 13, 2023 Impact and Health Equity Annual Event November 28, 2023 R&D Day
Please find full media release in English attached and on the following link:
Media release (PDF)
German version is available through the following link:
Medienmitteilung (PDF)
French version is available through the following link:
Communiqué aux médias (PDF)
临床结果上市批准并购财报加速审批
2022-12-22
·药时代
点击欣赏推介会全程——优秀BD是怎样炼成的？请点击左下方【阅读原文】报名！1靶向治疗：抗癌药物愿景长期以来，心血管疾病是全球中年人死亡的主要原因。这种情况最近在高收入国家发生了变化，现在癌症导致的死亡人数是心血管疾病的两倍。2018 年，癌症导致全球 960 万人死亡，1810 万新病例被诊断出来。女性最常发生的癌症是乳腺癌，而男性最常见的是前列腺癌。在过去的 60 年里，化疗仍然是癌症治疗的标志。在这种方法中，系统性地使用高细胞毒性药物。然而，这些化疗药物也会影响高增殖率的健康细胞，如肠上皮细胞。这种外周毒性是化疗经常发生副作用的原因。不良反应的发生在很大程度上取决于患者和应用的化疗药物。这不仅适用于化学治疗剂，而且适用于全身给药而不具有任何选择性的任何治疗剂分子。减少副作用的一种可能性是放弃全身给药的药物，只对受影响的组织局部应用伤害肿瘤的治疗。这种愿景催化了放疗的产生，但即便辐射可以针对局部的癌细胞，但使用的剂量可以造成照射区域内的所有细胞受到影响。尽管如此，放射治疗仍然是一种重要的治愈性治疗方式，超过 50% 的患者受益于这种治疗。尽管放射疗法经常与手术和化学疗法结合使用以增加抗肿瘤效果，但长期癌症幸存者发生第二次恶性肿瘤的风险更高，因为放射线也会损害健康组织的遗传物质。出于这种考虑，递送的药物剂量必须尽可能地低，以防止过量剂量对健康组织造成伤害。然而又必须首先满足有效消除癌细胞的前提。这看上去有些像一个投鼠忌器的难解矛盾。在过去的几十年里，人们一直心心念念着癌症的靶向治疗，并且开发了多种方法来提高肿瘤细胞的辐射敏感性。毫无疑问，所有这些方法都需要施用药物，并且选择性地寻找癌细胞。可以通过瞄准癌症的生化特征，促进选择性治疗药物的递送。例如癌细胞经常过度表达细胞表面蛋白，这些蛋白结合不同的配体，允许靶向肿瘤细胞。 肿瘤细胞的凋亡诱导剂，一旦与靶向肿瘤细胞的配体分子通过合理的手段结合在一起，理论上就有可能实现癌症的靶向治疗。尽管这个概念似乎很简单，但实现起来却相当复杂，如今仍然具有极强的挑战性。原则上，可以实现选择性给药的所有偶联物均由三个模块组成（图 1）。第一个成分是载体 (carrier)，它负责肿瘤靶向。除了适体（aptamer）之外，小分子和生物制剂（例如多肽、蛋白质和抗体）也可以充当载体角色。第二个成分是药物本身 (载荷, payload)，它可以诱导多种生物学功能，但在癌症治疗的背景下，主要使用细胞毒性分子或放射性核素 (radionuclide)。第三个模块 (手臂，linker) 链接前两者。视载荷特性可使用可裂解或不可裂解的手臂，以实现受控药物释放。 图1. 受体靶向药物偶联物的结构示意图。药物偶联物由三个模块组成：有效载荷、手臂和载体 （图片来源：Frontiers in Chemistry）。2载体载体，也称为肿瘤归巢剂（tumor-homing agent），这个名称形象地比喻了将载荷引入肿瘤细胞的化合物。小分子、适体和多糖都可以充当这种引路者的角色。单克隆抗体 (mAb) 已发展成为增长最快的药物类别，在过去几年中有 30 多种 mAb 获得批准，100 多种 mAb 处于临床开发阶段。很多抗体药物偶联物 (ADC) 也已获得FDA和EMA 的监管批准。它们都与细胞表面受体如 CD22、CD30、CD33 或人类表皮生长因子受体 2 (HER2) 结合，这些受体与 ADC 一起内化。在溶酶体中ADC 降解后，附着的细胞毒性有效载荷被释放并产生药效。尽管这些偶联物上市并证明了这种方法的可行性，但抗体存在严重的局限性。大多数 mAb它们体量太大而无法有效扩散到肿瘤细胞之中。除此之外，单克隆抗体可能产生免疫原性。此外，mAb 成本非常高昂。大多数单克隆抗体这些缺点可以通过使用更小的多肽等生物分子弥补。事实上，多肽作为多肽-药物偶联物 (PDC) 的载体分子具有几个优点。合成方式简明直接且有很高的扩大能力。多肽的化学修饰可以提高它的亲和力。此外，多肽可被蛋白水解酶快速降解，并通过肝脏和肾脏从血液循环中快速清除。多肽通常被认为是安全的，因为它们具有低免疫原性并产生无毒代谢物。此外，相对于抗体来说，低分子量的多肽可以实现对组织的有效渗透，从而产生更好的抗肿瘤效果。PDC 中使用的肽可分为两类：细胞穿透肽 (cell-penetrating peptides，CPPs) 和细胞靶向肽 (cell-targeting peptides，CTPs)。CPPs 跨细胞膜的摄取机制尚未完全清楚。由于细胞特异性低，CPPs 的广泛应用受到限制。相比之下，CTP 是更为理想的载体分子，它们具有与 mAb 相同的能力。它们以高亲和力结合肿瘤细胞表面过度表达的受体，但却不受单克隆抗体缺点的不利影响。3肿瘤治疗中的多肽受体靶标开发高效抗癌药物过程中面临的重大挑战之一，在于如何选择性地将药物输送到肿瘤部位，而不影响健康组织。细胞表面受体在靶向癌症治疗方法中备受关注，因为它们提供了允许选择性肿瘤靶向的所需特性（表 1）。 表1. 常见肿瘤细胞靶向受体4手臂很多手臂技术被尝试应用于PDC，具体选择取决于PDC的 作用机制。手臂必须在循环中表现出稳定性，以防止药物过早地以及非特异性释放。载荷提前释放是 PDC 关注的一个重点，因为提前释放细胞毒素而产生的体内积累会导致危险，甚至产生致命的副作用。同样重要的是要考虑手臂在体内代谢过程中的命运，以及由此产生的产物的毒性。与 ADC 一样，用于 PDC 的手臂分为可切割的或不可切割的。可切割手臂的降解可以是酶介导或者化学介导的。而不可切割的手臂不会被环境刺激降解，例如 pH 值、谷胱甘肽 (GSH) 或肿瘤微环境中发现的酶的变化。可裂解手臂包括酸裂解、二硫键可还原裂解。图2显示了PDC常用的手臂裂解方式，包括腙的酸解（产生醛/酮与肼，安全性上似乎要打一个大大的问号）、二硫键还原为硫醇、偶氮还原为胺、酯的酶解（酯酶作用产生羧酸与醇）、氨基甲酸酯酶解（CYP450与酯酶）为异氰酸酯和醇，前者会水解为胺与二氧化碳、酰胺酶解（蛋白酶）为羧酸与胺。 图2. PDC的手臂结构与裂解方式。（图片来源：Frontiers in Chemistry）5药物载荷研发人员开发了一系列细胞毒性药物，希望在治疗癌症的过程中实现它们的疗效。但令人壮志难酬的是，这些细胞毒性药物大多都不具备靶向肿瘤细胞的选择性，对健康细胞造成伤害并导致严重的副作用，因而药代学特性难以令人满意。靶向治疗提供了一种重新利用药物（drug repurposing）的方法。多肽载体的浮出水面也让研究者看见了靶向治疗的曙光。当细胞毒素以恰好的方式结合多肽载体时，因为它的精准递送，可以显著降低细胞毒素的剂量。选择的细胞毒性有效载荷通常具有低 IC50，通常在纳摩尔范围内。 PDC 中使用的有效载荷示例包括阿霉素(Doxorubicin，亦称多柔比星)、紫杉醇（taxol）、柔红霉素（Daunorubicin，亦称道诺霉素）、吉西他滨（Gemcitabine） 和 美登素（mertansine，亦称美登新）4（图 3）。 图3. 几种PDC中使用的细胞毒素分子结构。（图片来源：Chem. Soc. Rev.）细胞毒性有效载荷也可以包括放射性核素，比如FDA 批准的 177Lu-dotatate （图 4）。177Lu-dotatate 用于治疗胃肠胰神经内分泌肿瘤（GEP-NETs），是第一个 FDA批准的 PDC。在这个PDC中扮演归巢肽角色的多肽是生长抑素（somatostain），它通过酰胺与DOTA（1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid，1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）手臂链接，另一端, DOTA手臂与细胞毒性放射治疗剂 177Lu 偶联。177Lu-dotatate IV 给药，每 8 周一次，通常共4个周期治疗。 图4：PDC药物177Lu-dotatate化学结构与组成部分示意图（图片来源：Chem. Soc. Rev.）PDC 不仅限于用作治疗剂，而是广泛用作显像剂，例如FDA 批准含有放射性核素的 PDC：111In-DTPA-Octreotide (OctreoscanTM), 它用于治疗神经内分泌肿瘤。然而研究表明，OctreoscanTM对肿瘤消退的影响比较有限，因此，它退而求其次地主要用于了诊断目的。相比之下，177Lu-dotatate具有更大的治疗潜力。 放射性核素可以通过各种扫描技术，以精确定位的方式对肿瘤进行成像。5 归巢多肽结合物的使用可以实现选择性地结合受体而几乎不产生异位靶向。为了将显像剂嵌合到多肽分子中，研究人员经常经常使用双功能螯合剂，其中DOTA 和DTPA （二亚乙基三胺五乙酸）最受青睐（图5）。PDC 显然是一种多功能策略，不仅可用于运输载荷药物，也可以递送显像剂以识别肿瘤位置或确定肿瘤进展。 图5. 双螯合剂DOTA与DPTA化学结构。6总结尽管目前FDA只批准了两款PDC药物（不包括诊断试剂）：177Lu-dotatate (lutathera®) 和melflufen flufenamide （Pepaxto®）(后者已被从美国市场撤回)。 但有很多PDC目前处于临床或前临床阶段。根据 InsightAce Analytic 的最新研究，预计 2022-2030 年期间，全球肽-药物偶联物 (PDC) 市场的复合年增长率将达到 13.7%。按地区划分，北美以最大的份额主导着全球肽-药物偶联物 (PDC) 市场。PDC药物肿瘤穿透性强，生产成本低，免疫原性低。与其他偶联药物相比，PDC药物具有更广泛的产业基础和临床价值。随着相关技术问题的解决和配套技术的突破，PDC药物也将成为未来十年的研发和投资热点。更多创新生物制药公司将加入这场竞赛，使PDC药物的快速发展，造福更多的患者。[1] Vhora, I. et al. Receptor-targeted drug delivery: current perspective and challenges. Ther.Deliv. 2014, 5, 1007–1024. [2] Carrasco-Triguero, M. et al. Immunogenicity assays for antibody-drug conjugates: case study with adotrastuzumab emtansine. Bioanalysis. 2013, 5, 1007–1023. [3] Vhora, I. et al. Receptor-targeted drug delivery: current perspective and challenges. Ther.Deliv. 2014, 5, 1007–1024. [4] E. I. et al. G. Mez+o and A. G. Tzakos, On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site. Beilstein J. Org. Chem. 2018, 14, 930–954. [5]Hoppenz, et al., Peptide-Drug Conjugates and Their Targets in Advanced Cancer Therapies. Front. Chem. 2020, 8, 571. [6] Olivier, T. Et al. The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA. Translational Oncology. 2022, 18, 101374. 封面图来源：123rf推荐阅读第四届“健康中国思南峰会”在沪召开：数字化转型推动医疗健康产业变革【重磅录像】颜宁：“AI在结构生物学中的未达之地”二期临床刚成功，股票就大涨，看了这款mRNA癌症疫苗，我悟了……武田60亿美元买的药，其实是AI设计的干货 | 如何成为一名优秀的BD？这啥CAR-T啊？刚做完一期临床，就卖了40多亿美元...推荐阅读资本寒冬里，我们一起重温王健博士解读的「新药研发投融资之春夏秋冬四季」！沙利文发布：中国首个白血病领域CAR-T产品NDA受理，掀起商业化新浪潮我们在冬天里欢聚，一起讲述春天的故事！——第二届中国新药领袖闭门交流会成功举办！第四届“健康中国思南峰会”在沪召开：数字化转型推动医疗健康产业变革【重磅录像】颜宁：“AI在结构生物学中的未达之地”首款！FDA批准辉凌制药治疗膀胱癌全新基因疗法二期临床刚成功，股票就大涨，看了这款mRNA癌症疫苗，我悟了……动力学+铁死亡：深势科技首次公开RiDymo™平台管线应用进展武田60亿美元买的药，其实是AI设计的？重磅预告！【药时代奖学金】即将闪亮登场！药时代BD高阶研讨会火热报名中！
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