P-CCROSS is a randomized, prospective monocentric phase 4 study with a crossover study design. The aim of the study is to compare patient satisfaction (by means of questionnaires) and treatment compliance with IVF treatment with CFA (corifollitropin alfa) and PPOS (Progestin-Primed Ovarian Stimulation) versus conventional IVF treatment with a recombinant FSH/GnRH antagonist. The study will also compare patients undergoing elective fertility preservation versus PGT-A (pre-implantation genetic testing for aneuploidy) patients.The study will have a crossover design so that patients will receive both forms of treatment. The investigators will also compare the endocrine profile and ovarian response of CFA/PPOS versus rFSH/GnRH ovarian stimulation cycles.

开始日期2024-11-01

申办/合作机构

Ghent University Hospital

NCT06193135 / Not yet recruitingN/AIIT

Usefulness of Corifollitropin α as Alternative to Conventional Daily rFSH Protocols in Oocyte Donors Undergoing Pituitary Suppression With Medroxiprogesterona Acetate (MPA)

IVF patients frequently experience physical, emotional or physicological burden; this is particularly relevant in the case of oocyte donors, since young women undergo a procedure that is of no health benefit to them. One of the phases of the treatment that contributes most to this situation is ovarian stimulation; as it involves the administration of daily injections which, in addition to the discomfort of administration, causes anxiety to the patient about its correct administration and possible side effects and to physicians concerns about patient compliance.
Advances in pharmacology and knowledge of ovarian pathophysiology have led to the development of new protocols that simplify and reduce drug administration, decrease the potential risk of misapplication and contribute to an improved patient experience. In this context, Corifollitropin α, a long-acting recombinant FSH (rFSH) molecule, provides with a single subcutaneous injection similar results as daily administration of rFSH during a week.
On the other hand, conventional stimulation protocols used in ART resort to using a GnRH analogue (agonist or antagonist) to prevent early luteinization, which is defined as the presence of a progesterone value of > 1.5 ng/ml on the day of induced ovulation. Nevertheless, its use presents some disadvantages, such as it being sometimes complex to achieve desensitization or consistent hypothalamic block, risk of OHS when ovulation is triggered with HCG or its cost. Hence the interest in exploring new options to prevent a premature peak in LH. Nowadays, the oral administration of progestagens (progesterone-primed ovarian stimulation [PPOS]) during the follicular phase of ovarian stimulation (OS) has emerged as an attractive alternative to conventional protocols for preventing early luteinization. Moreover, PPOS produces a similar or even better, in some subgroups, response to OS (length of treatment, number of MII, cancelation rate, etc.), reproductive outcomes (pregnancy rate, live birth rate, etc) and safety (rate of ovarian hyperstimulation [OHSS] or congenital malformations).
Thus, PPOS would seem to be an effective option for personalized protocols, particularly when fresh embryo transfer (FET) is not to be performed, a circumstance that is likely to rise in frequency given the progressive increase in women's age at childbearing; for example, in oocyte donation, or in fertility preservation (FP) and preimplantation genetic testing for aneuploidy (PGT-A). However, very little data are available regarding cycle outcome following Corifollitropin α and PPOS as pituitary suppressor.
The present study, a prospective RCT, was designed to evaluate cycle characteristics (MII oocytes as the primary objective) and endocrinologic profiles of oocyte donors receiving Corifollitropin α and MPA as co-treatment compared with those receiving a daily dose of rFSH (follitropin β) as a control.

开始日期2024-03-01

申办/合作机构

Instituto Valenciano de Infertilidad SL

NCT06134479 / Recruiting临床3期IIT

Comparison of Sequential CFA vs CFA +rFSH for Elective Fertility Preservation.. The 2-shot Protocol.

This randomized was designed as non-inferiority trial aiming to compare the number of MII oocytes with 2-shot of Corifollitropin alpha (CFA) sequential administration: 150μg at stimulation day (SD) 1 and 100μg at SD 5 and 1-shot of CFA administration 150μg at SD 1 following by rFSH 200IU daily from SD 8 in women undergoing elective fertility preservation in a progestin-primed ovarian stimulation (PPOS) protocol and GnRH-agonist (GnRH-a) triggering.

开始日期2023-12-12

申办/合作机构

Organon & Co.

100 项与 Corifollitropin alfa 相关的临床结果

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100 项与 Corifollitropin alfa 相关的专利（医药）

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项与 Corifollitropin alfa 相关的文献（医药）

2024-09-01·FERTILITY AND STERILITY

Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials

Review

作者: Rienzi, Laura ; Alviggi, Carlo ; Iorio, Giuseppe Gabriele ; Carbone, Luigi ; Vaiarelli, Alberto ; Di Girolamo, Raffaella ; Esteves, Sandro C. ; Ronsini, Carlo ; Conforti, Alessandro ; Campitiello, Maria Rosaria ; Cimadomo, Danilo ; D'Hooghe, Thomas ; Guida, Maurizio ; Esteves, Sandro C ; Ubaldi, Filippo Maria ; D’Hooghe, Thomas ; Longobardi, Salvatore

IMPORTANCE:

The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials.

OBJECTIVE:

To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria.

DATA SOURCES:

We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024.The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number: CRD42022346117).

STUDY SELECTION AND SYNTHESIS:

After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336); testosterone (n = 418); high- vs. low-dose gonadotropin (n = 957); delayed-start protocol with gonadotropin hormone-releasing hormone antagonist (n = 398); letrozole (n = 612); clomiphene citrate (1,113); growth hormone (311); luteal phase stimulation (n = 57); dual triggering (n = 139); dual stimulation (168); luteinizing hormone (979); oestradiol pretreatment (n = 552); and corifollitropin alfa (n = 561).

MAIN OUTCOMES:

The primary outcome was live birth rate or ongoing pregnancy if data on live birth were unavailable. Secondary outcomes were number of oocytes retrieved, number of metaphase II oocytes, clinical pregnancy rate and miscarriage rate.

RESULTS:

Testosterone supplementation is associated with higher live birth rates compared with nonsupplemented women among all interventions evaluated (odds ratio: 2.19, 95% confidence interval [CI]: 1.11-4.32, four studies, 368 patients). Testosterone (weighted mean difference [WMD] 0.88, 95% CI: 0.03-1.72; 4 studies, n = 368 patients), dehydroepiandrosterone (WMD 0.60, 95% CI: 0.07-1.13; 4 studies, n = 418 patients), and delayed started protocol (WMD 1.32, 95% CI: 0.74 to 1.89; 3 studies, n = 398 patients) significantly improved the total number of eggs collected. Lower number of oocytes retrieved is achieved in women undergoing low dose gonadotropin regimen vs high dose (WMD: -1.57, 95% CI: -2.12 to -1.17; 2 studies, n = 905 patients), The other interventions did not produce significant improvements.

CONCLUSION AND RELEVANCE:

Specific interventions such as testosterone seem to correlate with a better live birth rate in women with DOR; these findings should be further explored in randomized trials.

2024-09-01·HUMAN REPRODUCTION

Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial

Article

作者: Goro, Seydou ; Carton, Isis ; Massin, Nathalie ; Chevalier, Nicolas ; Cédrin-Durnerin, Isabelle ; Dubourdieu, Sophie ; Bstandig, Bettina ; Michelson, Xénia ; Jung, Camille ; Guivarc’h-Lévêque, Anne

Abstract:

STUDY QUESTION:

Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol?

SUMMARY ANSWER:

Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38–42 years.

WHAT IS KNOWN ALREADY:

Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise.

STUDY DESIGN, SIZE, DURATION:

This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38–42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1–2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20–24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8.

MAIN RESULTS AND THE ROLE OF CHANCE:

Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of −0.1 oocyte 95% CI [−1.5; 1.3] P = 0.004 in the PP population and a mean difference of −0.44 oocyte [−1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively).

LIMITATIONS, REASONS FOR CAUTION:

Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias.

WIDER IMPLICATIONS OF THE FINDINGS:

Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification.

STUDY FUNDING/COMPETING INTEREST(S):

Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA.

TRIAL REGISTRATION NUMBER:

ClinicalTrials.gov NCT02884245.

TRIAL REGISTRATION DATE:

29 August 2016.

DATE OF FIRST PATIENT’S ENROLMENT:

4 November 2016.

2024-06-01·F&S reports

Continuous ovarian stimulation: a proof-of-concept study exploring the uninterrupted use of corifollitropin α in DuoStim cycles for enhanced efficiency and patient convenience (Alicante protocol)

Article

作者: Bernabeu, Rafael ; Fuentes, Ana ; Abellán, Esther ; Ortiz, Jose Antonio ; Bernabeu, Andrea ; Castillo, Juan Carlos

Objective:

To explore the use of weekly continuous dosing of corifollitropin α in DuoStim cycles.

Design:

Pilot-matched case-control study.

Setting:

Private fertility center.

Patients:

Cases were defined as DuoStim cycles performed from November 2022 to May 2023 receiving weekly continuous dosing of corifollitropin α (n = 15). Controls were chosen from a database comprising DuoStim cycles conducted at our institution during the years 2021/2022. Matching was done on a 1-to-1 basis, based on antimüllerian hormone values (±0.4 pmol/L) and age (n = 15).

Interventions:

Injections of corifollitropin α once every 8 days, along with uninterrupted oral administration of micronized progesterone 200 mg/d (for luteinizing hormone surge prevention) throughout the follicular and luteal phases for ovarian stimulation. Oocyte retrieval.

Main outcome measures:

Total number of cumulus-oocyte complexes and metaphase II oocytes obtained in follicular + luteal phase stimulation. Secondary outcomes evaluated fertilization rates, number of blastocysts, days of stimulation, number of injectables required, and gonadotropin cost.

Results:

The study group achieved similar total oocyte and MII yield vs. daily follicle-stimulating hormone protocol (13.3 ± 6.9 vs. 11.8 ± 6.1 and 10.4 ± 6.3 vs. 9.2 ± 4.6, respectively). All secondary outcomes showed no significant differences. The study group experienced a significant reduction of injections to complete a DuoStim cycle (4.5 ± 1.4 vs. 35.2 ± 12.2; mean deviation -30.7; 95% confidence interval, -37.5- to -23.9)].

Conclusions:

Corifollitropin α on a weekly basis throughout a DuoStim cycle yields an equivalent number of oocytes as standard daily follicle-stimulating hormone administration while drastically reducing the number of required injections.

Trial registration number:

NCT05815719. EudraCT: 2022-003177-32.

项与 Corifollitropin alfa 相关的新闻（医药）

2024-10-21

·CPHI制药在线

赛诺菲拆分新动作，这一业务缘何成为MNC弃子？

关注并星标CPHI制药在线近日，据Fierce Pharma报道，赛诺菲正在与美国私募股权公司Clayton,Dubilier&Rice进行谈判，可能出售其消费者健康业务部门Opella的50%控股权，该笔交易的价值或高达150亿欧元（约164亿美元）。 Opella是赛诺菲旗下消费者健康业务部门，总部位于法国，是非处方药和维生素、矿物质和补充剂市场的全球第三大公司。Opella拥有多个知名品牌，包括抗过敏药物Allegra、肌肉疼痛缓解产品Icy Hot、爽身粉Gold Bond等。根据赛诺菲新闻稿，Opella现拥有研发、生产、数字化的专用资源，拥有11000多名员工，管理13个生产基地和4个研究和创新中心。赛诺菲为何要剥离Opella？事实上，这是赛诺菲“全力致胜”（Play to Win）战略的关键一步，旨在将资源集中在创新药物和疫苗业务上，以提升研发生产力和市场竞争力。此次剥离Opella，赛诺菲将会获得大量现金注入，从而将更多资源投入到生物制药业务中。未来，赛诺菲将把自身免疫性疾病作为重点布局方向之一，并且可能会进军减肥赛道。除赛诺菲外，近年来，头部MNC（跨国医药集团）一直在剥离消费者健康业务。背后有什么原因？消费者健康业务成为MNC弃子 2020年2月，默沙东宣布将剥离其专注于女性健康的业务板块，2021年6月，公司正式从默沙东分拆，并重新启用Organon（中文名“欧加隆”）作为公司名。此后，Organon作为一家独立公司于纽交所上市（NYSE：OGN）。目前，Organon在女性健康、生物类似药以及经典品牌业务领域拥有超过60款药物和产品组合，包括皮下植入式避孕剂Nexplanon、长效促排卵针Elonva、针对产后出血的Jada System等女性生殖健康和生育方面的产品，以及免疫学和肿瘤学治疗产品。欧加隆在全球已实现大规模、广覆盖的发展，在比利时、巴西、印度尼西亚、墨西哥、荷兰和英国运营着6家制造工厂，产品销往全球140多个国家和地区。默沙东之后，强生、GSK等也相继剥离消费者健康部门。2022年11月，强生宣布，计划将其消费者健康部门剥离出来，作为独立公司上市。2023年8月，该部门作为新公司正式分拆出来，命名为Kenvue。 Kenvue拥有多款知名消费者健康品牌，如邦迪创可贴、泰诺(Tylenol)药品、李施德林漱口水等4个价值10亿美元的大品牌，以及20个超过1.5亿美元的品牌，每年业务总规模近150亿美元。随着今年5月13日，强生宣布出售在Kenvue仅有的9.5%股份，意味着强生彻底告别经营百年的消费者健康业务。强生董事会主席Joaquin Duato曾表示，分拆消费者健康业务，是为了进一步加强强生对制药和医疗技术业务转型创新的关注。 2024年5月，GSK宣布，计划出售其在消费者健康公司Haleon(赫力昂)的剩余所有股份。Haleon由GSK和辉瑞的消费保健部门于2018年12月合并组建而成。此次出售，意味着GSK彻底退出消费健康领域。对于默沙东、GSK、赛诺菲等全球大型药企来说，消费者健康业务剥离热潮已经持续了近十年。除此之外，MNC还在持续“瘦身”，剥离非核心业务。持续剥离背后，映射MNC创新转型迫切在剥离消费者健康业务之外，一些MNC也在终止公司的非核心业务。去年，强生关闭了其传染病和疫苗部门。今年9月底，外媒报道，强生正在关闭其制药部门的心血管和代谢药物部门。并将研发重点缩小到三个治疗领域：肿瘤学、免疫学和神经科学。辉瑞也在剥离旗下多个仿制药，同时专注于创新药。2021年3月，辉瑞宣布停止在中国生产生物仿制药，并将位于杭州的生物药基地出售给无锡药明生物。诺华在剥离了仿制药公司山德士后，又终止了研发管线中的非核心项目，诺华表示要聚焦心血管、肾脏及代谢，免疫，神经科学以及肿瘤这四个核心治疗领域。伴随着MNC将“聚焦创新”作为发展关键词，未来消费者健康业务的剥离将是大势所趋。如拜耳（Bayer）也曾考虑分拆其消费者健康业务，该业务包括非处方药品、营养补充品和皮肤护理产品。拜耳希望通过分拆这些业务，更专注于其制药和生命科学领域的核心业务。通过剥离，MNC将更专注于创新药物的研发，这对于全球患者来说无疑是一个好消息。参考来源： 1.https://www.fiercepharma.com/pharma/sanofi-enters-talks-private-equity-firm-purchase-controlling-stake-consumer-health-business. 2.https://www.reuters.com/markets/deals/jj-sell-all-shares-spun-off-unit-kenvue-2024-05-13/. END 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

并购免疫疗法疫苗生物类似药

2024-07-02

·PRNewswire

INOVIO Announces Appointment of Steven Egge as Chief Commercial Officer

Mr. Egge brings over 25 years of biopharmaceutical experience building commercial organizations and successfully launching novel therapeutic products INOVIO poised to become a commercial-stage company with plans to submit a Biologics License Application for INO-3107 in second half of 2024 under U.S. Food and Drug Administration's Accelerated Approval Pathway PLYMOUTH MEETING, Pa., July 2, 2024 /PRNewswire/ -- INOVIO (NASDAQ:INO), a biotechnology company focused on developing and commercializing DNA medicines to help treat and protect people from HPV-related diseases, cancer, and infectious diseases, today announced the appointment of Steven Egge as Chief Commercial Officer. Mr. Egge will lead the company's commercial strategy and operations as it prepares to potentially launch its first DNA medicine product, INO-3107 as a treatment for recurrent respiratory papillomatosis (RRP). "We are delighted to welcome Steve to INOVIO and look forward to adding his expertise to our leadership team as we continue advancing our preparations to commercially launch INO-3107 in 2025, should it receive approval by the FDA as a treatment for RRP," said Dr. Jacqueline Shea, INOVIO's President and Chief Executive Officer. "Steve joins us at an exciting time, as we prepare to become a commercial-stage company, while advancing multiple product candidates targeting unmet medical needs. His expertise launching new products, driving market share in competitive environments, and growing overall therapeutic areas will be advantageous to the development and implementation of our commercial plans, as will his experience across immunology and vaccines, HPV, and rare diseases." "This is a great time to join INOVIO as the company has the opportunity to market the first therapeutic option for patients suffering from RRP, a rare and debilitating HPV-related disease that significantly impacts quality of life," said Mr. Egge. "I look forward to working with the talented team at INOVIO and continuing the ongoing efforts to build out the company's commercial strategies and capabilities." Mr. Egge comes to INOVIO from Sumitomo Pharma (formerly Myovant Sciences, acquired by Sumitovant Biopharma, a subsidiary of Sumitomo Pharma, in 2023), where as Senior Vice President and General Manager for Women's Health he was responsible for building the commercial leadership team, accelerating the launch of Myfembree® and helping lead the company's expansion into new indications. Mr. Egge was at Merck for twenty years, where he held a number of senior commercial leadership roles, including leading Merck's HPV Vaccines Franchise as well as Chief Marketing Officer for the Vaccine Division, where he oversaw launches for new indications for GARDASIL®, a re-launch of ZOSTAVAX®, and launch planning for GARDASIL9® and VAXELIS®. Mr. Egge also served as Global Commercial Head for Merck's Fertility Franchise, where he oversaw the launch of ELONVA® in ex-U.S. markets. After Merck, Mr. Egge served as Senior Vice President at Genfit Corp., a French biotech company focused on liver diseases, where he led commercial planning and business development. About INOVIO's DNA Medicines Platform INOVIO's DNA medicines platform has two innovative components: precisely designed DNA plasmids, delivered by INOVIO's proprietary investigational medical device, CELLECTRA®. INOVIO uses proprietary technology to design its DNA plasmids, which are small circular DNA molecules that work like software the body's cells can download to produce specific proteins to target and fight disease. INOVIO's proprietary CELLECTRA® delivery devices are designed to optimally deliver its DNA medicines to the body's cells without requiring chemical adjuvants or lipid nanoparticles and without the risk of the anti-vector response historically seen with viral vector platforms. About INOVIO INOVIO is a biotechnology company focused on developing and commercializing DNA medicines to help treat and protect people from HPV-related diseases, cancer, and infectious diseases. INOVIO's technology optimizes the design and delivery of innovative DNA medicines that teach the body to manufacture its own disease-fighting tools. For more information, visit . CELLECTRA® is a trademark of INOVIO. GARDASIL®, GARDASIL9®, ZOSTAVAX® and ELONVA® are trademarks of Merck and Co., Inc. VAXELIS® is trademark of The MSP Vaccine Company. Myfembree® is trademark of Sumitomo Pharma Switzerland GmbH. Forward-Looking Statements This press release contains certain forward-looking statements relating to our business, including our plans to develop and commercialize DNA medicines and expectations regarding our research and development programs, including the planned submission of a BLA in the second half of 2024 and the planned commercial launch of INO-3107 if regulatory approval is obtained. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials, product development programs and commercialization activities and outcomes, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA medicines, our ability to support our pipeline of DNA medicine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by us or collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that we and our collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide us with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether we can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of our technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2023, our Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, and other filings we make from time to time with the Securities and Exchange Commission. There can be no assurance that any product candidate in our pipeline will be successfully developed, manufactured, or commercialized, that the results of clinical trials will be supportive of regulatory approvals required to market products, or that any of the forward-looking information provided herein will be proven accurate. Forward-looking statements speak only as of the date of this release, and we undertake no obligation to update or revise these statements, except as may be required by law. Contacts Media: Jennie Willson (267) 429-8567 [email protected] Investors: Thomas Hong (267) 440-4298 [email protected] SOURCE INOVIO Pharmaceuticals, Inc.

高管变更疫苗

2023-01-23

·生物制药小编

融合蛋白成功的基石：融合蛋白技术

目前已形成市场规模的一些治疗性蛋白是基于融合蛋白技术产生的。融合蛋白是指利用基因工程等技术将某种具有生物学活性的功能蛋白分子与其他蛋白（融合伴侣）融合而产生的新型蛋白。由于许多功能蛋白通常在血清中表现出很短的半衰期，而为了有效地利用这些功能白，必须反复给药，这大大限制了它们的治疗应用。通过融合伴侣的引入可以增强功能蛋白的活性和更长时间的耐受性，包括清除时间延长，引起局部刺激的能力减弱，半衰期增加，对降解的抵抗力增强，这无疑大大拓宽了功能蛋白的应用。目前人们目前已经开发了多种融合蛋白技术，例如免疫球蛋白融合技术、人血清白蛋白（HSA）融合技术（图1）。这些技术在融合蛋白药物的成功之路上发挥了举足轻重的基石作用。本文就一些经典的融合蛋白技术做一个简要介绍。免疫球蛋白融合技术使用基因工程技术，可以使用抗体的结构域来创造融合蛋白，从而进一步促进功能。所使用的抗体结构域可以是恒定区，也可以是可变片段。 Fc 融合目前最常用的融合伴侣为免疫球蛋白IgG的Fc段，抗体Fc是抗体恒定区的一部分，包括铰链区-CH2-CH3（图2）。与可变区相比，使用恒定区作为融合蛋白的伴侣有助于融合蛋白的大小调节和药代动力学特性。此外，使用Fc区域融合可以使下游处理过程更容易，因为其可以使用治疗性抗体的技术来产生和纯化Fc融合蛋白。与Fc段融合后通过增加分子量、FcRn介导的再循环机制可增加融合分子的稳定性、延长体内半衰期，同时也可利用Fc段介导ADCC、CDC等各种生物学功能。目前，全球已经上市了20个左右的Fc融合蛋白药物，明星产品依那西普、阿柏西普、康柏西普、度拉鲁肽均属于Fc融合蛋白。可变片段(Fv)融合利用免疫球蛋白可变区的融合蛋白工程策略，也已经进行了广泛的应用。使用可变区而不是恒定区不仅可以减小融合蛋白的大小，而且还限制了免疫球蛋白的可编程性仅限于靶向。它们可以产生最小的融合蛋白，可以轻松、快速地穿过组织或肿瘤。然而，在没有加入恒定区的情况下，Fv融合的应用存在一定的稳定性问题。抗体的抗原结合片段本身作为异源二聚体是足够稳定的，但由重链和轻链可变区组成的二聚体不稳定，重链可变区(VH)和轻链可变区(VL)之间的界面相互作用较弱。为了克服这一不稳定的杂二聚体的障碍，人们已经采用了成功的方法，聚焦于将多肽连接物子与VH和VL共价偶联。所使用的多肽连接物必须是柔性的，通常由丝氨酸和甘氨酸组成，约为15到20个氨基酸，并产生了由单链组成的Fv分子。与自然存在的VH-VL杂二聚体相比，这些生成的分子表现出更高的稳定性。另外还采用了一些额外的策略来进一步提高Fv片段的稳定性及其治疗用途。例如，有些单链抗体融合后可能有机会解离，并最终可能导致聚集。这可以通过掺入VH和VL之间的共价二硫键或通过引入突变来克服。 TNF-α、细胞因子融合蛋白和HLA多肽复合体的融合蛋白都是可以利用抗体的可变区进行生物工程的融合蛋白的例子。抗体-酶融合蛋白随着生物分子科学的发展，由酶和抗体组成的融合蛋白越来越多地被创造出来。例如，抗体-酶融合分子可以通过 “抗体靶向酶前药融合蛋白疗法” 靶向到肿瘤部位。这种方法的关键是抗体使有毒的酶被癌细胞内化，激活细胞死亡的途径。到目前为止，抗体-酶融合蛋白在各种临床前研究和人体研究中显示出作为药物的前景。此外，与标准化疗相比，抗体-酶融合蛋白的毒性相对最小。基于HSA的重组融合蛋白 HSA是人血浆中含量最高的蛋白质，占血浆总蛋白的40%- 60%，半衰期长达20天。使用HSA作为融合伙伴提供了一种灵活的方法来产生半衰期较长的治疗性蛋白质。该技术不仅延长了半衰期，而且使蛋白质更加稳定，并降低了免疫原性。效应蛋白可以通过其氨基末端或羧基末端与HSA融合。通过在末端融合HSA，效应蛋白的功能的几乎不会受到影响。 HSA融合药物的概念最早是由Human Genome Sciences公司提出的。基于HSA的融合技术受到了研究人员的极大关注，应用比较广的是抗体与HSA融合、细胞因子与HSA的融合、多肽与HSA的融合等(图3)。目前，HSA融合技术领先的公司主要是GSK、Teva、Cogenesis和CSL这四家药企。GSK开发的GLP-1-HSA产品Tanzeum已经在欧美上市，给药频率为每周1次。通过将人源GLP-1的第8位丙氨酸替换为甘氨酸，从而增加了降解的拮抗性，再将两条经过修饰后的肽链以二聚体形式与HSA融合，半衰期延长至6-8天。 CSL开发的FVIII-HSA产品Idelvion于2016年1月获批上市, 用于儿童及成年血友病B患者。其在体内半衰期可长达14天，用药频率为每1-2周一次，大幅延长凝血因子IX治疗制剂的半衰期（18-24h）。 XTEN融合技术 XTEN属于蛋白质聚合物的一类，没有重复结构。这是由Amunix开发的一类非结构化的可生物降解的蛋白质聚合物，旨在增加治疗性肽和蛋白质的半衰期。 XTEN聚合物被认为是由六种亲水，化学稳定的氨基酸A，E，G，P，S和T组成的非免疫原性多肽。它们可以通过使用重组DNA技术以融合蛋白的形式生产，也可以通过将它们与所选药物化学偶联来进行工程制造(图4)。通过使用这种方法，可以特定地控制生物活性物质沿XTEN主干的价态和位置。它具有众多优点，如可以使用大肠杆菌进行表达，免疫原性较低，并且它是可生物降解的。 XTEN融合蛋白技术最初由Amunix开发，目前被用于9个融合蛋白药物开发。其中生长激素XTEN融合蛋白处于III期临床研究阶段，半衰期延长到131h，明显高于天然生长激素。艾塞那肽融合XTEN后，猴子体内试验证实半衰期从30min提高到60h。 CTP融合蛋白技术CTP是人绒毛膜促性腺激素β亚基羧基末端肽，早期发现CTP是因为人们观察到绒毛膜促性腺激素和黄体化激素两者结构相似，但半衰期却差别很大，分别为2天和20分钟。绒毛膜促性腺激的不同之处在于，HCGb亚基(HCG-b)具有31个氨基酸残基CTP，该CTP由序列FQSSSS*KAPPPS*LPSPS*RLPGPS*DTPILPQ组成，具有四个O-糖基化位点(表示为S*)，以唾液酸残基结尾。它可以增加重组融合蛋白唾液酸含量，唾液酸能增加黏蛋白的黏度，遮蔽蛋白上的糖链,使其不被糖苷酶水解,保护蛋白质免受蛋白酶降解。同时可提高蛋白质糖基化程度，增加分子量，因此可以获得更长的药物体内半衰期。另外，CTP是人体自身的天然长效融合伴侣，所以免疫源性非常低。 CTP技术最初由Prolor Biotech开发。CTP已经与几种激素、细胞因子融合在一起，试图延长它们的半衰期。FSH-CTP（Org 36286）是第一个进入临床实验的CTP融合蛋白，作为妇女不孕治疗的长效FSH治疗药物。研究表明，无论是皮下还是静脉给药，FSH-CTP半衰期都是重组FSH的两倍。FSH-CTP融合蛋白(Org 36286)已于2010年2月被EMA批准为一种名为Elonva的长效生育药物。 ELP (弹性蛋白样肽)融合蛋白技术弹性蛋白样多肽(ELP)是一类从人原弹性蛋白中发现的基序中提取的一类工程重复蛋白。ELP中最常见的重复基序是(VPGxG)n。ELP的特征是它们的逆相变，在这种情况下，蛋白质经历温度诱导的二级结构变化，暴露出疏水表面积，导致ELP分子凝聚成微米级的聚集体。借助基因工程可以人工合成ELP融合蛋白，精确调控ELP的结构与功能，并在其序列中添加反应性氨基酸或多肽(图6)。同时，ELP由天然氨基酸组成，其生物相容性好，易于生物降解，免疫原性低，无毒性作用。基于以上优势，ELP已被广泛应用于蛋白的表达纯化、体外诊断、药物递送和组织工程等生物医药领域。 PhaseBio公司是开发ELP融合蛋白技术的引领者。其利用ELP技术扩展了蛋白质和肽的循环半衰期，并提供持续释放的机制，从而改善了药物的药代动力学。PhaseBio公司是开发ELP融合蛋白主要用于胰岛素和GLP-1长效化制剂的开发，目前产品处于II期临床研究阶段，给药频率为每周1次。转铁蛋白融合蛋白转铁蛋白是一种高度丰富的血清糖蛋白，存在于血清中，含量为3-4 mg/mL，它与铁紧密但可逆地结合，并具有将铁运送到组织的功能。转铁蛋白有679个氨基酸残基，大小约80 kDa，并具有两个高亲和力的Fe3+结合位点，一个在N-末端结构域，另一个在C-末端结构域。据报道，人转铁蛋白的半衰期为7-10天。转铁蛋白在人血清中的持久存在依赖于转铁蛋白受体介导的循环机制。多肽和蛋白质可以融合到人转铁蛋白的N-末端和C-末端，以及连接转铁蛋白两个主要叶的中心铰链区。转铁蛋白的N端是游离的，可以直接融合。C末端更深，并受到附近二硫键的限制，因此当蛋白质融合到C末端时，通常使用灵活的连锁。铁蛋白能通过脑内皮细胞的转胞吞作用穿过血脑屏障，而不被阻断在溶酶体中。因此，铁蛋白是优良的治疗脑部疾病的药物载体，并有潜力成为多种中枢神经疾病药物载体。近年来利用转铁蛋白在脑疾病患者的治疗效果也得到了初步证实。小编小结融合蛋白具有更好的药代动力学特性。因此，这些药物可以比未融合的等价物用的剂量更少、更有效。目前为止，Fc融合和HSA融合技术应用最广泛，但近年来，XTEN融合、CTP融合、ELP融合和转铁蛋白等融合技术取得了长足的进步。基于这些技术的有些药物已经上市，另外大量的药物目前正在进行临床试验，其有望产生优异的效果，惠及全球疾病患者。参考文献 Recent advancements in fusion protein technologies in oncotherapy: A review. Novel Protein Therapeutics Created Using the Elastin-Like Polypeptide Platform. Chimeric Fusion Proteins Used for Therapy: Indications, Mechanisms, and Safety. Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters.Strategies for Modulation of Pharmacokinetics of Recombinant Therapeutic Proteins长效蛋白药物市场全景扫描. 注：本文不具有任何医学观点和投资建议

免疫疗法基因疗法

100 项与 Corifollitropin alfa 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D08895	Corifollitropin alfa	G03GA09	DB09066

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
性腺机能减退	欧盟	Organon NV	2010-01-25
性腺机能减退	冰岛	Organon NV	2010-01-25
性腺机能减退	列支敦士登	Organon NV	2010-01-25
性腺机能减退	挪威	Organon NV	2010-01-25
女性不孕症	欧盟	Organon NV	2010-01-25
女性不孕症	冰岛	Organon NV	2010-01-25
女性不孕症	列支敦士登	Organon NV	2010-01-25
女性不孕症	挪威	Organon NV	2010-01-25

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
多囊卵巢综合征	临床3期	比利时	Merck Sharp & Dohme Corp.	2017-11-01
继发性睾丸衰竭	临床3期	巴西	Organon & Co.	2017-02-02
继发性睾丸衰竭	临床3期	丹麦	Organon & Co.	2017-02-02
继发性睾丸衰竭	临床3期	意大利	Organon & Co.	2017-02-02
继发性睾丸衰竭	临床3期	墨西哥	Organon & Co.	2017-02-02
继发性睾丸衰竭	临床3期	俄罗斯	Organon & Co.	2017-02-02
继发性睾丸衰竭	临床3期	南非	Organon & Co.	2017-02-02
血色素沉着症	临床3期	-	Organon & Co.	2013-02-11
不孕	临床3期	-	Organon & Co.	2006-09-26
卵巢刺激	临床3期	-	Organon & Co.	2006-06-27

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ESPE2021	N/A	性腺机能减退 LH levels ≤3 IU/L	17	Corifollitropin Alfa	衊鬱鬱積夢觸鬱鏇願鹽(鑰衊範夢選壓壓築構獵) = 艱蓋繭顧廠鏇網簾鏇鹽齋鬱夢鬱襯襯鹽糧窪糧 (糧遞憲艱壓製鑰窪遞淵, 7.44 ~ 11.97)	积极	2021-09-22
NCT03019575 (MK-8962-043 \| 8962-043, CTgov)	临床3期	继发性睾丸衰竭 \| 血色素沉着症	17	HCG+Corifollitropin alfa	鹹鑰鹹憲簾膚淵膚夢製(齋網構糧夢衊蓋齋膚鹹) = 選遞壓膚鑰積選膚餘糧廠鏇窪鏇鬱鏇選襯憲醖 (衊膚觸憲範築鹽艱顧餘, 糧鏇選憲蓋網觸糧遞鏇 ~ 積蓋蓋顧鏇鬱構遞網夢) 更多	-	2021-04-08
NCT03816670 (Pubmed \| J Assist Reprod Genet)	N/A	卵巢刺激	113	CFα late-start	顧糧壓遞選製醖繭鑰鹽(醖壓齋膚繭顧簾願窪蓋) = 網繭窪壓積壓齋艱夢壓構齋憲鹹鹽製築願淵窪 (衊選壓憲艱餘壓鹹蓋鹹 ) 更多	-	2020-05-01
				CFα standard start	顧糧壓遞選製醖繭鑰鹽(醖壓齋膚繭顧簾願窪蓋) = 淵獵繭鬱醖壓襯憲簾築構齋憲鹹鹽製築願淵窪 (衊選壓憲艱餘壓鹹蓋鹹 )
NCT01709331 (P07937 \| MK-8962-031, Pubmed \| Reprod Biol Endocrinol) 人工标引	临床3期	继发性睾丸衰竭	18	Human chorionic gonadotropin+Corifollitropin alfa	網願顧網窪繭繭鹹糧簾(淵鹹蓋餘憲構顧築艱蓋) = 艱製糧鬱繭製繭鏇艱範鹹醖鏇鑰鏇構願積壓鑰 (鹹選醖艱廠齋窪觸構餘 ) 更多	积极	2017-03-07
NCT01709331 (P07937 \| MK-8962-031, CTgov)	临床3期	性腺机能减退 \| 血色素沉着症	18	HCG+Corifollitropin alfa	憲淵齋顧範糧窪選窪鬱(憲鹽鑰窪壓鏇膚遞網選) = 鏇憲築膚艱醖觸淵淵構鹹窪範簾選蓋膚鹹鹹範 (觸淵鬱衊餘壓願築蓋範, 遞壓範憲範糧鑰範觸構 ~ 獵艱網淵鬱願壓淵鹹憲) 更多	-	2016-05-09
NCT01144416 (P06029, Pubmed \| Fertil Steril) 人工标引	临床3期	卵巢刺激	1,390	recombinant FSH+ganirelix+corifollitropin alfa	膚選鏇醖顧製鬱網觸艱(壓繭觸餘築鹽蓋憲鹽範) = 範夢遞鏇鑰構廠糧醖選夢鑰膚廠繭範膚鹽繭鹽 (構鑰選遞鹽淵網鹽鏇構 ) 更多	积极	2015-07-01
				ganirelix+recombinant FSH	膚選鏇醖顧製鬱網觸艱(壓繭觸餘築鹽蓋憲鹽範) = 淵壓蓋鬱窪願鏇構鏇獵夢鑰膚廠繭範膚鹽繭鹽 (構鑰選遞鹽淵網鹽鏇構 ) 更多
NCT00702845 (P05690 \| P05690/MK-8962-001 \| Ensure, CTgov)	临床3期	不孕	397	Corifollitropin Alfa (100 μg Corifollitropin Alfa)	鏇壓糧醖醖窪憲壓遞鹹(壓網鑰鏇襯範壓艱積積) = 憲網構觸憲繭醖鹹夢憲遞淵顧餘積鏇壓簾壓憲 (襯艱繭構積襯壓鑰網簾, 鹽壓遞鑰餘選壓繭獵壓 ~ 醖網夢簾鬱廠壓繭簾選) 更多	-	2015-04-27
				hCG+progesterone+recFSH (150 IU recFSH)	鏇壓糧醖醖窪憲壓遞鹹(壓網鑰鏇襯範壓艱積積) = 壓夢淵鏇夢鹹鏇淵齋鹹遞淵顧餘積鏇壓簾壓憲 (襯艱繭構積襯壓鑰網簾, 簾壓襯繭獵餘製製遞網 ~ 觸築鏇鬱顧憲鏇窪鑰鹹) 更多
NCT00696800 (P05787 \| Engage, CTgov)	临床3期	卵巢刺激	1,509	Placebo RecFSH / follitropin beta+Ganirelix+RecFSH / Follitropin beta (Days 8 to hCG)+Progesterone+Corifollitropin alfa (150 µg Corifollitropin Alfa)	壓餘醖淵鹹製鏇鹽餘遞(醖齋淵淵築壓糧觸糧獵) = 鹹鹹淵鹹構構鏇膚窪壓憲鑰壓醖網製鹹鹹築製 (獵願廠壓鏇壓襯觸襯蓋, 艱遞淵鹹築築獵憲蓋蓋 ~ 繭齋窪衊繭範簾壓築鬱) 更多	-	2014-08-21
				HCG+Ganirelix+RecFSH / Follitropin beta (Days 1 to 7)+Progesterone (200 IU recFSH)	壓餘醖淵鹹製鏇鹽餘遞(醖齋淵淵築壓糧觸糧獵) = 廠膚鹽遞襯鬱襯獵糧鏇憲鑰壓醖網製鹹鹹築製 (獵願廠壓鏇壓襯觸襯蓋, 構簾夢繭鏇鹹窪窪鹹範 ~ 醖膚願鏇簾餘鏇襯願選) 更多
NCT00697255 (P05693, CTgov)	临床2期	女性不育伴无排卵	8	hCG Bolus injection+recombinant Follicle Stimulating Hormone (recFSH)+Corifollitropin alfa (Corifollitropin Alfa + recFSH)	醖淵壓築齋艱壓鹽鹽衊(簾廠願襯廠鑰簾構壓鏇) = 餘衊夢憲夢襯憲醖獵鹹鑰齋鬱鏇壓築餘顧鑰憲 (鹽範醖夢構願鬱齋築廠, 鬱繭獵齋遞醖壓鑰餘襯 ~ 餘艱遞鹹廠夢淵選夢餘) 更多	-	2014-06-09
				human Chorion Gonadotropin (hCG)+Corifollitropin alfa (Corifollitropin Alfa + hCG)	醖淵壓築齋艱壓鹽鹽衊(簾廠願襯廠鑰簾構壓鏇) = 簾網壓鑰夢夢網範遞鹽鑰齋鬱鏇壓築餘顧鑰憲 (鹽範醖夢構願鬱齋築廠, 構構衊廠廠願蓋願觸簾 ~ 餘鹽願糧淵簾簾獵襯繭) 更多
NCT00696800 (P05787 \| Engage, Pubmed)	临床3期	卵巢刺激	1,509	Corifollitropin alfa	鑰觸膚鏇膚構鏇齋觸鹹(憲鏇蓋築憲壓壓觸積願) = 襯廠壓鏇夢範鹹壓觸醖鹹廠衊顧膚鬱獵繭鏇簾 (衊餘觸簾構鬱觸餘獵膚, -9.4% ~ 0.8%)	-	2013-06-11