TBX3

引言 在妊娠过程中，出血是一种常见且严重的并发症。妊娠早期出血通常发生在妊娠的前20周，可能预示着流产、异位妊娠或其他妊娠并发症。而产后出血（Postpartum Hemorrhage, PPH）则是产妇死亡的主要原因之一，每年全球约有10万名年轻且健康的女性因PPH而丧生。尽管PPH影响了超过十分之一的分娩，并且具有遗传性，但在遗传和分子层面上，PPH的研究仍然有限。 PPH的主要原因是子宫收缩乏力（uterine atony），占所有PPH病例的70%。其他原因包括胎盘滞留、分娩时的创伤以及先天性或后天性的凝血功能障碍。早期识别和正确管理PPH可以预防产妇的死亡和发病。因此，在分娩前评估PPH的风险具有重要的临床意义。虽然已有许多文献描述了详细的预测模型，但最近的综述表明，几乎一半的现有预测模型包含只能在产后获得的特征。 7月22日Nature Genetics的研究报道“Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage”，通过对来自北欧六个队列的多达302,894名女性的基因数据进行全基因组关联研究（Genome-Wide Association Studies, GWAS），识别出了与妊娠各阶段出血相关的五个位点。研究发现，与PPH相关的基因位点涉及HAND2、TBX3和RAP2C/FRMD7，这些基因在子宫内膜组织中的调控过程中起重要作用。这些位点的变异与孕酮受体（progesterone receptor）的结合位点相关，表明PPH可能与孕酮信号传导的失调有关。PPH还显示出与出生体重、妊娠期以及子宫肌瘤的强遗传相关性。 在研究中，早期妊娠出血尽管没有在全基因组水平上显示显著的关联信号，但与多种人类特征存在强遗传相关性，提示其可能具有复杂的多基因病因。研究结果表明，PPH可能是由孕酮信号传导失调引起，而早期出血则是一个复杂的性状，可能与潜在的健康状况和社会经济地位有关，并可能包含尚未识别的遗传因素。 总之，该研究通过识别与PPH相关的遗传位点，提供了对PPH遗传机制的深入理解，并为临床前预测PPH风险以及采取预防措施提供了潜在的分子标志物。研究还强调了需要进一步研究来探索PPH和早期妊娠出血的分子病理机制，以更好地了解这些复杂的妊娠相关出血问题。 产后出血（Postpartum Hemorrhage，PPH）是指分娩后24小时内失血量超过500毫升的情况，是导致产妇死亡的主要原因之一。每年全球约有10万名年轻且健康的女性因PPH而丧生。尽管PPH影响了超过十分之一的分娩，并且具有遗传性，但在遗传和分子层面上，PPH的研究仍然有限。PPH的主要原因是子宫收缩乏力（uterine atony），占所有PPH病例的70%。其他原因包括胎盘滞留、分娩时的创伤以及先天性或后天性的凝血功能障碍。早期识别和正确管理PPH可以预防产妇的死亡和发病。因此，在分娩前评估PPH的风险具有重要的临床意义。虽然已有许多文献描述了详细的预测模型，但最近的综述表明，几乎一半的现有预测模型包含只能在产后获得的特征。 该研究通过对来自北欧六个队列的多达302,894名女性的基因数据进行全基因组关联研究（Genome-Wide Association Studies, GWAS），旨在识别与妊娠各阶段出血相关的遗传位点。具体来说，研究团队对三种出血表型进行了研究：妊娠早期出血（28,898例）、产前出血（3,236例）和PPH（21,521例）。 研究对象来自六个北欧队列，包括丹麦、爱沙尼亚、芬兰、冰岛、挪威和英国的女性。使用Illumina基因芯片对所有样本进行基因分型，并使用全基因组测序数据进行基因组数据的校准和填补。使用了一个内部的泛斯堪的纳维亚参考Panel进行数据填补，以确保基因型数据的准确性。 将基因型数据与表型数据进行关联分析，使用固定效应模型计算每个基因变异与出血表型之间的关联。为了增加统计效力，结合六个队列的数据进行荟萃分析，使用固定效应逆方差方法（fixed-effects inverse variance method）对各队列的效应值进行加权合并。 对识别出的遗传位点进行功能注释，使用ENCODE项目和EpiMap数据库中的注释数据，分析这些位点在子宫组织中的调控作用。使用MAGMA软件进行组织特异性富集分析，以确定这些遗传变异在不同组织中的表达特异性。 研究概述和曼哈顿图（Credit: Nature Genetics） 图a提供了研究的概述，描述了研究所涉及的三种出血表型的时间分布：早期出血（Early bleeding）、产前出血（Antepartum bleeding）和产后出血（Postpartum hemorrhage, PPH）。早期出血发生在妊娠的前20周内，产前出血发生在妊娠20周后到分娩前，而PPH发生在分娩后。 图b展示了PPH的全基因组关联分析结果：图中显示了所有检测到的单核苷酸多态性（SNP），横轴表示染色体位置，纵轴表示与PPH相关的统计显著性（-log10(P值)）。通过功能性多重检验标准筛选出的显著SNP用绿色点表示，并标注了与之相关的基因名称（如HAND2、TBX3、RAP2C/FRMD7等）。 图c为PPH的两个主要病因：子宫收缩乏力（uterine atony）和胎盘滞留（retained placenta）分别绘制了曼哈顿图（Miami plot）。上半部分（顶部）显示的是与子宫收缩乏力相关的SNP，下半部分（底部）显示的是与胎盘滞留相关的SNP。绿色点表示通过多重检验标准筛选出的显著SNP，并标注了基因名称。 研究识别出了与PPH相关的五个位点，位于第4、6、10、12和X染色体上。这些位点涉及的候选基因包括HAND2、TBX3和RAP2C/FRMD7，且相关变异位点位于孕酮受体（progesterone receptor）的结合位点。 HAND2基因：在子宫内膜组织中的表达对胚胎着床和妊娠维持至关重要，之前的研究也表明该基因与早产和妊娠期长短相关。 TBX3基因：参与子宫功能的发育过程，对组织重塑和肌肉收缩有重要作用。 RAP2C/FRMD7基因：其功能尚不完全明确，但其变异与妊娠期有关。 HAND2基因在子宫内膜组织中的调控过程中起重要作用，这些基因变异与孕酮受体结合位点相关，表明PPH可能与孕酮信号传导的失调有关。PPH与出生体重、妊娠期和子宫肌瘤之间存在强遗传相关性，揭示了PPH的复杂遗传背景。 组织特异性富集分析（Tissue-specific enrichment analysis for PPH）（Credit: Nature Genetics） 单细胞层面的组织特异性富集分析（Single-cell tissue-specific enrichment analysis）：图a展示了使用MAGMA软件进行的单细胞层面的组织特异性富集分析结果。横轴表示统计显著性（-log10(P值)），纵轴列出了不同细胞类型。图中显示，平滑肌细胞（smooth muscle cells）和内皮细胞（endothelial cells）在PPH相关基因的表达中特别富集，并在FDR（false discovery rate）小于5%的情况下显著富集。 批量组织层面的组织特异性富集分析（Bulk tissue-specific enrichment analysis）：图b展示了批量组织层面的组织特异性富集分析结果。横轴表示统计显著性（-log10(P值)），纵轴列出了不同组织类型。图中显示，子宫内膜（endometrium）、平滑肌（smooth muscle）、精囊（seminal vesicle）和甲状腺（thyroid gland）组织在PPH相关基因的表达中特别富集，并在FDR小于5%的情况下显著富集。 研究发现，PPH与出生体重、妊娠期和子宫肌瘤之间存在强遗传相关性，这表明这些特征和疾病可能共享某些遗传基础。尽管妊娠早期出血在全基因组水平上未显示显著的关联信号，但与多种人类特征存在强遗传相关性，提示早期出血可能具有复杂的多基因病因。 染色体12上的位点：与足跟骨矿物质密度和男性前列腺特异性抗原水平有关，表明其在激素反应性组织中的作用。另外，这个位点与子宫肌瘤和子宫内膜异位症（endometriosis）相关。 染色体10和X上的位点：与子宫肌瘤和子宫内膜异位症相关。 染色体6上的位点：与教育程度的基因变异有关。 遗传相关性分析（Genetic correlation analysis）（Credit: Nature Genetics） 妊娠出血表型间的遗传相关性（Genetic correlations among pregnancy bleeding phenotypes）：图a展示了所有妊娠出血表型之间的遗传相关性（cross-trait genetic correlation）。纵轴表示不同的妊娠出血表型，包括早期出血（Early bleeding, any outcome）、妊娠成功的早期出血（Early bleeding, birth）、由子宫收缩乏力引起的PPH（PPH, atony）、由胎盘滞留引起的PPH（PPH, retained placenta）和总的PPH（Postpartum hemorrhage）。横轴表示遗传相关性系数及其95% CI。结果显示，PPH与早期出血在遗传上没有显著相关性，而由子宫收缩乏力和胎盘滞留引起的PPH在遗传上几乎无法区分（遗传相关性系数为0.77，95%CI 为0.49-1.05）。 PPH与其他疾病和特征的遗传相关性（Genetic correlations between PPH and other traits and disorders）：图b展示了PPH与多种疾病和特征的遗传相关性。纵轴列出了不同的疾病和特征，横轴表示遗传相关性系数及其95% CI。结果显示，PPH与胎儿和母体的出生体重（birth weight, fetal and maternal）以及母体妊娠期（gestational duration, maternal）有显著的正相关性，而与子宫肌瘤（uterine fibroids）有显著的负相关性。这些相关性在经过多重检验校正后依然显著。 早期出血与其他特征的遗传相关性（Genetic correlations between early bleeding and other traits）：图c展示了早期出血与多种特征的遗传相关性。纵轴列出了不同的特征，横轴表示遗传相关性系数及其95% CI。结果显示，早期出血与多种特征存在显著的遗传相关性，包括社会经济和心血管特征（如体重指数BMI、吸烟、血压等）以及精神疾病（如创伤后应激障碍PTSD）。 HAND2和TBX3基因在胚胎着床和妊娠期调控中起关键作用。RAP2C/FRMD7基因簇的功能尚不明确，但其变异与妊娠期相关。PPH与孕酮信号传导失调相关，这些发现强调了孕酮在维持妊娠中的重要作用。孕酮受体结合位点的富集也支持了这一结论。 早期识别和正确管理PPH可以显著降低产妇的死亡和发病风险。该研究的发现为在临床前预测PPH风险提供了潜在的分子标志物，有助于开发更有效的预防策略。 尽管早期出血在全基因组水平上未显示显著的关联信号，但其与多种人类特征的遗传相关性表明其可能具有复杂的多基因病因。这一发现提示需要进一步研究以揭示早期出血的分子病理机制。 该研究通过识别与PPH相关的遗传位点，提供了对PPH遗传机制的深入理解，并为在临床前预测PPH风险以及采取预防措施提供了潜在的分子标志物。研究还强调了需要进一步研究来探索PPH和早期妊娠出血的分子病理机制，以更好地了解这些复杂的妊娠相关出血问题。 通过这些研究结果，科学家们不仅能够更好地理解PPH的遗传背景，还能揭示其与其他妊娠相关特征的关联，强调了孕酮在维持妊娠中的重要作用。这些发现为开发更有效的PPH预防策略提供了理论基础，有助于提高产妇和胎儿的健康水平。 参考文献 Westergaard D, Steinthorsdottir V, Stefansdottir L, Rohde PD, Wu X, Geller F, Tyrmi J, Havulinna AS, Solé-Navais P, Flatley C, Ostrowski SR, Pedersen OB, Erikstrup C, Sørensen E, Mikkelsen C, Bruun MT, Aagaard Jensen B, Brodersen T, Ullum H; FinnGen; Danish Blood Donor Study Genomic Consortium; Estonian Biobank Research Team; Nordic Collaboration for Womens and Reproductive Health; Magnus P, Andreassen OA, Njolstad PR, Kolte AM, Krebs L, Nyegaard M, Hansen TF, Feenstra B, Daly M, Lindgren CM, Thorleifsson G, Stefansson OA, Sveinbjornsson G, Gudbjartsson DF, Thorsteinsdottir U, Banasik K, Jacobsson B, Laisk T, Laivuori H, Stefansson K, Brunak S, Nielsen HS. Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage. Nat Genet. 2024 Jul 22. doi: 10.1038/s41588-024-01839-y. Epub ahead of print. PMID: 39039282. https://www-nature-com.libproxy1.nus.edu.sg/articles/s41588-024-01839-y 责编|探索君 排版|探索君 转载请注明来源于【生物探索】 End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell 综述

- Participants from the completed Phase 2 hypothalamic obesity trial reported positive changes in sleep, energy levels during setmelanotide therapy in qualitative interviews - - Separate analysis of patients across MC4R pathway diseases showed one year of treatment with setmelanotide improved NIH, WHO weight classifications - - Previously reported stage one results from Phase 2 DAYBREAK trial showed potential setmelanotide efficacy in multiple MC4R pathway variants; stage two data expected in Q3 2024 - - Preclinical data demonstrated potential of RM-718 to reduce body weight and hunger - - Additional posters feature design of Phase 1 trial of RM-718 and real-world RESTORE study - BOSTON, June 03, 2024 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a global commercial-stage biopharmaceutical company focused on transforming the lives of patients and their families living with rare neuroendocrine diseases, today announced the presentation of the first patient and caregiver reported experiences from qualitative interviews following the completion of a Phase 2 trial that evaluated treatment with setmelanotide in hypothalamic obesity (HO). These results were among six Rhythm presentations at the Endocrine Society Annual Meeting & Expo (ENDO 2024) being held June 1-4 in Boston. “We continue to advance what we believe to be the most comprehensive clinical research program ever initiated for the treatment of hyperphagia and severe obesity associated with rare melanocortin-4 receptor (MC4R) pathway diseases,” said David Meeker, M.D., Chair, President and Chief Executive Officer of Rhythm. “For the first time, we presented patient and caregiver reported results showing that setmelanotide therapy in patients with hypothalamic obesity was associated with meaningful improvements in their lives beyond clinical outcomes and reductions in body mass index (BMI).” Christian Roth, M.D., Seattle Children’s Research Institute and Division of Endocrinology, Department of Pediatrics, University of Washington, presented, “Patient- and Caregiver-reported Experiences of Hunger, Weight and Energy in Acquired Hypothalamic Obesity Before and During Setmelanotide Therapy.” In qualitative interviews before setmelanotide therapy, five participants (three patients, two caregivers) all reported experiencing substantial weight gain, unrelenting hunger, drastically reduced energy or physical activity, and interrupted nighttime sleep, primarily due to hunger associated with acquired hypothalamic obesity. In their experiences following initiation of setmelanotide therapy, all study participants reported improved energy and ability and desire to be more active, and four of five participants reported reductions in hunger, positive changes in eating behavior and improvements in sleep. Rhythm and its collaborators also delivered two rapid-fire oral presentations and accompanying posters at ENDO 2024: Dr. Roth presented results from an analysis of the clinical characteristics of 58 individuals who participated in trials of setmelanotide across MC4R pathway diseases including hypothalamic obesity, proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency obesities, or Bardet-Biedl syndrome (BBS). After one year of treatment with setmelanotide, improvements of at least one obesity class were observed across all cohorts (HO: 92%; POMC deficiency: 89%; LEPR deficiency: 36%; BBS: 42%). Patients with LEPR deficiency and BBS had more severe weight categories at baseline but still showed general improvement in weight categories after one year of treatment.Danica Grujic, Ph.D., Senior Director, Non-Clinical Development, Translational Research & Development, Rhythm Pharmaceuticals, presented results from a preclinical study that evaluated treatment with RM-718, a selective MC4R agonist designed to be administered weekly with potential to avoid MC1R-related hyperpigmentation, in a rodent model of obesity, hyperphagia, and insulin resistance. Treatment was well-tolerated and stable weight and food intake reductions and improved insulin sensitivity were observed after three weeks. Rhythm and its collaborators also presented three additional posters at ENDO 2024: Elif Oral, M.D., Associate Professor in the Division of Metabolism, Endocrinology and Diabetes (MEND) at The University of Michigan, presented previously reported stage one results from the two-stage, double-blind, placebo-controlled DAYBREAK trial that show potential setmelanotide efficacy in individuals who carry variants in SEMA3[A-G], PLXNA[1-4], PHIP, TBX3, MAGEL2, or SIM1. At least one patient in each of those cohorts achieved ≥10% body mass index (BMI) reduction at the end of the 16-week, open-label run-in period. Overall, 49 responders were randomized into stage two, which is a 24-week, double-blind, randomized, placebo-controlled period. Setmelanotide was well tolerated with no new safety concerns.Dr. Roth presented the design of Rhythm’s first-in-human Phase 1 trial of once-weekly RM-718 in individuals with obesity or patients with HO.Caroline Huber, Director, Value & Evidence, Rhythm Pharmaceuticals, presented the design of Real-world Evidence of SeTmelanotide fOr Hyperphagia and ChRonic Weight ManagEment (RESTORE), the first study to assess the real-world effectiveness of setmelanotide to provide a greater understanding of patient outcomes, such as hyperphagia and quality of life, in a clinical practice setting. About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with rare neuroendocrine diseases. Rhythm’s lead asset, IMCIVREE® (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigational MC4R agonists LB54640 and RM-718, and a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide IndicationIn the United States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS. In the European Union and United Kingdom, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. In the European Union and United Kingdom, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Limitations of UseSetmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benignOther types of obesity not related to POMC, PCSK1 or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity. ContraindicationPrior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. WARNINGS AND PRECAUTIONS Skin Pigmentation and Darkening of Pre-Existing Nevi: Generalized increased skin pigmentation and darkening of pre-existing nevi have occurred because of its pharmacologic effect. Full body skin examinations prior to initiation and periodically during treatment should be conducted to monitor pre-existing and new pigmentary lesions. Heart rate and blood pressure monitoring: In Europe, heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide. Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Patients who have an erection lasting longer than 4 hours should seek emergency medical attention. Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Patients should be monitored for new onset or worsening depression or suicidal thoughts or behaviors. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue setmelanotide. Pediatric Population: The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. In Europe, the prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves. Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. ADVERSE REACTIONS Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. USE IN SPECIFIC POPULATIONS Lactation: Not recommended when breastfeeding. REPORTING OF SIDE EFFECTS If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in the package leaflet. You can also contact Rhythm Pharmaceuticals at +1 (833) 789-6337. To report directly via the Yellow Card Scheme please do so via: www.mhra.gov.uk/yellowcard. To report directly to the FDA contact 1-800-FDA-1088 or www.fda.gov/medwatch. [See section 4.8 of the Summary of Product Characteristics for information on reporting suspected adverse reactions in Europe.] By reporting side effects, you can help provide more information on the safety of this medicine. Please see the Summary of Product Characteristics and full Prescribing Information for additional Important Safety Information. Forward-looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the Company’s participation in and the content of its presentations at conferences including the ENDO 2024 conference; the promise and potential impact of the Company’s preclinical or clinical trial data; the initiation, timing, design, or results of any clinical trials or readouts; and the potential benefits of any of the Company’s products or product candidates for any specific disease indication or at any dosage, including the potential for setmelanotide to treat hyperphagia and severe obesity associated with melanocortin-4 receptor (MC4R) pathway diseases and additional genetic indications, as well as improve patient and caregiver quality of life, and the potential for RM-718 to reduce body weight and hunger and treat obesity. Statements using words such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, the ability to achieve necessary regulatory approvals, risks associated with data analysis and reporting, failure to identify and develop additional product candidates, unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, risks associated with the laws and regulations governing our international operations and the costs of any related compliance programs, the impact of competition, risks relating to product liability lawsuits, inability to maintain collaborations, or the failure of these collaborations, our reliance on third parties, risks relating to intellectual property, our ability to hire and retain necessary personnel, general economic conditions, and the other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the three months ended March 31, 2024 and our other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise. Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com Media Contact:Adam DaleyBerry & Company Public Relations212-253-8881adaley@berrypr.com

-- Phase 3 trial evaluating setmelanotide in pediatric patients ages 2-<6yo (N=12) over 52 weeks achieved primary endpoint -- -- Setmelanotide achieved 3.04 mean reduction in BMI-Z score and 18.4 percent mean reduction in BMI in patients ages 2-<6yo with obesity due to POMC/LEPR deficiency or BBS -- -- RM-718 showed potential to reduce body weight and hyperphagia with no off-target cardiovascular effects and no hyperpigmentation observed in pre-clinical studies; first in-human studies anticipated to begin in the first half of 2024 -- -- Responder rates of 25 to 56 percent demonstrated in six genetic cohorts of Phase 2 DAYBREAK trial of setmelanotide -- -- Company to host R&D webcast today at 8:00 a.m. ET-- BOSTON, Dec. 06, 2023 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a global commercial-stage biopharmaceutical company focused on transforming the lives of patients and their families living with hyperphagia and severe obesity caused by rare melanocortin-4 receptor (MC4R) pathway diseases, today hosted an R&D event for investors and analysts, “Rhythm Update on MC4R Pathway Programs.” During the event, the Company announced new topline data from its ongoing Phase 3, open-label pediatrics trial evaluating one year of setmelanotide therapy in patients between the ages of 2 and younger than 6 years with Bardet-Biedl syndrome (BBS) or proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency obesity and new preliminary data from the first stage of its exploratory Phase 2 DAYBREAK trial. Rhythm also presented pre-clinical data on its new drug candidate, RM-718, which is designed to be a more selective MC4R agonist with weekly administration, and its plans for Phase 1 clinical development. The Company hosted Amy Wood, Executive Director and Co-Founder of the Raymond A. Wood Foundation, and Jennifer Miller, MD, Professor of Pediatric Endocrinology, University of Florida, who shared insights on hypothalamic obesity and the severe impact of the disease on patient quality of life. Rhythm continues to advance the development of setmelanotide in patients with hypothalamic obesity and remains on track to complete Phase 3 study enrollment by the end of 2023. “Today, we are excited to showcase our commitment to understanding the MC4R pathway and developing the next generation of therapies,” said David Meeker, M.D., Chair, President and Chief Executive Officer of Rhythm. “Setmelanotide has demonstrated its potential to effect a clinically significant weight loss in children ages 2 to younger than 6 years old, potentially enabling us to treat patients younger in life when these diseases first present. With our DAYBREAK trial, we have shown potential for a meaningful, positive response to setmelanotide in several new gene cohorts.” Setmelanotide demonstrated clinically meaningful reductions in BMI and BMI-Z score in patients aged 2 to <6 (N=12)Today, Rhythm presented new data from its 52-week, Phase 3 pediatrics trial in patients between 2 and younger than 6 years old. The hyperphagia and severe obesity of rare genetically-caused MC4R pathway diseases can present early in life, and these data show potential efficacy in patients younger than 6. This trial is a multi-center, one-year, open-label trial in pediatric patients with obesity due to biallelic POMC, PCSK1 or LEPR deficiency or a clinical diagnosis of BBS with genetic confirmation. The primary efficacy endpoint is a responder analysis, based on the proportion of patients who experience a decrease from baseline in BMI-Z score of ≥0.2. Highlights from the data include: 83.3% of all patients (10 of 12) achieved ≥ 0.2 reduction in BMI-Z score from baseline to week 52;18.4 percent mean reduction from baseline in BMI at week 52 (N=12);3.04 mean reduction from baseline in BMI-Z score at week 52 (N=12);11 patients completed the trial, and all remain on therapy, as of Dec. 5, 2023; one patient discontinued and was lost to follow-up; andThe safety profile is consistent with past trials evaluating setmelanotide. Rhythm today also announced it has submitted a Type II variation application to the European Medicines Agency seeking regulatory approval and authorization for setmelanotide to treat obesity and control of hunger in pediatric patients between 2 and younger than 6 years old with BBS or POMC, PCSK1 or LEPR deficiency in the European Union. The Company anticipates submitting a supplementary New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in the first half of 2024 seeking a similar label expansion. RM-718 demonstrated potential to reduce body weight and hyperphagia with a favorable safety profile and no hyperpigmentation in pre-clinical studiesRhythm presented data from several pre-clinical studies showing that RM-718, a new, weekly, MC4R-specific agonist, demonstrated the potential to reduce body weight and hunger with a favorable safety profile. RM-718 is designed to be more highly targeted and MC1R sparing with the potential to not cause hyperpigmentation. The Company also showed data from pre-clinical studies demonstrating that RM-718 had no off-target cardiovascular effects in non-human primate studies. Rhythm also announced today that it completed submission of a new investigational drug application for RM-718 to the FDA. The Company anticipates beginning Phase 1 in-human trials in the first half of 2024, including a multiple-ascending dose study in patients with hypothalamic obesity. Data from Phase 2 DAYBREAK trial demonstrate potential efficacy of setmelanotide in multiple genetically-defined cohortsRhythm today also announced data from the open-label part of its exploratory Phase 2 DAYBREAK trial that demonstrate potential efficacy in patients in multiple genetically-defined cohorts. The Company presented data from the full analysis set for DAYBREAK, which includes 164 patients. A total of 112 patients completed the 16-week Stage 1 of the Phase 2 trial, with 52 patients who discontinued. The primary endpoint of the trial is the proportion of patients by genotype who achieve a BMI reduction of ≥5% from baseline in response to setmelanotide at the end of Stage 1. The rates of response from Stage 1 of the trial were: 30% of patients (12 of 40) with variants in the SEMA3 gene cohort;35.6% of patients (16 of 45) with variants in the PLXNs gene cohort;56.3% of patients (9 of 16) with variants in the PHIP gene cohort;40% of patients (2 of 5) with variants in the TBX3 gene cohort;30% of patients (3 of 10) with variants in the MAGEL2 gene cohort; and25% of patients (5 of 20) with variants in the SIM1 gene cohort. For those who completed Stage 1, the rates of response of patients who achieved a BMI reduction of greater than 5% from a post-hoc analysis were: 44.4% of patients (12 of 27) with variants in the PLXNs gene cohort;61.5% of patients (16 of 26) with variants in the SEMA3 gene cohort than 5%; and69.2% of patients (9 of 13) with variants in the PHIP gene cohort. A total of 49 patients who completed Stage 1 with a response to setmelanotide were randomized into Stage 2 of the trial. Stage 2 is a 24-week, double-blind, placebo-controlled withdrawal study. These patients were stratified into genetically defined cohorts and randomized 2:1 to receive setmelanotide or placebo. Rhythm anticipates announcing DAYBREAK Stage 2 data in the second half of 2024. Conference Call InformationA live webcast of the R&D call will be available under "Events and Presentations" in the Investor Relations section of the Rhythm Pharmaceuticals website at https://ir.rhythmtx.com/. The archived webcast will be available on Rhythm Pharmaceuticals’ website approximately two hours after the conference call and will be available for 30 days following the call. About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with hyperphagia and severe obesity caused by rare melanocortin-4 receptor (MC4R) diseases. Rhythm’s lead asset, IMCIVREE (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity caused by rare MC4R pathway diseases, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare MC4R pathway diseases, as well as a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide IndicationIn the United States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS. In the European Union, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet-Biedl syndrome (BBS) or genetically confirmed loss-of-function biallelic proopiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 6 years of age and above. Limitations of UseIn the United States and Europe, Setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benignOther types of obesity not related to POMC, PCSK1 or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity. WARNINGS AND PRECAUTIONS Skin Monitoring: Setmelanotide may lead to generalized increased skin pigmentation and darkening of pre-existing naevi because of its pharmacologic effect. Full body skin examinations should be conducted annually to monitor pre-existing and new skin pigmentary lesions before and during treatment with setmelanotide. Heart rate and blood pressure monitoring: Heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide. Prolonged penile erection: Spontaneous penile erections have been reported in clinical trials with setmelanotide. Patients who have a penile erection lasting longer than 4 hours should be instructed to seek emergency medical attention for potential treatment of priapism. Depression: In clinical trials, depression has been reported in patients treated with setmelanotide. Patients with depression should be monitored at each medical visit during treatment with setmelanotide. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors. Pediatric Population: The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. The prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves. Excipients: This medicinal product contains 10 mg benzyl alcohol in each ml. Benzyl alcohol may cause allergic reactions. Patients who are pregnant or breastfeeding should be advised of the potential risk from the excipient benzyl alcohol, which might accumulate over time and cause metabolic acidosis. This medicinal product should be used with caution in patients with hepatic or renal impairment, because of the potential risk from the excipient benzyl alcohol which might accumulate over time and cause metabolic acidosis. Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free.” ADVERSE REACTIONSThe most frequent adverse reactions are hyperpigmentation (51%), injection site reaction (39%), nausea (33%), and headache (26%). USE IN SPECIFIC POPULATIONS PregnancyThere are no data from the use of setmelanotide in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. However, administration of setmelanotide to pregnant rabbits resulted in decreased maternal food consumption leading to embryo-fetal effects. As a precautionary measure, setmelanotide should not be started during pregnancy or while attempting to get pregnant as weight loss during pregnancy may result in fetal harm. If a patient who is taking setmelanotide has reached a stable weight and becomes pregnant, consideration should be given to maintaining setmelanotide treatment as there was no proof of teratogenicity in the nonclinical data. If a patient who is taking setmelanotide and still losing weight gets pregnant, setmelanotide should either be discontinued, or the dose reduced while monitoring for the recommended weight gain during pregnancy. The treating physician should carefully monitor weight during pregnancy in a patient taking setmelanotide. Breast-feedingIt is unknown whether setmelanotide is excreted in human milk. A nonclinical study showed that setmelanotide is excreted in the milk of nursing rats. No quantifiable setmelanotide concentrations were detected in plasma from nursing pups. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from setmelanotide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother. FertilityNo human data on the effect of setmelanotide on fertility are available. Animal studies did not indicate harmful effects with respect to fertility. To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337. See Summary of Product Characteristics’ APPENDIX V for a list of European national reporting systems to communicate adverse reactions. Please see the full Prescribing Information for additional Important Safety Information. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, including the anticipated timing for initiation of clinical trials and release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals and timing thereof, including for our Phase 2 DAYBREAK trial, anticipated development plan for RM-718 and regulatory submissions for our Phase 3 pediatrics program, our business strategy and plans, including regarding commercialization of setmelanotide in the United States and Europe, the application of genetic testing and related growth potential, and expectations surrounding the potential market opportunity for our product candidates.. Statements using word such as “expect”, “anticipate”, “believe”, “may”, “will”, "aim" and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, risks relating to our liquidity and expenses, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the ability to achieve necessary regulatory approvals, risks associated with data analysis and reporting, failure to identify and develop additional product candidates, unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, risks associated with the laws and regulations governing our international operations and the costs of any related compliance programs, the impact of competition, risks relating to product liability lawsuits, inability to maintain our collaborations, or the failure of these collaborations, our reliance on third parties, risks relating to intellectual property, our ability to hire and retain necessary personnel, the impact of the COVID-19 pandemic and general economic conditions on our business and operations, including our preclinical studies, clinical trials and commercialization prospects, failure to realize the anticipated benefits of our acquisition of Xinvento B.V. or significant integration difficulties related to the acquisition, and the other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 and our other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise. Corporate Contact:David ConnollyExecutive Director, Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com Media Contact:Adam DaleyBerry & Company Public Relations212-253-8881adaley@berrypr.com