Vanda Pharmaceuticals Inc.（Vanda）today announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for VGT-1849B, a selective peptide nucleic acid-based JAK2 inhibitor for the treatment of polycythemia vera (PV).

Vanda Pharmaceuticals Inc.（Vanda）今天宣布，美国食品和药物管理局 (FDA) 已授予 VGT-1849B 孤儿药资格，这是一种选择性肽核酸类 JAK2 抑制剂，用于治疗真性红细胞增多症 (PV)。

PV is a chronic myeloproliferative disorder characterized by aberrant hematopoiesis of myeloid lineage with exuberant red cell production and increased release of pro-inflammatory cytokines. More than 95% of PV patients harbor the

PV是一种慢性骨髓增殖性疾病，其特征是髓系细胞异常造血，红细胞生成旺盛，并伴有促炎性细胞因子释放增加。超过95%的PV患者携带

JAK2

JAK2

V617F gain-of-function mutation leading to aberrant JAK2 production.

V617F功能获得性突变导致JAK2异常产生。

The prevalence of PV in

PV的患病率

the United States

美国

is estimated to affect 44 to 57 per 100,000 people.

估计每10万人中有44到57人受到影响。

VGT-1849B is an antisense oligonucleotide (ASO) that utilizes a novel backbone chemistry, OliPass Peptide Nucleic Acid (OPNA), that has been derived from peptide nucleic acid (PNA) by rationally introducing cationic lipid moieties onto nucleobases. By covalently attaching cationic lipid groups onto PNA, cell permeability and affinity for RNA are markedly improved..

VGT-1849B是一种反义寡核苷酸（ASO），它采用了一种新型的骨架化学结构——OliPass肽核酸（OPNA），这种结构通过在核酸碱基上合理引入阳离子脂质部分，从肽核酸（PNA）衍生而来。通过将阳离子脂质基团共价连接到PNA上，细胞渗透性和对RNA的亲和力显著提高。

By selectively targeting

通过有选择地针对

JAK2

JAK2

mRNA, VGT-1849B reduces downstream signaling and JAK2

mRNA，VGT-1849B减少下游信号传导和JAK2

V617F

V617F

-driven autonomous cell proliferation. VGT-1849B targets

驱动的自主细胞增殖。VGT-1849B 靶向

JAK2

JAK2

with high precision and effectively reduces JAK2 protein production, without any off-target kinase effects. Inhibiting JAK2 acts to suppress hematopoiesis, consequently reducing red blood cell, neutrophil, platelet, and lymphocyte production. The ability of VGT-1849B to reduce JAK2 protein may alleviate the disease burden that patients with PV face with a favorable safety profile, resulting in a higher quality of life for patients..

具有高精度并有效减少JAK2蛋白的产生，且没有任何脱靶激酶效应。抑制JAK2可起到抑制造血的作用，从而减少红细胞、中性粒细胞、血小板和淋巴细胞的生成。VGT-1849B减少JAK2蛋白的能力可能会减轻PV患者所面临的疾病负担，并具有良好的安全性，从而提高患者的生活质量。

JAK2 inhibitors have been shown to be efficacious in treating various JAK-dependent hematologic malignancies, including the treatment of PV. While there are several JAK inhibitors available such as Jakafi®, Inrebic®, Ojjaara®, and Vonjo®, none are solely selective to JAK2. Due to the highly conserved structure of the catalytic sites of protein kinases, JAK2 inhibitors may bind to off-target kinases, leading to increased toxicity and a worse overall safety profile.

JAK2抑制剂已被证明在治疗各种JAK依赖性血液系统恶性肿瘤（包括PV的治疗）中有效。尽管有几种JAK抑制剂可用，如Jakafi®、Inrebic®、Ojjaara®和Vonjo®，但它们都不是仅选择性针对JAK2的。由于蛋白激酶催化位点的结构高度保守，JAK2抑制剂可能会结合到脱靶激酶，导致毒性增加，整体安全性降低。

The adverse side effects that may occur from JAK inhibition emphasize the importance of selectively targeting JAK2 while avoiding inhibition of other JAK family members. By specifically targeting JAK2, we aim to reduce the risk of infection and toxic effects that are seen with inhibitors that also block JAK1, JAK3, TYK2, or other kinases outside of the JAK family..

JAK抑制可能产生的不良副作用强调了选择性靶向JAK2而避免抑制其他JAK家族成员的重要性。通过特异性靶向JAK2，我们旨在降低那些同时阻断JAK1、JAK3、TYK2或JAK家族以外其他激酶的抑制剂所引发的感染和毒性作用的风险。

If approved, VGT-1849B could offer targeted efficacy with an improved safety profile and convenient infrequent dosing.

如果获得批准，VGT-1849B 可提供针对性的疗效，同时具有更高的安全性，并且用药频率低、使用方便。

Orphan Drug Designation is granted by the FDA to investigational therapies addressing rare medical conditions and provides benefits to drug developers.

FDA授予孤儿药资格认定，以支持针对罕见病的在研疗法，并为药物研发者提供福利。

References

参考文献

P. Gou, W. Zhang, and S. Giraudier, 'Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms,'

P. Gou, W. Zhang, 和 S. Giraudier，《关于JAK2V617F体细胞突变在骨髓增生性肿瘤中导致不同表型的潜在机制的见解》，

Myeloproliferative Neoplasms. Int. J. Mol. Sci

骨髓增殖性肿瘤。国际分子科学杂志

, vol. 2022, p. 1013, 2022,  doi: 10.3390/ijms.

，第2022卷，第1013页，2022年，doi: 10.3390/ijms.

Grunwald, M. R.; Stein, B. L.; Boccia, R. V.; Oh, S. T.; Paranagama, D.; Parasuraman, S.; Colucci, P.; Mesa, R. Clinical and Disease Characteristics From REVEAL at Time of Enrollment (Baseline): Prospective Observational Study of Patients With Polycythemia Vera in

格鲁恩瓦尔德，M. R.；斯坦，B. L.；博西亚，R. V.；欧，S. T.；帕拉纳加马，D.；帕拉斯拉曼，S.；科卢奇，P.；梅萨，R. REVEAL研究在入组时（基线）的临床和疾病特征：真性红细胞增多症患者的前瞻性观察研究

the United States

美国

. Clin Lymphoma Myeloma Leuk 2018, 18 (12), 788-795.e2.

《临床淋巴瘤、骨髓瘤和白血病》2018年，第18卷（第12期），788-795.e2页。

https://doi.org/10.1016/j.clml.2018.08.009

https://doi.org/10.1016/j.clml.2018.08.009

.

。

About Vanda Pharmaceuticals Inc.

关于万达制药公司

Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit

万达是一家领先的全球生物制药公司，专注于开发和商业化创新疗法，以满足未被满足的高医疗需求并改善患者的生活。欲了解有关万达制药公司的更多信息，请访问

www.vandapharma.com

www.vandapharma.com

and follow us on X @vandapharma.

并在X上关注我们 @vandapharma。

About VGT-1849B

关于VGT-1849B

VGT-1849B is an antisense oligonucleotide (ASO) that utilizes a novel backbone chemistry, OliPass Peptide Nucleic Acid (OPNA) peptide nucleic acid, and selectively targets

VGT-1849B是一种反义寡核苷酸（ASO），它采用了一种新型的骨架化学结构，即OliPass肽核酸（OPNA）肽核酸，并且能够选择性地靶向

JAK2

JAK2

mRNA, reducing aberrant levels of JAK2 that may cause hematologic malignancies. OPNA was derived from PNA through rational chemical modifications to enhance cell permeability and RNA affinity. For therapeutic intervention, OPNA potently binds to target pre-mRNA, induces exon skipping, and yields an mRNA splice variant.

mRNA，减少可能导致血液恶性肿瘤的JAK2异常水平。OPNA通过合理的化学修饰从PNA衍生而来，以增强细胞渗透性和RNA亲和力。在治疗干预中，OPNA强力结合目标前体mRNA，诱导外显子跳跃，并产生一种mRNA剪接变体。

Unlike other types of RNA therapeutics, OPNA does not require formulation aid for .

与其他类型的RNA疗法不同，OPNA不需要辅助制剂。

in vivo

体内

therapeutic activity. OPNA oligonucleotide-based therapeutics have broad applicability in addressing a number of disorders caused by genetic variants.

治疗性活动。基于OPNA寡核苷酸的治疗方法在解决由基因变异引起的多种疾病方面具有广泛的应用性。