Dordaviprone

弥漫性中线神经胶质瘤（DMG）是一种极其难治的脑瘤，属于最严重的4级胶质瘤，且主要发病于儿童，诊断后平均预期寿命仅为10个月，5年生存率不到1%。此前受到广泛报道的郑州女孩心蕊就是罹患这一疾病而过世。由于主要发病于患者三脑室、丘脑、脑干、脊髓等位置，手术治疗很难达成。放疗是目前的主要手段，化疗带来的获益似乎有限。然而即便如此，复发实际上也是不可避免的，近年来也没有其他系统性疗法被证明是有效的，仅有几项初步临床展现出了一线可能的希望。本文将对目前可能有希望的疗法进行简单总结。ONC-201ONC-201是Chimerix公司的一款药物，本身是一种多巴胺受体D2/D3抑制剂和线粒体酪蛋白水解蛋白酶P（CIpP）变构激动剂。因为多巴胺受体抑制剂的性质，最初是打算将用于精神相关疾病的，但研究人员发现这种小分子还可以穿透血脑屏障，因此他们就将其用于脑瘤开发。适应症也因此选择了脑瘤中占据不小比例的胶质母细胞瘤（GBM）作为适应症，但临床最终失败，并没能改善患者的无进展生存期（PFS）。好在天无绝人之路。在这项试验的两个GBM组中，四名偶然入选的H3K27M突变患者中有两名表现出多处病变的持续消退。后续的多项在H3K27M突变患者中的临床轶事和肿瘤消退也证明了其疗效。这就使得研究人员将注意力转移到H3K27M突变上。而刚好H3K27M突变DMG肿瘤细胞侵袭性更高，具有更差的预后。因此研究人员就将适应症开发集中在了H3K27M突变DMG上。而DMG上的临床开发也并没有辜负他们的期待，ONC201单药治疗H3K27M-DMG患者展现出相当有希望的疗效，在非复发患者中已经超过了化疗的金标准——ONC201治疗患者的诊断中位OS为21.7月，而外部化疗对照组仅为12个月。近期，发表于Journal of Clinical Oncology为ONC-201补充了在复发H3K27M-DMG患者的初步疗效，其机制此前也得到了阐述。ONC-201作为多巴胺受体抑制剂之外的额外作用，它可以过度激活ClpP，导致线粒体蛋白质组成分的选择性降解，并随后激活整合的应激反应和细胞凋亡，最终造成线粒体降解来实现靶向H3K27M突变蛋白质的方式诱导肿瘤细胞凋亡。GD2-CAR-TGD2-CAR-T同样是H3K27M突变DMG的可能解决方案，二硫根神经节苷脂（GD2）是一种二唾液酸神经节苷脂，主要在神经母细胞瘤、黑素瘤、骨肉瘤、肺癌和乳腺癌等肿瘤中高表达。通过调控MAPK、PI3K/Akt和FAK/paxillin等信号通路，能够促进肿瘤细胞增殖、迁移，维持肿瘤干性，以及促进化疗耐药等。而这种蛋白同时高表达于H3K27M突变的癌细胞，所以GD2-CAR-T也可以用于针对这种疾病，不过与ONC-201不同的是，这毕竟是一种CAR-T，脑内用药副作用和风险有些大。因此目前的临床主要用于儿童和青壮年脑桥和脊髓DMG患者，而丘脑或小脑肿瘤患者就会被排除入组，因为这些位置过于关键，具有极大风险。2022年披露的一项临床结果表明，4例患者中有3例表现出临床和影像学改善，患者神经细胞有所改善。该研究主要展现了临床转化过程中应对炎症等CAR-T副作用的相关处理方式。目前仍然在伦敦大学和斯坦福大学等几个机构中探索最佳剂量、途径和方案，并确定GD2-CAR T细胞疗法在H3K27M + DMG患者中的疗效。总结总的来说，目前较为有希望的治疗方案主要是ONC-201和GD2-CAR-T，其他治疗方案如溶瘤病毒，ADC，BBB穿梭肽，TILs，抗体等方式大多位于临床早期或临床前研究。在我国人口基数巨大的情况下，可以期待该领域药物的开发能够为患者带来更多机遇。参考来源：1.Venneti S, Kawakibi AR, Ji S, Waszak SM, Sweha SR, Mota M, Pun M, Deogharkar A, Chung C, Tarapore RS, Ramage S, Chi A, Wen PY, Arrillaga-Romany I, Batchelor TT, Butowski NA, Sumrall A, Shonka N, Harrison RA, de Groot J, Mehta M, Hall MD, Daghistani D, Cloughesy TF, Ellingson BM, Beccaria K, Varlet P, Kim MM, Umemura Y, Garton H, Franson A, Schwartz J, Jain R, Kachman M, Baum H, Burant CF, Mottl SL, Cartaxo RT, John V, Messinger D, Qin T, Peterson E, Sajjakulnukit P, Ravi K, Waugh A, Walling D, Ding Y, Xia Z, Schwendeman A, Hawes D, Yang F, Judkins AR, Wahl D, Lyssiotis CA, de la Nava D, Alonso MM, Eze A, Spitzer J, Schmidt SV, Duchatel RJ, Dun MD, Cain JE, Jiang L, Stopka SA, Baquer G, Regan MS, Filbin MG, Agar NYR, Zhao L, Kumar-Sinha C, Mody R, Chinnaiyan A, Kurokawa R, Pratt D, Yadav VN, Grill J, Kline C, Mueller S, Resnick A, Nazarian J, Allen JE, Odia Y, Gardner SL, Koschmann C. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131.2.Isabel Arrillaga-Romany et al, ONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma, Journal of Clinical Oncology (2024). DOI: 10.1200/JCO.23.011343.Miguel Llordes G, Medina Pérez VM, Curto Simón B, Castells-Yus I, Vázquez Sufuentes S, Schuhmacher AJ. Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma. J Clin Med. 2023 Aug 12;12(16):5261. doi: 10.3390/jcm12165261.

– ONC201 ACTION Study Progressing; Reiterate Interim OS Data Expected in 2025, Final OS Data Expected in 2026 – – Phase 2 ONC201 Data Published in Peer-Reviewed Journal of Clinical Oncology – – $204 Million in Cash and Equivalents at December 31, 2023 – – Conference Call at 8:30 a.m. ET Today – DURHAM, N.C., Feb. 29, 2024 (GLOBE NEWSWIRE) -- Chimerix (NASDAQ:CMRX), a biopharmaceutical company whose mission it is to develop medicines that meaningfully improve and extend the lives of patients facing deadly diseases, today reported financial results for the fourth quarter and full-year ended December 31, 2023 and provided an operational update. “Following strong clinical development in 2023, we remain very focused on advancing the ONC201 ACTION study, completing ONC206 dose escalation this year and strengthening our executive team as we prepare for potential commercialization of ONC201,” said Mike Andriole, Chief Executive Officer of Chimerix. “We are making good progress enrolling our global Phase 3 ACTION study and are excited about the prospect of having interim overall survival data next year. In addition, we are pleased to share that the ONC201 Phase 2 data was recently published in the Journal of Clinical Oncology which further elucidates key characteristics of response and detailed patient-level data.” “During the fourth quarter, we were delighted to strengthen our Board of Directors with the addition of Lisa Decker, Ph.D., as well as strengthen the management team with the promotion of Michelle LaSpaluto to Chief Financial Officer and the additions of Tom Riga as Chief Operating and Commercial Officer and Pablo Lee, MD, as Vice President of Medical Affairs. We are confident their collective expertise will be invaluable assets to Chimerix as we seek to maximize our future growth potential for patients and shareholders,” added Mr. Andriole. ONC201 Journal of Clinical Oncology Publication In February 2024, “ONC201 (dordaviprone) in Recurrent H3 K27M-mutant Diffuse Midline Glioma,” was published in the Journal of Clinical Oncology (JCO), a peer reviewed journal of the American Society of Clinical Oncology (ASCO). The manuscript reports in detail the results of 50 patients with recurrent H3 K27M-DMG treated with monotherapy ONC201 who were evaluable for objective response by Response Assessment in Neuro-Oncology (RANO) high grade glioma (HGG) criteria. ONC201 demonstrated a median overall survival (mOS) of 13.7 months (95% CI: 8.0 - 20.3), with an overall two-year rate of survival of 35% (95% CI: 21-49) from the start of ONC201 treatment post-recurrence. Chimerix previously conducted a natural disease history study (n=43) in the recurrent setting evaluating patients who did not receive ONC201 which showed a mOS of 5.1 months (95% CI: 3.9 - 7.7) with an overall two-year survival rate of 11% (95% CI:3.3-24.2).The top-line data from this JCO publication were previously disclosed by Chimerix. The journal can be accessed here. The Phase 3 ACTION trial is currently enrolling patients at over 130 sites in 13 countries. The trial enrolls patients shortly after completion of front-line radiation therapy that is the standard of care. The study is designed to enroll 450 patients randomized 1:1:1 to receive ONC201 at one of two dosing frequencies or placebo. Participants are randomized to receive 625mg of ONC201 once per week (the Phase 2 dosing regimen), 625mg twice per week on two consecutive days or placebo. The dose will be scaled by body weight for patients <52.5kg. For more information, please visit clinicaltrials.gov ONC206 ONC206 is a second generation ClpP agonist and DRD2 antagonist that has demonstrated monotherapy anti-cancer activity in pre-clinical models in primary CNS tumors and solid tumors outside of the CNS. Phase I dose escalation trials continue at the National Institutes of Health (NIH) and the Pacific Pediatric Neuro-Oncology Consortium (PNOC) in adult and pediatric CNS tumor patients, respectively. To date, ONC206 has been generally well tolerated with no dose limiting toxicities. The dose escalation trials are currently dosing at more frequent dose schedules, which are expected to increase the duration of therapeutic exposure. Chimerix expects to report preliminary safety and pharmacokinetic data from these trials beginning in mid-2024. Fourth Quarter 2023 Financial Results Chimerix’s balance sheet at December 31, 2023 included $204.5 million of capital available to fund operations, no debt, and approximately 88.9 million outstanding shares of common stock. Chimerix reported a net loss of $18.2 million, or $0.20 per basic and diluted share, for the fourth quarter of 2023, compared to a net loss of $21.0 million, or $0.24 per basic and diluted share for the fourth quarter of 2022. Research and development expenses decreased to $15.6 million for the three-month period ended December 31, 2023, compared to $19.3 million for the same period in 2022. This decrease was primarily driven by one-time costs associated with a reduction in force related to the TEMBEXA divestiture in the comparable 2022 period. General and administrative expenses decreased to $5.2 million for the fourth quarter of 2023, compared to $5.3 million for the same period in 2022. Full Year 2023 Financial Results Chimerix reported a net loss of $82.1 million, or $0.93 per basic and diluted share, for the year ended December 31, 2023. For the year ended December 31, 2022, Chimerix recorded net income of $172.2 million, or $1.97 per basic and $1.94 per diluted share. The decrease was primarily driven by the gain on sale of TEMBEXA to Emergent BioSolutions in 2022. Revenues for 2023 decreased to $0.3 million, compared to $33.8 million in 2022. The decrease was primarily related to deliveries under international TEMBEXA procurement agreements in the comparable 2022 period. Research and development expenses decreased to $68.8 million for the year ended December 31, 2023, compared to $71.6 million for the year ended December 31, 2022. General and administrative expenses increased to $24.6 million for the year ended December 31, 2023, compared to $22.1 million for the year ended December 31, 2022. Conference Call and Webcast Chimerix will host a conference call and live audio webcast to discuss fourth quarter and full-year 2023 financial results and provide a business update today at 8:30 a.m. ET. To access the live conference call, please dial 646-307-1963 (domestic) or 800-715-9871 (international) at least five minutes prior to the start time and refer to conference ID 6933453. A live audio webcast of the call will also be available on the Investors section of Chimerix’s website, www.chimerix.com. An archived webcast will be available on the Chimerix website approximately two hours after the event. About Chimerix Chimerix is a biopharmaceutical company with a mission to develop medicines that meaningfully improve and extend the lives of patients facing deadly diseases. The Company’s most advanced clinical-stage development program, ONC201, is in development for H3 K27M-mutant glioma. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Forward-looking statements include those relating to, among other things, enrollment and timing of data for the Phase 3 ACTION study, the results of dose escalation trials of ONC206, and the impact of recent changes to the Board of Directors and management team. Among the factors and risks that could cause actual results to differ materially from those indicated in the forward-looking statements are risks related to the timing, completion and outcome of the Phase 3 ACTION study of ONC201; risks associated with repeating positive results obtained in prior preclinical or clinical studies in future studies; risks related to the clinical development of ONC206; and additional risks set forth in the Company's filings with the Securities and Exchange Commission. These forward-looking statements represent the Company's judgment as of the date of this release. The Company disclaims, however, any intent or obligation to update these forward-looking statements. CONTACT: Will O’ConnorStern Investor Relations212-362-1200will@sternir.com CHIMERIX, INC.CONSOLIDATED BALANCE SHEETS(in thousands, except share and per share data) December 31, December 31, 2023 2022 ASSETS Current assets: Cash and cash equivalents$27,661 $25,842 Short-term investments, available-for-sale 155,174 191,492 Accounts receivable 4 1,040 Prepaid expenses and other current assets 6,271 9,764 Total current assets 189,110 228,138 Long-term investments 21,657 48,626 Property and equipment, net of accumulated depreciation 224 227 Operating lease right-of-use assets 1,482 1,964 Other long-term assets 301 386 Total assets$212,774 $279,341 LIABILITIES AND STOCKHOLDERS' EQUITY Current liabilities: Accounts payable$2,851 $3,034 Accrued liabilities 15,592 17,381 Total current liabilities 18,443 20,415 Loan Fees 125 250 Lease-related obligations 1,177 1,819 Total liabilities 19,745 22,484 Stockholders’ equity: Preferred stock, $0.001 par value, 10,000,000 shares authorized at December 31, 2023 and 2022; no shares issued and outstanding as of December 31, 2023 and 2022 - - Common stock, $0.001 par value, 200,000,000 shares authorized at December 31, 2023 and 2022; 88,929,300 and 88,054,127 shares issued and outstanding as of December 31, 2023 and 2022, respectively 89 88 Additional paid-in capital 988,457 970,535 Accumulated other comprehensive gain (loss), net 7 (337) Accumulated deficit (795,524) (713,429) Total stockholders’ equity 193,029 256,857 Total liabilities and stockholders’ equity$212,774 $279,341 CHIMERIX, INC.CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE (LOSS) INCOME(in thousands, except share and per share data) Three Months Ended December 31, Years Ended December 31, 2023 2022 2023 2022 Revenues: Procurement revenue$- $- $- $31,971 Contract and grant revenue 4 439 275 942 Licensing revenue - - 49 536 Royalty revenue - 375 - 375 Total revenues 4 814 324 33,824 Cost of goods sold - - - 447 Gross Profit 4 814 324 33,377 Operating expenses: Research and development 15,644 19,281 68,788 71,631 General and administrative 5,170 5,347 24,601 22,132 Total operating expenses 20,814 24,628 93,389 93,763 Loss from operations (20,810) (23,814) (93,065) (60,386)Other income: Interest income and other, net 2,649 2,737 10,970 2,919 Gain on sale of business, net - - - 229,670 (Loss) income before income taxes (18,161) (21,077) (82,095) 172,203 Income tax expense - (117) - 36 Net (loss) income (18,161) (20,960) (82,095) 172,167 Other comprehensive income (loss): Unrealized income (loss) on investments, net 632 (300) 344 (316) Comprehensive (loss) income$(17,529) $(21,260) $(81,751) $171,851 Per share information: Net (loss) income, basic$(0.20) $(0.24) $(0.93) $1.97 Net (loss) income, diluted$(0.20) $(0.24) $(0.93) $1.94 Weighted-average shares outstanding, basic 88,910,300 88,049,138 88,604,026 87,555,110 Weighted-average shares outstanding, diluted 88,910,300 88,049,138 88,604,026 88,776,147