UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 1, 2024
(Exact name of registrant as specified in its charter)
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| (Address of principal executive offices) | (Zip Code) | |||||||
(919 ) 806-1074
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Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ¨
Item 2.02 Results of Operations and Financial Condition.
On May 1, 2024, Chimerix, Inc. (the “Company”) announced our financial results for the three months ended March 31, 2024 in the press release attached hereto as Exhibit 99.1 and incorporated herein by reference.
Item 7.01 Regulation FD Disclosure.
On May 1, 2024, the Company also made available an updated corporate presentation (the “Presentation”) that the Company intends to use, in whole or in part, in meetings with investors, analysts and others. The Presentation can be accessed through the “Investors” section of the Company’s website. A copy of the Presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated by reference herein.
The information in Item 2.02, Item 7.01 and the attached Exhibits 99.1 and 99.2 is being furnished and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that Section. The information in Item 2.02, Item 7.01 and the attached Exhibits 99.1 and 99.2 shall not be incorporated by reference into any registration statement or other document pursuant to the Securities Act of 1933, as amended.
| Item 9.01 | Financial Statements and Exhibits. | ||||
(d)Exhibits
| Exhibit No. | Description | |||||||
| 99.1 | ||||||||
| 99.2 | ||||||||
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). | |||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Chimerix, Inc. | |||||||||||
| Date: May 1, 2024 | |||||||||||
| By: | /s/ Michelle LaSpaluto | ||||||||||
| Name: | Michelle LaSpaluto | ||||||||||
| Title: | Chief Financial Officer | ||||||||||
Chimerix Reports First Quarter 2024 Financial Results and Provides Operational Update
– Dordaviprone (ONC201) ACTION Study Progressing; Reiterates Expectations for Interim Overall Survival (OS) Data in 2025 and Final OS Data in 2026 –
– No Dose Limiting Toxicity in ONC206 Phase 1 Studies to Date, Preliminary Phase 1 Safety and Pharmacokinetic (PK) Data Expected This Summer –
– Company to Advance Dordaviprone in Provisional Registration Process Following Positive Interaction with Therapeutic Goods Administration (TGA) in Australia –
– Conference Call at 8:30 a.m. ET Today –
DURHAM, N.C., May 1, 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 first quarter ended March 31, 2024 and provided an operational update.
“Patients, caregivers and physicians are in desperate need for novel therapies that offer clinical benefit in H3 K27M-mutant diffuse glioma, and we believe that dordaviprone (ONC201) has the potential to be a major therapeutic advance in the treatment of this disease,” said Mike Andriole, Chief Executive Officer of Chimerix.
“We remain intensely focused on completion of the ACTION study and will continue to be active and collaborative with regulators to bring dordaviprone to patients in need as soon as possible. In parallel, we are continuously evaluating options to accelerate access to dordaviprone in select markets where accelerated regulatory pathways exist as there are few treatment options for this ultra-rare disease beyond radiation therapy. As an example, our recent interaction with the Therapeutic Goods Administration (TGA) in Australia is a positive initial step that is aligned to this overall strategy. Having a pivotal Phase 3 study well underway is an important consideration in global regulatory conversations that contemplate accelerated approval, and the ongoing maturation of the ACTION study enables these conversations,” added Mr. Andriole.
“Furthermore, we continue to progress our second generation imipridone, ONC206, in Phase 1 dose escalation and are enthusiastic about the differentiated profile and activity seen with this molecule thus far. We expect to pursue novel development opportunities apart from dordaviprone and look forward to describing the future development path of ONC206 by the end of the year,” concluded Mr. Andriole.
Dordaviprone (ONC201)
Dordaviprone is an oral, first-in-class small molecule imipridone that selectively binds to the G-protein coupled dopamine receptor D2 (DRD2) and the mitochondrial protease ClpP.
Dordaviprone is being evaluated in the Phase 3 ACTION trial that is currently enrolling H3 K27M-mutant glioma patients at over 135 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 dordaviprone at one of two dosing frequencies or placebo. Participants are
randomized to receive 625mg of dordaviprone once per week (the Phase 2 dosing regimen), 625mg on two consecutive days per week or placebo. The dose is scaled by body weight for patients <52.5kg.
Chimerix expects interim overall survival (OS) data in 2025 and final OS data in 2026. For more information, please visit clinicaltrials.gov
Chimerix recently engaged in the process to evaluate eligibility for dordaviprone to be considered for Provisional Registration in Australia. The Provisional Registration process is a three-step process which begins with a Pre-Submission Meeting evaluating current data, as well as other program features, including the status of pivotal studies. Chimerix recently completed the Pre-Submission Meeting with the TGA and the TGA agreed that dordaviprone meets the criteria to advance to the second of three steps in the process, a Provisional Determination application. The meeting included an assessment that preliminary data is likely to provide a “major therapeutic advance” in H3 K27M-mutant glioma and that the ACTION study could provide pivotal confirmatory safety and efficacy data before the conclusion of the Provisional Registration period. Chimerix expects to work collaboratively with TGA as dordaviprone advances to the next step in the process over the coming months. Once submitted, the Provisional Determination review process is targeted for 20 working days. Should an application for Provisional Registration be submitted the review process is 255 working days. We expect a filing could occur around year end with possible commercial availability in 2026.
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. The dose escalation trials are currently dosing at a twice per day, three days per week schedule, which are expected to increase the duration of therapeutic exposure. To date, ONC206 has been generally well tolerated with no dose limiting toxicities as is currently being dosed in the expected therapeutic range. Chimerix expects to report preliminary safety and pharmacokinetic (PK) data from these studies beginning in mid-2024.
Corporate
In March 2024, Chimerix announced the appointment of Marc D. Kozin as the newest member of the Company’s Board of Directors. Mr. Kozin brings more than 35 years of experience in corporate and business strategy consulting and merger and acquisition advisory services. In addition, Patrick Machado has announced his retirement from the Chimerix Board effective at the Company’s 2024 Annual Meeting of Stockholders in June, after ten years of service.
First Quarter 2024 Financial Results
Chimerix reported a net loss of $21.9 million, or $0.25 per basic and diluted share, for the first quarter of 2024. During the same period in 2023, Chimerix recorded a net loss of $21.4 million, or $0.24 per basic and diluted share.
Research and development expenses were $18.8 million for the first quarter of 2024 and the same period in 2023.
General and administrative expenses decreased to $5.5 million for the first quarter of 2024, compared to $5.7 million for the same period in 2023.
Chimerix’s balance sheet at March 31, 2024 included $188.2 million of capital available to fund operations, approximately 89.6 million outstanding shares of common stock and no outstanding debt.
Conference Call and Webcast
Chimerix will host a conference call and live audio webcast to discuss first quarter 2024 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 1246220. 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, applications for Provisional Determination and Provisional Determination in Australia, plans for accelerated approval from other global regulators, completion of the ACTION study, and the characteristics and development of ONC206. 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 ability to obtain and maintain accelerated approval; 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’Connor
Stern Investor Relations
212-362-1200
Will@sternir.com
CHIMERIX, INC.
CONSOLIDATED BALANCE SHEETS
(in thousands, except share and per share data)
(unaudited)
| March 31, 2024 | December 31, 2023 | ||||||||||
| ASSETS | |||||||||||
| Current assets: | |||||||||||
| Cash and cash equivalents | $ | 19,026 | $ | 27,661 | |||||||
| Short-term investments, available-for-sale | 140,002 | 155,174 | |||||||||
| Accounts receivable | 1 | 4 | |||||||||
| Prepaid expenses and other current assets | 4,003 | 6,271 | |||||||||
| Total current assets | 163,032 | 189,110 | |||||||||
| Long-term investments | 29,133 | 21,657 | |||||||||
| Property and equipment, net of accumulated depreciation | 263 | 224 | |||||||||
| Operating lease right-of-use assets | 1,354 | 1,482 | |||||||||
| Other long-term assets | 260 | 301 | |||||||||
| Total assets | $ | 194,042 | $ | 212,774 | |||||||
| LIABILITIES AND STOCKHOLDERS' EQUITY | |||||||||||
| Current liabilities: | |||||||||||
| Accounts payable | $ | 3,823 | $ | 2,851 | |||||||
| Accrued liabilities | 15,112 | 15,592 | |||||||||
| Total current liabilities | 18,935 | 18,443 | |||||||||
| Line of credit commitment fee | — | 125 | |||||||||
| Lease-related obligations | 1,005 | 1,177 | |||||||||
| Total liabilities | 19,940 | 19,745 | |||||||||
| Stockholders’ equity: | |||||||||||
| Preferred stock, $0.001 par value, 10,000,000 shares authorized at March 31, 2024 and December 31, 2023; no shares issued and outstanding as of March 31, 2024 and December 31, 2023 | — | — | |||||||||
| Common stock, $0.001 par value, 200,000,000 shares authorized at March 31, 2024 and December 31, 2023; 89,692,902 and 88,929,300 shares issued and outstanding as of March 31, 2024 and December 31, 2023, respectively | 90 | 89 | |||||||||
| Additional paid-in capital | 991,583 | 988,457 | |||||||||
| Accumulated other comprehensive (gain) loss, net | (178) | 7 | |||||||||
| Accumulated deficit | (817,393) | (795,524) | |||||||||
| Total stockholders’ equity | 174,102 | 193,029 | |||||||||
| Total liabilities and stockholders’ equity | $ | 194,042 | $ | 212,774 | |||||||
CHIMERIX, INC.
CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(in thousands, except share and per share data)
(unaudited)
| Three Months Ended March 31, | |||||||||||
| 2024 | 2023 | ||||||||||
| Revenues: | |||||||||||
| Contract and grant revenue | — | 234 | |||||||||
| Licensing revenue | — | 49 | |||||||||
| Total revenues | — | 283 | |||||||||
| Operating expenses: | |||||||||||
| Research and development | 18,844 | 18,822 | |||||||||
| General and administrative | 5,546 | 5,679 | |||||||||
| Total operating expenses | 24,390 | 24,501 | |||||||||
| Loss from operations | (24,390) | (24,218) | |||||||||
| Other income: | |||||||||||
| Interest income and other, net | 2,521 | 2,846 | |||||||||
| Net loss | (21,869) | (21,372) | |||||||||
| Other comprehensive (loss) income: | |||||||||||
| Unrealized (loss) gain on debt investments, net | (185) | 106 | |||||||||
| Comprehensive loss | $ | (22,054) | $ | (21,266) | |||||||
| Per share information: | |||||||||||
| Net loss, basic and diluted | $ | (0.25) | $ | (0.24) | |||||||
| Weighted-average shares outstanding, basic and diluted | 89,259,106 | 88,294,624 | |||||||||
Chimerix Corporate Presentation May 1, 2024
2 Forward-Looking Statements This presentation 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, the enrollment and timing of data for the Phase 3 ACTION study, the expected results of Phase 3 ACTION study of ONC201 and dose escalation trials of ONC206, our ability to successfully commercialize our current and future product candidates, the potential for royalty and milestone revenue from strategic collaborations, and projections regarding the potential market opportunity, funding and timing of future data readouts for our products. 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.
3 Investment highlights and key catalysts ONC201 Ph 3 trial enrolling - interim OS data expected in 2025, final OS expected in 2026 First-Line H3 K27M-mutant diffuse glioma – The ACTION Study No approved therapies targeting H3 K27M diffuse glioma, an area of high unmet medical need First in class mechanism of action with clinical validation Patent protection thru 2037 (potential additional US patent term extension) ONC206 in dose escalation Investigator reported response in non-H3 K27M mutated recurrent glioblastoma patient Dose escalation on track for completion beginning in mid 2024 $188 million in capital to fund operations as of March 31, 2024, no debt Early-stage pipeline leverages external capital Pre-clinical programs potential to advance to clinic or partner (ONC212, CMX521) Robust business development search and evaluation process Ph 3 ACTION study actively enrolling Significant commercial potential Corporate capability and financial flexibility
4 Regulatory Approval RegistrationalPhase 2Phase 1PreclinicalProgram Deep pipeline across all development stages ONC201 (dordaviprone) H3 K27M-mutant glioma (orphan drug,1 fast track2 and rare pediatric disease designations3) IITs- signal finding, multiple oncology indications/combinations CMX521 SARS-CoV-2 CNS4 tumors ONC206 IND-enabling studies ONC212 TEMBEXA® transacted with Emergent BioSolutions Smallpox (orphan drug designation) 1 Malignant glioma 2 Adult recurrent H3 K27M-mutant high-grade glioma 3 H3 K27M-mutant glioma 4. Central Nervous System Non-CNS4 tumors
ONC201 (dordaviprone) Phase 2 Data Analysis
6 • H3 K27M mutation is predominantly found among diffuse midline gliomas (DMGs) in young adults and children • Frontline radiotherapy remains standard of care with transient benefit; resection often not feasible • DMGs harboring the H3 K27M mutation are WHO Grade IV; historically invariably lethal • Consistently longer OS of ONC201-treated H3 K27M DMG patients across: - Diverse external controls (historical, trials) - Sensitivity analysis (early event censoring) - Isolated tumor locations (thalamus, brainstem) ONC201 data suggests potential to address high unmet need ONC201 Phase 2 (n=50) Natural Disease History4 (n=43) 13.7 (8-20.3) 5.1 (3.9-7.7) Median OS, mo (95% CI) 57% (41-70) 23.6% (11.7-37.9) OS @ 12mo (95% CI) 35% (21-49) 11.1% (3.3-24.2) OS @ 24mo (95% CI) Histone H3 Mutations in CNS Tumors1 Recurrent H3 K27M DMG3 1 Lulla RR et al. Sci Adv. 2016;2(3):e1501354 2 Koschmann, Carl et al, “Clinical efficacy of ONC201 in H3 K27M-mutant diffuse midline glioma is driven by disruption of integrated metabolic and epigenetic pathways”, Cancer Discovery, Aug 16, 2023 3 In company sponsored studies 4 The median OS was 5.1 months for the subset of patients with H3 K27M-mutant diffuse glioma excluding DIPG, CSF dissemination, spinal or leptomeningeal disease (N=12), OS at 12 mos was 25.0%, OS at 24 mos was 16.7% Frontline H3 K27M DMG2
7 • ONC201 monotherapy exhibited durable, clinically meaningful efficacy in recurrent H3 K27M-mutant DMG - Overall Response Rate (ORR) of 30% (95% CI: 18 - 45%) by RANO HGG and/or LGG dual reader BICR - RANO-HGG criteria assessed by dual reader BICR • ORR 20% (95% CI: 10 – 34%) • Median Duration of Response (DOR) 11.2 months (95% CI: 3.8 – not reached) • Median time to response 8.3 months (range 1.9 – 15.9) • Disease control rate 40% (95% CI: 26 – 55%) • PFS at 6 months 35% (95% CI: 21 – 49%); PFS at 12 months 30% (95% CI: 17 – 44%) - RANO-LGG criteria assessed by dual reader BICR • ORR 26% (95% CI: 15 – 40%) - Overall survival • 12 months: 57% (95% CI:41 – 70%) • 24 months: 35% (95% CI: 21 – 49%) • Improvements observed in performance status and reduction in corticosteroid use • All Serious Adverse Events considered not related to ONC201 by sponsor Phase 2 efficacy for ONC201 in recurrent H3 K27M DMG
8 • Strict selection criteria to ensure responses attributable to single agent treatment • Responses require both imaging and clinical criteria • Dual reader blinded independent central review (BICR) • Growing consensus that assessment of enhancing and non-enhancing disease (RANO- HGG and RANO-LGG criteria) is needed for diffuse midline glioma ONC201 waterfall plot – 30% RANO HGG / LGG response RANO HGG (enhancing) • 20% response • 40% disease control RANO LGG (non-enhancing) • 26% response • 42% disease control ONC201 Ph 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma Change > 100%, PR=partial response, MR=minor response, SD=stable disease, NE=not evaluable, PD=progressive disease Arrillaga-Romany, et al, Journal of Clinical Oncology, Feb 2024
9 Clinically meaningful and durable RANO-HGG responses SPD=sum of products of perpendicular diameters (target enhancing lesions per BICR) Only patients with measurable target enhancing lesions by BICR at baseline and with post-baseline evaluations are included. Three patients did not have on-treatment monotherapy MRIs available for BICR; one patient censored prior to first on-treatment MRI ; one patient did not have measurable target lesion. 11.2 months (3.8 – not reached) Duration of response, median (95% CI) 8.3 months (1.9 – 15.9) Time to response, median (range) ONC201 Phase 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma
10 Clinical Pharmacology Studies n=235 • ONC201 was well tolerated at various dose levels (125 mg to 750 mg). • The majority of treatment-related adverse events across the clinical pharmacology studies were Grade 1 (mild) and transient. • Most common treatment-related AEs were grade 1 nausea and dizziness. • ONC201 in the clinical pharmacology program, which included: - Dose-escalation, food-effect, & formulation evaluation - Thorough QT Study - Drug-drug interaction (DDI) studies: Strong CYP3A4 inhibitor and Proton-pump inhibitor studies - Renal impairment study - Hepatic impairment study - Mass balance study - Formulation Bioequivalence studies ONC201 Safety Glioma Patient Studies Treatment-related Adverse Events in >5% 1. Based on available data from October 2023 Investigator brochure Related TEAEsTreatment-related Adverse Events, Integrated Safety Data Set, (N=422 glioma patients) 1 Grade > 3All grades 11.6%56.2%Any Treatment-related AE 2.1%20.1%Fatigue 015.4%Nausea 0.9%11.1%Vomiting 1.9%9.2%Lymphocyte count decreased 1.4%8.5%ALT increased 07.3%Headache 0.2%7.1%White blood cell count decreased 05.7%Decreased appetite 05.2%Hypophosphataemia Only 3% patients experienced a treatment-related AE that led to study drug modification or discontinuation.
ONC201 Phase 3 ACTION Study Summary
12 Now enrolling, a randomized, double-blind, placebo-controlled, multicenter international study in 450 newly diagnosed diffuse glioma patients whose tumor harbors an H3 K27M-mutation. Pivotal Phase 3 ACTION trial design 1. Excludes DIPG and spinal tumors • H3 K27M-mutant diffuse glioma1 • Radiation therapy recently completed • KPS > 70 at time of randomization • Stable steroid dose • No prior bevacizumab • No temozolomide within three weeks ONC201 twice weekly (625mg ONC201 day 1 + day 2) ONC201 weekly (625mg ONC201 day 1 + placebo day 2) Placebo (Placebo day 1 + placebo day 2) • Primary: Overall Survival • PFS (alpha-allocated) • Secondary: steroid response, performance status, QoL, neurologic function Key Patient Inclusion EndpointsTreatment
13 Design provides multiple paths for success Interim data expected in 2025 and final data in 2026 Second OS Interim • ~246 events • Success at HR~0.64 Final OS • ~327 events • Success at HR~0.73 PFS by RANO HGG(2) • ~286 events • Success at HR~0.68 1. Overall Survival (OS) 2. Progression-free survival (PFS). PFS may provide valuable data for regulatory discussions. 3. Hazard Ratio Independent comparisons for each ONC201 arm versus control will be made at each timepoint. Powering assumptions 0.65 expected HR for OS and 0.60 expected HR for PFS First OS(1) Interim • ~164 events • Success at HR(3)~0.52
ONC201 Market Opportunity Assessment
15 (1) Ostrom QT, et al. Neuro Oncol. 2022;24(Suppl 5):v1-v95; (2) Patient numbers and percentages are estimates (weighted avg per sample size) derived from a review of the literature from (2012-2023): (Aihara K, et al. Neuro Oncol. 2014;16(1):140-6; Feng J, et al. Hum Pathol. 2015;46(11):1626-32; Solomon DA, et al. Brain Pathol. 2016;26(5):569-80;Ryall S, et al. Acta Neuropathol Commun. 2016;4(1):93; Aboian MS, et al. AJNR Am J Neuroradiol. 2017;38(4):795-800; Wang L, et al. Hum Pathol. 2018;78:89-96; Castel D, et al. Acta Neuropathol Commun. 2018;6(1):117; Karremann M, et al. Neuro Oncol. 2018;20(1):123-131; Aboian MS, et al. AJNR Am J Neuroradiol. 2019;40(11):1804-1810; Dorfer C, et al. Acta Neurochir (Wien). 2021;163(7):2025-2035; Sievers P, et al. Neuro Oncol. 2021;23(1):34-43; Mackay A, et al. Cancer Cell. 2017;32(4):520-537 e5; Huang T, et al. Oncotarget. 2018;9(98):37112-37124; Schreck KC, et al. J Neurooncol. 2019;143(1):87-93; Chiba K, et al. World Neurosurg. 2020;134:e530-e539; Mukasa A, et al. Neuro Oncol. 2014;16(Suppl 3):iii9-iii10; Castel D, et al. Acta Neuropathol. 2015;130(6):815-27; Khuong-Quang DA, et al. Acta Neuropathol. 2012;124(3):439-47; Roux A, et al. Neuro Oncol. 2020;22(8):1190-1202; Giagnacovo M, et al. Childs Nerv Syst. 2020;36(4):697-704; Wu G, et al. Nat Genet. 2014;46(5):444-450; Wu G, et al. Nat Genet. 2012;44(3):251-3; Taylor KR, et al. Nat Genet. 2014;46(5):457-461; Saratsis AM, et al. Acta Neuropathol. 2014;127(6):881-95; Erker C, et al. Neuro Oncol. 2022;24(1):141-152; Buczkowicz P, et al. Acta Neuropathol. 2014;128(4):573-81; Daoud EV, et al. J Neuropathol Exp Neurol. 2018;77(4):302-311; Chai RC, et al. Acta Neuropathol Commun. 2020;8(1):40; Yi S, et al. Neurosurgery. 2019;84(5):1072-1081; Gessi M, et al. Acta Neuropathol. 2015;130(3):435-7; Alvi MA, et al. Mod Pathol. 2019;32(9):1236-1243; Crotty EE, et al. J Neurooncol. 2020;148(3):607-617; Dono A, et al. J Clin Neurosci. 2020;82(Pt A):1-8; Akinduro OO, et al. J Neurosurg Spine. 2021;35(6):834-843; Nakata S, et al. Brain Tumor Pathol. 2017;34(3):113-119; Nomura M, et al. Acta Neuropathol. 2017;134(6):941-956; Eschbacher KL, et al. Am J Surg Pathol. 2021;45(8):1082-1090; D'Amico RS, et al. J Neurooncol. 2018;140(1):63-73; Korshunov A, et al. Acta Neuropathol. 2015;129(5):669-78; Aibaidula A, et al. Neuro Oncol. 2017;19(10):1327-1337.) • ~40% of 4,000+ midline gliomas are expected to harbor the H3 K27M mutation2 • ~2% of 17,000+ non-midline gliomas are expected to harbor the H3 K27M mutation2 • Each year it is estimated that ~2,000 patients are affected by H3 K27M-mutant glioma in the U.S; ~5,000 patients in the top seven global markets (by extrapolation of the estimated US incidence rate to the top seven markets) • No approved therapies specifically for H3 K27M mutant glioma Thalamic 220 patients (52%) Pineal 40 patients (20%) Cerebellum 240 patients (22%) Brainstem (excluding pons) 270 patients (50%) Non-midline ~350 patients (~2%) Ventricle 250 patients (71%) Pons 290 patients (75%) Spinal cord 370 patients (49%) Approximately 21,000 gliomas reported in the U.S. each year, affecting all locations in the brain1 Estimated # of U.S. H3 K27M+ Patients by Tumor Location (rate of positivity)2
16 • No approved therapies for H3 K27M mutant glioma, ONC201 is the leading program targeting this mutation globally • Potential market opportunity ~$750 million • Approximately 5,000 patients in top seven markets1 • Ultra-orphan indication drug pricing • H3 K27M mutations most often in children / young adults • Low barriers to adoption - No effective alternative therapies - High unaided awareness among neuro-oncologists - Mutation routinely identified by existing diagnostics - Longer-term, potentially combinable with other glioma therapies • Patent protection for lead indication into 2037 - potential U.S. patent term extension (up to five years) H3 K27M-mutant glioma: rapid ramp to peak revenue expected 1. By extrapolation of the estimated US incidence rate to the top seven markets
17 Potential for ONC201 beyond brain tumors • Single agent responses in Ph 2 neuroendocrine trial of ONC201 observed in subset (PCPG) • PCPG are adrenal-related tumors with elevated DRD2 expression • Five patients have been treated > 1 year • Fewer short-term and potential long-term toxicities than other paraganglioma therapies ONC201 efficacy results in dopamine-secreting tumors outside the brain Ph 2 Study of ONC201 in Neuroendocrine Tumors in investigator- reported data from clinical trial NCT # (NT03034200) 1. https://aacrjournals.org/clincancerres/article/28/9/1773/694456/Phase-II-Study-of-ONC201-in-Neuroendocrine-Tumors
ONC201 Mechanism of Action
19 • ONC201 can selectively induce apoptosis in cancer cells by altering the activity of two protein targets • DRD2 antagonism - DRD2 is a G protein-coupled neuroreceptor that regulates Ras signaling - ONC201 antagonizes DRD2, inhibiting Ras signaling pathways • ClpP agonism - ClpP normally degrades misfolded proteins in mitochondria - ONC201 modifies ClpP conformation, promoting excess degradation of specific mitochondrial proteins important for cancer cell viability ONC201 directly engages DRD2 and ClpP ONC201 upregulates integrated stress response, inactivates Akt/ERK, and selectively induces tumor cell death ClpP=caseinolytic protease P; OXPHOS=oxidative phosphorylation; DRD2=Dopamine receptor D2; ATF4=activating transcription factor 4; CHOP=C/EBP-homologous protein; ERK=extracellular-regulated kinase;
20 Mechanism and frontline clinical efficacy in H3 K27M DMG Mitochondrial effects reverse H3 K27me3-loss hallmark of H3 K27M H3 K27me3-loss reversal evident in ONC201- treated H3 K27M patients Front-line ONC201 following RT survival benefit Increased confidence in Ph3 dose Provides ClpP connection to H3 K27M Anchors MOA directly to targeting H3 K27M Extends documented benefit to front-line, pediatrics, and brainstem
ONC206
22 ONC206: oral brain penetrant DRD2 antagonist + ClpP agonist 1. PDB 6CM4 2. PDB 6DL7 DRD21 ClpP2 ONC206 • Second generation imipridone • Increased potency • Indications beyond H3 K27M-mutant glioma • Monotherapy efficacy across multiple preclinical models of CNS and non-CNS tumors • Tumor regression in patient-derived xenografts • Oral dose escalation trials with intensified dosing are ongoing in CNS cancers • Monotherapy response in recurrent GBM patient without the H3 K27M mutation - Differentiated from ONC201 glioma responses that were exclusive to H3 K27M
23 CNS Tumors Glioblastoma1 Medulloblastoma2 ONC206 monotherapy activity CNS and non-CNS cancer models 1. Theeler et al, SNO 2020 2. Tzaridis et al, AACR 2024 3. Hu et al, Cancers 2020 4. Tucker et al, American Journal of Cancer Research, 2022 5. Baek et al, SABCS 2023 ARK1 Human Endometrial Cancer Xenograft (100mg/kg BW; 6 wks)3 Non-CNS Solid Tumors Cholangiocarcinoma1 Endometrial cancer3 Pheochromocytoma/paraganglioma Ovarian cancer4 Triple-negative breast cancer5 BCM2665 Human TNBC PDX (ONC206 100mg/kg BW; Carboplatin - CRB 50mg/kg QW )5 Transgenic Medulloblastoma Model2 (QW) n=5 (QW) n=5 (n=6) ONC206 (120mg/kg QW) n=5 ONC206 (100mg/kg QW) n=5 Control n=6
24 ONC206 dose escalation to more frequent dosing ongoing 1. Dose level 6 was conducted in adults only 2. Pediatric dose scaled by body weight 3. As of publication date May 1, 2024 • No DLTs observed with weekly dosing3 • Similar safety profile in adults and pediatrics • Majority of treatment-related AEs are mild to moderate • Most common treatment- related events are fatigue, lymphocyte count decreased, and vomiting • No dose related toxicity with dose escalation3 – dose escalation continuing 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1 2 3 4 5 6 7 8 9 10 11 O N C 20 6 m g /w e ek Dose level2 50 m g B ID 15 0 m g Q D 10 0 m g B ID 15 0 m g B ID 20 0 m g B ID 50 m g 10 0 m g 15 0 m g 20 0 m g 30 0 m g 35 0 m g Once weekly dosing 3 consecutive days dosing 1 Dose escalation on track for completion in mid 2024
25 1. Rapidly Emerging Antiviral Drug Development Initiative Ongoing pipeline development • ONC212 GPR132 + ClpP agonist - GLP-tox studies complete, potential to advance to IND, work performed with support from academic grants - Preclinical studies are ongoing to evaluate additional oncology indications and predictive biomarkers for ONC212 for clinical development • CMX521 anti-SARS-CoV-2 preclinical activity - Monotherapy efficacy in mouse-adapted SARS-CoV-2- MA10 model across multiple endpoints - $2m grant to fund research collaboration with University of North Carolina/READDI1
Corporate Update
27 Emergent BioSolutions is an experienced biodefense company collaborating with government agencies to protect public health Terms summary: • $238 million received upfront at closing in Q3 2022 • Up to an additional $124 million in potential BARDA procurement milestones • 20% royalty on future U.S. gross profit with volumes above 1.7 million courses of therapy • 15% royalty of all international gross profit • Up to an additional $12.5 million in development milestones TEMBEXA® deal term summary
28 Financial strength supports development through key catalysts ONC201 Ph 3 trial enrolling - interim OS data expected in 2025, final OS expected in 2026 First-Line H3 K27M-mutant diffuse glioma – The ACTION Study No approved therapies targeting H3 K27M diffuse glioma, an area of high unmet medical need First in class mechanism of action with clinical validation Patent protection thru 2037 (potential additional US patent term extension) ONC206 in dose escalation Investigator reported response in non-H3 K27M mutated recurrent glioblastoma patient Dose escalation on track for completion beginning in mid 2024 $188 million in capital to fund operations as of March 31, 2024, no debt Early-stage pipeline leverages external capital Pre-clinical programs potential to advance to clinic or partner (ONC212, CMX521) Robust business development search and evaluation process Ph 3 ACTION study actively enrolling Significant commercial potential Corporate capability and financial flexibility
Chimerix Corporate Presentation