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): November 7, 2024
(Exact name of registrant as specified in its charter)
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| incorporation) | ||||||||||||||
| (Address of principal executive offices) | (Zip Code) | |||||||
(919 ) 806-1074
(Registrant’s telephone number, including area code)
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
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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 November 7, 2024, Chimerix, Inc. (the “Company”) announced our financial results for the nine months ended September 30, 2024 in the press release attached hereto as Exhibit 99.1 and incorporated herein by reference.
Item 7.01 Regulation FD Disclosure.
On November 7, 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: November 7, 2024 | |||||||||||
| By: | /s/ Michelle LaSpaluto | ||||||||||
| Name: | Michelle LaSpaluto | ||||||||||
| Title: | Chief Financial Officer | ||||||||||
Chimerix Reports Third Quarter 2024 Financial Results and Provides Operational Update
– Phase 3 ACTION Study On-Track with First Interim Overall Survival Data Expected Third Quarter 2025 –
– IDMC Recommends Continuing Conduct of ACTION Study As-Is Following Preplanned Safety Review –
– Alignment with TGA to Submit Dordaviprone for Provisional Approval in Australia –
– Conference Call at 8:30 a.m. ET Today –
DURHAM, N.C., November 7, 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 third quarter ended September 30, 2024 and provided an operational update.
“We have sustained execution of the Phase 3 ACTION study and continue to be encouraged by the safety profile of dordaviprone following the Independent Data Monitoring Committee’s (IDMC) preplanned safety review which recommended continuing study conduct as-is, including at the more intense twice per week dose. Additionally, the Therapeutic Goods Administration (TGA) has granted orphan drug designation to dordaviprone, and we have alignment to file a New Drug Application (NDA) for Provisional Approval in Australia which we expect to occur in the coming months,” said Mike Andriole, Chief Executive Officer of Chimerix. “As we complete the dordaviprone NDA and look toward the balance of the year, we also expect to complete enrollment in a Phase 1 dose escalation study of ONC206 as we consider future development scenarios for this program.”
“In addition, we were delighted to announce the promotion of Dr. Josh Allen to the role of Chief Scientific Officer this quarter. Josh has been instrumental in the discovery and development of the imipridone class of compounds and expect his broad expertise in cancer biology and strong business acumen will underpin Chimerix early phase development for years to come,” added Mr. Andriole.
Dordaviprone (ONC201)
Dordaviprone, a first-in-class imipridone, has the potential to be the first treatment approved for H3 K27M-mutant diffuse glioma. It is an oral small molecule that crosses the blood-brain barrier and selectively binds to the mitochondrial protease ClpP and the dopamine receptor D2 (DRD2). Dordaviprone's unique mechanism of action includes alterations of key epigenetic modifications such as reversal of H3 K27me3-loss which is the hallmark of H3 K27M-mutant gliomas.
Dordaviprone is being evaluated in the Phase 3 ACTION trial that is currently enrolling H3 K27M-mutant diffuse glioma patients at over 145 sites in 15 countries. Chimerix expects interim OS data in the third quarter of 2025. For more information on the ACTION trial, please visit www.clinicaltrials.gov
Earlier this year, Chimerix initiated the evaluation process 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. The second step, the Provisional Determination Application, was approved during the third quarter 2024, as was the application for Orphan Drug Designation in Australia. The final step is the NDA submission for Provisional Registration which is expected to occur in the coming months with potential commercial availability as soon as year-end 2025.
ONC206
The imipridone ONC206 is a second generation ClpP agonist and DRD2 antagonist which also crosses the blood-brain barrier and is 10x more potent in vitro than dordaviprone. It has demonstrated monotherapy anti-cancer activity in vivo in central nervous system (CNS) tumor models, as well as in vivo solid tumors models outside of the CNS. The two Phase 1 dose escalation trials conducted in partnership with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and the National Institutes of Health (NIH) have enrolled over 80 pediatric and adult patients with unselected CNS tumors, with no dose limiting toxicity observed to date.
The safety profile of ONC206 has been consistent across both pediatric and adult populations, with the majority of treatment-related adverse events being mild to moderate, including fatigue, lymphocyte count decrease and vomiting. No significant change in the overall safety profile has been reported to date as dosing has escalated and intensified in frequency from once per week to twice per day on three consecutive days per week. Completion of enrollment in the remaining dose escalation cohorts is expected to occur in 2024.
Assessment of objective responses in patients where a monotherapy treatment effect can be reliably evaluated is ongoing in dose cohorts at or above target exposure thresholds. The company expects to assess any objective responses in the first half of 2025, allowing sufficient time for response onset and confirmation in current and future dose cohorts.
Additionally, ONC206 nonclinical studies remain ongoing to identify candidate oncology indications and biomarkers to inform future development plans.
Corporate
In September 2024, Chimerix promoted Joshua E. Allen, PhD, to the role of Chief Scientific Officer after previously serving as Chief Technology Officer. Dr. Allen co-discovered the anti-cancer activity of ONC201 and co-invented the imipridone class of compounds. He has continuously advanced the research and development of dordaviprone from academic discovery to its registration program, along with the creation and clinical introduction of biologically distinct derivatives. He received his Ph.D. in Biochemistry and Molecular Biophysics from the University of Pennsylvania. Several research publications, patents, grants, and awards reflect his scientific and entrepreneurial efforts in oncology, including recognition on the Forbes 30 under 30 list. Prior to joining Chimerix, Dr. Allen served as Chief Scientific Officer at Oncoceutics.
Third Quarter 2024 Financial Results
Chimerix reported a net loss of $22.9 million, or $0.26 per basic and diluted share, for the third quarter of 2024. During the same period in 2023, Chimerix recorded a net loss of $24.0 million, or $0.27 per basic and diluted share.
Research and development expenses increased to $19.6 million for the third quarter of 2024, compared to $17.4 million for the same period in 2023.
General and administrative expenses decreased to $5.2 million for the third quarter of 2024, compared to $9.3 million for the same period in 2023. This decrease is due to a one-time non-cash expense related to historical equity grants recognized during the 2023 period.
Chimerix’s balance sheet at September 30, 2024 included $152.4 million of capital available to fund operations, approximately 89.9 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 third 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 6580777. 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, dordaviprone (ONC201), is in development for H3 K27M-mutant diffuse glioma. The Company is conducting Phase 1 dose escalation studies of ONC206 to evaluate safety and PK data.
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, expectations regarding interim OS data from the ACTION study, plans for Provisional Registration and commercialization in Australia, expectations regarding completion of enrollment and assessment of responses in the ONC206 dose escalation trials, 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 our clinical candidates; 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)
| September 30, 2024 | December 31, 2023 | ||||||||||
| ASSETS | |||||||||||
| Current assets: | |||||||||||
| Cash and cash equivalents | $ | 23,645 | $ | 27,661 | |||||||
| Short-term investments, available-for-sale | 112,585 | 155,174 | |||||||||
| Accounts receivable | 155 | 4 | |||||||||
| Prepaid expenses and other current assets | 4,517 | 6,271 | |||||||||
| Total current assets | 140,902 | 189,110 | |||||||||
| Long-term investments | 16,201 | 21,657 | |||||||||
| Property and equipment, net of accumulated depreciation | 281 | 224 | |||||||||
| Operating lease right-of-use assets | 1,089 | 1,482 | |||||||||
| Other long-term assets | 195 | 301 | |||||||||
| Total assets | $ | 158,668 | $ | 212,774 | |||||||
| LIABILITIES AND STOCKHOLDERS' EQUITY | |||||||||||
| Current liabilities: | |||||||||||
| Accounts payable | $ | 5,340 | $ | 2,851 | |||||||
| Accrued liabilities | 16,904 | 15,592 | |||||||||
| Total current liabilities | 22,244 | 18,443 | |||||||||
| Line of credit commitment fee | — | 125 | |||||||||
| Lease-related obligations | 644 | 1,177 | |||||||||
| Total liabilities | 22,888 | 19,745 | |||||||||
| Stockholders’ equity: | |||||||||||
| Preferred stock, $0.001 par value, 10,000,000 shares authorized at September 30, 2024 and December 31, 2023; no shares issued and outstanding as of September 30, 2024 and December 31, 2023 | — | — | |||||||||
| Common stock, $0.001 par value, 200,000,000 shares authorized at September 30, 2024 and December 31, 2023; 89,936,053 and 88,929,300 shares issued and outstanding as of September 30, 2024 and December 31, 2023, respectively | 90 | 89 | |||||||||
| Additional paid-in capital | 996,389 | 988,457 | |||||||||
| Accumulated other comprehensive gain, net | 258 | 7 | |||||||||
| Accumulated deficit | (860,957) | (795,524) | |||||||||
| Total stockholders’ equity | 135,780 | 193,029 | |||||||||
| Total liabilities and stockholders’ equity | $ | 158,668 | $ | 212,774 | |||||||
CHIMERIX, INC.
CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(in thousands, except share and per share data)
(unaudited)
| Three Months Ended September 30, | Nine Months Ended September 30, | ||||||||||||||||||||||
| 2024 | 2023 | 2024 | 2023 | ||||||||||||||||||||
| Revenues: | |||||||||||||||||||||||
| Contract and grant revenue | $ | 26 | $ | 11 | $ | 155 | $ | 271 | |||||||||||||||
| Licensing revenue | — | — | — | 49 | |||||||||||||||||||
| Total revenues | 26 | 11 | 155 | 320 | |||||||||||||||||||
| Operating expenses: | |||||||||||||||||||||||
| Research and development | 19,646 | 17,396 | 56,918 | 53,144 | |||||||||||||||||||
| General and administrative | 5,173 | 9,304 | 15,252 | 19,431 | |||||||||||||||||||
| Total operating expenses | 24,819 | 26,700 | 72,170 | 72,575 | |||||||||||||||||||
| Loss from operations | (24,793) | (26,689) | (72,015) | (72,255) | |||||||||||||||||||
| Other income: | |||||||||||||||||||||||
| Interest income and other, net | 1,914 | 2,703 | 6,582 | 8,321 | |||||||||||||||||||
| Net loss | (22,879) | (23,986) | (65,433) | (63,934) | |||||||||||||||||||
| Other comprehensive loss: | |||||||||||||||||||||||
| Unrealized gain (loss) on debt investments, net | 466 | 188 | 251 | (288) | |||||||||||||||||||
| Comprehensive loss | $ | (22,413) | $ | (23,798) | $ | (65,182) | $ | (64,222) | |||||||||||||||
| Per share information: | |||||||||||||||||||||||
| Net loss, basic and diluted | $ | (0.26) | $ | (0.27) | $ | (0.73) | $ | (0.72) | |||||||||||||||
| Weighted-average shares outstanding, basic and diluted | 89,701,117 | 88,620,666 | 89,531,017 | 88,500,813 | |||||||||||||||||||
Chimerix Corporate Presentation November 7, 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, expectations regarding interim OS data from the ACTION study, expectations regarding completion of enrollment and assessment of responses in the ONC206 dose escalation trials, the characteristics and development of our product candidates, 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 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.
3 Investment highlights and key catalysts Dordaviprone Ph 3 trial enrolling - interim OS data expected in third quarter 2025 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 now dosing within the expected therapeutic range Pharmacokinetic data from dose escalation studies demonstrate dose proportionate exposure No unexpected safety events and no dose limiting toxicities to date Exhibits monotherapy activity in multiple non-clinical CNS models as well as tumors outside the CNS $152 million in capital to fund operations as of September 30, 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 Program Preclinical Phase 1 Phase 2 Registrational Regulatory Approval Deep pipeline across all development stages Dordaviprone (ONC201) H3 K27M-mutant glioma (orphan drug,1 fast track2 and rare pediatric disease designations3) IITs- signal finding, multiple oncology indications/combinations CMX521 Novel coronaviruses 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
Dordaviprone(ONC201) 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 dordaviprone treated H3 K27M DMG patients across: - Diverse external controls (historical, trials) - Sensitivity analysis (early event censoring) - Isolated tumor locations (thalamus, brainstem) Dordaviprone data suggests potential to address high unmet need Natural Disease History4 (n=43) ONC201 Phase 2 (n=50) Median OS, mo (95% CI) 5.1 (3.9-7.7) 13.7 (8-20.3) OS @ 12mo (95% CI) 23.6% (11.7-37.9) 57% (41-70) OS @ 24mo (95% CI) 11.1% (3.3-24.2) 35% (21-49) 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 • Dordavirprone 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 dordaviprone by sponsor Dordaviprone phase 2 efficacy in recurrent H3 K27M Diffuse Midline Glioma (DMG)
8 • Strict selection criteria to ensure responses attributable to single agent treatment • RANO requires both confirmed radiographic response and other forms of clinical benefit (eg no increase in steroid utilization, no deterioration in performance status, et al) • Assessments done by dual reader blinded independent central review (BICR) • Growing consensus that assessment of enhancing and non-enhancing disease (RANO- HGG and RANO-LGG criteria) is clinically relevant for diffuse midline glioma Dordaviprone waterfall plot – 30% RANO HGG / LGG response RANO HGG (enhancing) • 20% response • 40% disease control RANO LGG (non-enhancing) • 26% response • 42% disease control Dordaviprone 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 Arrillaga-Romany, et al, Journal of Clinical Oncology, Feb 2024 Duration of response, median (95% CI) 11.2 months (3.8 – not reached) Time to response, median (range) 8.3 months (1.9 – 15.9) Dordaviprone Phase 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma
10 Clinical Pharmacology Studies n=245 • 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 clinical pharmacology program includes: - 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 Dordaviprone safety Glioma Patient Studies Treatment-related Adverse Events in >5% 1. Based on available data from ONC201 Investigator brochure, version 11 Treatment-related Adverse Events, Integrated Safety Data Set, (N=422 glioma patients) 1 Related TEAEs All grades Grade > 3 Any Treatment-related AE 51.4% 9.7% Fatigue 18.5% 1.7% Nausea 14.5% 0 Vomiting 10.4% 0.9% Lymphocyte count decreased 8.1% 1.9% Headache 6.6% 0 ALT increased 6.4% 0.7% White blood cell count decreased 5.5% 0.2% Only 10 patients (2.4%) experienced a treatment-related AE that led to study drug modification or discontinuation.
Dordaviprone 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 Dordaviprone twice weekly (625mg ONC201 day 1 + day 2) Dordavirpone 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 third quarter of 2025 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 dordaviprone 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
Dordaviprone 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, dordaviprone 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 imipridones beyond brain tumors • Single agent responses in PCPG: adrenal-related tumors with high malignant DRD2 expression • Investigator initiated trial at Cleveland Clinic in a heavily refractory and pretreated patient population (n=14) • Superior tolerability and administration profiles relative to to SOC therapies 5/14 patients treated > 1 year 11/14 patients experienced tumor regression Results of Phase II Study of dordaviprone (ONC201) in Neuroendocrine Tumors at the Cleveland Clinic1 1. https://aacrjournals.org/clincancerres/article/28/9/1773/694456/Phase-II-Study-of-ONC201-in-Neuroendocrine-Tumors
Dordaviprone Mechanism of ActionDordaviprone Mechanism of Action
19 • Dordaviprone can selectively induce apoptosis in cancer cells by altering the activity of two protein targets • ClpP agonism - Dordaviprone modifies ClpP conformation to increase degradation of mitochondrial proteins important for metabolism, epigenetics, and cancer cell viability • DRD2 antagonism - DRD2 is a G protein-coupled neuroreceptor that regulates Ras signaling - Dordaviprone antagonizes DRD2, inhibiting Ras signaling pathways Dordaviprone directly engages ClpP and DRD2 Dordaviprone 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 • 10x higher in vitro potency relative to dordaviprone • Monotherapy efficacy across multiple preclinical models of Central Nervous System (CNS) and non-CNS tumors • Tumor regression in patient-derived xenografts • Oral dose escalation trials with intensified dosing are nearing completion in CNS cancers ONC206: second generation oral brain penetrant ClpP agonist + DRD2 antagonist 1. PDB 6CM4 2. PDB 6DL7 DRD21 ClpP2 ONC206
23 ONC206 Phase 1 dose escalation and intensification to expected therapeutic range in CNS cancer patients1,2 Expect to complete enrollment of dose escalation in 2024 1. In partnership with Nation al Institutes of Health (NIH) 2. In partnership with Pacific Pediatric Neuro-Oncology Consortium (PNOC) 3. In adults only - 83 patients enrolled [Adults (n=30); Peds (n=53)] -Biologically active concentrations achieved with continuing escalation at intensified dose frequency - Well-tolerated with intensified dose frequency at exposures achieving efficacy in vivo Eligibility Criteria All CNS tumors Received SOC therapies No limit on prior recurrences 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 ee k Dose level2 50 m g BI D 15 0 m g Q D 10 0 m g BI D 15 0 m g BI D 20 0 m g BI D 3 Once weekly dosing 3 consecutive days dosing 3
24 ONC206 is appears well-tolerated in adult and pediatric patients to date 1. Adverse Events evaluable for safety.. Data extraction from Adult study and Pediatric study (PNOC Arms A and D) as of July2024 2. To date no additional SAE’s in patients dosed after July 8th 2024 data cut-off Related AEs1 Integrated Data Set N=77 All grades Grade ≥ 3 Any Treatment-related AE 60% 5% Fatigue 26% 1% Lymphocyte count decreased 16% 3% Vomiting 17% 0% Bilirubin increased 6% 0% Diarrhea 6% 0% Headache 9% 0% Nausea 9% 0% ALT increased 5% 1% Neutrophil count decreased 6% 0% White blood cell decrease 6% 0% • Majority of treatment-related adverse events (TRAEs) are mild to moderate in severity • Most frequent TRAEs are fatigue, lymphopenia, and vomiting • Occur in a minority of patients • Typical AEs in advanced CNS tumors • No substantial changes in the AE profile as a function of dose or frequency • Similar safety profile in adults and pediatrics Data cutoff : 08July20242
25 50mg QW N=10 100mg QW N=11 150mg QW N=11 200mg QW N=11 250mg QW N=10 350 mg QW N=33 50mg BID; TIW N=9 150mg QD; TIW N=9 100mg BID; TIW N=33 150mg BID; TIW 200mg BID; TIW Weekly Dosing Multi-day/ week dosing Weekly Dose 2 50 mg 100 mg 150 mg 200 mg 250 mg 350 mg 300 mg 450 mg 600 mg 900 mg 1200mg Treatment- related AE, all grades 60% 73% 64% 64% 80% 67% 44% 44% 0% Grade 1 60% 64% 55% 64% 70% 67% 33% 44% 0% Grade 2 33% 45% 45% 45% 60% 33% 11% 33% 0% Grade 3 10% 18% 9% 0% 0% 0% 0% 0% 0% Grade 4/5 0% 0% 0% 0% 0% 0% 0% 0% 0% ONC206 dose escalation and increased dose frequency well-tolerated in adult and pediatric patients to date Majority of treatment related AEs1 are mild to moderate in severity with fatigue most common 1. Adverse Events. Data extraction from Adult study and Pediatric study (PNOC Arms A and D) as of July2024 2. Weight-based dosing utilized in pediatric patients <60 kg 3. DL6 and DL9 data in adults only 4. Adults only Incidence of ONC206-Related AEs1 En ro lle d4 To B e E nr ol le d
26 ONC206 patient exposures with intensified dosing exceed exposures associated with nonclinical efficacy 1. PK summary based on adult data; pediatric PK in DL 1-7 have been similar to adult 2. Average IC50 of 562 nM across 1088 cancer cell lines representing 25 tumor types 3. In vivo models include High-grade glioma (50 mg/kg QW), medulloblastoma (50 mg/kg BID TIW, 100 mg/kg and 120 mg/kg QW, 100 mg/kg BIW), endometrial (125 mg/kg QW, 100 mg/kg BIW), ovarian (125 mg/kg QW), TNBC (100 mg/kg BIW, 50 mg/kg BID TIW), hepatocellular (80 mg/kg BIW), cholangiocarcinoma (50 mg/kg QW) and SCLC (50 mg/kg BID TIW). Average AUC in positive nonclinical models ~5000 ng*hr/mL . 4. Mean AUC tissue:plasma ratio in single oral dose healthy mouse study 5. Adults only Patient Exposures in Expected Therapeutic Range: • Cmax exceeds IC50 in diverse CNS and non-CNS solid tumor cell lines2 • AUC exceeds plasma exposures in nonclinical solid tumor models demonstrating efficacy3 • Favorable tumor/ tissue: plasma ratios in target organs of nonclinical models4 • adrenals ~7x, uterus ~6x, lung ~6x, prostate ~4x, CNS ~2x • Intensified dosing increased time above IC50 to >24hr while being well-tolerated • Continued dose escalation expected to further enhance duration of exposure to biologically active concentration Relative PK Data from ongoing studies1 Dose Level; Frequency Weekly Dose (mg) Cmax > IC502 Weekly AUC > in vivo model3 Time above IC502 O nc e- W ee kl y D os in g 50 mg; QW 50 0.8x 0.2x 0 hr 150 mg; QW 150 >3x 0.6x 3 hr 200 mg; QW 200 >7x 1.5x 7 hr 350 mg; QW 350 >9x 2.4x 17 hr M ul ti- da y/ W ee k D os in g 50 mg; BID/TIW 300 0.8x 0.9x 0 hr 150mg; QD/TIW 450 >4x 2.0x 19 hr 100mg; BID/TIW 600 >2x 3.4x 28 hr 150 mg; BID/TIW 900 Enrolled5 200 mg; BID/TIW 1200 To be enrolled
ONC206 Mechanism of Action
28 • ClpP and DRD2 are direct binding targets that control mitochondrial and prosurvival functions, respectively, in a range of human cancers • ClpP agonism and DRD2 antagonism occurs at nanomolar concentrations • Anti-cancer activity is dependent on ClpP and/or DRD2 depending on tumor type • Downstream effects of engaging ClpP/DRD2 in vitro and in vivo include altered mitochondrial metabolism, integrated stress response, bioenergetics, MYC expression, Akt/ERK signaling and apoptosis 1-4 ONC206 is a second generation dual ClpP agonist/DRD2 antagonist 1. Maranto et al, AACR Brain Cancer Conference 2023 2. Prabhu et al, AACR 2020 3. Hu et al, Cancers 2020; 4. Batsios et al, bioRxiv 2024 ClpP catalytic activity is stimulated by ONC2061 ClpP-dependent in vitro activity of ONC206 in T98G high grade glioma cells1 DRD2-dependent in vitro activity of ONC206 in endometrial cancer ARK2 cells 3 DRD2 signaling is inhibited by ONC206 2 ClpP DRD2 5. Baek et al, SABCS 2023 6. Hu et al, Cancers 2020; 7. Ishida et al, Clin Can Res 2018
29 • Nanomolar activity across CNS tumors, including high-grade glioma and medulloblastoma • In vitro and in vivo data demonstrates enhanced efficacy with increasing dose and sustained exposure • Tumor regression and survival extension in transgenic and patient-derived medulloblastoma models ONC206 exhibits monotherapy activity in multiple CNS cancer models 1. Jung et al, SNO 2017 2. Maranto et al, AACR Brain Cancer Conference 2023 3. Tzaridis et al, AACR 2024 Transgenic SHH (SmoA1) Medulloblastoma Model3High-grade glioma SF8628 cells2Patient-derived high-grade glioma cultures1 Nanomolar IC50 Efficacy enhanced with duration Efficacy enhanced with dose (hr)
30 • Broadly active across 1088 cancer cell lines representing 25 tumor types with an average IC50 of 562 nM 1 • In vivo efficacy improves with dose intensification in chemo-refractory TNBC, including tumor regressions2 • Improved efficacy relative to ONC201 in endometrial cancer3 ONC206 shows monotherapy efficacy & tolerability in several non-CNS solid tumors pheochromocytoma, triple-negative breast (TNBC)2, endometrial3, cholangiocarcinoma1, ovarian4, hepatocellular cancer5, small cell lung cancer 1. Prabhu et al, AACR 2020 2. Baek et al, SABCS 2023 3. Hu et al, Cancers 2020 4. Tucker et al, American Journal of Cancer Research, 2022 5. Cao et al, Neoplasia 2024 ARK1 Human Endometrial Cancer Xenograft (ONC201/ONC206 100mg/kg BIW; 6 wks)3 BCM2665 Human TNBC PDX2 Tumor Regressions with Increased Dose Frequency Enhanced in vivo efficacy hPheo cell lines Enhanced in vitro efficacy in human PCPG cell line
31 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 broad spectrum coronavirus preclinical activity - Developed thru Phase 1 in norovirus - 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
33 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
34 Investment highlights and key catalysts Dordaviprone Ph 3 trial enrolling - interim OS data expected in third quarter 2025 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 now dosing within the expected therapeutic range Pharmacokinetic data from dose escalation studies demonstrate dose proportionate exposure No unexpected safety events and no dose limiting toxicities to date Exhibits monotherapy activity in multiple non-clinical CNS models as well as tumors outside the CNS $152 million in capital to fund operations as of September 30, 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