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 4, 2023
(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)
N/A
(Former name or former address, if changed since last report)
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 May 4, 2023, Chimerix, Inc, (the “Company”) announced our financial results for the three months ended March 31, 2023 in the press release attached hereto as Exhibit 99.1 and incorporated herein by reference.
Item 7.01 Regulation FD Disclosure.
On May 4, 2023, 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 Exhibit 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 Exhibit 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 4, 2023 | |||||||||||
| By: | /s/ Michael T. Andriole | ||||||||||
| Name: | Michael T. Andriole | ||||||||||
| Title: | Chief Business and Financial Officer | ||||||||||
Chimerix Reports First Quarter 2023 Financial Results and Provides Operational Update
– European Union Study Authorization for Phase 3 ACTION Received, Reiterate First Efficacy Data Expected Early 2025 –
– Completion of ONC206 Dose Escalation Expected by First Half 2024 –
– Conference Call at 8:30 a.m. ET Today –
DURHAM, NC, May 4, 2023 -- Chimerix (Nasdaq:CMRX), a biopharmaceutical company whose mission 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, 2023 and provided an operational update.
“2023 is off to a strong start and has been highlighted by multiple presentations of data in support of our imipridone platform during the recent American Association for Cancer Research Annual Meeting (AACR) and our sponsorship at the Canadian Neuro-Oncology Meeting (CNO) this week,” said Mike Sherman, Chief Executive Officer of Chimerix. “Dr. Carl Koschmann’s ONC201 presentation at AACR marks the first known example of any therapy reversing the H3 K27 trimethyl loss (H3 K27me3-loss) seen in H3 K27M-mutant glioma patients. This shows that dordaviprone (ONC201) can reverse the epigenetic signature which is thought to be a defining characteristic of the disease. Recent literature suggests that reversing the H3 K27M mutation that increases H3 K27 trimethylation in established tumor models results in significant antitumor effects and prolongation of survival. This finding provides additional objective evidence of ONC201 biological activity in this patient population to complement the tumor response observed in the Phase 2 clinical studies. We have also recently completed multiple clinical pharmacology studies, the findings of which have been consistent with our expectations. These studies comprise key elements of a future new drug application (NDA) for ONC201 following positive data from the ACTION study. Our focus has been on accelerating every aspect possible of the Phase 3 ACTION study in order to expedite patient access to this potentially life-altering drug. To that end, we have now received authorization for the ACTION study from nine countries including the United States, the United Kingdom, South Korea, Israel and key markets across Western Europe, as our ramp of site activations continues.”
“In addition, we are making good progress advancing the Phase 1 dose escalation studies for our second generation compound, ONC206. As these are open-label studies, in addition to the previously announced objective response observed to ONC206 monotherapy, we hope to identify additional signals of activity this year and look forward to completing dose escalation by first half of 2024,” added Mr. Sherman.
ONC201 for Treatment of H3 K27M-Mutant Diffuse Glioma
In April, Chimerix and along with collaborators presented multiple datasets related to the imipridone platform at the AACR Annual Meeting in Orlando, FL. Key results presented by collaborators at the University of Michigan demonstrated that H3 K27M-mutant glioma patients treated with ONC201 experienced a statistically significant reversal of the H3 K27me3-loss epigenetic signature throughout their tumor compared to patients who did not receive ONC201. Gliomas with the H3 K27M-mutation undergo H3 K27me3-loss, which is a negative prognostic variable among gliomas and thought to be a defining characteristic of the disease. Concordant findings were also reported in preclinical models that were mechanistically linked to specific metabolic changes induced in tumors by ONC201.
Ongoing Development of ONC206
ONC206 is a second generation, potentially differentiated imipridone DRD2 antagonist and ClpP agonist, that has demonstrated monotherapy anti-cancer activity in pre-clinical models. ONC206 is currently being evaluated in Phase I dose escalation trials enrolling patients with advanced central nervous system tumors. In March 2023, the Company reported an investigator-assessed response that emerged during dose escalation in the PNOC study. The responder is a patient with recurrent glioblastoma without the H3K27M-mutation who received ONC206 monotherapy.
Preclinical work is ongoing that is designed to further elucidate the ONC206 mechanism of action, identify potential pharmacodynamic biomarkers, and assess the monotherapy efficacy profile of ONC206 in tumors that do not harbor the H3K27M mutation. These activities will inform data-driven clinical development plans.
First Quarter 2023 Financial Results
Chimerix reported a net loss of $21.4 million, or $0.24 per basic and diluted share, for the first quarter of 2023. During the same period in 2022, Chimerix recorded a net loss of $24.8 million, or $0.28 per basic and diluted share.
Research and development expenses decreased to $18.8 million for the first quarter of 2023, compared to $19.0 million for the same period in 2022.
General and administrative expenses increased to $5.7 million for the first quarter of 2023, compared to $5.6 million for the same period in 2022.
Chimerix's balance sheet at March 31, 2023 included $246.1 million of capital available to fund operations, approximately 88.6 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 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 8594205.
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 the Phase 3 ACTION Study
The ACTION study is a worldwide, randomized, double-blind, placebo-controlled, multicenter study of ONC201 designed to enroll 450 newly diagnosed diffuse glioma patients whose tumor harbors an H3 K27M-mutation. Treatment with ONC201 begins shortly after completion of radiation therapy. Participants are randomized 1:1:1 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 is scaled by body weight for pediatric patients. Overall survival (OS) will be assessed for efficacy at three alpha-allocated timepoints: two interim assessments by the Independent Data Monitoring Committee (IDMC) at 164 events and 246 events, respectively, and a final assessment at 327 events. The final Progression Free Survival analysis will be performed after 286 events, with progression assessed using RANO HGG criteria by blinded independent central review (BICR).
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, the probability of success of the Phase 3 ACTION study, the potential filing and approval of and NDA for ONC201 and subsequent commercial opportunity, the implications of the monotherapy radiographic partial response observed during ONC206 dose escalation; the ability to reproduce clinical and pre-clinical findings, and projections regarding funding and timing of future data readouts. 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.
CONTACTS:
Michelle LaSpaluto
919-972-7115
ir@chimerix.com
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, 2023 | December 31, 2022 | ||||||||||
| ASSETS | |||||||||||
| Current assets: | |||||||||||
| Cash and cash equivalents | $ | 15,951 | $ | 25,842 | |||||||
| Short-term investments, available-for-sale | 198,801 | 191,492 | |||||||||
| Accounts receivable | 668 | 1,040 | |||||||||
| Prepaid expenses and other current assets | 9,330 | 9,764 | |||||||||
| Total current assets | 224,750 | 228,138 | |||||||||
| Long-term investments | 31,322 | 48,626 | |||||||||
| Property and equipment, net of accumulated depreciation | 267 | 227 | |||||||||
| Operating lease right-of-use assets | 1,848 | 1,964 | |||||||||
| Other long-term assets | 346 | 386 | |||||||||
| Total assets | $ | 258,533 | $ | 279,341 | |||||||
| LIABILITIES AND STOCKHOLDERS' EQUITY | |||||||||||
| Current liabilities: | |||||||||||
| Accounts payable | $ | 2,847 | $ | 3,034 | |||||||
| Accrued liabilities | 13,584 | 17,381 | |||||||||
| Total current liabilities | 16,431 | 20,415 | |||||||||
| Loan fees | 125 | 250 | |||||||||
| Lease-related obligations | 1,666 | 1,819 | |||||||||
| Total liabilities | 18,222 | 22,484 | |||||||||
| Stockholders’ equity: | |||||||||||
| Preferred stock, $0.001 par value, 10,000,000 shares authorized at March 31, 2023 and December 31, 2022; no shares issued and outstanding as of March 31, 2023 and December 31, 2022 | — | — | |||||||||
| Common stock, $0.001 par value, 200,000,000 shares authorized at March 31, 2023 and December 31, 2022; 88,583,567 and 88,054,127 shares issued and outstanding as of March 31, 2023 and December 31, 2022, respectively | 89 | 88 | |||||||||
| Additional paid-in capital | 975,254 | 970,535 | |||||||||
| Accumulated other comprehensive loss, net | (231) | (337) | |||||||||
| Accumulated deficit | (734,801) | (713,429) | |||||||||
| Total stockholders’ equity | 240,311 | 256,857 | |||||||||
| Total liabilities and stockholders’ equity | $ | 258,533 | $ | 279,341 | |||||||
CHIMERIX, INC.
CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
(in thousands, except share and per share data)
(unaudited)
| Three Months Ended March 31, | |||||||||||
| 2023 | 2022 | ||||||||||
| Revenues: | |||||||||||
| Contract and grant revenue | $ | 234 | $ | — | |||||||
| Licensing revenue | 49 | 15 | |||||||||
| Total revenues | 283 | 15 | |||||||||
| Cost of goods sold | — | 114 | |||||||||
| Gross profit | 283 | (99) | |||||||||
| Operating expenses: | |||||||||||
| Research and development | 18,822 | 19,040 | |||||||||
| General and administrative | 5,679 | 5,632 | |||||||||
| Total operating expenses | 24,501 | 24,672 | |||||||||
| Loss from operations | (24,218) | (24,771) | |||||||||
| Other income: | |||||||||||
| Interest income and other, net | 2,846 | 4 | |||||||||
| Net loss | (21,372) | (24,767) | |||||||||
| Other comprehensive loss: | |||||||||||
| Unrealized gain (loss) on debt investments, net | 106 | (52) | |||||||||
| Comprehensive loss | $ | (21,266) | $ | (24,819) | |||||||
| Per share information: | |||||||||||
| Net loss, basic and diluted | $ | (0.24) | $ | (0.28) | |||||||
| Weighted-average shares outstanding, basic and diluted | 88,294,624 | 87,088,804 | |||||||||
Chimerix Corporate Presentation Q2 2023
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 probability of success of the Phase 3 ACTION study, the potential filing and approval of an NDA for ONC201 and subsequent commercial opportunity, the implications of the monotherapy radiographic partial response observed during ONC206 dose escalation; the ability to reproduce clinical and pre-clinical findings, and projections regarding funding and timing of future data readouts. 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 • Terminal disease with no effective therapeutic options • High awareness for program within neuro-oncology community • U.S. patent exclusivity through at least 2037 • Global revenue potential of ~$750m in first indication alone • Phase 2 study designed to isolate single agent activity in difficult treatment setting • Durable responses associated with OS and other forms of clinical benefit • Numerous independent and natural disease history studies support potential survival advantage • Genetically selected patient population limits patient heterogeneity • Leadership team successfully executed large scale studies and regulatory approvals • Strong balance sheet fully funds ACTION study and potential ONC206 catalysts • Opportunity for continued non- dilutive TEMBEXA milestones and royalties adds flexibility • Track record of objectivity in creating paths to capture value Low barriers to commercial potential for ONC201 High probability of success for Phase 3 ACTION study of ONC201 Corporate capability and financial flexibility
4 Preclinical Phase 1 Phase 2 Registrational Approved Collaborators Smallpox (orphan drug designation) SARS-CoV-2 IND-enabling studies CNS4 tumors IITs- signal finding, multiple oncology indications/combinations H3 K27M-mutant glioma (orphan drug,1 fast track2 and rare pediatric disease designations3) Deep pipeline across all development stages 1 Malignant glioma 2 Adult recurrent H3 K27M-mutant high-grade glioma 3 H3 K27M-mutant glioma 4. Central Nervous System 5. Rapidly Emerging Antiviral Drug Development Initiative ONC212 ONC206 CMX521 5 TEMBEXA® transacted with Emergent BioSolutions APPROVED June 4, 2021 ONC201 (Dordaviprone) National institutes Of Health
ONC201 (dordaviprone) Phase 2 Efficacy 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 • Studies consistently indicate longer OS of ONC201-treated glioma patients relative to diverse external controls H3 K27M-mutant diffuse glioma: high unmet need Natural Disease History: Recurrent H3 K27M and/or DMG3 (n=43) ONC201 Phase 2: Recurrent H3 K27M DMG (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) No ONC201 (n=274): 12mo mOS P=0.05P<0.0001 No ONC201 (n=99): 8.1mo mOS Histone H3 Mutations in CNS Tumors1 Recurrent H3 K27M DMGFrontline H3 K27M DMG ONC201 (n=37): 16.2mo mOS ONC201 (n=35): 26.3mo mOS External analysis reported at SNO 20222 Company Sponsored Studies 1 Lulla RR et al. Sci Adv. 2016;2(3):e1501354 2 Sunjong Ji, B.S. et al, “Clinical efficacy and predictive biomarkers of ONC201 in H3 K27M-mutant diffuse midline glioma”, Society of Neuro-oncology 2022 3 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% No ONC201 (n=274): 12mo mOS No ONC201 (n=99): 8.1mo mOS P< 01 =0.05
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 SAEs considered not related to ONC201 by sponsor Phase 2 efficacy for ONC201 in recurrent H3 K27M DMG
8 Objective • To evaluate monotherapy efficacy of ONC201 in recurrent H3 K27M-mutant diffuse midline glioma Eligibility • Age ≥2yo and received ONC201 under studies ONC006, ONC013, ONC014, ONC016, or ONC018 • Diffuse glioma with a known H3 K27M mutation and involvement of a midline structure of the brain • Progressive and measurable disease on contrast-enhanced brain MRI by RANO-High Grade Glioma (HGG) criteria • Prior therapy with at least radiation • Washouts prior to first ONC201 dose: - Radiation: 90 days - Temozolomide: 23 days / Antibodies (e.g., bevacizumab): 42 days / Other anticancer therapies: 28 days • Baseline Performance Status ≥60 • Corticosteroids stable or decreasing for at least 3 days prior to baseline scan • Excluded: DIPG, primary spinal tumors, atypical and non-astrocytic hist., leptomeningeal spread, CSF dissemination FDA-aligned criteria for Phase 2 efficacy analysis to isolate ONC201 single agent activity
9 • 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
10 RANO-HGG responses observed across age groups Responses by age group: <18 years: 1/4 (25%) 18-40 years: 5/32 (16%) >40 years: 4/14 (29%) RANO-HGG response of 8-year-old subject suggests activity in this population ONC201 Ph 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma
11 RANO HGG response correlation to performance status (PS) supports early-line trial Predictably, patients with higher PS were more likely to respond to treatment 100: 1/2 (50%) 90: 4/14 (29%) 80: 4/20 (20%) 70: 1/7 (14%) 60: 0/7 (0%) Supports hypothesis that treating earlier in disease course may enhance efficacy ONC201 Ph 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma
12 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. 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) ONC201 Phase 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant Diffuse Midline Glioma
13 Treatment-related Adverse Events, Integrated Safety Data Set, (N=211 glioma patients) 2 Related TEAEs All grades Grade > 3 Any Treatment-related AE 55.5% 11.8% Fatigue 21.8% 2.8% Nausea 20.4% 0 Vomiting 14.2% 0.5% Headache 8.5% 0.5% Lymphocyte count decreased 6.6% 0.5% Decreased appetite 5.7% 0 White blood cell count decreased 4.7% 0.5% ALT increased 4.3% 0.5% Hypophosphataemia 4.3% 0 Neutrophil count decreased 3.8% 0.5% Anaemia 3.3% 0 Diarrhea 3.3% 0 ONC201 safety 1. Based on available data as 25Apr2023 for ONC201-101 2. Reported in ONC201 Investigator Brochure Healthy Adult Dose Escalation Study1 Incidence of ONC201-Related Adverse Events (AE) Treatment-related Adverse Events in > 3% Glioma Patients • In addition to healthy adult dose escalation study above, clinical pharmacology studies included: food-effect, safety pharmacology, special populations, and drug-drug interaction studies • Treatment-related AEs were generally Grade 1 and transient across the clinical pharmacology program. • The most commonly reported treatment-related events were mild dizziness, headache and nausea. 125 mg N=33 375 mg N=15 625 mg N=45 Any treatment-related AE 36.0% 20.0% 53.0% Grade 1 36.0% 20.0% 53.0% Grade 2 0 0 0 Grade 3-5 0 0 0
14 All patients RANO HGG Responders RANO HGG and/or LGG Responders N 50 10 15 PFS at 12 months (number of patients censored) 30%1 90% (0) 67% (2) OS at 24 months (number of patients censored)2 35%1 80% (2) 53% (5) Corticosteroids response3 (number of patients evaluable) 47% (15) 100% (4) 100% (5) Performance status response4 (number of patients evaluable) 21% (34) 60% (5) 67% (9) RANO responses correspond with survival & clinical benefit 1. Kaplan-Meier median Progression-Free Survival or Overall Survival 2. Censored patients include those who are lost to follow-up or have withdrawn prior to the time point, as well as those who have not yet reached the time point. These patients are counted in the denominator but not counted as survivors (i.e., imputed as failure) 3. Corticosteroid response: ≥50% reduction in average daily corticosteroid dose compared to baseline with stable or improved KPS/LPS. Must be confirmed at next analysis timepoint. Corticosteroids converted into a dexamethasone equivalent dose. Baseline ≥4mg dexamethasone at baseline were evaluable. 4. Performance status response: increase in KPS/LPS compared to baseline with stable or reduced corticosteroid use. Must be confirmed at next analysis timepoint. Baseline KPS/LPS ≤80 were evaluable. ONC201 Ph 2 Efficacy Analysis by BICR in Recurrent H3 K27M-mutant DMG • No deaths were reported in patients who experienced a RANO-HGG response 24 months2 • RANO response strongly associated with reduction in steroid use and improvement in performance status
15 Experimental Agent Ph2 Design Biomarker Response criteria Confounded by anti-angiogenic pseudo response ORR Duration of response 6 month PFS Approved? ONC201– Ph2 rDMG Single agent H3 K27M RANO BICR No 20-30% 11.2 35% To be determined Temozolomide Single agent - Levin No 5% ? 21% Yes (OS) Bevacizumab Various - Various Yes 20-70% 4-6 18-50% Yes (AA per ORR, PFS) Cediranib Single agent - MacDonald Yes 27% ? 26% No Rindopepimut Combo + Avastin EGFRv3 RANO Yes 30% 7.8 28% No Depatuxizumab mafodotin Single agent - RANO No 7% 6.7 29% No Enzastaurin Combo + Avastin - RANO Yes 22% ? 21% No Strong rationale for phase 3 success relative to recent GBM trials Positive Neutral Negative Characteristics WKA Yung, et al, British Journal Cancer, Aug 8, 2000; Teri Kreisl, et all, Journal Clinical Onocoloy,2009, Feb 10;27(5);740-5; Tracy Batchelor, et. all, Journal of Clinical Oncology, vol28, issue 17, Jun 10, 2010; David Reardon, et al, Clin Cancer Research Apr 2020; 26(7)1586-1594; Martin van den Bent, et al, Cancer Chemo & Pharma, 26 Oct 2017 80, 1209-1217; Yazmin Odia, et al, Journal Neuro-Oncology 127, 127-125 (2016)
ONC201 Phase 3 ACTION Study Summary
17 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
18 Multiple unique aspects to ONC201 data support translation to phase 3 success Isolated, durable single agent activity Consistency across multiple endpoints Enhanced activity not required, but likely • Responses not confounded by combination treatments • Responses were gradual, durable, and multi-focal • Responses observed via most stringent criteria in blinded assessment • Earlier setting associated with higher response rate (performance status, tumor volume) • Addition of higher-dose study arm • Biomarker selection supports patient homogeneity • Responses highly associated with other forms of clinical benefit • PFS and OS favorable to historical benchmarks • Multiple separate analyses suggest longer survival of patients who received ONC201
19 Design provides multiple paths for success Interim data expected in early 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
20 Potential to increase ONC201 efficacy with dose schedule • Once per week ONC201 dosing effective as monotherapy in Phase 2 studies • Twice per week dosing on two consecutive days expected to increase duration of therapeutic exposure - Increased exposure time can increase glioma sensitivity to ONC201 in vitro - Generally well tolerated in Phase 1 without dose limiting toxicity or AEs leading to dose modification • Phase 3 ACTION study will evaluate once per week and twice per week dosing schedules at 625mg (or body weight equivalent) 24 hours48+ hours Incubation Time
ONC201 Market Opportunity Assessment
22 • 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 markets • Ultra-orphan indication drug pricing • H3 K27M mutations most often in children / young adults (little exposure to Medicare) • 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
23 Regulatory designations 1. Subject to continuation of Rare Pediatric Disease Voucher Program and proceeds from voucher will be split 50/50 with legacy Oncoceutics shareholders US - Orphan Drug Designation (ODD) (treatment of glioblastoma and treatment of malignant glioma) EU - ODD for treatment of glioma Fast Track Designation (FTD) for adult recurrent H3 K27M-mutant high-grade glioma Rare Pediatric Disease Designation for treatment of H3 K27M mutant glioma - Potential to receive rare pediatric voucher1
24 • Single agent responses in Ph 2 neuroendocrine trial of ONC201 observed in subset (paraganglioma) • Paraganglioma 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 interim efficacy results in dopamine-secreting tumors outside the brain 1. ASCO oral presentation June 2021 -75 -50 -25 0 25 50 75 B es t c ha ng e in tu m or b ur de n fr om ba se lin e (% ) 50% ORR in paraganglioma PD Ph 2 Study of ONC201 in Neuroendocrine Tumors in investigator-reported data from ongoing clinical trial NCT # (NT03034200)
ONC201 Mechanism of Action
26 • ONC201 can selectively induce apoptosis in cancer cells by altering activity of two proteins • 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, selectively inducing tumor cell death ClpP=caseinolytic protease P; DRD2=Dopamine receptor D2; ATF4=activating transcription factor 4; CHOP=C/EBP-homologous protein; ERK=extracellular-regulated kinase; AKT=protein kinase B
27 H3 K27M glioma primed for ONC201 sensitivity Chi et al., Society of Neuro-Oncology, 2017; Piccardo et al., Eur J. Nucl Med Mol Imaging, 2019 Ex vivo high grade glioma growth sensitivity to ONC201 by H3 status DRD2 pathway inhibited by ONC201 is enriched in H3 K27M glioma H3 K27M glioma often located in dopamine-rich environment 18F-DOPA PET DRD2 overexpression in H3 K27M glioma H3 K27M is hypersensitive to ONC201
28 H3 K27M central characteristic reversed by ONC201 https://www.cell.com/trends/cancer/fulltext/S2405-8033%2819%2930202-X, Zhang et al, Science Translational Medicine, 2023; Koshmann et al, AACR 2023 H3 K27M causes loss of global H3 K27 trimethylation (H3 K27me3-loss) Removal of H3 K27M mutation results in reversal H3 K27me3-loss and prolonged OS in glioma models ONC201 reverses H3 K27me3-loss in H3 K27M glioma patients’ tumors CRISPR-Cas9 deletion of H3 K27M (left) specifically increases H3 K27me3 and (right) prolongs OS P = 0.039
ONC206
30 ONC206: oral brain penetrant DRD2 antagonist + ClpP agonist 1. PDB 6CM4 2. PDB 6DL7 DRD21 ClpP2 ONC206• Second generation imipridone designed to expand to new indications • Efficacy in cell culture, xenograft and transgenic central nervous system (CNS) and other tumor models • Oral dose escalation trials ongoing in CNS cancers • Monotherapy response reported by investigator in early dose escalation cohort for a patient in recurrent non-H3 K27M GBM - Dordaviprone responses amongst CNS tumors exclusively in H3K27M gliomas
31 CNS Tumors Glioblastoma1 Medulloblastoma2 ONC206 monotherapy active in models of CNS and other cancers 1. Theeler et al, SNO 2020 2. Malhotra et al, ISPNO, 2020 3. Hu et al, Cancers 2020 4. Tucker et al, American Journal of Cancer Research, 2022 Weeks P<0.05 ARK1 Human Endometrial Cancer Xenograft (100mg/kg BW; 6 wks)3 Non-CNS Solid Tumors Endometrial cancer3 Ovarian cancer4 Cholangiocarcinoma1 Transgenic Medulloblastoma Model2 Su rv iv al Control ONC206 (100mg/kg QW) ONC206 (120mg/kg QW)
32 • Consecutive day dosing may increase therapeutic response - In vitro data demonstrates enhanced efficacy with 72 hour sustained exposure - Toxicology data enables safe escalation to more prolonged exposures • PK models from ongoing adult Phase 1 trial data suggest a therapeutic and safe exposure possible with twice daily, three times weekly dosing Dose intensification expected to enhance therapeutic exposure 1. Internal modeling 72 hours Incubation Time C el l V ia bi lit y (% ) Pr ed ic te d pl as m a O N C 20 6 (n g/ m L) Time (hours) HGG in vitro response to ONC206 enhanced with exposure time PK model from ongoing adult Phase 1 trial1
33 ONC206 dose escalation: pediatric and adult CNS tumors • Monotherapy dose escalation trials enrolling in parallel for adult and pediatric CNS tumors • Response reported by investigator from early cohort (100mg QW) without H3 K27M mutation - 18-year-old patient with recurrent temporal lobe glioblastoma - Regression on MRI & metabolic reduction via PET imaging, continuing on therapy over 10 months - Details to be presented at future medical conference National Institutes of Health
34 • GBM is a rapidly progressive disease with low survival rates, few drug approvals last 25 years: - Temozolomide (TMZ) approved 1999 - Bevacizumab approved 2009 • Existing therapies rarely offer durable effect - 3-year survival from diagnosis • Chimerix retains global operational rights to ONC2062 • Worldwide market opportunity exceeds $2Bn - TMZ revenue peaked at approximately $1.4 billion in 2009, prior to going generic o Inflation adjusted peak: > $2.5Bn - New GBM therapy: 50% penetration at average price of contemporary oncology drug approvals exceeds $2Bn ~30,000 new cases of GBM annually in the top 7 markets; >$2Bn market opportunity 1 wjso.biomedcentral.com/articles/10.1186/1477-7819-10-220 2 Royalties and milestones are owed to legacy Oncoceutics shareholders by virtue of the 2021 merger agreement 1 out of 201
Preclinical Development ONC212 and CMX521
36 • Distinct molecular target (GPR132) and efficacy profile relative to ONC201/ONC206 • Efficacy in preclinical models of advanced cancers • GLP-tox studies complete, potential to advance to IND • Partnerships established for early-stage clinical trials with Brown University and MD Anderson Cancer Center ONC212: GPR132 + ClpP Agonist 1. Lev et al, Oncotarget 2017 Pancreatic cancer model shows the potential of ONC2121 Vehicle ONC201 ONC212
37 • Ribonucleoside analog that is a viral polymerase inhibitor - Inhaled nebulized liquid aerosol formulation; minimal systemic exposure • Monotherapy efficacy in mouse-adapted SARS-CoV-2-MA10 model across multiple endpoints - Lung viral titer - Viral RNA parallel viral lung titer (plaque forming unit) - Clinical scoring (animal health) - Lung pathology - Animal weight loss CMX-521: anti-SARS-CoV-2 preclinical activity Not significant Viral Lung Titer Replicating SARS-COV-2-MA101 Treatment initiation Hours post-infection (HPI) $2 million grant to fund prodrug formulations that could enable oral administration with improved lung delivery 1. Replicates lung pathology of human infection 4-days post-infection. One day in mouse is 5-7 days in humans (adjusted disease course).
Corporate Update
39 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
40 Financial strength supports development through key catalysts Low barriers to commercial potential for ONC201 High probability of success for Phase 3 ACTION study of ONC201 Corporate capability and financial flexibility Fully funded Ph 3 program with multiple potential paths to approval First-Line H3 K27M-mutant diffuse glioma – The ACTION Study Trial initiated November 2022 Interim OS data expected early 2025, full OS data expected 2026 ONC206 in early dose escalation studies at NIH and PNOC Confirmed response in Non-H3 K27M recurrent glioblastoma patient $246 million cash balance at March 31, 2022, 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
Chimerix Corporate Presentation