UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 2.02. | Results of Operations and Financial Condition. |
On October 5, 2022, Eliem Therapeutics, Inc. (Eliem, or the Company) issued a press release providing program updates, announcing expected upcoming milestones and providing an update on the Company’s unaudited cash, cash equivalents and marketable securities as of September 30, 2022. In such press release, the Company reported that its unaudited cash, cash equivalents and marketable securities were approximately $129.8 million as of September 20, 2022, which amount includes the receipt of $6.2 million in tax reimbursements in the third quarter of 2022. A copy of such press release is attached to this Current Report as Exhibit 99.1.
| Item 7.01. | Regulation FD Disclosure. |
A copy of a slide presentation that Eliem will use at investor conferences and presentations is attached to this Current Report as Exhibit 99.2 and is incorporated herein solely for purposes of this Item 7.01 disclosure.
The information in Items 2.02 and 7.01 (including Exhibits 99.1 and 99.2) is being furnished, not filed, for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any filing under the Exchange Act or the Securities Act of 1933, as amended, whether filed before or after the date hereof and regardless of any general incorporation language in such filing.
| Item 8.01. | Other Events. |
Program Updates and Anticipated Key Milestones
Eliem also provided the following program updates and announced expected upcoming milestones.
ETX-155 Program: ETX-155 is a novel GABAA receptor positive allosteric modulator (GABAA PAM) that is being developed for the treatment of major depressive disorder (MDD) and epilepsy. Following the observation of lower-than-expected drug exposure levels in the three subjects evaluated in a Phase 1b photosensitive epilepsy (PSE) trial, the Company initiated a Phase 1, single and repeat dose, clinical trial in healthy subjects to confirm the pharmacokinetic profile of ETX-155 in advance of a planned Phase 2a clinical trial in subjects with MDD. The drug exposure levels from the recently executed single dose part of the Phase 1 pharmacokinetic trial (N=42) were compared with the population pharmacokinetic model built with data from healthy subjects evaluated in the original, previously disclosed Phase 1 trials (N=70). Results demonstrated that at the 60-milligram dose, there was no meaningful difference between exposures obtained with different batches, and that the low exposures observed in the Phase 1b PSE trial are within the range of previously reported moderate variability. In addition, and upon extensive investigation, no irregularities or differences were observed with chemistry, manufacturing, and controls (CMC) associated with the drug product and the drug substance batches used in the PSE trial or with other newly produced drug substance and product.
Given the encouraging safety, tolerability, and pharmacokinetic profile of the 60-milligram dose in the prior two Phase 1 repeat dose trials and well-tolerated single dose data with a 75-milligram dose in the ongoing Phase 1 pharmacokinetic trial, the Company plans to evaluate a 75-milligram dose of ETX-155 in the repeat dose part of the ongoing Phase 1 pharmacokinetic trial in healthy subjects prior to making a decision on the dose for the planned Phase 2a MDD trial. Final results from the Phase 1 pharmacokinetic trial, including the repeat dose cohort, are expected in the fourth quarter of 2022. The Company currently anticipates initiating the Phase 2a MDD trial in the first quarter of 2023 using either the 60-milligram or 75-milligram dose of ETX-155, depending on the final exposure, safety and tolerability results from the ongoing Phase 1 pharmacokinetic trial. Assuming initiation in the first quarter of 2023, the topline data for the Phase 2a MDD trial would be expected in mid-2024.
The Company also has determined it will not reinitiate the PSE proof-of-concept trial but will continue to pursue development of ETX-155 in focal onset seizures (FOS), given existing clinical validation of the GABAA PAM mechanism in this indication.
Kv7.2/3 channel opener program: The Company’s preclinical program targets the Kv7.2/3 potassium channel (Kv7), a target that has clinical validation in pain and epilepsy. The Company has filed foundational intellectual property claims on its novel Kv7 compounds. In addition, while pursuing further lead evaluation, the Company has initiated the scaling up of two pre-candidates to enable the initiation of IND-enabling safety studies, expected in the first quarter of 2023, with Phase 1 studies planned to initiate in the first half of 2024. The Company’s novel Kv7 compounds have demonstrated high potency and differentiated selectivity in electrophysiology assays, and in vivo anticonvulsant activity in the maximal electroshock seizure (MES) rat model. Preclinical data on the Kv7 compounds are planned to be reported later in the fourth quarter of 2022.
Anxiolytic for generalized anxiety disorder (GAD): The Company has discontinued early preclinical development of a novel, non-sedating anxiolytic for the potential treatment of GAD because none of the compounds investigated achieved the required profile.
1
Forward-Looking Statements
Statements in this report that are not statements of historical fact are forward-looking statements, including, without limitation, statements relating to: the advancement of Eliem’s pipeline; the continued development and clinical and therapeutic potential of ETX-155 and Eliem’s Kv7.2/3 channel opener program; Eliem’s plan to study a 75-milligram repeat dose in the ongoing Phase 1 pharmacokinetic trial of ETX-155 and expected timing for the availability of final results from that trial; Eliem’s belief that it is positioned to commence the referenced phase 2a trial of MDD in the first quarter of 2023; Eliem’s plans to continue to pursue development of ETX-155 in focal onset seizures; Eliem’s planned activities and expectations for the Kv7.2/3 channel opener program, including the initiation of Phase 1 studies, and the timing thereof; Eliem’s plans to report preclinical data on the Kv7 program later in the fourth quarter of 2022; and Eliem’s commitment to developing therapies targeting neuronal excitability disorders. Words such as “advancing,” “anticipates,” “assuming,” “believe,” “compelling,” “continue,” “excited,” “expected,” “focus,” “initiate,” “on track,” “plans,” “positioned,” “potential,” “progress,” “pursue,” “will,” “would,” or other similar expressions, identify forward-looking statements, but the absence of these words does not necessarily mean that a statement is not forward-looking. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements. The forward-looking statements in this press release are based upon Eliem’s current plans, assumptions, beliefs, expectations, estimates and projections, and involve substantial risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements due to these risks and uncertainties as well as other factors, which include, without limitation: the clinical, therapeutic and commercial value of ETX-155 and the Kv7 program; risks related to the potential failure of ETX-155 or the Kv7 program to demonstrate safety and efficacy in clinical testing; Eliem’s ability to initiate and conduct clinical trials and studies of ETX-155 or the Kv7 program sufficient to achieve a positive completion; the availability of data at the expected times; Eliem’s ability to obtain and protect intellectual property rights, and operate without infringing on the intellectual property rights of others; the uncertain timing and level of expenses associated with Eliem’s preclinical and clinical development activities; the sufficiency of Eliem’s capital and other resources; risks and uncertainties related to regulatory application, review and approval processes and Eliem’s compliance with applicable legal and regulatory requirements; market competition; changes in economic and business conditions; impacts on Eliem’s business due to external events, including health pandemics or other contagious outbreaks, such as the current COVID-19 pandemic; and other factors discussed under the caption “Risk Factors” in Eliem’s Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2022. The forward-looking statements made in this report speak only as of the date of report. Eliem expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Eliem’s expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit Number |
Description | |
| 99.1 | Press release of Eliem Therapeutics, Inc., dated October 5, 2022 | |
| 99.2 | Investor Presentation dated October 2022 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
2
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 thereunto duly authorized.
| Eliem Therapeutics, Inc. | ||||||
| Date: October 5, 2022 | By: | /s/ James B. Bucher | ||||
| James B. Bucher | ||||||
| Executive Vice President and General Counsel | ||||||
3
Exhibit 99.1
Eliem Therapeutics Provides Update on Pipeline Progress
Company is positioned to initiate Phase 2a trial in major depressive disorder (MDD) in the first quarter of 2023
ETX-155 demonstrating exposures in single dose 60-milligram cohorts of ongoing Phase 1 pharmacokinetic trial that are consistent with prior clinical trials
Progressing into IND-enabling studies for two Kv7 pre-candidates
SEATTLE and CAMBRIDGE, United Kingdom, Oct. 05, 2022 (GLOBE NEWSWIRE) — Eliem Therapeutics, Inc. (Nasdaq: ELYM), a clinical-stage biotechnology company focused on developing novel therapies for neuronal excitability disorders to address unmet needs in psychiatry, epilepsy, chronic pain, and other disorders of the peripheral and central nervous systems, today provided an update on its pipeline programs, including the announcement of interim results from its ongoing Phase 1 clinical trial of ETX-155.
“I am tremendously grateful for the extraordinary effort put forth by our team to bring the ETX-155 program back on track while taking the time to understand the pharmacokinetic profile in order to have the right exposure levels to progress to Phase 2a. Based on the compound’s favorable safety, tolerability, pharmacokinetic profile, and preclinical efficacy to date, we believe we are now well positioned to evaluate the efficacy and safety of ETX-155 in patients with MDD, which represents an important milestone for Eliem,” said Bob Azelby, chief executive officer of Eliem Therapeutics. “We are also very excited about advancing two pre-candidates from our Kv7 program into IND-enabling studies. Both ETX-155 and Kv7 represent compelling product opportunities with the potential to be clinically differentiated drugs within classes where there is strong precedent clinical validation in depression and epilepsy, respectively. We remain well capitalized to bring these programs through key clinical data catalysts.”
ETX-155 program: ETX-155 is a novel GABAA receptor positive allosteric modulator (GABAA PAM) that is being developed for the treatment of major depressive disorder (MDD) and epilepsy. Following the observation of lower-than-expected drug exposure levels in the three subjects evaluated in a Phase 1b photosensitive epilepsy (PSE) trial, the Company initiated a Phase 1, single and repeat dose, clinical trial in healthy subjects to confirm the pharmacokinetic profile of ETX-155 in advance of a planned Phase 2a clinical trial in subjects with MDD. The drug exposure levels from the recently executed single dose part of the Phase 1 pharmacokinetic trial (N=42) were compared with the population pharmacokinetic model built with data from healthy subjects evaluated in the original, previously disclosed Phase 1 trials (N=70). Results demonstrated that at the 60-milligram dose, there was no meaningful difference between exposures obtained with different batches, and that the low exposures observed in the Phase 1b PSE trial are within the range of previously reported moderate variability. In addition, and upon extensive investigation, no irregularities or differences were observed with chemistry, manufacturing, and controls (CMC) associated with the drug product and the drug substance batches used in the PSE trial or with other newly produced drug substance and product.
Given the encouraging safety, tolerability, and pharmacokinetic profile of the 60-milligram dose in the prior two Phase 1 repeat dose trials and well-tolerated single dose data with a 75-milligram dose in the ongoing Phase 1 pharmacokinetic trial, the Company plans to evaluate a 75-milligram dose of ETX-155 in the repeat dose part of the ongoing Phase 1 pharmacokinetic trial in healthy subjects prior to making a decision on the dose for the planned Phase 2a MDD trial. Final results from the Phase 1 pharmacokinetic trial, including the repeat dose cohort, are expected in the fourth quarter of 2022. The Company is positioned to initiate the Phase 2a MDD trial in the first quarter of 2023 using either the 60-milligram or 75-milligram dose of ETX-155, depending on the final exposure, safety and tolerability results from the ongoing Phase 1 pharmacokinetic trial. Assuming initiation in the first quarter of 2023, the topline data for the Phase 2a MDD trial would be expected in mid-2024.
The Company also has determined it will not reinitiate the PSE proof-of-concept trial but will continue to pursue development of ETX-155 in focal onset seizures (FOS), given compelling existing clinical validation of the GABAA PAM mechanism in this indication.
Kv7.2/3 channel opener program: The Company’s preclinical program targets the Kv7.2/3 potassium channel (Kv7), a target that has clinical validation in pain and epilepsy. The Company has filed foundational intellectual property claims on its novel Kv7 compounds. In addition, while pursuing further lead evaluation, the Company has initiated the scaling up of two pre-candidates to enable the initiation of IND-enabling safety studies, expected in the first quarter of 2023, with Phase 1 studies planned to initiate in the first half of 2024. The Company’s novel Kv7 compounds have demonstrated high potency and differentiated selectivity in electrophysiology assays, and in vivo anticonvulsant activity in the maximal electroshock seizure (MES) rat model. Preclinical data on the Kv7 compounds are planned to be reported later in the fourth quarter of 2022.
Anxiolytic for generalized anxiety disorder (GAD): The Company has discontinued early preclinical development of a novel, non-sedating anxiolytic for the potential treatment of GAD because none of the compounds investigated achieved the required profile.
Cash position: The Company’s unaudited cash, cash equivalents, and investments as of September 30, 2022 were $129.8 million, including receipt of $6.2 million in tax reimbursements within the quarter, which is expected to fund operations into 2025.
About Eliem Therapeutics, Inc.
Eliem Therapeutics, Inc. is a clinical-stage biotechnology company focused on developing novel therapies for neuronal excitability disorders to address unmet needs in psychiatry, epilepsy, chronic pain, and other disorders of the peripheral and central nervous systems. These disorders often occur when neurons are overly excited or inhibited, leading to an imbalance, and our focus is on restoring homeostasis. We are developing a pipeline of clinically differentiated product candidates focused on validated mechanisms of action with broad therapeutic potential to deliver improved therapeutics for patients with these disorders. Eliem channels its experience, energy, and passion for improving patients’ quality of life to fuel our efforts to develop life-changing novel therapies. At its core, the Eliem team is motivated by the promise of helping patients live happier, more fulfilling lives. https://eliemtx.com/
Forward-Looking Statements
This press release contains forward-looking statements, including, without limitation, statements relating to: the advancement of Eliem’s pipeline; the continued development and clinical and therapeutic potential of ETX-155 and Eliem’s Kv7.2/3 channel opener program; Eliem’s plan to study a 75-milligram repeat dose in the ongoing Phase 1 pharmacokinetic trial of ETX-155 and expected timing for the availability of final results from that trial; Eliem’s belief that it is positioned to commence the referenced Phase 2a trial of MDD in the first quarter of 2023; Eliem’s plans to continue to pursue development of ETX-155 in focal onset seizures; Eliem’s planned activities and expectations for the Kv7.2/3 channel opener program, including the initiation of Phase 1 studies, and the timing thereof; Eliem’s plans to report preclinical data on the Kv7 program later in the fourth quarter of 2022; Eliem’s belief that ETX-155 and Kv7 represent compelling product opportunities with the potential to be clinically differentiated drugs; Eliem’s belief that it is well capitalized and that its current cash, cash equivalents and short- and long-term marketable securities will fund operations into 2025; and Eliem’s commitment to developing therapies targeting neuronal excitability disorders. Words such as “advancing,” “assuming,” “believe,” “compelling,” “continue,” “excited,” “expected,” “focus,” “initiate,” “on track,” “plans,” “positioned,” “potential,” “progress,” “pursue,” “will,” “would,” or other similar expressions, identify forward-looking statements, but the absence of these words does not necessarily mean that a statement is not forward-looking. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements. The forward-looking statements in this press release are based upon Eliem’s current plans, assumptions, beliefs, expectations, estimates and projections, and involve substantial risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements due to these risks and uncertainties as well as other factors, which include, without limitation: the clinical, therapeutic and commercial value of ETX-155 and the Kv7 program; risks related to the potential failure of ETX-155 or the Kv7 program to demonstrate safety and efficacy in clinical testing; Eliem’s ability to initiate and conduct clinical trials and studies of ETX-155 or the Kv7 program sufficient to achieve a positive completion; the availability of data at the expected times; Eliem’s ability to obtain and protect intellectual property rights, and operate without infringing on the intellectual property rights of others; the uncertain timing and level of expenses associated with Eliem’s preclinical and clinical development activities; the sufficiency of Eliem’s capital and other resources; risks and uncertainties related to regulatory application, review and approval processes and Eliem’s compliance with applicable legal and regulatory requirements; market competition; changes in economic and business conditions; impacts on Eliem’s business due to external events, including health pandemics or other contagious outbreaks, such as the current COVID-19 pandemic; and other factors discussed under the caption “Risk Factors” in Eliem’s Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2022. This filing is available on the SEC’s website at www.sec.gov. Additional information will also be set forth in Eliem’s other reports and filings it will make with the SEC from time to time. The forward-looking statements made in this press release speak only as of the date of this press release. Eliem expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking
statements contained herein to reflect any change in Eliem’s expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
Investors
Chris Brinzey
ICR Westwicke
chris.brinzey@westwicke.com
339-970-2843
Media
Marites Coulter
Verge Scientific
Mcoulter@vergescientific.com
415.819.2214
Exhibit 99.2 Clinical Stage Neurology Company Focused on Neuronal Excitability Disorders Corporate Presentation | October 5, 2022
Forward-Looking Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this presentation, including statements regarding our future financial condition, results of operations, business strategy and plans, and objectives of management for future operations, as well as statements regarding industry trends, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially,” “predict,” “should,” “will” or the negative of these terms or other similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things, risks related to: the success, cost and timing of our product development activities and clinical trials; our expectations about the timing of achieving regulatory approval and the cost of our development programs; our ability to obtain funding for our operations, including funding necessary to complete further development and commercialization of our product candidates; the impact of the COVID-19 pandemic on our operations; the commercialization of our product candidates, if approved; our plans to research, develop and commercialize our product candidates; our plans to develop additional product candidates; our ability to obtain, maintain, expand, protect and enforce our intellectual property rights; our ability to operate our business without infringing, misappropriating or otherwise violating the intellectual property rights of third parties; our ability to attract collaborators with development, regulatory and commercialization expertise; future agreements with third parties in connection with the commercialization of our product candidates; the size and growth potential of the markets for our product candidates and our ability to serve those markets; the rate and degree of market acceptance of our product candidates; regulatory developments in the United States and foreign countries; regulatory application, review and approval processes and our compliance with applicable legal and regulatory requirements; our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately; the success of competing products that are or may become available; and our ability to attract and retain key scientific or management personnel. These risks are not exhaustive. New risk factors emerge from time to time and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. More information about the risks and uncertainties faced by Eliem is contained under the caption “Risk Factors” set forth in Eliem’s Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2022, which is available on the SEC’s website at www.sec.gov, and in other subsequent reports and filings Eliem will make with the SEC from time to time. You should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation. Certain information contained in this presentation relates to, or is based on, studies, publications, surveys and other data obtained from third-party sources and the Company's own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this presentation, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and investors are cautioned not to unduly rely upon these statements. 2
Highly experienced management team Clinical and preclinical pipeline based on clinically validated mechanisms of action Rethinking Two differentiated programs in depression and epilepsy with treatment for expansion opportunities in chronic pain nervous system disorders ~$130M* cash runway into 2025 allows for topline clinical data readouts and advancement of preclinical asset into clinic * Unaudited cash, cash equivalents and investments as of September 30, 2022, 3 including receipt of $6.2m in tax reimbursements within the quarter
Deep expertise in neuroscience Powered by successful and talented research, clinical development executives from pioneering organizations and commercialization • Lyrica, Neurontin, Trobalt, Vyepti, Vixotrigine, Nimotop, Aptiom, Lunesta, Geodon General Management, Commercial & Corporate Development Leadership experience in both large pharma and small biotech Robert Azelby, MBA Erin Lavelle James Bucher, J.D. • Large: Amgen, GSK, Novartis, Biogen, Chief Executive Officer Chief Operating Officer & EVP and General Counsel Bayer, Pfizer Chief Financial Officer • Small: Alder, Juno, Convergence, Cavion, Exelixis Research & Development Highly skilled in public/private capital raising and corporate development with successful exits Valerie Morisset, Ph.D. Joanne Palmer, Ph.D. Mark Versavel, M.D., Ph.D. • Exits: Alder, Convergence, Juno, EVP R&D and Chief Scientific Officer Chief Development Officer Interim Chief Medical Officer Immunomedics, Cascadian, Cavion 4 4
Addressing multiple interrelated diseases with two distinct, clinically validated mechanisms of action Approaching interrelated disease states with Depression distinct MOAs (GABA PAM and Kv7.2/3) A / Anxiety Innovating within clinically validated mechanisms of action ETX-155 Kv7 Chronic Pain Epilepsy Multiple “pipeline-in-a-product” opportunities 5
Eliem Pipeline: Two programs with clinically validated MOAs intended to address large markets Product Candidate Lead indications Preclinical Phase 1 Phase 2 Phase 3 (Mechanism) Major depressive disorder Positioned for Phase 2a (MDD) initiation in Q1 2023 ETX-155 (GABA receptor PAM) A Epilepsy Kv7 Program Epilepsy IND-enabling safety studies Depression (Kv7.2/3 channel planned in Q1 2023 Pain opener) GABA PAM: GABA receptor positive allosteric modulator 6 A A
Proof of concept Phase 2a trial in Major Depressive Disorder (MDD) ETX-155 positioned for Q1 2023 initiation 7
ETX-155: A differentiated neuroactive steroid GABA positive allosteric modulator A Clinical validation for MOA (GABA PAM) A Dual potent activity at synaptic and extrasynaptic GABA receptors, with high intrinsic efficacy A No clinically meaningful food effect Convenient once-daily dosing with ~40-hr half-life Well tolerated at exposure levels that have translated to clinical efficacy for other GABA PAMs A Strong IP position with patent protection to 2039 8
Clinical development focused on MDD with opportunity to expand into other large markets with considerable unmet need Proof of concept planned Potential future indication opportunities Major Depressive Perimenopausal Epilepsy / Focal Disorder (MDD) Depression (PMD) Onset Seizure (FOS) • Reduced GABA levels à • Reduced neurosteroid levels à • GABAergic deficits à 1 increased MDD severity PMD symptoms epileptic state MoA Rationale • Clinically validated • Clinically validated in neurosteroid- • Clinically validated in orphan (zuranolone) driven PPD (zuranolone) epilepsies (ganaxolone) • Faster onset of action • Same as MDD • Novel MoAsà better seizure control Unmet Needs • Improved tolerability/efficacy • Novel MoAs directly addressing reduced neurosteroid levels • Positive impact on mood as #1 4 • Novel MoAs comorbidity is depression Estimated annual ~32m ~8m ~2m 2 3 5 prevalence (US+EU) (~9m failed ≥1 prior therapy) (~2m with no history of MDD) (~0.8m with uncontrolled seizures) 1. Luscher et al, Mol Psychiatry, 2011;16(4):383-406 2. Decision Resources Group (DRG)– Unipolar Depression Disease Landscape and Forecast 3. Freeman et al, JAMA Psychiatry, 2014;72(1):36-43 4. Kanner AM, Biol Psychiatry, 2003;54(3):388-98 9 5. DRG – Epilepsy Disease Landscape and Forecast, May 2021
ETX-155 Differentiation: Similar dual GABA R potency to clinically validated A GABA PAMs, with differentiated pharmacokinetics A GABA R Clinical Validation A Pharmacokinetics (positive RCT) Potency Company Molecule Extra- Synaptic Food effect Half-life MDD PPD Epilepsy synaptic No ~40 hrs - - - ETX-155 zuranolone Yes 14-18 hrs - (SAGE-217) ZTALMY® Yes 2-3 hrs - - (ganaxolone) Sources: Zuranolone: Hoffmann et al, Clin Pharmacokinet, 2020;59(1):111-120; Hoffmann et al, ASCP 2018, poster #782; Botella et al, J Med * Evening QD dosing for ETX-155, zuranolone; Chem, 2017;60(18)7810-7819; Phase 3 WATERFALL topline data press release 10 Ganaxolone: ZTALMY Prescribing Information; Hulihan et al., American Epilepsy Society Annual Meeting 2020, poster TID dosing for ganaxolone
ETX-155 does not have a clinically meaningful food effect: potential to impact efficacy, safety, and compliance Reported Fed/Fasted Ratios for GABA PAM class Presence of a food effect may impact: A Efficacy Cmax AUC(0-t) 3.5 Exposure reduced or increased if medication not taken with food 3 3.0x 2.9x 2.5 Safety and Tolerability 2.6x FOOD EFFECT Clinically meaningful higher Timing/severity of AEs associated with Cmax 2 exposure if taken with food 1.5 1.6x 1.25x Compliance 3 More strict daily routine required to maintain 1 NO FOOD EFFECT 0.8x drug levels within the required range for FOOD EFFECT 0.5 Clinically meaningful lower efficacy and safety exposure if taken with food 0 1 2 Zuranolone Ganaxolone ETX-155 Tablet, 30mg, Capsule, 30mg, Capsule, human human 5 mg/kg, dog ETX-155 has not been assessed in a head-to-head study against zuranolone or 1. Hoffmann et al, Clin Pharmacokinet, 2020;59(1):111-120; Hoffmann et al, ASCP 2018, poster #782 2. U.S. Patent No. 9,029,355 ganaxolone, and the study designs and analytical methods for all product candidates may be different. As a result, such data may not be directly comparable. 3. Range of fed/fasted ratios for AUC and Cmax required to claim absence of food effect on bioavailability, per FDA Guidance 11 For Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, December 2002 Fed/Fasted Ratio
Phase 1 Study in Healthy Subjects: Encouraging safety & tolerability profile observed with no severe or serious adverse events Most common treatment-emergent AEs ETX-155 Phase 1 Repeat-Dose Results (In ≥10% of ETX-155 treated subjects across repeat dose studies) • Favorable pharmacokinetics 7-day Repeat 14-day Repeat • Steady state reached at day 8 Combined Dose Dose • ~40-hour half-life at steady state • 60 mg evening dosing was well tolerated ETX-155 ETX-155 ETX-155 Placebo Placebo Placebo 60 mg 60 mg 60 mg • No SAEs or discontinuations (n=6) (n=5) (n=11) (n=9) (n=15) (n=24) • All AEs were mild/moderate and transient n (%) n (%) n (%) n (%) n (%) n (%) • CNS AE details • The rate of CNS AEs were comparable in ETX-155 and ≥1 TEAE 5 (56) 3 (50) 9 (60) 4 (80) 14 (58) 7 (64) placebo groups • Most CNS AEs occurred at Tmax (3-4 hrs post-dose) Somnolence 1 (11) 2 (33) 6 (40) 2 (40) 7 (29) 4 (36) • 7 reports of somnolence out of 24 ETX-155-treated patients (no subject reported somnolence more than Fatigue 0 0 4 (27) 1 (20) 4 (17) 1 (9) once during dosing period) Headache 2 (22) 2 (33) 1 (7) 0 3 (13) 2 (18) • Leeds Sleep Evaluation Questionnaire indicates no difference in next-morning alertness or disruption in Dizziness 1 (11) 0 2 (13) 0 3 (13) 0 sleep quality compared to placebo 12
Analysis of ETX-155 pharmacokinetic profile confirmed comparable 60mg exposures obtained with different batches, enabling path forward in Phase 2a MDD trial Original Phase 1 studies PSE study findings (April ‘22) Extensive Investigation • SAD (5-200mg, n=6 active/cohort) • Proof-of-concept model in patients 1) CMC investigations on all batches of with photosensitive epilepsy (PSE) API and DP • MAD 7-day (60mg AM and PM, n=9 à No findings active/cohort) • Single-dose of 135 mg ETX-155 • MAD 14-day (60mg PM, n=15 • N=3 patients; evaluation of activity 2) Dog PK to compare preclinical active/cohort) in this model was inconclusive due exposure across all batches to ~50% lower-than-expected à Comparable across batches • Well tolerated, especially with PM exposures dosing 3) 5 single dose cohorts of healthy • Achievement of predicted • Encouraging PK profile subjects to confirm PK profile therapeutic exposure levels is Ø Moderate CV% of ~30% à Comparable exposure across batches Ø Half-life of ~40 hrs critical for success of planned Phase 4) Comparison of exposures from all Ø Steady state at day 8 2a MDD trial Ø Moderate acc. ratio of ~2 batches with population PK model • Prompted investigation to Ø No food effect based on original Phase 1 data understand potential root causes Ø Exposures within preclinical efficacy à Exposures at 60mg fit the model range prior to progressing to MDD trial 5) Confirmed 75mg well tolerated as a • Enabled selection of a Phase 2 single-dose clinical dose of 60mg à Plan to evaluate 75mg in repeat-dose Investigation concluded there was no meaningful difference between 60mg exposures obtained with different batches 13
At steady-state, modeled exposures of ETX-155 60mg and 75mg doses are well within the therapeutic range Modeled 60mg and 75mg ETX-155 AUC at steady state 0-24 Preclinical Robust ED range (3 mg/kg) Mean: 2810 Benchmark zuranolone modeled AUC for 0-24 30mg and 50mg capsules at steady state* Mean: 2248 Mean: 1540 Mean: 924 Preclinical MED range (1 mg/kg) Center lines represent the median, the top and bottom of the boxes represent the 25th and 75th percentiles (i.e. interquartile range) * Derived from 30mg pharmacokinetic data in Bullock et al, Marcé of North America Congress, Oct 21-24, 2021, extrapolated to 50 mg based on dose linearity; modeled CV% derived from Hoffmann et al, 2018 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21-24, 2018 The two graphs are not generated from head-to-head trials and therefore are not direct comparisons. ETX-155 preclinical AUC ranges are derived from rat PK study for 1 mg/kg and 3 14 mg/kg groups, which were efficacious dose levels in depression, anxiety, seizure, and EEG preclinical models; ED: Efficacious Dose; MED: Minimal Efficacious Dose
Positioned to progress ETX-155 into Phase 2a RCT in MDD in Q1 2023 with topline data expected in mid-2024 Screening Outpatient Treatment Follow-up Primary Endpoint Week 28 days 14 days Change from baseline in HAMD17 1 2 3 4 over days 4, 8, 15, 22, and 29 Secondary Endpoints ETX-155 qd x 28 days MDD Phase 2a Change from baseline in HAMD17 130 patients at days 4, 8, 15, 22, 29 and 42* 1:1 randomization Placebo 50% response rate in HAMD17 qd x 28 days at days 4, 8, 15, 22, 29 and 42* d1 d8 d15 d22 d29 d42 * Day 42 assessments are exploratory 15 HAMD17: Hamilton Depression Rating Scale
ETX-155 Market Opportunity 16
nd One-third (7M) of the US MDD treated patient opportunity is in 2 line and beyond US Epidemiology, 2030 estimates Reference branded MDD drug peak sales Drug Class Peak Sales Peak Year Diagnosed and Drug-treated 21M MDD patients Lexapro SSRI $3.0B 2011 Effexor SNRI $2.7B 2008 Zoloft SSRI $2.6B 2005 Second Line MDD 4.6M (Failed 1 ADT class) Cymbalta SNRI $2.6B 2013 Prozac SSRI $2.4B 2001 Third Line+ MDD 2.5M (Failed ≥2 ADT classes) $14-21B Total Branded Opportunity nd in 2 line + Assumes $6,000 WAC, 6 months on therapy/yr 17 Source: DRG Unipolar Depression Disease Landscape and Forecast, 2021
Zuranolone precedent GABA PAM efficacy in line with approved MDD drugs, A achieving statistical significance and ~50% reduction in HAMD17 despite smaller delta to placebo Estimated Mean HAMD17 at Mean HAMD17 change from Baseline end of treatment Year of Baseline Duration of Drug: Study* Reference Study HAMD17 Treatment Delta to Active Placebo Active Placebo (top dose, if >1 arm) placebo 1980s- -7.6 -10.4 38 studies of SSRIs/SNRIs Kirsch 2002 21.0 – 29.7 4-8 weeks -2.8 ~14 ~17 1990s (range: -5.9 to -14.2) (range: -3.0 to -10.5) Cymbalta: Study 1 Cymbalta label 2001 21 9 weeks -10.9 -6.1 -4.9 10.1 14.9 Cymbalta: Study 2 Cymbalta label 2001 20 9 weeks -10.5 -8.3 -2.2 9.5 11.7 Cymbalta: Study 3 Cymbalta label 2001 18 8 weeks -8.6 -5.0 -3.6 9.4 13 Cymbalta: Study 4 Cymbalta label 2001 20 8 weeks -12.1 -8.8 -3.3 7.9 11.2 Pristiq: Study 332 Liebowitz et al 2008 23 8 weeks -11.5 -9.5 -2.0 11.5 13.5 Pristiq: Study 333 Boyer et al 2008 24 8 weeks -13.7 -10.7 -3.0 10.3 13.3 Rexulti: Pyxis Study Thase et al (a) 2013 21 6 weeks -5.89 -3.59 -2.29 15.1 17.4 Rexulti: Polaris Study Thase et al (b) 2013 21 6 weeks -6.26 -4.57 -1.69 14.7 16.4 Rexulti: Sirius Study Hobart et al 2016 21 6 weeks -7.1 -5.9 -1.16 13.9 15.1 Average of all drugs -9.7 -7.0 -2.7 11.6 14.4 6-8 wks (-5.9 to -13.7) (-3.6 to -10.7) (-1.16 to -4.9) (7.9 to 15.1) (11.7 to 17.4) (range) Waterfall 2020-21 26.8 2 weeks -14.1 -12.3 -1.7 12.7 14.6 Sage zuranolone data Coral 2021 26.8 2 weeks -13.7 -12.9 -0.8 13.1 13.7 ~50% reduction in mean HAMD17 from severe depression (>24) to mild depression (8-16) 18 * Studies reporting HAMD as primary endpoint shown here; recent MDD registrational trials for Trintellix, Spravato, and Axsome used MADRS as endpoint, rather than HAMD17, so are not included
Zuranolone precedent suggests potential GABA PAM advantages relative to existing A ADTs: would be attractive in a “direct to patient” commercial marketplace Background Potential Differentiation Points • SSRI’s treatment duration undefined – many • “Treat depressive episode”: zuranolone uses a patients on SSRIs for multiple years/life two-week regimen, 80% of patients needed only 4 weeks of therapy in a year • SSRI’s can take 6 to 8 weeks to work, if they work; not accounting for titration period • Rapid onset: zuranolone achieved activity by day 3, with no titration, which should enable patient • Side effects including weight gain, sexual to know within two weeks if product is working dysfunction, withdrawal symptoms • Transient side effects: somnolence/fatigue but • Unsatisfied market with new MDD patient on no weight gain, sexual dysfunction, or withdrawal therapy for ~ 5.5 months, adherence rates observed in zuranolone trials 1 of 51% at week 16, 21% at week 33 • Enhanced adherence: two-week course of therapy should dramatically improve adherence Short treatment duration combined with rapid effect enables dosing aligned with the depressive episode 19 1. Sawada et al, BMC Psychiatry, 2009;9(38).
ETX-155: Being Developed as a Potentially Clinically Differentiated Oral Neuroactive Steroid ETX-155 Opportunities Improve Efficacy: Increasing AUC • Absence of clinically meaningful food effect • Significantly longer half-life • Higher exposures observed at well tolerated doses Improve Tolerability • CNS AE rates similar to placebo in healthy subjects • No difference from placebo in sleep quality and next day alertness • No reports of somnolence on more than one day in repeat dosing studies Improve Durability • Evaluate longer dosing regimens (i.e., 28 days) 20 Statements are not based on data resulting from head-to-head trials and are not direct comparisons of safety or efficacy
Pre-candidates identified IND-enabling safety studies planned for Kv7 Opener Q1 2023 21
Kv7.2/3 Program: Developing a differentiated Kv7.2/3 opener for multiple neuronal excitability indications Kv7 Opportunity Eliem Kv7 Program Goal Maintain efficacy with improved tolerability Human genetic validation and safety Strong clinical validation in pain and Program Status epilepsy (retigabine, flupirtine, XEN1101) Foundational IP filed Metabolic/safety liabilities with existing Multiple lead and backup candidates in molecules novel chemical space Improved metabolic stability Clear translational path to clinical efficacy Potent at Kv7.2/3, selective vs Kv7.1/4, and active in MES rat model Two pre-candidates being scaled up for IND-enabling safety studies anticipated to initiate in Q1 2023 22 MES: maximal electroshock seizure
Highly experienced management team Clinical and preclinical pipeline based on clinically validated mechanisms of action Rethinking Two differentiated programs in depression and epilepsy with treatment for expansion opportunities in chronic pain nervous system disorders ~$130M* cash runway into 2025 allows for topline clinical data readouts and advancement of preclinical asset into clinic * Unaudited cash, cash equivalents and investments as of September 30, 2022, 23 including receipt of $6.2m in tax reimbursements within the quarter
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