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Item 7. Management’s Discussion and Analysis

2025-03-24 compared with 2024-03-14 · 71 added, 49 removed, 145 unchanged (45% of the section changed)

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We are a clinical-stage biotechnology company focused on developing treatments for patients suffering from complex rare diseases using our novel cell penetrating peptide ("CPP") technology platform.

Our lead product candidate, nomlabofusp (nomlabofusp is the International Nonproprietary Name ( "INN") and the United States Adopted Name ("USAN") for CTI-1601), is a subcutaneously administered, recombinant fusion protein intended to deliver tissue frataxin ("FXN"), an essential protein, to the mitochondria of patients with Friedreich's ataxia (“FA”).

Our lead product candidate, nomlabofusp (nomlabofusp is the International Nonproprietary Name and the United States Adopted Name for CTI-1601), is a subcutaneously administered, recombinant fusion protein intended to deliver tissue frataxin ("FXN"), an essential protein, to the mitochondria of patients with Friedreich's ataxia (“FA”).

FA is a rare, progressive, and fatal disease in which patients are unable to produce sufficient FXN due to a genetic abnormality.

Currently, there are no treatment options that address the core deficit of FA, low levels of FXN.

Nomlabofusp represents the first potential therapy designed to increase FXN levels in patients with FA.

Nomlabofusp represents the first potential therapy designed to systemically increase FXN levels in patients with FA.

We believe that our CPP platform, which enables a therapeutic molecule to cross a cell membrane in order to reach intracellular targets, has the potential to enable the treatment of other rare and orphan diseases.

We intend to use our proprietary platform to target additional orphan indications characterized by deficiencies in or alterations of intracellular content or activity.

Since our inception, we have devoted substantially all of our resources to developing nomlabofusp, building our intellectual property portfolio, developing third-party manufacturing capabilities, business planning, raising capital, and providing general and administrative support for such operations.

Since our inception, we have devoted substantially all of our resources to developing nomlabofusp, building our intellectual property portfolio, developing third-party manufacturing capabilities, business planning, raising capital, developing sales and marketing capacities, and providing general and administrative support for such operations.

Nomlabofusp Program Update

Clinical Trials

We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial in patients with FA.

We have completed two Phase 1 clinical trials and a Phase 2 dose exploration trial, and have an ongoing Phase 2 OLE trial in patients with FA and an ongoing PK run-in study in adolescent patients with FA.

In May 2021, we reported positive top-line data from our Phase 1 FA program after completing dosing of the single ascending dose ("SAD") trial in December 2020 and of the multiple ascending dose ("MAD") trial in March 2021.

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Data from the cohort indicated nomlabofusp was generally well tolerated and showed increases in FXN levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14.

In June 2023, we met with the FDA.

Following that meeting, we submitted a complete response to the FDA’s partial clinical hold that included unblinded safety, PK and frataxin data from the Phase 2 trial’s completed 25 mg cohort.

In July 2023, following the FDA’s review of our complete response to the partial clinical hold, the FDA cleared initiation of a second cohort (50 mg) of our four-week, placebo-controlled, Phase 2 dose exploration trial and to initiate our OLE trial with daily dosing of 25 mg.

In January 2024, we initiated the OLE trial evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver, with the first patient dosed in March 2024.

Participants who complete treatment in the Phase 2 dose exploration trial, or who previously completed a prior clinical trial of nomlabofusp are potentially eligible to screen for the OLE.

The OLE will evaluate the safety and tolerability and PK and measures of frataxin levels in peripheral tissues as well as other exploratory PD (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp.

Clinical measures collected during the trial will be compared to data from a synthetic control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study ("FACOMS") database.

Dose escalation in the OLE trial will be

considered based on safety, tolerability, PK, and tissue FXN levels from the Phase 2 trial’s 50 mg cohort as well as available data from the 25 mg dose of nomlabofusp in the OLE trial and is contingent on FDA review as part of the partial clinical hold.

Initial data from the OLE trial is expected in the fourth quarter of 2024.

In February 2024, we reported positive top-line data and successful completion of the two cohorts (25 mg and 50 mg groups) of our four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp in participants with FA.

Nomlabofusp was generally well tolerated and demonstrated dose dependent increases in FXN levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts.

In July 2023, the FDA cleared initiation of a second cohort (50 mg) of our four-week, placebo-controlled, Phase 2 dose exploration trial of nomlabofusp in patients with FA and the initiation of our OLE trial with daily dosing of 25 mg.

In February 2024, we reported positive top-line data and successful completion of the Phase 2 dose exploration study.

Nomlabofusp was generally well tolerated throughout the four-week treatment periods, had a predictable pharmacokinetic profile and led to dose dependent increases in FXN levels in all evaluated tissues (skin and buccal cells) after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts.

Participants in the 25 mg (n=13) and 50 mg (n=15) cohorts were randomized 2:1 to receive subcutaneous injections of nomlabofusp or placebo.

Recently, we had discussions with the FDA regarding the use of tissue FXN levels as a novel surrogate endpoint.

The FDA has acknowledged that frataxin deficiency appears to be critical to the pathogenic mechanism of FA, and that there continues to be an unmet need for treatments for FA patients that address the underlying disease pathophysiology.

We intend to pursue an accelerated approval using FXN levels, supportive PD and clinical information, and safety data from the OLE study, along with additional non-clinical pharmacology information needed to support the novel surrogate endpoint approach.

We are beginning to plan for a confirmatory study and are targeting a BLA submission in the second half of 2025.

Nomlabofusp has been granted Orphan Drug (U.S.

and Europe), Rare Pediatric Disease (U.S.), Fast Track (U.S.), and PRIME (Europe) designations for FA.

We have also begun to engage with regulators and investigators outside the U.S.

as we prepare to expand our clinical program to additional geographies.

With approximately 75% of individuals with FA living outside the U.S., establishing global clinical trial capabilities is important for addressing the pressing unmet needs of the FA community.

Patients who completed treatment in our Phase 2 dose exploration study or who previously completed a prior clinical trial of nomlabofusp are eligible to screen and possibly participate in the OLE study.

In March 2024, we dosed the first patient in our OLE trial, evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver.

The OLE study will evaluate the safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues as well as other exploratory

pharmacodynamic markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp.

In addition, following the completion of enrollment, as well as at least one participant completing one year of dosing, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study ("FACOMS") database.

On May 30, 2024, we announced that the FDA's Center for Drug Evaluation and Research ("CDER") had selected nomlabofusp as one of a few programs for participation in the Support for Clinical Trials Advancing Rare Disease Therapeutics ("START") Pilot Program.

The objective of the program is to accelerate the development of drugs for rare diseases that lead to significant disability or death by facilitating frequent advice and regular communication with the FDA staff to expedite the review process of biologics and drugs.

In September 2024, we received access to the Medicines and Healthcare Regulatory Agency ("MHRA") Innovative Licensing and Access Pathway (“ILAP”) for the treatment of adults and children with FA.

The ILAP is facilitating patient access to novel treatments by accelerating time to market through opportunities for enhanced engagements with UK regulatory authorities and other stakeholders.

Along with the receipt of the ILAP designation, nomlabofusp has already been granted orphan drug designations in the U.S.

and the European Union (the “EU”), and access to the PRIME scheme in the EU.

In December 2024, we reported positive initial data from our ongoing OLE study.

This data included safety, FXN levels, clinical, pharmacokinetic data and dose escalation:

• Nomlabofusp was generally well tolerated for up to 260 days in subjects.

The most common adverse events were injection site reactions, with most being mild, brief in duration, and self-limited.

Two participants had serious adverse events (one seizure and one anaphylactic reaction) that resolved within 24 hours and withdrew from the study;

• Long-term 25 mg tissue FXN levels showed positive mean change from baseline of 1.32 pg/μg in buccal cells and 9.28 pg/μg in skin cells at Day 90 and that 25 mg of nomlabofusp increased and maintained tissue FXN levels over time, increasing from a mean level of 15% of HV at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90;

• Tissue FXN levels appear to reach steady-state levels by Day 30 in buccal cells;

• Early clinical data showed trends toward improvement across a number of clinical outcomes for long-term 25 mg daily nomlabofusp including:

(1) decreased values indicating early trends towards improvement in the Modified Friedreich Ataxia Rating Scale (mFARS) and the FARS-Activities of Daily Living ("ADL"), Modified Fatigue Impact Scale and 9 hole peg test at 90 days relative to baseline;

• Key pharmacokinetic data showed rapid absorption after subcutaneous administration with exposure appearing to reach steady state in plasma by day 30 with no further accumulation, which is consistent with data from our Phase 1 and Phase 2 studies.

Also in December 2024, we announced that we were increasing the dose in the OLE to 50 mg of nomlabofusp daily for then currently enrolled and all future OLE study participants.

In March 2025, we announced that our Safety Monitoring Team has deemed anaphylaxis as an adverse drug reaction likely associated with nomlabofusp and therefore, we expect to see additional reactions.

To reduce the risk of allergic reactions, including anaphylaxis, we amended the OLE protocol to administer premedication for the first month of dosing.

The OLE study is ongoing with seven sites activated and participants continuing to enroll.

All study participants are currently receiving the 50 mg dose of nomlabofusp.

We plan to provide an update on OLE data on at least 30 to 40 study participants, some of whom have been receiving nomlabofusp for more than a year, in September 2025.

In January 2025, we initiated dosing of adolescents (12-17 years old) in a PK run-in study for pediatric patients with FA.

Study participants in the PK run-in study are randomized 2:1 to receive either nomlabofusp at a weight-base dose expected to match the PK of adults receiving the 50 mg dose, or placebo, daily for seven days.

Following assessment of safety and PK data, participants will be eligible to screen for the OLE study.

The data from this cohort is expected to be presented during the nomlabofusp program update in September 2025.

In March 2025, we announced that FDA stated in written correspondence associated with a meeting through the START pilot program that they are open to considering the use of FXN concentration as a reasonably likely surrogate endpoint (“RLSE”) and the acceptability of FXN’s use as an RLSE would ultimately be a matter of review of the data in a future marketing application.

FDA recommended focusing on assessments of skin FXN concentrations rather than buccal FXN concentrations due to more consistent sampling and less variability.

FDA acknowledged that data we recently submitted appear to support a relationship between increased FXN concentrations in skin cells and relevant tissues such as the heart, dorsal root ganglion and skeletal muscle.

also acknowledged that the nonclinical studies we submitted were performed at relevant human doses.

FDA also suggested that we consider exploring the relationship between increases in FXN in skin and changes in pharmacodynamic (PD) markers such as lipid profiles and/or clinical measures to provide additional support for the use of FXN as an RLSE.

We plan to continue discussions with FDA regarding the adequacy of the safety data set for a BLA submission seeking accelerated approval targeted for year-end 2025.

Additionally, we have obtained feedback from both FDA and EMA on the global Phase 3 study protocol and we are on track to initiate the study by mid-2025 with potential sites in the U.S., E.U., U.K, Canada, and Australia.

Financing Activities, Including Recent Material Financings

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("Zafgen") and, prior to the 2020 merger with Zafgen, capital contributions from Chondrial Holdings, LLC.

In September 2022, we sold 25,558,750 shares of common stock in an underwritten offering for net proceeds of $75.2 million, after issuance costs.

In February 2024, we sold 19,736,842 shares of common stock in an underwritten public offering, for net proceeds of approximately $161.6 million.

In February 2024, we completed an underwritten public offering in which we issued and sold 19,736,842 shares of our common stock at a public offering price of $8.74 per share.

We received net proceeds of approximately $161.8 million after deducting underwriting discounts, commissions and other offering expenses.

In May 2024, we entered into a Sales Agreement (the "ATM Agreement") with Guggenheim Securities, LLC in connection with the establishment of an “at-the-market” offering program providing for the sale of up to an aggregate of $100 million of shares of our common stock from time to time.

To date, we have made no sales under the ATM agreement.

Critical Accounting Policies and Significant Judgments and Estimates

Our consolidated financial statements are prepared in accordance with GAAP.

Our consolidated financial statements are prepared in accordance with Generally Accepted Accounting Principles ("GAAP").

The preparation of our consolidated financial statements and related disclosures requires us to make estimates and assumptions that affect the reported amount of assets, liabilities, costs and expenses, and related disclosures.

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We expect to increase our investment in research and development in order to advance nomlabofusp through additional clinical trials.

As a result, we expect that our research and development expenses will increase in the foreseeable future as we pursue clinical development of nomlabofusp and/or any other product candidates we develop.

As a result, we expect that our research and development expenses will continue to increase in the foreseeable future as we pursue clinical development of nomlabofusp and/or any other product candidates we develop.

Stock Compensation Expense

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Prior to May 28, 2020, we were a private company and lacked company-specific historical and implied volatility information for our common stock.

Prior to January 1, 2023, the Company estimated its expected common stock price volatility solely based on the historical volatility of publicly traded peer companies with comparable characteristics including enterprise value, risk profiles and position within the industry.

Prior to January 1, 2023, the Company estimated its expected common stock price volatility solely based on the historical volatility of publicly traded peer companies with comparable

characteristics including enterprise value, risk profiles and position within the industry.

Beginning on January 1, 2023, the Company began blending its historical data starting in June 2020 (following its merger with Zafgen in 2020) with its historical peer group.

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The following commentary is a discussion and analysis of our financial condition as of December 31, 2024 and results of operations and cash flows for the year ended December 31, 2024 compared to the year ended December 31, 2023 and should be read in conjunction with the consolidated financial statements and accompanying notes.

The discussion and analysis of our financial condition as of December 31, 2022, and results of operations and cash flows for the year ended December 31, 2022, compared to the year ended December 31, 2021, is included in item 7, Management’s Discussion and Analysis of Financial and Results of Operations of our Annual Report on Form 10-K for the year ended December 31, 2022.

Comparison of the years ended December 31, 2024 and 2023

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Loss from operations

Other income (expense), net

Other income, net

Research and development expenses

Research and development expenses for the twelve months ended December 31, 2023 increased $3.4 million compared to the twelve months ended December 31, 2022 due to continued and increased clinical development of nomlabofusp and related regulatory and bioanalysis.

The increase in research and development expenses compared to the prior year period was primarily driven by an increase of $1.9 million in personnel expense, an increase of $1.3 million in clinical expense, an increase of $1.1 million in regulatory and statistical consulting expenditures, an increase of $0.5 million in assay development costs, and an increase of $0.3 million in stock-based compensation expense associated with stock option grants made in 2022 and 2023, partially offset by a decrease of $2.0 million in drug manufacturing costs.

Research and development expenses for the twelve months ended December 31, 2024 increased $45.6 million compared to the twelve months ended December 31, 2023 due to continued and increased clinical development of

nomlabofusp and related regulatory and bioanalysis.

The increase in research and development expenses was primarily driven by an increase of $36.1 million in nomlabofusp manufacturing costs including production scale-up, costs and manufacturing costs related to producing drug product doses to be used in ongoing and planned clinical trials, an increase of $4.5 million in personnel expense due to increased clinical, regulatory, quality and manufacturing headcount, an increase of $1.3 million of professional fees related to regulatory, quality, medical, and clinical consulting costs, an increase of $1.2 million in clinical costs primarily associated with the OLE study which began dosing patients in the first quarter of 2024, an increase of $1.0 million in stock compensation costs associated with the incremental 2024 grants for existing and new employees, an increase of $0.9 million related to our participation in the Friedreich’s Ataxia Research Alliance's ("FARA's") TRACK-FA Neuroimaging Consortium conducting a natural history study designed to establish disease-specific neuroimaging biomarkers to track disease progression in the brain and spinal cord and provide a basis for utilizing these biomarkers in clinical trials, an increase of $0.3 million in internal lab costs related primarily to gene expression and lipid studies and an increase of $0.2 million in facility costs associated with the new lab space.

General and administrative expenses

General and administrative expenses for the twelve months ended December 31, 2024 increased $3.5 million compared to the twelve months ended December 31, 2023.

The increase in general and administrative expense was primarily driven by an increase of $0.7 million in stock-based compensation expense associated with stock option grants made in 2022 and 2023, an increase of $0.5 million in personnel expense, an increase of $0.5 million in operational costs primarily related to technology and an increase of $0.4 million in professional fees primarily related to legal, accounting and consulting services, partially offset by a decrease of $0.3 million in insurance expense.

Other income (expense), net

Other income (expense), net was $4.8 million of income in the twelve months ended December 31, 2023 compared to $1.2 million in the twelve months ended December 31, 2022.

The increase in general and administrative expenses was primarily driven by an increase of $1.5 million in professional fees primarily related to consulting costs related to commercial activity and other public company related expenses, an increase of $1.4 million in personnel expense due to increased headcount, an increase of $0.4 million of other expense related to computer software, information technology services and recruiting and an increase of $0.2 million in stock compensation costs associated with 2024 grants to existing and new employee grants.

Other income, net

Other income, net was $10.3 million of income in the twelve months ended December 31, 2024 compared to $4.8 million in the twelve months ended December 31, 2023.

The increase primarily relates to interest income on a higher investment base and higher investment yields on that base during the current period.

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Net cash provided by financing activities

Net decrease in cash, cash equivalents and restricted cash

Net increase (decrease) in cash, cash equivalents and restricted cash

Net cash used in operating activities

During the year ended December 31, 2023, net operating activities used $33.5 million of cash, resulting from our net loss of $36.9 million, adjusted for noncash expenses of $6.0 million, and changes in our operating assets and liabilities of resulting in a use of cash of $2.5 million.

During the year ended December 31, 2024, net operating activities used $70.8 million of cash, resulting from our net loss of $80.6 million, adjusted for noncash expenses of $3.7 million, and changes in our operating assets and liabilities provided cash of $6.2 million.

Our net loss was attributed to operating expenses of $90.9 million, offset by other income (net) of $10.3 million.

The change in operating assets and liabilities was primarily due to a decrease in accounts payable and accrued expenses and an increase in prepaid assets.

The change in operating assets and liabilities was primarily due to an increase in accounts payable, an increase in accrued expenses and offset by an increase in prepaid assets, all associated with increasing expenditures and development activity.

During the year ended December 31, 2023, operating activities used $33.5 million of cash, resulting from our net loss of $36.9 million, adjusted for noncash expenses of $6.0 million, and changes in our operating assets and liabilities resulting in a use of cash of $2.5 million.

Our loss was primarily attributed to operating expenses of $36.5 million.

The change in operating assets and liabilities was primarily due to an increase in accrued expenses due to the growth in our operating activities following the partial release of the clinical hold in late 2022.

Our net loss was attributed to operating expenses of $41.8

million, offset by other income (net) of $4.8 million.

The change in operating assets and liabilities was primarily due to a decrease in accounts payable and accrued expenses and an increase in prepaid assets.

Net cash provided by (used in) investing activities

During the year ended December 31, 2023, investing activities provided $33.4 million of net cash, resulting from $134.8 million of maturities and sales of marketable securities, which was offset by purchases of $101.2 million in marketable securities.

During the year ended December 31, 2024, investing activities used $85.4 million of net cash, resulting from purchases of $227.9 million in marketable securities, which was offset by $143.0 million of maturities and sales of marketable securities.

Net cash provided by financing activities

During the year ended December 31, 2024, financing activities provided $161.9 million of cash primarily from an offering of common stock.

During the year ended December 31, 2023, financing activities provided less than $0.1 million of cash from the exercise of stock options and warrants.

During the year ended December 31, 2022, financing activities provided $75.3 million of cash from sale of common stock in an underwritten public offering, net of issuance costs.

Operating Capital Requirements

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• expand our operational, financial, commercial and management systems and personnel, including personnel to support our clinical development and future commercialization efforts and our operations as a public company.

In February 2024, we sold 19,736,842 shares of common stock in an underwritten public offering, net of underwriting discounts and commissions and offering costs of approximately $161.6 million.

We anticipate that

these net proceeds, together with our current cash, cash equivalents and marketable securities will fund operations into 2026.

In February 2024, we completed an underwritten public offering in which we issued and sold 19,736,842 shares of our common stock and received net proceeds of approximately $161.8 million after deducting underwriting discounts, commissions and other offering expenses.

We anticipate that our current cash, cash equivalents and marketable securities will fund operations into the second quarter of 2026.

If we encounter unexpected delays in our clinical trials or if there are other unanticipated changes to our operating plan from our current assumptions that negatively impact our operations, we may reduce expenditures in order to further extend our existing cash resources.

Until we can generate substantial revenue, if ever, we expect to seek additional funding through a combination of public or private equity offerings, debt/royalty financings, collaborations, strategic alliances and licensing arrangements or other sources.

The incurrence of indebtedness would result in increased fixed payment obligations and we may be required to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, minimum cash balances, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business.

Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 7. Management’s Discussion and Analysis