Sonlicromanol (DB16333): A Comprehensive Clinical and Scientific Review

1. Sonlicromanol: An Overview

1.1. Introduction to Sonlicromanol (KH176)

Sonlicromanol, also identified by its development code KH176, is an orally administered small molecule drug candidate currently under investigation.[1] It is being developed as a potentially first-in-class, disease-modifying therapy for primary mitochondrial diseases (PMD), a group of rare and often devastating conditions with limited treatment options.[3] Sonlicromanol is considered one of the most clinically advanced drug candidates for PMD currently in development.[3]

The primary developmental focus for Sonlicromanol is on patients with PMD arising from the m.3243A>G mutation in the mitochondrial MT-TL1 gene. This specific genetic variation is the most common cause of PMD and is associated with a spectrum of clinical presentations, including Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), Maternally Inherited Diabetes and Deafness (MIDD), mixed phenotypes (MP), and Chronic Progressive External Ophthalmoplegia (CPEO).[1] This targeted approach towards a genetically defined subgroup, while addressing the most prevalent form of PMD, is strategically significant. Focusing on a specific mutation allows for a more homogeneous patient population in clinical trials, which can be particularly advantageous in the context of rare diseases where patient numbers are inherently small. Such precision may reduce variability in patient responses and enhance the statistical power of studies to detect a therapeutic effect, aligning with the principles of personalized medicine.

1.2. Chemical Properties and Formulation

Sonlicromanol is classified as a small molecule therapeutic. Its fundamental chemical and physical properties are summarized below.

Table 1: Sonlicromanol - Key Identifiers and Properties

Property	Detail	Reference(s)
Name (English)	Sonlicromanol	User Query
DrugBank ID	DB16333	User Query1
CAS Number	1541170-75-5 (free base)	User Query1
Type	Small Molecule	User Query1
IUPAC Name	(2S)-6-Hydroxy-2,5,7,8-tetramethyl-N--3,4-dihydrochromene-2-carboxamide	1
Other Names/Codes	KH-176, KH176	1
Molecular Formula	C19​H28​N2​O3​	1
Molar Mass	332.444 g⋅mol−1	1
Appearance	White solid	1
Solubility (Water)	0.224 mg/mL	1
Solubility (Other)	Soluble in DMSO	17
Log P	2.39	1
Formulation	Oral; powder for dissolution in water (KHENERFIN study)	1
Developer	Khondrion BV	10

Sonlicromanol hydrochloride (CAS 2162149-24-6) is also a known salt form.[17] The oral formulation, including a powder for dissolution used in the KHENERFIN study, underscores the aim for convenient administration suitable for chronic use.[19]

1.3. Developer: Khondrion BV

Sonlicromanol is under development by Khondrion BV, a clinical-stage biopharmaceutical company based in Nijmegen, The Netherlands. Khondrion specializes in the discovery and development of therapies targeting mitochondrial diseases.[2]

The advancement of Sonlicromanol through late-stage clinical trials has been supported by a combination of funding sources. Notably, Khondrion secured an Innovation Credit of up to €5 million from the Netherlands Enterprise Agency, a Dutch government body, which was matched by significant investment from the company's private backers to fund the initial wave of the pivotal Phase 3 clinical trial.[10] Additionally, the European Union's Horizon 2020 SME instrument program awarded a €2.3 million grant to support the execution of the Phase 2b clinical trial.[7] This diversified funding strategy, drawing from both public and private sectors, reflects a measure of external validation and confidence in Sonlicromanol's therapeutic potential and Khondrion's capacity to navigate the complex drug development landscape. Such financial backing is particularly crucial for companies focused on rare diseases, where the journey to market can be long and resource-intensive.

2. Mechanism of Action

2.1. Overview of Multi-Modal Action

Sonlicromanol is characterized by a unique, multi-modal mechanism of action, often described as a "triple mode of action." This encompasses reductive distress modulation, oxidative distress modulation (including the prevention of ferroptotic cell death), and anti-inflammatory properties.[4] The therapeutic effects are largely mediated by its active metabolite, KH176m (also referred to as KH183).[1] The drug is designed to target key underlying pathological processes in PMD by positively influencing crucial metabolic and inflammatory pathways that are dysregulated in these conditions.[12]

2.2. Redox Modulation and Antioxidant Properties

A cornerstone of Sonlicromanol's mechanism is its function as a potent intracellular redox-modulating agent.[17] Mitochondrial dysfunction, a hallmark of PMD, leads to increased production of reactive oxygen species (ROS), such as superoxide (O2⋅−​) and hydrogen peroxide (H2​O2​), resulting in cellular oxidative stress.[1] Sonlicromanol and its active metabolite KH176m directly scavenge these harmful ROS, thereby protecting cellular components from oxidative damage.[2]

Beyond direct scavenging, Sonlicromanol enhances the cell's own antioxidant defense systems. It interacts with and activates the thioredoxin system and its associated peroxiredoxin enzyme machinery.[14] This system plays a critical role in reducing oxidized proteins and detoxifying peroxides. Furthermore, Sonlicromanol has been shown to attenuate induced lipid peroxidation.[14] Lipid peroxidation is a destructive process that damages cell membranes and can lead to ferroptosis, an iron-dependent form of regulated cell death. By preventing lipid peroxidation, Sonlicromanol may protect against this cell death pathway.[4]

2.3. Anti-inflammatory Effects

Sonlicromanol exhibits significant anti-inflammatory activity, primarily through the selective inhibition of microsomal prostaglandin E synthase-1 (mPGES-1).[1] The enzyme mPGES-1 is a key player in the inflammatory cascade, responsible for the synthesis of prostaglandin E2​ (PGE2​), a potent pro-inflammatory mediator involved in pain, fever, and swelling. By inhibiting mPGES-1, Sonlicromanol reduces PGE2​ production, thereby dampening the inflammatory response that often accompanies mitochondrial disease.[4]

2.4. Impact on Mitochondrial Function and Cellular Energy

In addition to its redox-modulating and anti-inflammatory effects, Sonlicromanol aims to directly improve mitochondrial function and cellular energy metabolism.[2] One of the proposed mechanisms involves the activation of NADH:ubiquinone oxidoreductase, also known as Complex I, which is the first and largest enzyme complex in the mitochondrial electron transport chain (ETC).[2] By enhancing the efficiency of Complex I, Sonlicromanol may help to increase the production of adenosine triphosphate (ATP), the cell's primary energy currency.[2]

Furthermore, Sonlicromanol has been reported to activate the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.[2] Nrf2 is a master regulator of the cellular antioxidant response; its activation leads to the upregulation of a broad array of antioxidant and cytoprotective genes, further bolstering the cell's defenses against oxidative stress.

The multifaceted mechanisms of Sonlicromanol—encompassing direct ROS scavenging, enhancement of endogenous antioxidant systems like Nrf2 and thioredoxin/peroxiredoxin, inhibition of the pro-inflammatory enzyme mPGES-1, and potential modulation of mitochondrial Complex I—are not merely independent actions but are likely to be synergistic. In complex, multifactorial conditions such as PMD, where oxidative stress, inflammation, and energy deficiency are intricately linked, such an integrated therapeutic approach may offer advantages over strategies targeting only a single pathological pathway. For instance, reducing oxidative stress through ROS scavenging and Nrf2 activation could protect mitochondrial components like Complex I from further damage. Simultaneously, mitigating inflammation via mPGES-1 inhibition could create a more favorable cellular environment, potentially allowing damaged mitochondria to function more effectively or recover. This comprehensive "triple mode of action" [4] is a distinguishing feature of Sonlicromanol.

The described mechanisms, particularly the capacity to prevent lipid peroxidation and ferroptosis [4], lend credence to the assertion by its developer, Khondrion, that Sonlicromanol is a "disease-modifying" therapy.[3] If Sonlicromanol can effectively slow down or prevent the underlying cellular damage and death characteristic of PMD, it would indeed alter the natural course of the disease, moving beyond purely symptomatic relief. The validation of such disease-modifying effects in clinical trials is crucial and often relies on long-term assessment of functional outcomes and potentially, biomarkers indicative of reduced cellular damage and inflammation.

3. Preclinical Research and Rationale

3.1. In Vitro Studies

The therapeutic rationale for Sonlicromanol is supported by compelling preclinical data from various in vitro models. In studies utilizing patient-derived fibroblasts, which carried a range of genetic backgrounds associated with mitochondrial disease, Sonlicromanol demonstrated a protective effect against perturbations in cellular redox status.[24] This finding suggests its potential applicability across different genetic forms of mitochondrial dysfunction.

Furthermore, in a more complex model using induced pluripotent stem cell (iPSC)-derived human neurons from patients with the m.3243A>G mutation (a key target population for Sonlicromanol), the compound was shown to improve neuronal network function and positively modulate transcriptome changes.[14] These results are particularly relevant given the significant neurological involvement in many PMDs.

3.2. In Vivo Animal Model Findings

In vivo studies, primarily in the Ndufs4-/- mouse model which recapitulates features of Leigh disease (a severe PMD), have provided further evidence of Sonlicromanol's potential. Long-term administration of Sonlicromanol to these mice led to several beneficial outcomes:

• Neuroprotection: It preserved the microstructural coherence of the brain's external capsule, an area involved in cognitive processes, an effect attributed to the reduction of lipid peroxidation.[14] It also normalized the increased lipid peroxidation observed in the cerebral cortex of these animals.[24]
• Functional Improvements: Treated mice showed significant improvements in motor coordination and gait, as assessed by rotarod performance and gait analysis.[14]
• Retinal Protection: Sonlicromanol reduced the degeneration of retinal ganglion cells, suggesting a protective effect on ocular structures often affected in mitochondrial diseases.[14]
• Increased Lifespan: Treatment with Sonlicromanol was associated with an increased lifespan in this severe disease model.[23]
• Mechanism Confirmation: The drug was shown to counteract the biological consequences of Complex I dysfunction in these mice, partly by scavenging ROS and preventing lipid peroxidation.[23]

Importantly, preclinical pharmacokinetic studies have demonstrated that Sonlicromanol possesses high bioavailability and, crucially, the ability to cross the blood-brain barrier (BBB).[14]

The preclinical findings offer a strong foundation for the clinical development of Sonlicromanol. The demonstration of BBB penetration [14] is of paramount importance, as many PMDs, such as MELAS, involve significant central nervous system manifestations including cognitive impairment and stroke-like episodes. The positive effects observed on neurological parameters in animal models—such as preserved brain microstructure, reduced lipid peroxidation in cognition-related brain areas, and protection of retinal ganglion cells [14]—provide a direct translational rationale for investigating Sonlicromanol's efficacy on neurological symptoms in human patients.

Moreover, the breadth of positive effects observed in these preclinical models, spanning motor function, brain health, retinal protection, and even lifespan [14], reflects the multi-systemic nature of mitochondrial diseases themselves. PMDs typically affect multiple organ systems due to the ubiquitous role of mitochondria in cellular energy production. The diverse benefits seen with Sonlicromanol in animal studies suggest that it may offer widespread therapeutic effects rather than targeting only a single symptom or organ system. This multi-systemic relevance supports the inclusion of a variety of outcome measures in human clinical trials, covering domains such as motor function, cognition, mood, pain, and overall quality of life, all of which can be significantly impacted by PMD and, based on preclinical evidence, could potentially be improved by Sonlicromanol.

4. Clinical Development Program

4.1. Overview of Clinical Trials Landscape

Sonlicromanol has undergone an extensive clinical development program, progressing through several phases of investigation prior to the currently planned pivotal Phase 3 KHENERFIN study. This program includes initial Phase 1 studies in healthy volunteers, a Phase 2a study (KHENERGY), a significant Phase 2b study (KHENERGYZE) with its associated long-term open-label extension (KHENEREXT), and a paediatric Phase 2 study (KHENERGYC).[8] This systematic progression has been crucial in building the evidence base for Sonlicromanol.

Table 2: Overview of Key Clinical Trials for Sonlicromanol

Trial ID (NCT/EudraCT)	Study Name	Phase	Status (as per latest available info)	Patient Population (Brief)	Key Focus/Objective	Reference(s)
N/A	Phase 1 HV	1	Completed	Healthy Volunteers	Safety, Tolerability, PK	24
N/A (EudraCT referenced in publications)	KHENERGY	2a	Completed	Adult PMD (m.3243A>G)	Safety, Tolerability, PK, Exploratory Efficacy (mood, alertness)	14
NCT04165239 / EudraCT 2019-000599-40	KHENERGYZE	2b	Completed	Adult PMD (m.3243A>G)	Dose-selection, Efficacy, Safety, PK	14
Part of KHENERGYZE program	KHENEREXT	2b (OLE)	Completed	Adult PMD (m.3243A>G) from KHENERGYZE	Long-term Safety, Tolerability, Efficacy	4
NCT04846036 / EUCTR2020-003124-16-NL	KHENERGYC	2	Prematurely Ended (per EUCTR)	Paediatric PMD (motor symptoms)	PK, Safety, Efficacy (motor function)	20
NCT06451757	KHENERFIN	3	Active - Not Recruiting (as of Mar 2025)	Adult PMD (m.3243A>G, fatigue, myopathy)	Pivotal Efficacy (fatigue, muscle function), Safety	13

4.2. The KHENERGYZE Study (NCT04165239) and KHENEREXT Open-Label Extension

The KHENERGYZE study (NCT04165239; EudraCT: 2019-000599-40) was a cornerstone of Sonlicromanol's Phase 2b development. It was designed as an international, multi-center, randomized, double-blind, placebo-controlled, three-way cross-over study.[7] The study enrolled adult patients with genetically confirmed m.3243A>G mutation and primary mitochondrial disease, encompassing phenotypes such as classic MELAS, MIDD, and mixed presentations.[4] A total of 27 patients were randomized, with 24 completing all treatment periods.[14] Participants were randomized on a 1:1:1 basis to receive one of three treatments: Sonlicromanol 50 mg twice daily (BID), Sonlicromanol 100 mg BID, or placebo BID. Each treatment period lasted 28 days, separated by a wash-out period of at least two weeks.[7] The primary objectives of KHENERGYZE were to evaluate the safety and efficacy of Sonlicromanol for dose-selection purposes, and to further characterize its pharmacokinetics.[14] The study included outcome measures previously assessed in the Phase 2a study, alongside new endpoints, notably cognition-related assessments developed by Cogstate, and measures in other clinical domains not previously studied.[3]

Following completion of the KHENERGYZE study, eligible patients were offered participation in KHENEREXT, a 12-month (52-week) open-label extension (OLE) study. In KHENEREXT, all participants received Sonlicromanol 100 mg BID.[4] Fifteen patients entered the KHENEREXT study, with 12 included in the primary analysis set for the extension phase.[14] Some patients continued treatment for up to 78 weeks under this program.[13] The main goals of KHENEREXT were to assess the long-term tolerability, safety, and efficacy of Sonlicromanol.[4]

4.3. The KHENERGYC Paediatric Study (NCT04846036 / EUCTR2020-003124-16-NL)

The KHENERGYC study was designed to evaluate Sonlicromanol in a paediatric population. It was planned as a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study targeting 24 children, from birth up to and including 17 years of age, with a genetically confirmed PMD known to affect oxidative phosphorylation and who were suffering from motor symptoms.[8] The trial was intended to be conducted in two phases: an initial adaptive pharmacokinetic (PK) study involving four days of treatment, followed by a 6-month phase dedicated to evaluating efficacy and safety.[9]

The primary efficacy endpoint for KHENERGYC was the change in motor symptom severity, as measured by the Gross Motor Function Measure-88 (GMFM-88), over the 6-month treatment period.[8] Secondary endpoints were comprehensive, including assessments of fine manual motor skills (e.g., Nine Hole Peg Test), physical performance, spasticity, dystonia, ataxia, disability, quality of life, caregiver burden, overall safety, pharmacokinetics, and various biomarkers.[8]

The KHENERGYC study was registered on ClinicalTrials.gov (NCT04846036) in April 2021 and on the EU Clinical Trials Register (EUCTR2020-003124-16-NL) in October 2020.[9] The first patients were reported to have been dosed in April 2021.[8] However, according to the EU Clinical Trials Register, the trial status for KHENERGYC is listed as "Prematurely Ended".[25] The specific reasons for this premature termination are not detailed in the available documentation.[25] This premature end has significant implications for the availability of paediatric-specific data for Sonlicromanol.

4.4. The KHENERFIN Pivotal Phase 3 Study (NCT06451757)

Building on the findings from the earlier phases, Khondrion is advancing Sonlicromanol into a pivotal Phase 3 trial named KHENERFIN (NCT06451757). This study is designed as a randomized, double-blind, placebo-controlled, parallel-group, multi-center trial.[12] It aims to enroll approximately 150 adult patients (aged ≥18 years) who have a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G variant, and who suffer from chronic fatigue and mitochondrial myopathy.[13] Participants will receive either Sonlicromanol, administered as a powder dissolved in water, or placebo, twice daily for a duration of 52 weeks.[13]

The primary efficacy endpoints for the KHENERFIN study are:

1. Change from Baseline to Week 52 in the Fatigue domain of the Neuro-QoL Short Form v1.0 (Neuro-QoL SFv1-F).[13]
2. Change from Baseline to Week 52 in the performance on the Five Times Sit-to-Stand Test (5XSST).[13]

The selection of these primary endpoints reflects a patient-centric approach, as chronic fatigue and muscle weakness are among the most burdensome symptoms reported by individuals with PMD.[13] Furthermore, these domains showed encouraging, statistically significant improvements in the 52-week open-label extension phase of the Phase 2b program [13], providing a strong rationale for their use in the pivotal trial. This strategic choice, focusing on outcomes that are both clinically meaningful to patients and supported by prior positive signals, enhances the potential for the Phase 3 trial to demonstrate clear therapeutic benefits.

Regulatory clearance for the KHENERFIN trial has been obtained, with the U.S. Food and Drug Administration (FDA) clearing the Investigational New Drug (IND) application in November 2024.[12] The trial is anticipated to be initiated in the second half of 2025.[10] As of March 2025, the status of NCT06451757 was listed as Active - Not Recruiting.[19]

4.5. Supporting Studies

The later-phase trials were built upon foundational earlier studies:

• Phase 1 (Healthy Volunteers): This initial human study established that Sonlicromanol was well tolerated in single doses up to 800 mg and multiple doses up to 400 mg. The pharmacokinetic profile observed was supportive of a twice-daily dosing regimen. However, it was noted that at higher blood concentrations (exceeding 1000 ng/ml), changes in cardiac electrophysiology, specifically QTc interval prolongation and T-wave morphology alterations, were observed.[24]
• Phase 2a (KHENERGY Study): This randomized, placebo-controlled study involved 18 adult patients with the m.3243A>G mutation. Treatment with Sonlicromanol 100 mg BID was found to be well tolerated and appeared safe. While no significant improvements were detected in gait parameters, the study did observe positive effects on mood-related outcomes and alertness.[3] This study provided consistent pharmacokinetic, safety, and tolerability data, forming the basis for subsequent, larger trials.[8]

The clinical development of Sonlicromanol demonstrates a logical and iterative pathway. Starting with Phase 1 studies in healthy volunteers to assess initial safety and pharmacokinetics, the program progressed to a Phase 2a study (KHENERGY) in a small patient cohort to gain early insights into safety, tolerability, and potential efficacy signals in the target population. This was followed by a more robust Phase 2b study (KHENERGYZE) designed for dose selection and a broader evaluation of efficacy across multiple domains, utilizing a cross-over design. The subsequent long-term open-label extension (KHENEREXT) was critical for gathering data on the durability of effect and long-term safety. Each of these phases systematically built upon the knowledge gained from the preceding one, informing the design and objectives of the next. This methodical approach to evidence generation and de-risking is standard in drug development and is generally viewed favorably by regulatory authorities, ultimately leading to the design of the pivotal Phase 3 KHENERFIN trial.

However, a significant challenge in the overall development program is the "Prematurely Ended" status of the KHENERGYC paediatric trial.[25] While Khondrion has an EMA-agreed Paediatric Investigation Plan (PIP) [5], indicating a commitment to developing Sonlicromanol for children, the interruption of the KHENERGYC study means that crucial paediatric-specific pharmacokinetic, safety, and efficacy data are currently lacking or significantly delayed from this specific endeavor. This creates an undeniable data gap and uncertainty regarding the path forward for making Sonlicromanol available to this vulnerable population. The reasons for the trial's termination, which are not provided in the available documents, would be critical for understanding and planning future paediatric development efforts.

5. Clinical Efficacy Findings

5.1. Efficacy in Adult Patients with m.3243A>G Mutation (KHENERGYZE/KHENEREXT)

The Phase 2b program, comprising the KHENERGYZE randomized controlled trial (RCT) and its open-label extension (KHENEREXT), has yielded promising efficacy signals for Sonlicromanol in adult patients with the m.3243A>G mutation. It was generally observed that Sonlicromanol was efficacious in patients who were affected at baseline, with improvements noted across a variety of clinically relevant domains. Notably, long-term treatment during the KHENEREXT study appeared to result in more pronounced changes from baseline compared to the shorter RCT periods.[12] Overall, the Phase 2b program was reported to show strong patient benefits across multiple outcome measures.[12]

Table 3: Summary of Key Efficacy Outcomes from KHENERGYZE/KHENEREXT Studies (Adults, m.3243A>G)

Endpoint	Study Phase	Sonlicromanol Dose	Result	P-value	Reference(s)
Neuro-QoL SF-Fatigue	KHENEREXT (OLE)	100 mg BID	Statistically significant improvement	p=0.0036	15
Neuro-QoL SF-Fatigue	52-week OLE	100 mg BID	Clinically meaningful & statistically significant improvement	p=0.004	13
Five Times Sit-To-Stand Test (5XSST)	KHENEREXT (OLE) / Phase 2b	100 mg BID	Most patients showed improvement	N/A (qualitative)	14
Five Times Sit-To-Stand Test (5XSST)	52-week OLE	100 mg BID	Clinically meaningful & statistically significant improvement	p=0.0161	13
Beck Depression Inventory (BDI) Total	KHENERGYZE (RCT)	At least one dose (50 or 100 mg BID)	Signal of improvement vs. placebo	p=0.0143	14
Cognitive Failure Questionnaire (CFQ)	KHENERGYZE (RCT)	At least one dose (50 or 100 mg BID)	Signal of improvement vs. placebo	p=0.0113	14
HADS - Depression Subscale	KHENERGYZE (RCT)	At least one dose (50 or 100 mg BID)	Signal of improvement vs. placebo	p=0.0256	14
Test of Attentional Performance (TAP) with alarm	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0102	14
Test of Attentional Performance (TAP) without alarm	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0047	14
BDI - Somatic Subscale	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0261	14
BDI - Total Score	KHENEREXT (OLE)	100 mg BID	Clinically meaningful improvement (trend)	p=0.0563	14
SF12 - Physical Component	KHENEREXT (OLE)	100 mg BID	Clinically meaningful improvement	Not specified	14
Mini-Balance Evaluation Systems Test (mini-BESTest)	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0009	14
McGill Pain Questionnaire	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0105	14
EuroQol EQ-5D-5L - Visual Analog Scale	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0213	14
EuroQol EQ-5D-5L - Index	KHENEREXT (OLE)	100 mg BID	Statistically and/or clinically meaningful improvement	p=0.0173	14
Newcastle Mitochondrial Disease Adult Scale (NMDAS)	Phase 2b program	100 mg BID	Markedly improved patient scores	Not specified	16

Key efficacy findings include:

• Fatigue and Muscle Function: Statistically significant improvements were observed in the Neuro-Quality of Life Short Form-Fatigue Scale (Neuro-QoL SF-Fatigue) during the KHENEREXT study (p=0.0036) [15], with this outcome also reported as clinically meaningful and statistically significant (p=0.004) in the 52-week OLE data that informed the Phase 3 design.[13] Similarly, most patients demonstrated improvement in the Five Times Sit-To-Stand Test (5XSST), a measure of lower limb muscle function and endurance.[12] The 5XSST also showed clinically meaningful and statistically significant improvement (p=0.0161) in the 52-week OLE.[13]
• Mood and Cognition: In the KHENERGYZE RCT, signals of improvement compared to placebo were noted for at least one Sonlicromanol dose on the Beck Depression Inventory (BDI, p=0.0143), the Cognitive Failure Questionnaire (CFQ, p=0.0113), and the depression subscale of the Hospital Anxiety and Depression Scale (HADS, p=0.0256).[12] The KHENEREXT OLE showed statistically and/or clinically meaningful improvements in the Test of Attentional Performance (TAP) both with alarm (p=0.0102) and without alarm (p=0.0047), as well as on the BDI somatic subscale (p=0.0261) and a trend for BDI total score (p=0.0563).[12] Earlier, the Phase 2a KHENERGY study had also reported positive effects on mood-related outcomes and alertness.[3] However, one report concerning the Phase 2b trial indicated that Sonlicromanol did not achieve significant improvement in cognitive function as measured by a specific identification task, although an improvement trend versus placebo was observed when scores were adjusted for baseline severity.[16] This suggests that the cognitive benefits of Sonlicromanol might be domain-specific or require more sensitive or prolonged assessment. While general alertness and attention appear to improve, effects on other cognitive domains like executive function or memory may be less clear-cut from the current data.
• Quality of Life and Pain: The KHENEREXT study demonstrated improvements in the physical component of the SF12 quality of life measure, the mini-Balance Evaluation Systems test (mini-BESTest, p=0.0009), the McGill Pain Questionnaire (p=0.0105), and both the Visual Analog Scale (p=0.0213) and Index score (p=0.0173) of the EuroQol EQ-5D-5L.[12]
• Global Health: The Phase 2b program reportedly led to markedly improved patient scores on the Newcastle Mitochondrial Disease Adult Scale (NMDAS), a tool used to assess the overall severity of mitochondrial disease in adults.[16]

The pattern of efficacy emerging from the adult Phase 2b program, particularly the KHENEREXT OLE, is encouraging. Consistent benefits in patient-reported outcomes such as fatigue, mood, and quality of life, coupled with objective improvements in muscle function (5XSST) and balance, point towards a broad therapeutic impact. The statistical significance achieved on key endpoints like the Neuro-QoL Fatigue and 5XSST in the OLE is particularly noteworthy and provides a solid foundation for the ongoing Phase 3 trial.

5.2. Efficacy in Paediatric Population (KHENERGYC)

As previously noted, the KHENERGYC paediatric study (NCT04846036 / EUCTR2020-003124-16-NL) was prematurely ended.[25] Consequently, no efficacy results from this trial are reported in the available source materials. The primary efficacy endpoint was intended to be the Gross Motor Function Measure-88 (GMFM-88).[8] This premature termination results in a significant data gap regarding Sonlicromanol's efficacy in children with PMD.

6. Safety and Tolerability Profile

6.1. Across Clinical Trials

Sonlicromanol has demonstrated a generally favorable safety and tolerability profile across its clinical development program in both adult PMD patients and healthy volunteers.[12]

• In Phase 1 studies involving healthy volunteers, Sonlicromanol was well tolerated in single oral doses up to 800 mg and in multiple doses up to 400 mg.[24]
• The Phase 2a KHENERGY study, which administered Sonlicromanol 100 mg BID to adult patients with the m.3243A>G mutation, also found the drug to be well tolerated and to appear safe.[24]
• The subsequent Phase 2b KHENERGYZE study and its open-label extension, KHENEREXT, further reinforced this safety profile. Patients in these studies, receiving Sonlicromanol for up to one year (and some even longer), reported good tolerability and a favorable overall safety profile.[12] This positive long-term safety has been further corroborated by experiences in named patient programs, where some individuals have received Sonlicromanol for over two and a half years, confirming its favorable safety with extended use.[10]

This consistent theme of good tolerability and a favorable safety profile observed across multiple trials and with prolonged exposure is a significant strength for Sonlicromanol, particularly as it is intended for chronic administration in a patient population that is often medically fragile.

6.2. Adverse Event Profile

While general statements affirm good tolerability, specific detailed adverse event profiles from the PMD patient trials (KHENERGY, KHENERGYZE/KHENEREXT) are not extensively provided in the available documents. The focus is more on the overall positive safety assessment.

However, an important observation from the Phase 1 study in healthy volunteers relates to potential cardiac effects at high exposures. At blood concentrations of Sonlicromanol exceeding 1000 ng/ml, changes in cardiac electrophysiology were noted, including prolongation of the QTc interval and alterations in T-wave morphology.[24] This finding suggests a potential for dose-limiting cardiotoxicity if such high concentrations are reached. While the therapeutic doses used in patient trials appear to be well-tolerated without similar issues being highlighted, this observation underscores the importance of careful dose selection to maintain a sufficient safety margin. It also implies that cardiac safety monitoring may be a relevant consideration, especially in patients with pre-existing cardiac conditions or those on concomitant medications that could affect Sonlicromanol's metabolism or have additive cardiac effects. The long-term safety data from patient trials at therapeutic doses suggest that this threshold for cardiac effects is not typically reached with the current dosing regimens used in PMD patients.

6.3. Long-term Safety Data

The KHENEREXT study, which provided a 52-week open-label extension (with some patients continuing for up to 78 weeks), along with ongoing named patient programs where individuals have received Sonlicromanol for more than two and a half years, collectively indicate a favorable safety profile with long-term administration.[10] This long-term data is crucial for a drug intended to treat a chronic, progressive condition like PMD.

Table 4: Summary of Sonlicromanol Safety Profile

Study Phase/Name	Population	Key Safety/Tolerability Observations	Specific AEs of Note	Long-term Safety Notes	Reference(s)
Phase 1	Healthy Volunteers	Well tolerated up to single 800 mg / multiple 400 mg doses.	QTc prolongation & T-wave changes at blood concentrations >1000 ng/ml.	N/A	24
Phase 2a (KHENERGY)	Adult PMD (m.3243A>G)	100 mg BID well tolerated and appeared safe.	Not specified beyond general tolerability.	N/A	24
Phase 2b (KHENERGYZE/ KHENEREXT)	Adult PMD (m.3243A>G)	Good tolerability, favourable safety profile reported by all patients for up to 1 year.	Not specified beyond general tolerability.	Favourable safety profile confirmed with treatment up to 78 weeks.	13
Named Patient Program	Adult PMD (m.3243A>G)	N/A (inferred good tolerability)	N/A	Favourable safety profile confirmed with >2.5 years of treatment.	10

7. Pharmacokinetics

7.1. Absorption, Distribution, Metabolism, Excretion (ADME)

Sonlicromanol is designed for oral administration and has demonstrated oral bioavailability in preclinical and clinical studies.[7] It is generally characterized by excellent pharmacokinetic properties.[14] Following oral administration in healthy volunteers during Phase 1 studies, Sonlicromanol exhibited a rapid absorption profile, with the time to reach maximum plasma concentration (Tmax) being approximately 2 hours.[9]

A critical pharmacokinetic feature of Sonlicromanol is its ability to cross the blood-brain barrier (BBB).[12] This is highly relevant for its intended use in PMDs, many of which have significant neurological manifestations. Sonlicromanol is metabolized to an active metabolite, KH176m (also identified as KH183), which contributes to its therapeutic effects.[1]

Pharmacokinetic data from the Phase 2b KHENERGYZE study were found to be comparable to those observed in the earlier Phase 2a KHENERGY study, indicating consistency in its pharmacokinetic behavior in the target patient population.[12] The overall pharmacokinetic profile of Sonlicromanol supports a twice-daily dosing regimen, which was used in the clinical trials.[24]

The prematurely ended KHENERGYC paediatric study had among its objectives the confirmation of a pediatric-equivalent dose (PED) and the investigation of multiple-dose pharmacokinetics of both Sonlicromanol and its active metabolite KH183 after 4 days and 6 months of treatment in children.[9] Due to the study's early termination, these paediatric pharmacokinetic data remain undetermined from this trial.

The combination of oral bioavailability, relatively rapid absorption, ability to penetrate the CNS, and a pharmacokinetic profile amenable to twice-daily dosing renders Sonlicromanol well-suited for the chronic management of conditions like PMD, particularly those with neurological involvement. The capacity to cross the BBB is a key advantage for addressing the central nervous system symptoms that are prevalent in many mitochondrial disorders.

However, mirroring the situation with efficacy and safety data, the premature termination of the KHENERGYC study [25] signifies a critical gap in paediatric-specific pharmacokinetic information. The determination of appropriate dosing regimens for children, including the establishment of a pediatric-equivalent dose (PED) which was a specific aim of KHENERGYC [9], cannot be made based on this trial. This lack of data presents a hurdle for any future paediatric development and will need to be addressed through new dedicated studies if Sonlicromanol is to be considered for use in children.

8. Regulatory Status and Designations

Sonlicromanol has received significant attention from regulatory agencies in both the United States and Europe, reflecting its potential to address unmet medical needs in rare mitochondrial diseases.

8.1. Food and Drug Administration (FDA, USA)

• Investigational New Drug (IND) Clearance: In November 2024, the FDA cleared Khondrion's IND application for Sonlicromanol. This clearance permits the initiation of the pivotal Phase 3 KHENERFIN trial in adult patients with PMD due to the m.3243A>G mutation.[5]
• Orphan Drug Designation (ODD): Sonlicromanol has been granted ODD by the FDA for the treatment of all inherited mitochondrial respiratory chain disorders (FDA ORPHAN DRUG 450714).[3]
• Rare Pediatric Disease (RPD) Designation: The FDA has also granted RPD designation to Sonlicromanol for the treatment of MELAS.[3]

8.2. European Medicines Agency (EMA, Europe)

• Paediatric Investigation Plan (PIP) Acceptance: The EMA has accepted Khondrion's PIP for the development of Sonlicromanol in children, covering the age range from birth to less than 18 years, with genetically confirmed mitochondrial disease.[5] An approved PIP is a regulatory prerequisite for filing a Marketing Authorisation Application (MAA) for any new medicinal product in the European Union that will be used in children.
• Orphan Drug Designations (ODD): The European Commission has granted ODD for Sonlicromanol for the following conditions:
• Leigh syndrome (Designation EU/3/14/1336, granted in October 2014).[3]
• MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) (Designation EU/3/15/1543, granted in August 2015).[3]
• Maternally Inherited Diabetes and Deafness (MIDD) (Designation granted in July 2019).[3]

Table 5: Sonlicromanol - Regulatory Designations and Milestones

Regulatory Agency	Type of Designation/Milestone	Specific Indication (if applicable)	Date Granted/Achieved (if available)	Designation Code (if available)	Reference(s)
FDA (USA)	IND Clearance for Phase 3	Adult PMD (m.3243A>G)	Nov 2024	N/A	13
FDA (USA)	Orphan Drug Designation (ODD)	All inherited mitochondrial respiratory chain disorders	Not specified	450714	13
FDA (USA)	Rare Pediatric Disease (RPD) Designation	MELAS	Not specified	N/A	3
EMA (Europe)	Paediatric Investigation Plan (PIP) Acceptance	Children (birth to <18 years) with genetically confirmed mitochondrial disease	Jan 2021 (announced)	N/A	5
EMA (Europe)	Orphan Drug Designation (ODD)	Leigh syndrome	Oct 2014	EU/3/14/1336	6
EMA (Europe)	Orphan Drug Designation (ODD)	MELAS	Aug 2015	EU/3/15/1543	6
EMA (Europe)	Orphan Drug Designation (ODD)	Maternally Inherited Diabetes and Deafness (MIDD)	July 2019	Not specified in snippets, but distinct from MELAS/Leigh ODDs	6

The array of Orphan Drug Designations from both the FDA and EMA, coupled with the RPD designation in the US and PIP acceptance in Europe, signifies robust regulatory acknowledgment of Sonlicromanol's potential to address substantial unmet medical needs in the rare disease space of mitochondrial disorders. These designations are not merely symbolic; they confer important incentives such as market exclusivity periods post-approval, reduced regulatory fees, and protocol assistance, all of which are vital for facilitating and de-risking the development of therapies for small patient populations. The FDA's clearance of the IND for the Phase 3 trial and the EMA's acceptance of the PIP further underscore the positive engagement with regulatory bodies and the perceived medical necessity for such a therapeutic agent.

While the EMA's acceptance of the PIP establishes a clear regulatory framework and signals Khondrion's intent for paediatric development in Europe, the premature termination of the KHENERGYC trial [25] introduces a practical challenge. There is now a gap in the clinical data required to fulfill the obligations of the PIP and to support a future paediatric indication. This situation highlights a potential future hurdle in aligning the execution of the development program with the agreed-upon regulatory plans for the paediatric population, necessitating a revised strategy to generate the required data.

9. Other Potential Therapeutic Applications

Beyond its primary focus on primary mitochondrial diseases, the mechanisms of action of Sonlicromanol suggest potential utility in other conditions.

9.1. Oncology

Preclinical investigations have indicated that Sonlicromanol may possess anti-cancer properties, particularly in the context of cancers that overexpress microsomal prostaglandin E synthase-1 (mPGES-1), such as certain types of prostate cancer.[1] The active metabolite of Sonlicromanol has been shown to inhibit the growth of cancer spheroids in preclinical models of prostate cancer, an effect attributed to the targeting of mPGES-1.[8] However, this is an early-stage observation, and further research is explicitly stated as necessary to determine the actual applicability of Sonlicromanol in the field of oncology.[1]

9.2. Post-COVID Symptoms

There has been an announcement by Khondrion and Amsterdam UMC regarding an initiative to commence a Phase 2 clinical trial to evaluate Sonlicromanol in the context of combating long-term post-COVID symptoms.[4] The rationale likely stems from the known anti-inflammatory and redox-modulating properties of Sonlicromanol, which could be relevant to the underlying pathophysiology of some post-COVID conditions. No further details regarding the status, design, or results of this exploratory trial are available in the provided documents.

The exploration of Sonlicromanol in these diverse areas—oncology and post-COVID syndrome—illustrates a strategy of mechanism-driven indication expansion. By leveraging the drug's established modes of action, such as mPGES-1 inhibition and its broader anti-inflammatory and redox-modulating capabilities, Khondrion is investigating its potential in conditions where these pathways are pathologically relevant. If successful, these exploratory avenues could significantly broaden Sonlicromanol's therapeutic applicability beyond its core focus on PMD. However, it is important to recognize that these investigations are likely at a much earlier stage of development compared to the advanced PMD program.

10. Discussion and Future Outlook

10.1. Summary of Sonlicromanol's Potential

Sonlicromanol (KH176) has emerged as a promising, late-stage, orally administered small molecule candidate for the treatment of primary mitochondrial diseases (PMD), with a particular focus on individuals carrying the m.3243A>G mutation. Its therapeutic potential is rooted in a multi-modal mechanism of action that addresses key pathological features of PMD, including oxidative stress, inflammation, and mitochondrial energy dysfunction. Clinical data from the Phase 2b program in adults (KHENERGYZE and its extension KHENEREXT) have provided encouraging signals of efficacy, particularly in improving fatigue, muscle function, mood, and quality of life, alongside a consistently favorable safety and tolerability profile, even with long-term administration.

10.2. Strengths and Limitations of Current Data

The development program for Sonlicromanol possesses several notable strengths:

• Consistent Safety and Tolerability: Data from Phase 1, 2a, 2b, and long-term extension/named patient programs consistently indicate that Sonlicromanol is well-tolerated at therapeutic doses in PMD patients.
• Positive Efficacy Signals in Patient-Relevant Endpoints: The Phase 2b OLE (KHENEREXT) demonstrated statistically significant improvements in endpoints directly relevant to patient burden, such as the Neuro-QoL Fatigue and the 5XSST, forming a strong basis for Phase 3.
• Strong Preclinical Rationale: Extensive preclinical work has elucidated its mechanisms and demonstrated efficacy in relevant animal models, including evidence of BBB penetration.
• Clear Regulatory Pathway and Support: Multiple Orphan Drug Designations from both FDA and EMA, RPD designation, FDA IND clearance for Phase 3, and EMA PIP acceptance collectively signal strong regulatory support.

However, certain limitations and considerations regarding the current data exist:

• Phase 2b RCT Design: The cross-over design of the KHENERGYZE RCT, while efficient for dose exploration, can have complexities in interpretation due to potential carry-over effects for some endpoints, although the subsequent OLE data provide more straightforward long-term insights.
• Nuanced Cognitive Effects: While some positive signals on attention and alertness have been observed, the impact on broader cognitive functions requires further clarification, as one specific cognitive task in Phase 2b did not show significant improvement without baseline adjustment.
• Significant Paediatric Data Gap: The premature termination of the KHENERGYC paediatric trial means there is a current lack of clinical efficacy, safety, and pharmacokinetic data for Sonlicromanol in children from this study.
• Pivotal Phase 3 Data Pending: The ultimate confirmation of Sonlicromanol's efficacy and safety for regulatory approval hinges on the results of the ongoing KHENERFIN Phase 3 trial.

10.3. Unmet Needs and Sonlicromanol's Positioning

Primary mitochondrial diseases represent a group of severe, progressive conditions with a profound impact on patients' lives and, with the exception of Leber hereditary optic neuropathy (LHON) for which some treatments exist, a near-complete lack of approved disease-modifying therapies.[5] This constitutes a significant unmet medical need. If Sonlicromanol successfully navigates Phase 3 trials and gains regulatory approval, it could become a first-in-class pharmacological treatment for a substantial subgroup of PMD patients (those with the m.3243A>G mutation), offering hope for not only symptomatic improvement but also potential modification of the disease course.

10.4. Future Research and Development Considerations

The path forward for Sonlicromanol involves several key considerations:

• KHENERFIN Phase 3 Trial: The successful completion and positive outcome of this pivotal trial are paramount for regulatory submission and potential approval for adult PMD patients with the m.3243A>G mutation.
• Addressing the Paediatric Data Gap: A clear strategy, likely involving a new or redesigned clinical trial, will be necessary to generate the required safety, efficacy, and pharmacokinetic data in children to fulfill PIP obligations and explore a paediatric indication. Understanding the reasons behind KHENERGYC's premature termination will be crucial in planning these next steps.
• Further Cognitive Investigation: Given the nuanced findings on cognition, future studies might benefit from employing more specific and sensitive neuropsychological assessment batteries, potentially as secondary or exploratory endpoints, if cognitive improvement remains a therapeutic goal.
• Biomarker Development: Continued exploration for biomarkers that correlate with clinical response to Sonlicromanol, reflect target engagement, or indicate modulation of underlying disease pathology could aid in patient selection, treatment monitoring, and further elucidating its disease-modifying effects.
• Long-Term Safety Monitoring: Ongoing and future long-term safety surveillance will remain important.
• Alternative Indications: The development of Sonlicromanol for other potential indications, such as oncology or post-COVID syndrome, will necessitate dedicated preclinical research and structured clinical trial programs distinct from the PMD pathway.

10.5. Potential Impact on Treatment Landscape for Mitochondrial Diseases

Sonlicromanol stands at a critical juncture. The successful outcome of the KHENERFIN Phase 3 trial would be a landmark achievement, potentially providing the first approved, broadly impactful, disease-modifying oral therapy for a common form of PMD. This would fundamentally alter the treatment landscape for these devastating disorders.

The journey of Sonlicromanol also highlights the complexities of drug development for rare diseases. Its multi-modal mechanism targeting fundamental pathological processes like oxidative stress and inflammation, if validated, could offer a paradigm for treating other complex, multifactorial conditions.

While the development program for adult patients with the m.3243A>G mutation is advancing robustly towards pivotal assessment, the path for paediatric use requires careful re-evaluation due to the interruption of the KHENERGYC study. This creates a notable question mark despite clear regulatory intent (PIP, RPD designation) to serve this population.

Finally, although the immediate focus is on the m.3243A>G mutation, Sonlicromanol's broad mechanism of action and its comprehensive Orphan Drug Designation in the US for "all inherited mitochondrial respiratory chain disorders" [3] suggest a potential for its utility to extend to a wider spectrum of PMD patients in the longer term. Khondrion's stated objective to make Sonlicromanol available to the "broader PMD patient community" [13] supports this outlook. Initial approval for the m.3243A>G population could pave the way for subsequent investigations into its efficacy in other genetic forms of mitochondrial disease, potentially significantly expanding its impact if such studies yield positive results.

Works cited

1. Sonlicromanol - Wikipedia, accessed May 19, 2025, https://en.wikipedia.org/wiki/Sonlicromanol
2. What is Sonlicromanol used for? - Patsnap Synapse, accessed May 19, 2025, https://synapse.patsnap.com/article/what-is-sonlicromanol-used-for
3. Khondrion shares progress of sonlicromanol ... - Khondrion, accessed May 19, 2025, https://www.khondrion.com/news/khondrion-shares-progress-of-sonlicromanol-development-programme-at-mitochondrial-medicine-2020-virtual-conference
4. Khondrion to participate in the 16th Annual Dutch Inborn Error Meeting and the United Mitochondrial Disease Foundation (UMDF) Bench to Bedside seminar, accessed May 19, 2025, https://www.khondrion.com/news/khondrion-to-participate-in-the-16th-annual-dutch-inborn-error-meeting-and-the-united-mitochondrial-disease-foundation-umdf-bench-to-bedside-seminar
5. Khondrion receives EMA agreement on its Paediatric Investigation Plan for sonlicromanol, accessed May 19, 2025, https://www.globenewswire.com/news-release/2021/01/18/2159727/0/en/Khondrion-receives-EMA-agreement-on-its-Paediatric-Investigation-Plan-for-sonlicromanol.html
6. Khondrion granted Orphan Drug Designation for KH176 for the treatment of MIDD from European Commission, accessed May 19, 2025, https://www.khondrion.com/news/khondrion-granted-orphan-drug-designation-for-kh176-for-the-treatment-of-midd-from-european-commission
7. KHON2bTREAT, accessed May 19, 2025, https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5c99dd71d&appId=PPGMS
8. Our science - Khondrion, accessed May 19, 2025, https://www.khondrion.com/our-science
9. A randomised placebo-controlled, double-blind phase II study to explore the safety, efficacy, and pharmacokinetics of sonlicromanol in children with genetically confirmed mitochondrial disease and motor symptoms (“KHENERGYC”) - PubMed Central, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9044835/
10. Khondrion Secures up to €5 Million Innovation Credit from Dutch ..., accessed May 19, 2025, https://www.morningstar.com/news/pr-newswire/20250506ln76691/khondrion-secures-up-to-5-million-innovation-credit-from-dutch-government-plus-additional-funding-from-current-investors-to-advance-phase-3-clinical-trial-in-m3243ag-primary-mitochondrial-disease
11. Khondrion receives EMA agreement on its Paediatric Investigation Plan for sonlicromanol, accessed May 19, 2025, https://www.khondrion.com/news/khondrion-receives-ema-agreement-on-its-paediatric-investigation-plan-for-sonlicromanol
12. Sonlicromanol - Synapse - Global Drug Intelligence Database, accessed May 19, 2025, https://synapse.patsnap.com/drug/8bcac4cb8597423d97c1855144755072
13. Khondrion receives FDA clearance of IND application for pivotal Phase 3 clinical trial of sonlicromanol for the treatment of primary mitochondrial disease - GlobeNewswire, accessed May 19, 2025, https://www.globenewswire.com/news-release/2024/11/14/2981036/0/en/Khondrion-receives-FDA-clearance-of-IND-application-for-pivotal-Phase-3-clinical-trial-of-sonlicromanol-for-the-treatment-of-primary-mitochondrial-disease.html
14. academic.oup.com, accessed May 19, 2025, https://academic.oup.com/brain/article-pdf/148/3/896/60439835/awae277.pdf
15. Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation - PMC, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11884763/
16. For rare mitochondrial disease, a small molecule shows promise | Drug Discovery News, accessed May 19, 2025, https://www.drugdiscoverynews.com/for-rare-mitochondrial-disease-a-small-molecule-shows-promise-16309
17. Sonlicromanol | KH-176 | CAS#1541170-75-5 - MedKoo Biosciences, accessed May 19, 2025, https://www.medkoo.com/products/12748
18. SONLICROMANOL - GSRS, accessed May 19, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/JCU3O35RDS
19. KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of ..., accessed May 19, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06451757/khenerfin-study-a-trial-to-evaluate-the-efficacy-and-safety-of-sonlicromanol-in-primary-mitochondrial-diseases
20. Database of Drug Development for Rare Diseases - DDrare, accessed May 19, 2025, https://ddrare.nibn.go.jp/cgi-bin/disease_who_e.cgi?id=21&query=%22intervention%3ASonlicromanol%22
21. SONLICROMANOL HYDROCHLORIDE - Inxight Drugs - ncats, accessed May 19, 2025, https://drugs.ncats.io/drug/858M8246UL
22. Our focus - Khondrion, accessed May 19, 2025, https://www.khondrion.com/our-focus
23. The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury, accessed May 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8266721/
24. Publication of the KHENERGY study results - Khondrion, accessed May 19, 2025, https://www.khondrion.com/news/publication-of-the-khenergy-study-results
25. EU Clinical Trials Register, accessed May 19, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003124-16/NL
26. 21 - DDrare: Database of Drug Development for Rare Diseases, accessed May 19, 2025, https://ddrare.nibn.go.jp/ddrare_Mar2023/ddrare_Mar2022/cgi-bin/disease_who_e.cgi?id=21&query=%22Sonlicromanol%22
27. sonlicromanol - FirstWord Pharma, accessed May 19, 2025, https://firstwordpharma.com/river/tag/fw_product/sonlicromanol