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Efficacy

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Clinical study overview

The GEMINI pivotal study was a Phase 3, double-blind, placebo-controlled study that evaluated AUVELITY vs placebo for 6 weeks in 327 patients (N=163 AUVELITY and N=164 Placebo) with MDD. The study met its primary endpoint of symptom improvement on the MADRS total score at Week 6. Key secondary endpoints were change in MADRS total score from baseline to Week 1 and Week 2, response (≥50% improvement in MADRS total score) at Week 6, and remission (MADRS total score ≤10) at Week 2.1,2 See full study design.

AUVELITY demonstrated rapid and sustained symptom improvement across multiple scales

Significant symptom improvement on the MADRS scale as early as Week 1 and sustained at Week 6 vs placebo1-3*

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LS mean change from baseline in MADRS total score in the 6-week ASCEND study.

Efficacy across subgroups: Examination of demographic subgroups by age, sex, and race did not suggest differences on the primary endpoint.1

P-values for Weeks 3 and 4 were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were not imputed.

Minimal clinically important difference (MCID) estimates for MADRS ranged from 1.6 to 1.9 between treatment groups.4

§Endpoints analyzed using MMRM.

BID=twice a day, LS=least square; MADRS=Montgomery‑Åsberg Depression Rating Scale; mITT=modified intention‑to‑treat; MMRM=mixed model with repeated measures

Significantly more patients taking AUVELITY had symptoms that were very much improved/much improved at Week 1, with this increase being sustained at Week 62,3,5,6*

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Bar graph with percentage of patients achieving very much/much improved ratings in the 6-week GEMINI study.

P-values for Weeks 2-4 were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were considered failures.

Endpoints analyzed using a chi-squared test.

BID=twice a day; CGI-I=Clinical Global Impression-Improvement; mITT=modified intention-to-treat

Rapid and substantial symptom improvement at Week 22

MADRS Total Score ≤10 (protocol-defined remission)2*

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Bar graph with percentage of patients achieving MADRS total score ≤10 in the 6-week GEMINI study.

P-values for Weeks 3, 4, and 6 were not adjusted for multiplicity and are therefore not presented.

Significantly more patients taking AUVELITY achieved MADRS Total Score ≤10 at Week 2 vs placebo (protocol‑defined remission)

*mITT population.

Missing data were considered failures.

Endpoint analyzed using a chi‑squared test.

BID= twice a day; MADRS=Montgomery-Åsberg Depression Rating Scale; mITT=modified intention-to-treat

Substantial symptom improvement at Week 62

≥50% Improvement (protocol-defined response)2*

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Bar graph with percentage of patients achieving response in the 6-week GEMINI study.

P-values for Weeks 1-4 were not adjusted for multiplicity and are therefore not presented.

Significantly more patients taking AUVELITY achieved ≥50% improvement in MADRS total score at Week 6 vs placebo (protocol‑defined response)

*mITT population.

Missing data were considered failures.

Endpoint analyzed using a chi-squared test.

BID=twice a day; MADRS=Montgomery-Åsberg Depression Rating Scale; mITT=modified intention-to-treat

Greater reduction on the CGI-S scale from Week 1 to Week 6 vs placebo2,5,6*

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LS mean change from baseline in CGI-S in the 6-week GEMINI study.

P-values for Weeks 1-4 were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were not imputed.

Endpoint analyzed using a MMRM.

BID=twice a day; CGI-S=Clinical Global Impression-Severity; LS=least square; mITT=modified intention-to-treat; MMRM=mixed model with repeated measures

Patient-reported outcome measures over 6 weeks with AUVELITY2,5

Q-LES-Q-SF changes vs placebo2,5,7,8*

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LS mean change from baseline in Q-LES-Q-SF score in the 6-week GEMINI study.

Enjoyment and satisfaction experienced by patients were reported in various areas of daily functioning.7,8

P-values for comparisons were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were not imputed.

BID=twice a day; LS=least square; mITT=modified intention-to-treat; Q‑LES‑Q‑SF=Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form

Improvement on Sheehan Disability Scale (SDS)2,5,9*

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LS mean change from baseline in SDS total score in the 6-week GEMINI study.

Functioning, evaluated by SDS, was reported in the domains of work/school, social and family life.9

P-values for comparisons were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were not imputed.

BID=twice a day; LS=least square; mITT=modified intention-to-treat; SDS=Sheehan Disability Scale

Improvement on QIDS-SR-16 score vs placebo2,5,10*†

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LS mean change from baseline in QIDS-SR-16 score in the 6-week GEMINI study.

Depressive symptom severity was reported based on domains such as sleep, mood, and suicidal ideation.10

P-values for comparisons were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were not imputed.

BID=twice a day; LS=least square; mITT=modified intention-to-treat; QIDS‑SR‑16=Quick Inventory of Depressive Symptomatology‑Self‑Report (16 items)

More patients taking AUVELITY reported being very much/much improved on the PGI-I scale at Week 1 through Week 62,3,5,11*†

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Bar graph with percentage of patients reporting much or very much improved on PGI-I in the 6-week GEMINI study.

Global improvement or worsening of mental illness was reported.11

P-values for comparisons were not adjusted for multiplicity and are therefore not presented.

*mITT population.

Missing data were considered failures.

BID=twice a day; mITT=modified intention-to-treat; PGI-I=Patient Global Impression of Improvement

GEMINI Phase 3 Study

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Diagram of GEMINI phase 3 study design
327 patients with moderate to severe MDD were randomized to receive treatment for 6 weeks as follows: once daily for the first 3 days and twice daily thereafter. 163 patients received Auvelity and 164 patients received placebo. The study had an up to 4 weeks screening period.

Primary endpoint: LS mean change from baseline in MADRS total score at Week 6.1,2

Select secondary endpoints:1,2

The following endpoints were evaluated hierarchically:

  • Change in MADRS total score from baseline to Week 2
  • Percentage of subjects achieving remission (MADRS total score ≤10) at Week 2
  • Change in MADRS total score from baseline to Week 1
  • Percentage of responders (≥50% reduction in MADRS total score from baseline) at Week 6
  • CGI-I at Week 6
  • Change in CGI-S from baseline to Week 6
  • CGI-I at Week 1
  • Percentage of subjects achieving remission (MADRS total score ≤10) at Week 1
  • Change in SDS from baseline to Week 6

Statistical significance was achieved on the first 7 multiplicity tests (bolded above).

Other endpoints: SDS, QIDS‑SR‑16, Q‑LES‑Q‑SF, and PGI‑I.2

Efficacy assessments were performed at weeks 1, 2, 3, 4 and 6 on the mITT population. The mITT population was defined as all randomized patients who took at least 1 dose of study drug and had at least 1 post‑baseline assessment.2

The MADRS is a clinician‑rated scale used to assess depressive symptom severity. Patients are rated on 10 items to assess feelings of sadness, inner tension, reduced sleep or appetite, difficulty concentrating, lassitude, lack of interest, pessimism, and suicidality. Scores range from 0 to 60, with higher scores indicating more severe depression.1

Key inclusion criteria: Male or female 18‑65 years of age; DSM‑5 criteria for current MDD without psychotic features; MADRS total score ≥25; and CGI‑S score ≥4 at baseline.1,2

Key exclusion criteria: Bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as ≥2 failed adequate antidepressant treatments in the current major depressive episode), alcohol/substance use disorder within the past year, clinically significant risk of suicide, and history of seizure disorder.2

Demographics and Baseline Characteristics

  • Demographic and baseline disease characteristics were generally similar across both treatment groups.2
  • Patients had a median age of 41 years (range: 18 to 65 years), and were 67% female, 55% Caucasian, 35% Black, and 5% Asian.1
  • At baseline for AUVELITY and placebo groups:2
    • Mean body mass index was 29.3 kg/m2 (AUVELITY) and 29.3 kg/m2 (placebo)
    • Mean MADRS total score was 33.6 (AUVELITY) and 33.2 (placebo)
    • Mean CGI-S score was 4.6 for both groups

BID=twice a day; CGI‑I=Clinical Global Impression‑Improvement; CGI‑S=Clinical Global Impression‑Severity; DSM-5=Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; LS=least squares; MADRS=Montgomery‑Åsberg Depression Rating Scale; mITT=modified intention-to-treat; PGI-I=Patient Global Impression of Improvement; QIDS-SR-16=Quick Inventory of Depressive Symptomatology–Self-Report (16 items); Q‑LES‑Q‑SF=Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form; SDS=Sheehan Disability Scale

Clinical study overview

The ASCEND study was a Phase 2, double‑blind, active‑controlled confirmatory study that evaluated AUVELITY vs bupropion SR 105 mg for 6 weeks in 80 patients (N=43 AUVELITY and N=37 bupropion) with MDD. The study met its primary endpoint of symptom improvement across 6 weeks on the MADRS total score (overall treatment effect). A select secondary endpoint was remission (MADRS total score ≤10).1,12 See study design

AUVELITY demonstrated statistically significant overall symptom improvement over 6 weeks1,12

Symptom improvement vs bupropion1,12,13*

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LS mean change from baseline in MADRS total score in the 6-week ASCEND study.
P-values by week were not adjusted for multiplicity and are therefore not presented.
Primary endpoint achieved over 6 weeks:Overall LS mean change from baseline in the MADRS total score vs bupropion (overall treatment effect) was -13.7 vs -8.8; P<0.00112‡

*mITT population.

Missing data were imputed by last observation carried forward (LOCF).

Primary endpoint analyzed using MMRM.

BID=twice a day; LS=least squares; MADRS=Montgomery-Åsberg Depression Rating Scale; mITT=modified intention-to-treat; MMRM=mixed model of repeated measures; SR=sustained-release

More patients achieved a MADRS Total Score ≤10 with AUVELITY vs bupropion from Week 1 to 612,14

MADRS total score ≤10 (protocol-defined remission)12,14*†

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Bar graph with percentage of patients achieving achieving MADRS total score ≤10 in the 6-week ASCEND study.
P-values were not adjusted for multiplicity and are therefore not presented.

~3x more patients achieved MADRS total score ≤10 on AUVELITY vs bupropion at Week 6 (protocol‑defined remission)

*mITT population.

Missing data were imputed by last observation carried forward (LOCF).

BID=twice a day; MADRS=Montgomery-Åsberg Depression Rating Scale; mITT=modified intention-to-treat; SR=sustained-release

ASCEND Phase 2 Study

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Diagram of ASCEND phase 2 study design
80 patients with moderate to severe MDD were randomized to receive treatment for 6 weeks as follows: once daily for the first 3 days and twice daily thereafter. 43 patients received Auvelity and 37 patients received placebo. The study had an up to 4 weeks screening period.

Primary endpoint: LS mean change from baseline in the MADRS total score, calculated at each time point and averaged (overall treatment effect).1,12

Select secondary endpoint: Clinical remission (MADRS total score ≤10).12

Efficacy assessments were performed at weeks 1, 2, 3, 4 and 6 on the mITT population (N=80). The mITT population was defined as all randomized patients who took at least 1 dose of study drug, had at least 1 post‑baseline assessment, and whose diagnosis and severity of MDD were confirmed, based on clinical review, by an independent assessor who was blinded to treatment assignment. A total of 17 randomized subjects were excluded from the mITT by the independent assessor.12

The MADRS is a clinician‑rated scale used to assess depressive symptom severity. Patients are rated on 10 items to assess feelings of sadness, inner tension, reduced sleep or appetite, difficulty concentrating, lassitude, lack of interest, pessimism, and suicidality. Scores range from 0 to 60, with higher scores indicating more severe depression.1

Key inclusion criteria: Male or female 18‑65 years of age; DSM‑5 criteria for current MDD without psychotic features; MADRS total score ≥25; and CGI‑S score ≥4 at baseline.12

Key exclusion criteria: Bipolar disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as ≥2 failed adequate antidepressant treatments in the current major depressive episode), substance use disorder within the past year, lifetime history of psychotic disorder, clinically significant risk of suicide, and history of seizure disorder.12

Demographics and Baseline Characteristics

  • Demographic and baseline disease characteristics were similar across both treatment groups.12
  • Patients had a median age of 36 years (range 18 to 64 years), and were 64% female, 63% Caucasian, 33% Black, and 1% Asian.12,13
  • At baseline for AUVELITY and bupropion SR groups, mean MADRS total score was 31.8 and 32.2 respectively.12

DSM-5=Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; LS=least square; MADRS=Montgomery‑Åsberg Depression Rating Scale; mITT=modified intention-to-treat; SR=sustained-release

Mechanism of Action

Pivotal Study Safety Profile

Indication

AUVELITY is indicated for the treatment of major depressive disorder (MDD) in adults.

Important Safety Information

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

  • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.
  • Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors.
  • AUVELITY is not approved for use in pediatric patients.

CONTRAINDICATIONS

Seizure: Do not use AUVELITY in patients with a seizure disorder.

Current or prior diagnosis of bulimia or anorexia nervosa: A higher incidence of seizure was observed in such patients treated with bupropion.

Undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs: Due to risk of seizure.

Monoamine Oxidase Inhibitors (MAOIs): Do not use AUVELITY concomitantly with, or within 14 days of stopping, an MAOI due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome. Conversely, at least 14 days must be allowed after stopping AUVELITY before starting an MAOI antidepressant. Do not use AUVELITY with reversible MAOIs such as linezolid or intravenous methylene blue.

Hypersensitivity: Do not use in patients with known hypersensitivity to dextromethorphan, bupropion, or any component of AUVELITY. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion. Arthralgia, myalgia, fever with rash, and other serum sickness-like symptoms suggestive of delayed hypersensitivity have also been reported with bupropion.

WARNINGS AND PRECAUTIONS

Suicidal Thoughts and Behaviors in Pediatrics and Young Adults: Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing AUVELITY, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Seizure: Bupropion, a component of AUVELITY, can cause seizure and the risk is dose related. Because the risk of seizure with bupropion is dose-related, screen patients for use of other bupropion-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion-containing products is clinically warranted, inform patients of the risk. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure.

Increased Blood Pressure and Hypertension: Treatment with bupropion, a component of AUVELITY, can cause elevated blood pressure and hypertension. The risk of hypertension is increased if AUVELITY is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity. Assess blood pressure before initiating treatment with AUVELITY and monitor periodically during treatment. Monitor blood pressure, particularly in patients who receive the combination of bupropion and nicotine replacement.

Activation of Mania/Hypomania: Antidepressant treatment can precipitate a manic, mixed, or hypomanic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating AUVELITY, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). AUVELITY is not approved for use in treating bipolar depression.

Psychosis and Other Neuropsychiatric Reactions: AUVELITY contains bupropion and dextromethorphan. Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability.

Because the risks of neuropsychiatric reactions are dose-related, screen patients for use of other bupropion- or dextromethorphan-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions and instruct patients to contact a healthcare provider if such reactions occur.

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressants, including AUVELITY, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including AUVELITY, in patients with untreated anatomically narrow angles.

Dizziness: AUVELITY may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that AUVELITY therapy does not affect them adversely.

Serotonin Syndrome: AUVELITY contains dextromethorphan. Concomitant use with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants increases the risk of serotonin syndrome, a potentially life-threatening condition. Prior to initiating therapy with AUVELITY, screen patients for use of other dextromethorphan-containing products. If concomitant use of AUVELITY with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome, and monitor for symptoms. Discontinue AUVELITY and/or concomitant serotonergic drug(s) immediately if symptoms of serotonin syndrome occur and initiate supportive symptomatic treatment.

Embryo-fetal Toxicity: Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. Discontinue treatment in pregnant females and advise the patient about the potential risk to a fetus. Use alternative treatment for females who are planning to become pregnant.

DRUG INTERACTIONS

Strong Inhibitors of CYP2D6: Concomitant use with AUVELITY increases plasma concentrations of dextromethorphan. Dosage adjustment is necessary. Monitor patients for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

Strong CYP2B6 Inducers: Concomitant use with AUVELITY decreases plasma concentrations of dextromethorphan and bupropion and may decrease efficacy of AUVELITY. Avoid co-administration of AUVELITY.

CYP2D6 Substrates: Concomitant use with AUVELITY can increase the exposures of drugs that are substrates of CYP2D6. It may be necessary to decrease the dose of CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Digoxin: Concomitant use with AUVELITY may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with AUVELITY.

Drugs that Lower Seizure Threshold: Concomitant use with AUVELITY may increase risk of seizure. Use AUVELITY with caution. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure.

Dopaminergic Drugs: Concomitant use with AUVELITY can result in central nervous system toxicity. Use AUVELITY with caution.

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for neurotoxicity, advise patients that breast-feeding is not recommended during treatment with AUVELITY and for 5 days following final dose.

Renal Impairment: Dosage adjustment is recommended in patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m2). AUVELITY is not recommended in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2).

Hepatic Impairment: AUVELITY is not recommended in patients with severe hepatic impairment.

ADVERSE REACTIONS

Most common adverse reactions (≥5% and twice the rate of placebo): dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%).

Please see full Prescribing Information, including Boxed Warning for suicidal thoughts and behaviors.

AUV HCP ISI 10/2022

REFERENCES

  1. 1. AUVELITY [Prescribing Information]. Axsome Therapeutics, Inc.: New York, NY.
  2. 2. Iosifescu DV, Jones A, O’Gorman C, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: A phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345.
  3. 3. Data on File. AXS0010921.
  4. 4. Duru G and Fantino B. The clinical relevance of changes in the Montgomery-Åsberg Depression Rating Scale using the minimum clinically important difference approach. Curr Med Res Opin. 2008;24(5):1329–35.
  5. 5. Data on File. AXS0020921.
  6. 6. Busner J and Targum SD. The clinical global impressions scale: Applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28–37.
  7. 7. Sheehan Disability Scale (SDS) - Overview. https://memorialparkpsychiatry.com/doc/sheehan_disability_scale.pdf.Accessed September 1, 2022.
  8. 8. Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16). https://www.mdapp.co/quick-inventory-of-depressive-symptomatology-qids-calculator-604/. Accessed June 16, 2021.
  9. 9. Quality of Life Enjoyment and Satisfaction Questionnaire Short Form. https://datashare.nida.nih.gov/instrument/quality-of-life-enjoyment-and-satisfaction-questionnaire-short-form. Accessed June 17, 2021.
  10. 10. Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF). http://www.maternalwellnessclinic.ca/Q-LES-Q.pdf. Accessed June 17, 2021.
  11. 11. Mohebbi M, Dodd S, Dean OM, et al. Patient centric measures for a patient centric era: Agreement and convergent between ratings on The Patient Global Impression of Improvement (PGI-I) scale and the Clinical Global Impressions - Improvement (CGI-S) scale in bipolar and major depressive disorder. Eur Psychiatry. 2018;53:17–22.
  12. 12. Tabuteau H, Jones A, Anderson A, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: A randomized double-blind controlled trial. Am J Psychiatry. 2022;179(7):490-499.
  13. 13. Data on File. AXS0040921.
  14. 14. Data on File. AXS0050921.