UCB presents new data highlighting developments across expansive neurology portfolio at 76th American Academy of Neurology (AAN) Annual Meeting

Published
  • Diverse and patient-focused data set comprises 17 abstracts including one oral presentation
  • Features new data analyses for UCB's generalized myasthenia gravis (gMG) treatments, including post hoc and open-label extension results from the pivotal Phase 3 MycarinG study and additional Interim Analyses of RAISE-XT for the approved treatments RYSTIGGO®▼ (rozanolixizumab-noli) and ZILBRYSQ®▼ (zilucoplan)
  • Data on BRIVIACT® (brivaracetam), FINTEPLA®▼ (fenfluramine), and STACCATO® alprazolam showcase commitment to patients and momentum of UCB's epilepsy and rare syndromes portfolio

ATLANTA, April 12, 2024 /PRNewswire/ -- UCB (Euronext Brussels: UCB), a global biopharmaceutical company, today announced the latest research from its expansive neurology portfolio and pipeline to be presented at the 76th American Academy of Neurology (AAN) Annual Meeting, April 13-18, 2024, in Denver, Colorado, USA.

A total of 17 abstracts, including an oral presentation, will feature data from studies of four approved and one investigational medicine and technologies for generalized myasthenia gravis (gMG), epilepsies including Dravet syndrome and focal (partial) epileptic seizures.

Key UCB scientific and patient-focused data to be presented at AAN include:

gMG

  • Post hoc and open-label extension analyses from the pivotal Phase 3 MycarinG study for rozanolixizumab, including impact of treatment on physical fatigue and muscle fatigability in adult patients with gMG
  • An oral presentation on long-term safety and efficacy of zilucoplan in gMG in an interim analysis of RAISE-XT
  • An interim analysis of a Phase 3b study on efficacy, and patient preference for subcutaneous zilucoplan in Myasthenia Gravis after switching from intravenous complement component 5 inhibitors
  • Results from a discrete choice study looking at patient preferences in gMG treatment attributes

Epilepsy and rare epilepsy syndromes

  • Focal-onset seizures (FOS) - interim results of 12-month real-world study (BRITOBA) evaluating adjunctive brivaracetam in earlier treatment lines in adults
  • Epilepsy - subgroup data from the international EXPERIENCE analysis assessing brivaracetam in epilepsy patients with cognitive or learning disability or psychiatric comorbidities
  • Prolonged seizures - three Phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-use inhaled alprazolam (an investigational treatment for potential termination of prolonged epileptic seizures) in different populations
  • Dravet syndrome - a retrospective analysis using US claims data of healthcare utilization and persistence in patients with Dravet syndrome
  • Epilepsy disease management - expert consensus recommendations from the Seizure Termination Project*, highlighting best practice for rapid and early seizure termination and timing for intervention

"The new analyses from the Phase 3 MycarinG and Phase 3 RAISE XT open-label extension (OLE) studies being presented at this year's AAN meeting reinforce the potential of our recently approved gMG treatments, RYSTIGGO®▼ and ZILBRYSQ®▼, to offer targeted treatments for gMG patients, tailored to their individual needs and preferences," commented Donatello Crocetta, Head of Global Rare Disease & Rare Medical, UCB. "These data further underscore UCB's innovative approach to evolving science into meaningful treatment solutions that help improve long term patient outcomes of people living with this rare neuromuscular disease, and more widely as part of the integrated neurology portfolio's commitment to patient-focused solutions."

"The data being presented at this year's AAN meeting showcase how we are transforming experiences and outcomes for people living with epilepsy and rare epilepsy syndromes and highlight our work in redefining the future of epilepsy care," said Mike Davis, Global Head of Epilepsy & Rare Syndromes, UCB. "Everything we do is centered around people and families living with epilepsies, helping them achieve their ideal and maximize their life opportunities."

UCB presentations during AAN 2024

Lead author

Abstract title

Presentation Details

(Timings MDT)

gMG

A Habib

Clinically Meaningful Improvement in Physical Fatigue and Muscle Weakness Fatigability with Rozanolixizumab: Post-Hoc Analysis of MG Symptoms PRO Responder Rate in the MycarinG study

Neighborhood 11, Session P4: 11-001

April 15, 2024

11:45 AM - 12:45 PM MDT

J Zhou

Characteristics, Treatment Patterns and Disease Burden of Juvenile Myasthenia Gravis in the United States

Disclaimer: Rystiggo and Zilbrysq are not indicated for the use in juvenile myasthenia gravis (JMG) by any regulatory authority worldwide

Neighborhood 11, Session P4: 11-017

April 15, 2024

11:45 AM - 12:45 PM MDT

O Qureshi

Interactions of Fcg receptors with an IgG4 format, anti-FcRn monoclonal antibody, rozanolixizumab

Neighborhood 14, Session P4: 14-002

April 15, 2024

11:45 AM - 12:45 PM MDT

C Mansfield

Patient Preferences for Myasthenia Gravis Treatments: A Discrete-Choice Experiment

Neighborhood 11, Session P4: 11-013

April 15, 2024

11:45 AM - 12:45 PM MDT

V Bril

The Safety and Efficacy of Chronic Weekly Rozanolixizumab Treatment in Patients with gMG (MG0004)

Neighborhood 14, Session P4: 14-017

MG0004

April 15, 2024

11:45 AM - 12:45 PM MDT

JF Howard

Long-Term Safety and Efficacy of Zilucoplan in Myasthenia Gravis: Additional Interim Analyses of RAISE-XT

Oral Presentation

S15: 002

April 15, 2024

1:12 PM MDT

Z Mahuwala

Drivers of New Rozanolixizumab Treatment Cycles in Patients with Generalized Myasthenia Gravis in the Phase 3 MycarinG and Open-Label Extension Studies

Neighborhood 11, Session P10: 11-003

MG0003

April 17, 2024

11:45 AM - 12:45 PM MDT

R Pascuzzi

Response to Rozanolixizumab Across Treatment Cycles in Patients with Generalized Myasthenia Gravis: A Post-hoc Analysis

Neighborhood 11, Session P10: 11-005

April 17, 2024

11:45 AM - 12:45 PM MDT

M Freimer

Efficacy and Patient Preference for Subcutaneous Zilucoplan in Myasthenia Gravis After Switching from Intravenous Complement Component 5 Inhibitors: An Interim Analysis of a Phase 3b Study

Neighborhood 11, Session P10: 11-006

April 17, 2024

11:45 AM - 12:45 PM MDT

Epilepsy & Rare Epilepsy Syndromes

V Villanueva

12-Month Effectiveness and Tolerability of Brivaracetam in Patients With Epilepsy and Cognitive or Psychiatric Comorbidities: Subgroup Data From the International EXPERIENCE Pooled Analysis

Poster Presentation

P009

April 16, 2024

5:30 – 6:30 PM MDT

S Knake

Brivaracetam Adjunctive Therapy in Earlier Treatment Lines in Adults With Focal-onset Seizures in Europe and Canada: Interim Results of 12-month Real-world Data From BRITOBA

Poster Presentation

P008

April 16, 2024

5:30 – 6:30 PM MDT

P Perucca

Pregnancy Outcomes Following Exposure to Lacosamide: Prospective Data From Spontaneous and Solicited Reports

Poster Presentation

P011

April 15, 2024

11:45 AM12:45 PM MDT

D Miller

**Pulmonary Safety of Staccato® Alprazolam in Healthy Participants and Participants with Mild Asthma: Phase 1, Randomized, Double-Blind, Placebo-Controlled Trial

Poster Presentation

P009

April 17, 2024

8:00 – 9:00 AM MDT

P Klein

**Pharmacokinetics and Tolerability of Single-dose Staccato® Alprazolam in Adolescents with Epilepsy and Population PK Analysis to Support Dose Selection in Adolescents

Poster Presentation

P002

April 17, 2024

8:00 – 9:00 AM MDT

R Roebling

**Pharmacokinetics of Staccato® Alprazolam in Healthy Adult Participants: Phase 1, Randomized, Placebo-Controlled Ethno-Bridging Study

Poster Presentation

P007

April 17, 2024

8:00 – 9:00 AM MDT

JE Pina Garza

*Expert Consensus Recommendations on Seizure Emergencies Suitable for Rapid and Early Seizure Termination (REST) and Timing of Intervention

Poster Presentation

P003

April 17, 2024

8:00 – 9:00 AM MDT

S Jaganathan

Healthcare Utilization and Persistence in Patients with Dravet Syndrome: A Retrospective Analysis Using US Claims Data

Poster Presentation

P003

April 14, 2024

8:00 – 9:00 AM MDT

*The Seizure Termination Project was funded by UCB Pharma.

**STACCATO® alprazolam is an investigational product. The safety and efficacy has not been established and it is not approved by the Food and Drug Administration, or by any health authority worldwide.

For further information, contact UCB:

Global Rare Disease CommunicationsJim BaxterT+ 32.2.473.78.85.01jim.baxter@ucb.com 

Global CommunicationsNick FrancisT +44 7769 307745email nick.francis@ucb.com

Rare Disease CommunicationsDaphne TeoT +1 (770) 880-7655email daphne.teo@ucb.com

Epilepsy and Rare Syndromes CommunicationsBecky MaloneT +1 (919) 605-9600email becky.malone@ucb.com

Corporate Communications, Media RelationsLaurent SchotsT+32.2.559.92.64Laurent.schots@ucb.com

Investor RelationsAntje Witte   T +32.2.559.94.14antje.witte@ucb.com

Important Safety Information about RYSTIGGO®▼ (rozanolixizumab) in the EU1 ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

Rystiggo is indicated as an add-on to standard therapy for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.1

The most commonly reported adverse reactions were headache (48.4 %), diarrhea (25.0 %) and pyrexia (12.5 %). The adverse reactions from the placebo-controlled study in gMG are as follow: Very common (≥ 1/10) headache, diarrhea and pyrexia; Common (≥ 1/100 to < 1/10) rash, angioedema, arthralgia and injection site reactions. Headache was the most common reaction reported in 31 (48.4 %) and 13 (19.4 %) of the patients treated with rozanolixizumab and placebo, respectively. All headaches, except 1 (1.6 %) severe headache, were either mild (28.1 % [n=18]) or moderate (18.8 % [n=12]) and there was no increase in incidences of headache with repeated cyclic treatment.

Rozanolixizumab is contra-indicated in patients with hypersensitivity to the active substance or to any of the excipients.

Treatment with rozanolixizumab in patients with impending or manifest myasthenic crisis has not been studied. The sequence of therapy initiation between established therapies for MG crisis and rozanolixizumab, and their potential interactions, should be considered.Aseptic meningitis (drug induced aseptic meningitis) has been reported following rozanolixizumab treatment at a higher dose with subsequent recovery without sequelae after discontinuation. If symptoms consistent with aseptic meningitis occur, diagnostic workup and treatment should be initiated as per standard of care.

Due to its mechanism of action, the use of rozanolixizumab may increase the patient's susceptibility to infections. Treatment with rozanolixizumab should not be initiated in patients with a clinically important active infection until the infection is resolved or is adequately treated. During treatment with rozanolixizumab, clinical signs and symptoms of infections should be monitored. If a clinically important active infection occurs, withholding rozanolixizumab until the infection has resolved should be considered.

Hypersensitivity reactions including mild to moderate rash or angioedema were observed in patients treated with rozanolixizumab. Patients should be monitored during treatment with rozanolixizumab and for 15 minutes after the administration is complete for clinical signs and symptoms of hypersensitivity reactions. If a hypersensitivity reaction occurs during administration, rozanolixizumab infusion should be discontinued and appropriate measures should be initiated if needed. Once resolved, administration may be resumed

Immunization with vaccines during rozanolixizumab therapy has not been studied. The safety of immunization with live or live-attenuated vaccines and the response to immunization with vaccines are unknown. All vaccines should be administered according to immunization guidelines and at least 4 weeks before initiation of treatment. For patients that are on treatment, vaccination with live or live attenuated vaccines is not recommended. For all other vaccines, they should take place at least 2 weeks after the last infusion of a treatment cycle and 4 weeks before initiating the next cycle.

Refer to the European Summary of Product Characteristics for other adverse reactions and full prescribing information. https://www.ema.europa.eu/en/documents/product-information/rystiggo-epar-product-information_en.pdf

Important Safety Information about ZILBRYSQ®▼ (zilucoplan) in the EU2▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Zilbrysq is indicated as an add-on to standard therapy for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.2

The most frequently reported adverse reactions were injection site reactions (injection site bruising (13.9%) and injection site pain (7.0%) and upper respiratory tract infections (nasopharyngitis (5.2%), upper respiratory tract infection (3.5%) and sinusitis (3.5%). The adverse reactions from the pooled placebo controlled (n=115) and open-label extension (n=213) studies in gMG are as follows: Very common adverse reactions: (≥ 1/10): Upper respiratory tract infections and Injection site reactions; Common adverse reactions (≥ 1/100 to < 1/10) Diarrhea, Lipase increased, Amylase increased and Morphea; Uncommon adverse reaction (≥ 1/1000 to < 1/100) blood eosinophils increased. Zilucoplan is contra-indicated in patients with hypersensitivity to the active substance or to any of the excipients, in patients who are not currently vaccinated against Neisseria meningitidis and in patients with unresolved Neisseria meningitidis infection. Due to its mechanism of action, the use of zilucoplan may increase the patient's susceptibility to infections with Neisseria meningitidis. As a precautionary measure, all patients must be vaccinated against meningococcal infections, at least 2 weeks prior to the start of treatment. If treatment needs to start less than 2 weeks after vaccination against meningococcal infections, the patient must receive appropriate prophylactic antibiotic treatment until 2 weeks after the first vaccination dose. Meningococcal vaccines reduce but do not completely eliminate the risk of meningococcal infections. Vaccines against serogroups A, C, Y, W, and where available, serogroup B, are recommended for preventing the commonly pathogenic meningococcal serogroups. Vaccination and prophylactic antibiotic treatment should occur according to most current relevant guidelines. During treatment, patients should be monitored for signs and symptoms of meningococcal infection and evaluated immediately if infection is suspected. In case of a suspected meningococcal infection, appropriate measures such as treatment with antibiotics and discontinuation of treatment, should be taken until the meningococcal infection can be ruled out. Patients should be instructed to seek immediate medical advice if signs or symptoms of meningococcal infections occur. Prescribers should be familiar with the educational materials for the management of meningococcal infections and provide a patient alert card and patient/carer guide to patients treated with zilucoplan. In addition to Neisseria meningitidis, patients treated with zilucoplan may also be susceptible to infections with other Neisseria species, such as gonococcal infections. Patients should be informed on the importance of gonorrhea prevention and treatment. Prior to initiating zilucoplan therapy, it is recommended that patients initiate immunizations according to current immunization guidelines. Refer to the European Summary of Product Characteristics for other adverse reactions and full prescribing information. https://www.ema.europa.eu/en/documents/product-information/zilbrysq-epar-product-information_en.pdf. EC Date of approval 01 Dec 2023.

Important Safety Information about FINTEPLA®▼ (fenfluramine) in the EU3This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Indications: Treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older.

Dosage and Administration: Please refer to SmPC for full information. Should be initiated and supervised by physicians with experience in the treatment of epilepsy. Fintepla is prescribed and dispensed according to the Fintepla controlled access programme. Dravet syndrome: Patients who are not taking stiripentol: Starting dose is 0.1 mg/kg twice daily (0.2 mg/kg/day). After 7 days, if tolerated, can increase dose to 0.2 mg/kg twice daily (0.4 mg/kg/day). After an additional 7 days, if tolerated and further seizure reduction required, can increase dose to a maximum of 0.35 mg/kg twice daily (0.7 mg/kg/day), which is the recommended maintenance dose. Patients requiring more rapid titration may increase the dose every 4 days. Do not exceed maximum daily dose of 26 mg (13 mg twice daily). Patients who are taking stiripentol: Starting dose is 0.1 mg/kg twice daily (0.2 mg/kg/day). After 7 days, if tolerated, can increase dose to 0.2 mg/kg twice daily (0.4 mg/kg/day), which is the recommended maintenance dose. Patients requiring more rapid titration may increase the dose every 4 days. Do not exceed a total dose of 17 mg (8.6 mg twice daily). Lennox-Gastaut syndrome: Starting dose is 0.1 mg/kg twice daily (0.2 mg/kg/day). After 7 days, the dose should be increased to 0.2 mg/kg twice daily (0.4 mg/kg/day), if tolerated. After an additional 7 days, if tolerated, dose should be increased to 0.35 mg/kg twice daily (0.7 mg/kg/day), which is the recommended maintenance dose. Do not exceed maximum daily dose of 26 mg (13 mg twice daily). Discontinuation: When discontinuing treatment, decrease the dose gradually. As with all anti-epileptic medicines, avoid abrupt discontinuation when possible to minimize the risk of increased seizure frequency and status epilepticus. A final echocardiogram should be conducted 3-6 months after the last dose of treatment with fenfluramine. Renal impairment: Generally, no dose adjustment is recommended when administered to patients with mild to severe renal impairment, however, a slower titration may be considered. If adverse reactions are reported, a dose reduction may be needed. Has not been studied in patients with end-stage renal disease. Not known if fenfluramine or its active metabolite, norfenfluramine, is dialyzable. Hepatic impairment: Hepatic impairment: Generally, no dose adjustment is recommended when Fintepla is administered without concomitant stiripentol to patients with mild and moderate hepatic impairment (Child-Pugh Class A and B). In patients with severe hepatic impairment (Child-Pugh C) not receiving concomitant stiripentol, the maximum dosage is 0.2mg/kg twice daily, and the maximal total daily dose is 17 mg. There are limited clinical data on the use of Fintepla with stiripentol in patients with mild impaired hepatic function. A slower titration may be considered in patients with hepatic impairment and a dose reduction may be needed if adverse reactions are reported. No clinical data is available on the use of Fintepla with stiripentol in moderate and severe hepatic impairment, therefore not recommended for use. Elderly: No data available. Pediatric population: Safety and efficacy in children below 2 years of age not yet established. No data available. Contraindications: Hypersensitivity to active substance or any excipients. Aortic or mitral valvular heart disease and pulmonary arterial hypertension. Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome.

Warnings and Precautions: Aortic or mitral valvular heart disease and pulmonary arterial hypertension: Prior to starting treatment, patients must undergo an echocardiogram to establish a baseline and exclude any pre-existing valvular heart disease or pulmonary hypertension. Conduct echocardiogram monitoring every 6 months for the first 2 years and annually thereafter. If an echocardiogram indicates pathological valvular changes, consider follow-up earlier to evaluate whether the abnormality is persistent. If pathological abnormalities seen on echocardiogram, evaluate the benefit versus risk of continuing fenfluramine treatment with the prescriber, caregiver and cardiologist. Once treatment is discontinued for any reasons, a final echocardiogram should be conducted 3-6 months after the last dose of treatment with fenfluramine. If echocardiogram findings suggestive of pulmonary arterial hypertension, perform a repeat echocardiogram as soon as possible and within 3 months to confirm these findings. If echocardiogram finding is confirmed suggestive of an increased probability of pulmonary arterial hypertension defined as intermediate probability, conduct a benefit-risk evaluation of continuation of Fintepla by the prescriber, carer and cardiologist. If echocardiogram suggests a high probability, it is recommended fenfluramine treatment should be stopped. Decreased appetite and weight loss: Fenfluramine can cause decreased appetite and weight loss - an additive effect can occur in combination with other anti-epileptic medicines such as stiripentol. Monitor the patient's weight. Undertake risk-benefit evaluation before starting treatment if history of anorexia nervosa or bulimia nervosa. Fintepla controlled access programme: A controlled access programme has been created to 1) prevent off-label use in weight management in obese patients and 2) confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking Fintepla. Somnolence: Fenfluramine can cause somnolence which could be potentiated by other central nervous system depressants. Suicidal behaviour and ideation: Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic medicines in several indications. Advise patients and caregivers to seek medical advice should any signs of suicidal behaviour and ideation emerge. Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents; with agents that impair metabolism of serotonin such as MAOIs; or with antipsychotics that may affect the serotonergic neurotransmitter systems. Carefully observe the patient, particularly during treatment initiation and dose increases. Increased seizure frequency: A clinically relevant increase in seizure frequency may occur during treatment, which may require adjustment in the dose of fenfluramine and/or concomitant anti-epileptic medicines, or discontinuation of fenfluramine, should the benefit-risk be negative. Cyproheptadine: Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy of fenfluramine. If cyproheptadine is added to treatment with fenfluramine, monitor patient for worsening of seizures. If fenfluramine treatment is initiated in a patient taking cyproheptadine, fenfluramine's efficacy may be reduced. Glaucoma: Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Discontinue therapy in patients with acute decreases in visual acuity. Consider discontinuation if ocular pain of unknown origin. Effect of CYP1A2 or CYP2B6 inducers: Co-administration with strong CYP1A2 inducers or CYP2B6 inducers will decrease fenfluramine plasma concentrations, which may lower the efficacy of fenfluramine. If co-administration is considered necessary, the patient should be monitored for reduced efficacy and a dose increase of fenfluramine could be considered provided that it does not exceed twice the maximum daily dose (52 mg/day). If a strong CYP1A2 or CYP2B6 inducer is discontinued during maintenance treatment with fenfluramine, consider gradual reduction of the fenfluramine dosage to the dose administered prior to initiating the inducer. Effect of CYP1A2 or CYP2D6 inhibitors: Initiation of concomitant treatment with a strong CYP1A2 or CYP2D6 inhibitor may result in higher exposure and, therefore, adverse events should be monitored, and a dose reduction may be needed in some patients. Excipients: Contains sodium ethyl para-hydroxybenzoate (E 215) and sodium methyl para-hydroxybenzoate (E 219) - may cause allergic reactions (possibly delayed). It also contains sulfur dioxide (E 220) which may rarely cause severe hypersensitivity reactions and bronchospasm. Patients with rare glucose-galactose malabsorption should not take this medicine. The product contains less than 1 mmol sodium (23 mg) per the maximum daily dose of 12 mL; essentially 'sodium-free'. Contains glucose - may be harmful to teeth. Interactions: Pharmacodynamic interactions with other CNS depressants increase the risk of aggravated central nervous system depression. An increase in dose may be necessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer. In in vitro studies co-administration with a strong CYP1A2 or CYP2D6 inhibitor may result in higher exposure (see section 4.4 of the SmPC). Co-administration with CYP2D6 substrates or MATE1 substrates may increase their plasma concentrations. Co-administration with CYP2B6 or CYP3A4 substrates may decrease their plasma concentrations. Pregnancy and lactation: Limited data in pregnant women. As a precaution, avoid use of Fintepla in pregnancy. It is unknown whether fenfluramine/metabolites are excreted in human milk. Animal data have shown excretion of fenfluramine/metabolites in milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fintepla taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Drive and use machines.: Fintepla has moderate influence on the ability to drive/ use machines as it may cause somnolence and fatigue. Advise patients not to drive or operate machinery until they have sufficient experience to gauge whether it adversely affects their abilities.Adverse effects: Dravet syndrome: Very common (≥1/10): Upper respiratory tract infection, decreased appetite, somnolence, diarrhoea, pyrexia, fatigue, blood glucose decreased, echocardiogram abnormal (Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic). Common (≥1/100 to

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