Carlo Antozzi, MD, discusses results from the phase 3 Vivacity-MG3 study of nipocalimab in antibody positive adults with generalized myasthenia gravis (MG).

MG is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eye and eyelid, facial expressions, chewing, talking, and swallowing. Weakness tends to increase during periods of activity and improve after periods of rest. The condition results from a defect in the transmission of nerve impulses to muscles, which is due to the presence of antibodies against acetylcholine. The exact reason this occurs is not known.

The Vivacity-MG3 clinical trial (NCT04951622) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of nipocalimab in antibody positive adults with generalized MG. Nipocalimab is an investigational FcRn blocker designed to reduce levels of circulation immunoglobulin G (IgG).

In total, 199 patients, 153 of whom were antibody positive, enrolled in the trial. The primary endpoint, of demonstrating statistically significant and clinically meaningful improvement over 24 weeks in the MG Activities of Daily Living (MG-ADL) score, was met. Additionally, nipocalimab demonstrated a 75% reduction in median-pre-dose total IgG from baseline, as well as reduction in levels of antibodies such as AChR and MuSK. The safety profile of nipocalimab was also tolerable with no concerning adverse events compared to placebo.

A Biologics License Application has been submitted to the U.S. Food and Drug Administration as well as a Marketing Authorization Application to the European Medicines Agency for approval of this treatment.

Chapters:
Vivacity-MG3 Study Overview 00:00
FcRn Blockers 3:13
Treatment Utilization 4:22
Next Steps 6:25

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David Meeker, MD, Chief Executive Officer of Rhythm Pharmaceuticals, discusses the U.S. Food and Drug Administration’s (FDA) approval of setmelamotide for children 2 years and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS) or genetically confirmed pro-opiomelanocortin (POMC), including proprotein convertase subtilisin/kexin type 1 (PCSK1), deficiency or leptin receptor (LEPR) deficiency.

BBS, POMC, PCSK1, and LEPR deficiencies are rare melanocortin-1 receptor (MC4R) pathway diseases. Common characteristics include hyperphagia, impaired satiety, persistent and abnormal food-seeking behaviors, and early-onset obesity.

Setmelanotide, or Imcivree, is an MC4R agonist that targets the impairment in the hypothalamic MC4R pathway. Activation of this pathway helps increase satiety signals and energy expenditure.

The approval follows results of clinical trials where setmelanotide was observed to significantly and sustainably reduce measures of weight and hunger. Safety and tolerability has also been favorable, with common adverse events being skin hyperpigmentation, injection site reactions, diarrhea, nausea, and headache.

The treatment was originally approved in November 2020 for patients 6 years and older with POMC, PCSK1, and LEPR deficiencies, and June 2022 for patients with BBS.

Chapters:
MC4R Pathway Diseases Overview 00:00
Differences From Prader-Willi Syndrome 3:01
Diagnosis and Genetic Testing 3:57
Setmelanotide Overview 8:04
Clinical Trials 9:53

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Alix Arnaud, Director of Health Economic and Value Assessment BP at Sanofi, discusses the effects of caplacizumab combination therapy in patients with acquired thrombotic thrombocytopenic purpura (TTP).

TTP is a rare blood disorder characterized by low platelets, small areas of bleeding under the skin, low red blood cell count, and hemolytic anemia. TTP causes blood clots to form in small blood vessels throughout the body. These clots can impede blood flow to a variety of orgrans, such as the brain, kidneys, and heart. Complications may include neurological problems (such as personality changes, headaches, confusion, and slurred speech), fever, abnormal kidney function, abdominal pain, and cardiac problems. Acquired TTP usually begins in adulthood, but can affect children. An episode of TTP usually occurs suddenly and lasts for days or weeks, but it may continue for months. Relapses (or flareups) can occur in up to 60% of people who have the acquired TTP. Acquired TTP is caused when a person's body mistakenly makes antibodies that block the activity of the ADAMTS13 enzyme.

Caplacizumab (CPLZ) targets the Willebrand factor, inhibiting the interaction of glycoprotein Ib-IX-V receptors in the platelets. It is approved for the treatment of adults with TTP in combination with plasma exchange (PEX) and immunosuppression (IS).

A literature review was conducted to assess the outcomes of this combination therapy (CPLZ+PEX+IS) in comparison to treatment with plasma exchange and immunosuppression with or without rituximab, in treating TTP.

To ensure comparability, the analysis focused on patients who received frontline CPLZ within 72 hours of PEX initiation, excluding delayed treatment cases. New exacerbation and relapse definitions were adopted to align with evolving treatment standards.

The analysis included 35 publications covering 1,286 CPLZ-treated and 871 control-treated episodes. Due to clinical heterogeneity, random effects models were preferred for pooled estimates. Results demonstrated that CPLZ significantly accelerated platelet count normalization, reducing time to normaliztion by 51% compared to control ( 3.59 vs. 7.36 days). CPLZ also lowered mortality risk, with an estimated number needed to treat 25 patients.

CPLZ shortened hospital stays by 30% (12.31 vs. 17.65 days) and PEX duration by 41% (6.41 vs. 10.92 days). Additionally, it significantly reduced exacerbation rates. While CPLZ was associated with a higher risk of bleeding events, the increase was primarily in minor, manageable cases, with no significant difference in major bleeding risks. Relapse rates at one year did not significantly differ between treatment groups.

These findings reinforce CPLZ’s role in improving key clinical outcomes for TTP patients, highlighting its ability to reduce disease burden while maintaining long-term efficacy.

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Alix Arnaud, Director of Health Economic and Value Assessment BP at Sanofi, discusses the cost of efanesoctocog alfa compared with other Factor VIII replacement therapies for major surgeries in patients with hemophilia A.

Hemophilia A is an inherited bleeding disorder in which the blood does not clot normally. People with hemophilia A will bleed more than normal after an injury, surgery, or dental procedure. Bleeding into the joints, muscles, brain, or organs can cause pain and other serious complications. Hemophilia A is caused by having low levels of a protein called factor VIII, necessary for forming blood clots. The disorder is caused by changes in the F8 gene.

The objective of this analysis was to compare factor consumption and costs associated with major surgeries using four different Factor VIII (FVIII) replacement therapies—octocog alfa, rurioctocog alfa pegol, efmoroctocog alfa, and efanesoctocog alfa. Data were gathered from U.S. prescribing information and Phase 3 clinical trials, with 2024 wholesale acquisition costs (WAC) used for cost estimations.

For octocog alfa, rurioctocog alfa pegol, and efmoroctocog alfa, achieving pre-operative FVIII targets required administration every 8–24 hours, continuing for at least seven days post-surgery. In contrast, efanesoctocog alfa required a single pre-operative loading dose of 50 IU/kg, followed by maintenance doses every 2–3 days.

Median factor consumption per major surgery varied significantly, with median values of 910 IU/kg for octocog alfa, 629 IU/kg for rurioctocog alfa pegol, 493 IU/kg for efmoroctocog alfa, and only 163 IU/kg for efanesoctocog alfa. Corresponding costs followed the same trend, with efanesoctocog alfa demonstrating the lowest perioperative cost at $78,165, compared to $157,339 for octocog alfa, $142,525 for rurioctocog alfa pegol, and $115,747 for efmoroctocog alfa.

Efanesoctocog alfa showed substantial cost savings and reduced factor consumption, using 5.5 times fewer IU than octocog alfa and saving $79,174. Compared to rurioctocog alfa pegol, it used 3.9 times less factor and saved $64,360, while against efmoroctocog alfa, it used three times less factor and saved $37,581.

These findings highlight the potential efficiency of efanesoctocog alfa in reducing both treatment burden and costs for patients with hemophilia A undergoing major surgeries.

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Kelly Knupp, MD, Pediatric Epileptologist at the University of Colorado, discusses the phase 3 EMPEROR clinical trial for pediatric patients with Dravet syndrome.

Dravet syndrome is the most severe of a group of conditions known as SCN1A-related seizure disorders. Symptoms include seizures which first occur in infancy that are often triggered by high temperatures. In childhood, many types of seizures may occur and they may increase in frequency. Seizures may be difficult to treat. Other symptoms include loss of motor skills, intellectual disability, speech impairment, and difficulty with movement. Most cases of Dravet syndrome occur when the SCN1A gene is not working correctly.

The EMPEROR clinical trial will be a phase 3, global, randomized, double-blind, sham-controlled study evaluating zorevunersen in pediatric patients with Dravet syndrome. Protocols have recently been finalized, with plans to initialize the trial mid-2025.

Zorevunersen is an investigational proprietary antisense oligonucleotide designed to upregulate NaV1.1 protein expression by targeting the non-mutant copy of SCN1A gene. It was recently granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration.

The study will evaluate two loading doses of 70mg followed by two maintenance doses of 45mg over 52 weeks compared to sham in patients ages 2-17 years with Dravet syndrome. The primary endpoint is reduction in major motor seizure frequency and key secondary endpoints include improvements in cognition and behavior.

The EMPEROR study follows a phase 1/2a study and open-label extension, where patients experienced an 87% median reduction in seizure frequency following treatment with zorevunersen. Improvements were also observed in cognition and behavior with a generally well-tolerated safety profile.

Chapters:
Introduction 00:00
Dravet Syndrome Overview 00:22
Diagnostic Testing 2:23
Current Management 3:34
Zorevunersen Overview 4:31
EMPEROR Clinical Trial 5:20
Disease Comorbidities 7:00

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Gus Baker, PhD, International Bureau for Epilepsy, discusses a social media listening study looking at the experiences of women of childbearing age with epilepsy.

A social media listening study was conducted to identify key topics of conversation, unmet needs, and emotions of women of childbearing age with epilepsy related to their motherhood journeys.

A total of 245,00 posts across various social media platforms over a 12-month period were analyzed. Keyword filtering was used to identify conversations. These included unintentional and planning pregnancy, conception and fertility, early/late pregnancy and childbirth, and breastfeeding and motherhood. Analysis of conversations surrounding these keywords revealed four key themes:

- Uncertainty and fear surrounding changes to treatment
- Fears and concerns around safety of antiseizure medications on pregnancy
- Difficulty with balancing seizure control and health of pregnancy
- Difficulties in motherhood due to obstacles, barriers, and lack of information

These themes highlight the importance of providing consistent and comprehensive information to women of childbearing age with epilepsy to help them make better informed decisions regarding their treatment and motherhood journeys.

Chapters:
Introduction 00:00
Study Direction 2:06
Study Overview 4:08
Take Home Message 7:04
Social Listening 8:30

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Danya Kaye, UCB Pharma, discusses a study observing the profound burden of prolonged seizures in patients with epilepsy.

The objective of this study was to explore the experiences of people with epilepsy living with prolonged seizures and their caregivers, identify unmet needs, determine greatest areas of burden, and assess the impact of their condition on quality of life. Prolonged seizures are defined as seizures that last two or more minutes and usually do not stop on their own or worsen over time. A pre-interview survey and qualitative interviews were conducted with 35 participants.

Prolonged seizures were observed to cause a range of symptoms. However, the biggest challenges were noted as the impact of prolonged seizures on emotional well-being and mental health, magnified by the impact on caregivers and family units. Anxiety and depression were experienced by 26 of the 29 respondents.

Prolonged seizures were reported as a key driver in worsening quality of life, associated with frequency, emotional impact of emergency response, and recovery period. The recovery process was reported as a challenge due to physical injuries, feeling weak or tired, being unable to return to work or care for others, and other effects of prolonged seizures.

Overall, prolonged seizures were observed to have a profound effect on patients and caregivers, placing a significant burden on patients and their families and negatively affecting quality of life.

Chapters:
Introduction 00:00
Study Objective 00:25
Prolonged Seizures 1:14
Study Presentation 2:26
Take Home Message 6:47
Language Differences 9:09

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Dina Matos, Executive Director of the CARES Foundation, discusses the recent approval of crinecerfont to treat patients with congenital adrenal hyperplasia (CAH) by the U.S. Food and Drug Administration (FDA).

CAH refers to a group of genetic conditions that affect the adrenal glands. Affected people lack an enzyme the adrenal glands need to make one or more of these hormones and often overproduce androgens. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after. People with milder forms may not be diagnosed with the condition until adolescence or adulthood when they experience early signs of puberty or fertility problems.

The FDA has recently approved crinecerfont capsules and oral solution for glucocorticoid replacement treatment in patients with classic CAH. Crinecerfont is a potent and selective oral corticotropin-releasing factor type 1 receptor antagonist. It is the first and only classic CAH treatment that directly reduces excess ACTH and downstream adrenal androgen production.

The FDA approval follows results from the CAHtalyst pediatric and adult phase 3 global registrational studies. In both studies, crinecerfont was observed to enable lower steroid doses and decreased androgen levels. Both studies met their primary endpoints. Additionally, crinecerfont was well-tolerated with few adverse effects.

Chapters:
Introduction 00:00
CAH Overview 00:58
Diagnostic Journey 2:41
Crinecerfont Overview 5:20
Next Steps 7:19

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Hugues Chanteaux, PhD, Quantitative Clinical Pharmacology Lead at UCB, discusses results from a study evaluating two different routes of alprazolam administration, inhaled (“Staccato") versus oral administration in patients with acute seizures.

NCT05626439 was a phase 1, single center, open-label, randomized, single-dose, 2-way crossover study evaluating Staccato alprazolam 2 mg versus oral alprazolam 2 mg in healthy adult participants. Staccato alprazolam uses a handheld device that can provide rapid systemic delivery of the treatment via inhalation. Alprazolam is a benzodiazepine that binds to the GABA-A receptor that mediates calming or inhibitory effects on the nervous system.

A total of 21 participants were randomized in the study. The Staccato device enabled rapid systemic delivery of alprazolam, achieving clinically relevant plasma concentrations within 2 minutes post-dose, compared to 45 minutes for oral administration. The peak concentration of Staccato alprazolam 2 mg was higher than oral alprazolam 2 mg, though overall drug exposure was lower. Distribution and elimination were similar between both methods, with inhalation showing significantly faster absorption. Urinary excretion of unchanged alprazolam was minimal for both forms. These findings suggest that the Staccato device is an efficient delivery method for acute seizure treatment.

Chapters:
Introduction 00:00
Clinical Trial 00:27
Implications for Practitioners 1:54

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