Clinical News: June 2024

June 28, 2024

Your monthly source for drug information highlights

Clinical News

Your monthly source for drug information highlights

Hot topic

MDMA-ASSISTED THERAPY FOR PTSD REJECTED BY FDA PANEL

The U.S. Food and Drug Administration’s (FDA) Psychopharmacologic Drugs Advisory Committee convened in early June 2024 to review the NDA for midomafetamine (MDMA) capsules in combination with psychological intervention (“MDMA-assisted therapy”) for the treatment of post-traumatic stress disorder (PTSD) in adults. The committee voted 9 to 2 against the available data showing that MDMA is effective in patients with PTSD. The committee also voted 10 to 1 against whether the benefits of MDMA with the FDA’s proposed Risk Evaluation and Mitigation Strategies (REMS) outweigh the risks. Although the FDA is not required to follow its advisory panels’ guidance, it is usually taken into consideration during the decision process. A decision regarding approval of MDMA capsules is expected by the Prescription Drug User Fee Act (PDUFA) date of August 11, 2024. MDMA, also known as “molly” or “ecstasy,” is administered orally in a clinic and acts on multiple neurotransmitters (e.g., serotonin, noradrenaline, dopamine) potentially alleviating fear responses and allowing for trauma-focused therapy sessions.

The committee reviewed data from two randomized, double-blind, placebo-controlled, phase 3 studies (Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD [MAPP1 and MAPP2]) assessing MDMA in combination with psychological intervention (e.g., psychotherapy, other services provided by a qualified HCP) versus placebo in combination with psychological intervention in 194 adults with severe or moderate to severe PTSD. The Institute for Clinical and Economic Review (ICER) also reviewed the results from these two short-term studies and performed a meta-analysis of the data, which is detailed in ICER’s Revised Evidence Report. Compared with the control arm, patients receiving MDMA-assisted therapy were more likely to be treatment responders (relative risk [RR], 1.32) as well as achieve a loss of diagnosis of PTSD (RR, 1.7) and meet criteria for PTSD remission (RR, 2.86). However, ICER has raised substantial concerns regarding the validity of the results. Per ICER, due to the physiological effects of MDMA, patients in the MDMA study arm were in essence unblinded as most could correctly determine they had received the MDMA-assisted therapy. The potential for bias was further enhanced as experts stated the investigators, therapists, and patients involved in the trial held very strong beliefs regarding the efficacy of MDMA-assisted therapy, and therapists involved in the study persuaded favorable patient reports and dissuaded negative patient reports. This could potentially include the discouragement of substantial harm from the therapy, impacting the benefits versus risks analysis. ICER was only able to perform a limited review of these concerns and was unable to determine the frequency of misreporting. As a result, ICER concluded evidence for MDMA-assisted therapy is insufficient. Furthermore, MDMA-assisted therapy could not be adequately compared with trauma-focused psychotherapies due to insufficient evidence. The final ICER Evidence Report on MDMA-assisted therapy for PTSD is expected on June 27, 2024.

More trending topics

BEHAVIORAL HEALTH CORNER

According to data from the 2022 National Survey of Children’s Health (NSCH), 11.4% of children in the U.S. (7.1 million) have received an attention-deficit/hyperactivity disorder (ADHD) diagnosis and 10.5% (6.5 million) currently have ADHD. Estimates are for children 3 to 17 years of age and demonstrate about one million more children having ever received an ADHD diagnosis in 2022 compared with 2016. Most children currently diagnosed have at least one co-occurring disorder (77.9%) and more than half (58.1%) have moderate to severe ADHD. Almost a third (30.1%) of children with current ADHD have not received any ADHD-specific therapy; however, 44.4% had received behavioral therapy in the past year and 53.6% (3.4 million children) received ADHD medication. ADHD medication use was lower in children 3 to 5 years of age (23.6%) compared with children 6 to 11 years of age (56.9%) and adolescents aged 12 to 17 years (53.4%). Medication use was also greater in children with moderate (59.7%) and severe (77.9%) ADHD compared to children with mild ADHD (39.7%). Although the overall prevalence of children receiving behavioral therapy for ADHD in the prior year was lower than those who were taking medication, when behavioral therapy for ADHD was combined with any mental health counseling, the proportion of patients (58.3%) was comparable to the proportion receiving medication. ADHD is one of the most common neurodevelopmental disorders in pediatric patients in the U.S. and is an increasing public health concern.

Shortages of stimulants for the treatment of ADHD continue to be reported. Availability of generic methylphenidate HCl extended-release (ER) tablets is variable depending on the manufacturer. Brand-name Relexxi from Vertical as well as brand-name Concerta from Janssen are currently available. Shortages of the generic version of Vyvanse, lisdexamfetamine dimesylate capsules and chewable tablets persist. Brand-name Vyvanse capsules and chewable tablets remain available from Takeda. Generic amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate immediate release (IR) tablet shortages also continue from a few manufacturers. Brand name Adderall IR tablets from Teva are available.

CLINICAL CORNER

The FDA has issued an alert regarding labeling updates for glatiramer acetate injection (Copaxone, Glatopa) including a new warning that states using an autoinjector that is incompatible with a specific glatiramer acetate injection product can increase the risk for dosing errors (e.g., missed dose, partial dose). Some glatiramer acetate injection products can be administered using an optional compatible autoinjector; however, other products require injection using the prefilled syringe. Patients should confirm their autoinjector is compatible each time a new prescription for glatiramer acetate is received.

COVID-19 NOTABLE DEVELOPMENTS

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened on June 5, 2024 and voted unanimously for the 20242025 COVID-19 vaccines to contain the monovalent JN.1 lineage. Following the advisory meeting, on June 6, 2024, the FDA initially advised manufacturers of COVID-19 vaccines approved and authorized in the U.S. that beginning in fall 2024 the vaccines should be monovalent JN.1 vaccines. However, with continued monitoring of the circulating strains, the FDA subsequently determined the preferred JN.1-lineage for the 2024-2025 formula COVID-19 vaccine is the KP.2 strain to align more closely with currently circulating SARS-CoV-2 viruses. The change to KP.2 is not expected to delay availability of the vaccines.

FDA SPOTLIGHT
  • The FDA has released the 11th annual report on drug shortages that is annually submitted to Congress. For the 2023 calendar year, 55 new drug shortages occurred and 236 were prevented.
  • The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee convened on June 10, 2024 to discuss the BLA for Eli Lilly’s investigational IV donanemab. The committee voted unanimously in favor of approval of the monoclonal antibody for the treatment of early Alzheimer’s disease.
  • The FDA has announced the Oncology Center of Excellence Equity Program, a public health initiative intended to enhance access to clinical studies of oncology products for underrepresented populations. Targeted populations include racial and ethnic minorities, those who live in rural areas, sexual/gender minorities, and those with barriers (e.g., economic, linguistic, cultural) to health care services.
  • The agency has launched a new campaign, “Prescribe with Confidence”, to aid in awareness about opioid use disorder (OUD) and facilitate access to evidence-based resources for HCPs. The intent of the campaign is to increase the number of HCPs who can recognize OUD and prescribe medication to treat OUD as appropriate.
WEIGHT MANAGEMENT CORNER

The American Heart Association (AHA) has published a Presidential Advisory forecasting the extent of cardiovascular disease (CVD) and stroke expected in the U.S. through 2050. It is estimated more than 61% of U.S. adults (> 184 million individuals) will likely have CVD including hypertension by 2050. Diabetes rates are expected to increase from roughly 16% to over 26%. Moreover, obesity rates are anticipated to increase from about 43% to over 60%, with adults 20–64 years of age, the hardest hit due to unhealthy diets. A third of children are expected to have obesity in 2050 with 2- to 5-year-olds predicted to have the largest increase in obesity. Lack of exercise and poor diets are each contributing factors in up to 60% of all children.

Long-term data from the SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity; n=17,604) showed that with semaglutide 2.4 mg SC once weekly, weight loss continued to week 65 and then weight was sustained through week 208 (sustained average change, -10.18%). Furthermore, a secondary analysis on kidney outcomes in patients with overweight or obesity and established CVD without diabetes mellitus who were enrolled in the SELECT trial found that after a median follow-up of 182 weeks, the main composite kidney endpoint occurred in 1.8% of participants taking semaglutide 2.4 mg SC once weekly compared to 2.2% of patients on placebo (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63 to 0.96; p=0.02). This composite endpoint was defined as death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m², persistent ≥ 50% reduction in eGFR versus baseline, or onset of persistent macroalbuminuria.

Shortages of GLP-1 agonists that are indicated for select patients as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management are being reported by the FDA. Novo Nordisk’s liraglutide (Saxenda) has limited availability as does the liraglutide (Victoza) formulation indicated for select patients with type 2 diabetes mellitus (T2DM). Eli Lilly’s tirzepatide (Zepbound) has limited availability in some strengths, as does the tirzepatide (Mounjaro) formulation indicated as an adjunct to diet and exercise in adults with T2DM. The GLP-1 agonist dulaglutide (Trulicity), indicated for select patients with T2DM, also has limited availability in some strengths.

BEHAVIORAL HEALTH CORNER

According to data from the 2022 National Survey of Children’s Health (NSCH), 11.4% of children in the U.S. (7.1 million) have received an attention-deficit/hyperactivity disorder (ADHD) diagnosis and 10.5% (6.5 million) currently have ADHD. Estimates are for children 3 to 17 years of age and demonstrate about one million more children having ever received an ADHD diagnosis in 2022 compared with 2016. Most children currently diagnosed have at least one co-occurring disorder (77.9%) and more than half (58.1%) have moderate to severe ADHD. Almost a third (30.1%) of children with current ADHD have not received any ADHD-specific therapy; however, 44.4% had received behavioral therapy in the past year and 53.6% (3.4 million children) received ADHD medication. ADHD medication use was lower in children 3 to 5 years of age (23.6%) compared with children 6 to 11 years of age (56.9%) and adolescents aged 12 to 17 years (53.4%). Medication use was also greater in children with moderate (59.7%) and severe (77.9%) ADHD compared to children with mild ADHD (39.7%). Although the overall prevalence of children receiving behavioral therapy for ADHD in the prior year was lower than those who were taking medication, when behavioral therapy for ADHD was combined with any mental health counseling, the proportion of patients (58.3%) was comparable to the proportion receiving medication. ADHD is one of the most common neurodevelopmental disorders in pediatric patients in the U.S. and is an increasing public health concern.

Shortages of stimulants for the treatment of ADHD continue to be reported. Availability of generic methylphenidate HCl extended-release (ER) tablets is variable depending on the manufacturer. Brand-name Relexxi from Vertical as well as brand-name Concerta from Janssen are currently available. Shortages of the generic version of Vyvanse, lisdexamfetamine dimesylate capsules and chewable tablets persist. Brand-name Vyvanse capsules and chewable tablets remain available from Takeda. Generic amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate immediate release (IR) tablet shortages also continue from a few manufacturers. Brand name Adderall IR tablets from Teva are available.

CLINICAL CORNER

The FDA has issued an alert regarding labeling updates for glatiramer acetate injection (Copaxone, Glatopa) including a new warning that states using an autoinjector that is incompatible with a specific glatiramer acetate injection product can increase the risk for dosing errors (e.g., missed dose, partial dose). Some glatiramer acetate injection products can be administered using an optional compatible autoinjector; however, other products require injection using the prefilled syringe. Patients should confirm their autoinjector is compatible each time a new prescription for glatiramer acetate is received.

COVID-19 NOTABLE DEVELOPMENTS

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) convened on June 5, 2024 and voted unanimously for the 20242025 COVID-19 vaccines to contain the monovalent JN.1 lineage. Following the advisory meeting, on June 6, 2024, the FDA initially advised manufacturers of COVID-19 vaccines approved and authorized in the U.S. that beginning in fall 2024 the vaccines should be monovalent JN.1 vaccines. However, with continued monitoring of the circulating strains, the FDA subsequently determined the preferred JN.1-lineage for the 2024-2025 formula COVID-19 vaccine is the KP.2 strain to align more closely with currently circulating SARS-CoV-2 viruses. The change to KP.2 is not expected to delay availability of the vaccines.

FDA SPOTLIGHT

  • The FDA has released the 11th annual report on drug shortages that is annually submitted to Congress. For the 2023 calendar year, 55 new drug shortages occurred and 236 were prevented.
  • The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee convened on June 10, 2024 to discuss the BLA for Eli Lilly’s investigational IV donanemab. The committee voted unanimously in favor of approval of the monoclonal antibody for the treatment of early Alzheimer’s disease.
  • The FDA has announced the Oncology Center of Excellence Equity Program, a public health initiative intended to enhance access to clinical studies of oncology products for underrepresented populations. Targeted populations include racial and ethnic minorities, those who live in rural areas, sexual/gender minorities, and those with barriers (e.g., economic, linguistic, cultural) to health care services.
  • The agency has launched a new campaign, “Prescribe with Confidence”, to aid in awareness about opioid use disorder (OUD) and facilitate access to evidence-based resources for HCPs. The intent of the campaign is to increase the number of HCPs who can recognize OUD and prescribe medication to treat OUD as appropriate.

WEIGHT MANAGEMENT CORNER

The American Heart Association (AHA) has published a Presidential Advisory forecasting the extent of cardiovascular disease (CVD) and stroke expected in the U.S. through 2050. It is estimated more than 61% of U.S. adults (> 184 million individuals) will likely have CVD including hypertension by 2050. Diabetes rates are expected to increase from roughly 16% to over 26%. Moreover, obesity rates are anticipated to increase from about 43% to over 60%, with adults 20–64 years of age, the hardest hit due to unhealthy diets. A third of children are expected to have obesity in 2050 with 2- to 5-year-olds predicted to have the largest increase in obesity. Lack of exercise and poor diets are each contributing factors in up to 60% of all children.

Long-term data from the SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity; n=17,604) showed that with semaglutide 2.4 mg SC once weekly, weight loss continued to week 65 and then weight was sustained through week 208 (sustained average change, -10.18%). Furthermore, a secondary analysis on kidney outcomes in patients with overweight or obesity and established CVD without diabetes mellitus who were enrolled in the SELECT trial found that after a median follow-up of 182 weeks, the main composite kidney endpoint occurred in 1.8% of participants taking semaglutide 2.4 mg SC once weekly compared to 2.2% of patients on placebo (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.63 to 0.96; p=0.02). This composite endpoint was defined as death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m², persistent ≥ 50% reduction in eGFR versus baseline, or onset of persistent macroalbuminuria.

Shortages of GLP-1 agonists that are indicated for select patients as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management are being reported by the FDA. Novo Nordisk’s liraglutide (Saxenda) has limited availability as does the liraglutide (Victoza) formulation indicated for select patients with type 2 diabetes mellitus (T2DM). Eli Lilly’s tirzepatide (Zepbound) has limited availability in some strengths, as does the tirzepatide (Mounjaro) formulation indicated as an adjunct to diet and exercise in adults with T2DM. The GLP-1 agonist dulaglutide (Trulicity), indicated for select patients with T2DM, also has limited availability in some strengths.

Drug information happenings & highlights

DRUG INFORMATION HIGHLIGHTS

  • In the FLOW trial, 3,533 patients with T2DM and chronic kidney disease were randomized to either semaglutide (Ozempic) 1 mg SC weekly or placebo and were followed for a median of 3.4 years, after early trial cessation based on a prespecified interim analysis. The risk of a primary outcome event (composite of onset of kidney failure, ≥ 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular [CV] causes) was reduced by 24% with semaglutide versus placebo (331 versus 410 first events; HR, 0.76, 95% CI, 0.66 to 0.88, p=0.0003). Confirmatory secondary outcomes also showed a benefit of semaglutide, and serious adverse reactions occurred in fewer patients in the semaglutide arm than placebo (49.6% versus 53.8%).
  • The CDC has recommended influenza surveillance systems continue to operate at heightened levels during the summer to aid in detection of rare cases of human H5N1 virus infection. Furthermore, the agency recommends an increase in the number of positive influenza A virus samples subtyped. The intent of the increased monitoring through the summer is due to the ongoing outbreak of H5N1 among poultry and U.S. dairy cattle.
  • The CDC has published an MMWR outlining recommendations for use of doxycycline postexposure prophylaxis (PEP) for bacterial sexually transmitted infection prevention in select populations. The recommended dose for doxycycline PEP is 200 mg taken within 72 hours of sexual contact.
  • Sanofi-Aventis has announced discontinuation of insulin glargine 100 IU/mL injection, an unbranded biologic for Lantus, due to a business decision. Lantus remains on the market.
  • Actelion/Philips Respironics has announced discontinuation of the I-neb® AAD® system as well as associated supplies (e.g., medication discs used for administering the solution). Iloprost (Ventavis) solution in the strengths of 10 ug/mL and 20 ug/mL is also being discontinued.
  • Par has announced discontinuation of the 40 mg/1 mL strength of brand-name Delestrogen (estradiol valerate) injection. Generics from other manufacturers remain available.

DRUG INFORMATION HAPPENINGS

  • The AHA and American College of Cardiology (ACC) published updated recommendations for management of lower extremity peripheral artery disease (PAD). The guideline defines four clinical subsets of PAD (asymptomatic PAD, chronic symptomatic PAD, chronic limb-threatening ischemia, acute limb ischemia) and details effective treatment to prevent major adverse CV events and major adverse limb events.
  • The American Academy of Neurology (AAN), American Epilepsy Society, and Society for Maternal-Fetal Medicine has issued a guideline for use of antiseizure medications (ASMs) in people with epilepsy of childbearing potential (PWECP). According to the guideline, HCPs should recommend ASMs and doses that optimize seizure control and fetal outcomes at the earliest possible opportunity prior to conception. To reduce the risk for major congenital malformations, lamotrigine, levetiracetam, or oxcarbazepine should be considered when appropriate, and valproic acid should be avoided when possible.
  • The European Society of Endocrinology and the Endocrine Society have released a clinical guideline for diagnosis and management of glucocorticoid-induced adrenal insufficiency. The guideline includes recommendations for tapering of systemic glucocorticoid therapy for non-endocrine conditions, diagnosis and approach to glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome, and diagnosis and treatment of adrenal crisis.
  • The ACC and the AHA published updated clinical practice guidelines for the management of hypertrophic cardiomyopathy (HCM). New recommendations include: (1) for younger patients (e.g., age ≤ 45 years of age) with a mild phenotype of nonobstructive HCM due to a pathogenic or likely pathogenic cardiac sarcomere genetic variant, valsartan may be useful to slow unfavorable cardiac remodeling; (2) in patients with HCM who develop persistent systolic dysfunction with LVEF < 50%, discontinue cardiac myosin inhibitors; and (3) mavacamten is contraindicated in pregnant women due to potential teratogenic effects.

The content in this publication is not a substitute for professional medical advice. For questions regarding any medical condition or if you need medical advice, please contact your health care provider.

All brand names are property of their respective owners.

Glossary

BLA = Biologics License Application

CDC = Centers for Disease Control and Prevention

COVID-19 = coronavirus 2019

GLP-1 = glucagon-like peptide-1

HCl = hydrochloride

HCP = health care professional

IV = intravenous

LVEF = left ventricular ejection fraction

MMWR = Morbidity and Mortality Weekly Report

NDA = New Drug Application

SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2

SC = subcutaneous

Editorial team

EDITOR-IN-CHIEF: Maryam Tabatabai, PharmD

EXECUTIVE EDITOR: Anna Schreck Bird, PharmD

DEPUTY EDITORS: Erik Hamel, PharmD; Olivia Pane, PharmD, CDCES

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