Susan Haigney

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FDA announced on July 17, 2024 that Endo Inc.’s subsidiary, Endo USA, is voluntarily recalling one lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV) 0.25 mg tablets (also seen as Clonazepam Orally Disintegrating Tablets, USP (C-IV) 0.125 tablets 60-count) because an incorrect strength appears on the cartons of some packs. The product strength is listed as 0.125 mg and not 0.25 mg. The error was made by a third-party packager. The inside blister strips have the correct strength of 0.25 mg noted.

The recalled lot, which was distributed through wholesale distributors to retail pharmacies nationwide,includes Clonazepam Orally Disintegrating Tablets, USP 0.25 mg 60-count carton, lot 550147301, expiration date August 2026, and Clonazepam Orally Disintegrating Tablets, USP 0.125 mg 60-count carton, lot 550147301, expiration date August 2026; National Drug Code (NDC) number 49884-306-02. The product is packaged in cartons of 60 tablets.

Clonazepam Orally Disintegrating Tablets are used as an adjunct in the treatment of the Lennoz-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures, as well as panic disorders. Significant sedation, dizziness, ataxia, and confusion may result in children and adults who take a larger dose than prescribed. There is potential for life-threatening respiratory depression, especially in patients with concomitant pulmonary disease, patients prescribed doses near the maximum dosing allowed, and patients taking other medications. “In the event that a patient inadvertently took a 0.25 mg dose rather than the intended 0.125 mg dose, they are advised to consult a physician,” the company stated in the press release (1).

The company stated it has not yet received any reports of adverse events related to the recall. Adverse events may be reported to FDA through its MedWatch program.

Written notification is being sent to wholesale distributors and retailers so that the impacted lot can be returned. “Consumers in possession of any unused prescribed 60 tablet cartons of Clonazepam Orally Disintegrating tablets, USP 0.25mg, which may also appear as Clonazepam Orally Disintegrating tablets USP 0.125mg bearing the lot number 550147301 have been advised to discontinue use of the product,” the company stated in the release.

Recalls can result in quality issues that impact drug supplies. In February 2024, FDA’s Center for Drug Evaluation and Research (CDER) released its report, 

. The report describes the center’s key safety programs and activities involved in promoting and protecting public health (2). Postmarketing surveillance and risk evaluations are performed by FDA on products to identify new adverse events that were not present in the approval process. New information is investigated by the agency and may require changes in prescribing information or modification of a Risk Evaluation and Mitigation Strategy. CDER’s pharmacovigilance efforts in 2023 included reviews of 15 newly identified safety signals (NISS). One of these NISS was related to naloxone hydrochloride product administration. There were attempts to administer a syringe that had no needle. In response, FDA required changes to carton labeling to include a warning that said, “Needle not included.”

FDA. Endo USA, Inc. Issues Voluntary, Nationwide Recall of One Lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV) Lot Number 550147301 Due to Mislabeling: Incorrect Strength on Product Carton. Press Release, July 17, 2024. 

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/endo-usa-inc-issues-voluntary-nationwide-recall-one-lot-clonazepam-orally-disintegrating-tablets-usp

Haigney, S. FDA’s Drug Safety Priorities for 2023. 

https://www.pharmtech.com/view/fda-s-drug-safety-priorities-for-2023

Articles

The company has issued a voluntary recall of one lot of Clonazepam Orally Disintegrating Tablets, USP (C-IV), because of incorrect strength published on product carton.

Endo Recalls Clonazepam Because of Mislabeling

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Lantheus Holdings, a radiopharmaceutical company, announced on July 15, 2024 that it has acquired Meilleur Technologies. The acquisition includes the worldwide exclusive rights to ß amyloid positron emission tomography (PET) imaging agent, NAV-4694, expanding Lantheus’ Alzheimer’s disease pipeline. Currently in Phase III development, NAV-4694 is being used in both academic and industry trials and complements Lantheus’ next-generation F18-labeled PET imaging agent candidate, MK-6240, which targets tau tangles in Alzheimer’s disease (AD).

Lantheus will provide upfront payments as part of the acquisition agreement. Additional development and commercial milestone and royalty payments will be made by Lantheus. The sellers will provide transition and clinical development services for a time after the agreement closes.

“We are excited by the potential of NAV-4694 for earlier identification of Alzheimer’s patients, empowering clinicians to select suitable candidates for timely therapeutic interventions,” said Rick Hiatt, chief executive officer, Meilleur Technologies, in a press release. “With Lantheus’ expertise in radiopharmaceutical diagnostics and ability to scale operations, I am confident that Lantheus is the ideal company to bring this late-stage biomarker through pivotal trials and into commercialization to one day benefit patients at risk of Alzheimer’s disease.”

A degenerative neurological disease, Alzheimer’s impacts nearly 12 million people in the United States, with numbers expected to increase to more than 20 million by 2050 (1,2). The National Institute on Aging and the Alzheimer’s Association recommend that protein-based biomarkers, including both amyloid- and tau-PET imaging, may be used to diagnose Alzheimer’s (1,3).

Both industry and the public have had an invested interest in finding treatments for Alzheimer’s. In March 2024, FDA issued a 

for developing treatments for early Alzheimer’s (4). The purpose of the guidance document is to assist sponsors who are in the clinical phases of development of drugs for treating the stages of sporadic Alzheimer’s disease that occur before dementia becomes overt. FDA states in the document that there has been an effort to use biomarkers that reflect underlying AD pathophysiological changes and to include study subjects with early Alzheimer’s. “These efforts are particularly important because there may be an opportunity to intervene very early in the disease process of AD, given the slowly progressive course of AD and the development of characteristic pathophysiological changes that greatly precede the development of clinically evident findings,” the document states. “Delaying or, preferably, halting or reversing the pathophysiological process that will lead to the initial clinical deficits of AD is the ultimate goal of presymptomatic or very early symptomatic intervention, and treatment directed at this goal must begin before there are overt clinical symptoms. This opportunity carries with it the need to understand ways to assess treatment benefit in these earlier stages of disease” (5).

In July 2024, the agency approved a once-monthly monoclonal antibody injection for intravenous infusion to treat adults with early symptomatic AD, including those with mild cognitive impairment or who are in the mild dementia stage of the disease with confirmed amyloid pathology (6). The therapy targets amyloid plaques, excessive buildup of which in the brain can result in thinking or memory issues consistent with AD (6).

Lantheus. Lantheus Acquires NAV-4694, a Next-Generation ß Amyloid PET Imaging Agent for Alzheimer’s Disease. Press Release. July 15, 2024. 

https://investor.lantheus.com/news-releases/news-release-details/lantheus-acquires-nav-4694-next-generation-ss-amyloid-pet

Alzheimer’s Association. 2024 Alzheimer’s Disease Facts and Figures. 

Jack CR, et.al. Revised Criteria for Diagnosis and Staging of Alzheimer's Disease: Alzheimer's Association Workgroup. 

Haigney, S. FDA Give Guidance on Developing Treatments for Early Alzheimer’s. 

Early Alzheimer’s Disease: Developing Drugs for Treatment, Guidance for Industry, Draft Guidance

Eli Lilly and Company. Lilly's Kisunla (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease. Press Release. July 2, 2024.

The acquisition provides Lantheus with worldwide exclusive rights to ß amyloid PET imaging agent, NAV-4694, for its Alzheimer’s disease diagnostic and treatment portfolio.

Lantheus Acquires Meilleur Technologies, PET Imaging Agent

The European Medicines Agency (EMA) announced on July 12, 2024 that its Pharmacovigilance Risk Assessment Committee (PRAC) has recommended that patients who take glucagon-like peptide-1 receptor agonists (GLP-1 RAs) treatment for type 2 diabetes and obesity consider the risk of aspiration and pneumonia aspiration before going under general anesthesia or deep sedation.

After reviewing data from EudraVigilance case reports, scientific literature, and clinical and non-clinical data, PRAC was unable to find a causal link between GLP-1 analogues and aspiration; however, the committee decided to issue the risk recommendation because GLP-1 RAs create delayed gastric emptying. “[Because of] the presence of clinical trial cases and post marketing cases, the PRAC considered that healthcare professionals and patients should be informed on this potential consequence of delayed gastric emptying,” the committee stated in a press release (1). Product information will be updated to include a warning for patients to inform their doctor if they are using GLP-1 RAs before scheduling surgery or going under deep sedation.

Back in April 2024, PRAC reviewed the potential risk of suicidal tendencies in patients taking GLP-1 RAs but found no link. The review was done after reports were received of users of liraglutide and semaglutide having thoughts of suicide and self-harm. “After reviewing the available evidence from non-clinical studies, clinical trials, post-marketing surveillance data and the available studies, the PRAC considers that no update to the product information is warranted. The marketing authorization holders for these medicines will continue to monitor these events closely, including any new publications, as part of their pharmacovigilance activities and report any new evidence on this issue in their Periodic Safety Update Reports (PSURs),” EMA stated in a press release (2).

PRAC also warned about the possibility of anaphylactic reactions occurring years after treatment initiation of glatiramer acetate, which is used to treat relapsing forms of multiple sclerosis (1). After reviewing data from the European Union, the committee concluded that glatiramer acetate is associated with anaphylactic reactions that can happen immediately or months, or years, after treatment. According to EMA, there have been reports of fatalities. A direct healthcare professional communication to inform healthcare professionals about the risk will be issued. Treatment must be discontinued if a reaction occurs, according to PRAC.

In addition to these two risk recommendations, PRAC announced at its July 2024 meeting that it has selected a new chair, Ulla Wändel Liminga. A pharmacist by training, Liminga is a trained pharmacist from Sweden who is scientific director of Pharmacovigilance at the Swedish Medical Products Agency–MPA. Liminga has expertise in pharmacology, toxicology and pharmacovigilance and has been a PRAC delegate since 2012. PRAC’s previous chair, Sabine Straus, retired as chair after serving for two three-year mandates.

“As a chair, I want to build on the collective experience of PRAC and continue to ensure that our outcomes are proportionate and robust, and that patient safety and public health remain our priority,” Liminga said in a press release (3). “The critical factors to continued success in an ever-evolving internal and external environment will be a continued focus on high-quality scientific assessments and close collaboration withinPRAC, with EMA and its committees, and the EU regulatory network.”

EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 July 2024. Press Release. July 12, 2024. 

https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-july-2024#contact-point-68561

EMA Statement on Ongoing Review of GLP-1 Receptor Agonists

EMA. EMA’s Safety Committee Elects New Chair. Press Release. July 11, 2024. https://www.ema.europa.eu/en/news/emas-safety-committee-elects-new-chair

PRAC is recommending that patients who use glucagon-like peptide-1 receptor agonists (GLP-1 RAs) consider the risk of delayed gastric emptying before undergoing surgery with general anesthesia or deep sedation.

EMA’s PRAC Offers Recommendations for Glucagon-like Peptide-1 Receptor Agonists and Glatiramer Acetate

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GSK announced on July 3, 2024 that it has restructured its existing collaboration with CureVac into a new licensing agreement that will focus on messenger RNA (mRNA) development. The two companies have collaborated since 2020 on mRNA vaccines for infectious diseases and have vaccine candidates for influenza and COVID-19 in Phase II clinical development. There is also an avian influenza vaccine in Phase I development.

Under the agreement, GSK will gain full rights to develop, manufacture, and commercialize mRNA vaccine candidates for influenza and COVID-19 globally. CureVac will receive €400 million (US$432.34 million) upfront with an additional €1.05 billion (US$1.133 billion) in milestone payments and tiered royalties. Previous financial considerations from the prior collaboration have been replaced. CureVac will retain exclusive rights to additional undisclosed and preclinically validated infectious disease targets and will be able to independently develop and partner mRNA vaccines in any other infectious disease or other indication.

GSK has invested in vaccine platform technologies and sees mRNA as an adaptable vaccine technology that can be applied to changing viral pathogens because of its ability to support rapid strain change. The company intends to continue to develop mRNA capabilities through partnerships, artificial intelligence/machine learning-based sequence optimization, nanoparticle design, and manufacturing.

“We are excited about our flu/COVID-19 programs and the opportunity to develop best-in-class mRNA vaccines to change the standard of care. With this new agreement, we will apply GSK’s capabilities, partnerships and intellectual property to CureVac’s technology, to deliver these promising vaccines at pace,” Tony Wood, chief scientific officer at GSK, said in a press release (1).

“The collaboration with GSK has been instrumental in developing promising, late clinical-stage vaccine candidates, leveraging our proprietary mRNA platform. This new licensing agreement puts us in a strong financial position and enables us to focus on efforts in building a strong R&D pipeline,” Alexander Zehnder, chief executive officer, CureVac, said in the release.

CureVac also announced on July 3, 2024 that it was restructuring its strategy to focus on high-value mRNA projects in oncology and areas of unmet needs. The restructuring includes a reduction in workforce and refocused technology innovation, research, and development. The company plans to have operational expenses decrease more than 30% from 2025 onward as a result of the restructuring.

“We have achieved remarkable progress in advancing our mRNA platform, evidenced by promising Phase II data for influenza and COVID-19 and the recent licensing agreement with GSK,” Zehnder said in a press release (2). “Now, we can embark on a new chapter for CureVac. The new GSK agreement not only provides substantial financing but also allows us to streamline our operations and focus on technology innovation, research, and development. It enables us to prioritize our oncology programs and further leverage our technology in other areas where mRNA is uniquely suited to develop novel treatment approaches. While the approximately 30% workforce reduction is a difficult decision on a personal level, I am convinced that this is a necessary step to ensure the long-term success of CureVac. As we implement this change, we are grateful to all our employees for their dedication, passion and commitment in advancing mRNA-based therapies to patients.”

GSK and CureVac to Restructure Collaboration into New Licensing Agreement

. Press Release. July 3, 2024.
2. CureVac. 

CureVac Initiates Strategic Restructuring to Algin Resources with Focus on High-Value mRNA Pipeline Opportunities

The companies have restructured their existing collaboration into a licensing agreement that invests in mRNA development.

GSK and CureVac Enter into Licensing Agreement

The European Medicines Agency (EMA) announced on June 28, 2024 that its Committee for Medicinal Products for Human Use (CHMP) recommended 10 medicines for marketing approval in June. The approvals included the first nasal spray form of epinephrine, a biosimilar to treat autoimmune diseases, two generic medicines, and treatments for cancer.

Maybe most notable of the positive opinions is for Eurneffy (epinephrine), which is the first emergency treatment for allergic reactions administered through the nose. Epinephrine treats anaphylaxis, a severe allergic reaction that could result in death, and is traditionally administered via injection. According to EMA, a fear of needles may delay administration of the drug, making nasal delivery more appealing. Adrenaline delivered through a nasal spray is quickly absorbed through the nasal mucosa and distributed in the body.

Eurneffy was evaluated in 537 people aged 19–55 years of age in 14 clinical trials that compared Eurneffy with injectable adrenaline to review blood pressure, heart rate, absorption, and removal from the body. According to the EMA, results from adrenaline delivered through a nasal spray were comparable to intramuscular injected adrenaline. While there were no significant adverse reactions reported during studies, CHMP did recommend additional risk minimization to prevent potential inappropriate use of the product (1).

CHMP also recommended Winrevair (sotatercept) for the treatment of pulmonary arterial hypertension (PAH), in combination with other specific PAH therapies, to improve exercise capacity in adults. The first activin signaling inhibitor therapy approved to treat PAH, according to EMA, sotatercept is administered every three weeks as a single injection. It is a copy of the activin receptor, ActRIIA, which is over-active in patients with PAH. In mimicking the ActRIIA receptor, sotatercept prevents activin from attaching to these receptors and activating them, therefore regulating the growth of new blood vessel cells in the lungs.

“Pulmonary arterial hypertension is a rare, long-term, debilitating and life-threatening condition in which patients have abnormally high blood pressure in the arteries in the lungs. Many patients experience breathing difficulty that limits their physical activity. Despite approved therapies, long-term prognosis remains poor: it is estimated that around 50% of patients will die within five to seven years after diagnosis,” EMA stated in a press release (2).

In addition to these positive opinions, CHMP also recommended the first messenger RNA (mRNA) vaccine targeting a different pathogen than SARS-CoV-2. mResvia (respiratory syncytial virus [RSV] mRNA vaccine) was approved to treat adults 60 years of age and older with lower respiratory tract disease and acute respiratory disease caused by RSV.

Treatments approved for cancers included Balversa (erdafitinib), to treat of adults with unresectable or metastatic urothelial carcinoma; Ordspono (odronextamab), which treats follicular lymphoma and diffuse large B-cell lymphoma; Enzalutamide Viatris (enzalutamide), to treat prostate cancer; and Nilotinib Accord (nilotinib) for the treatment of Philadelphia chromosome positive chronic myelogenous leukemia.

Other positive opinions were granted to treatments for paroxysmal nocturnal hemoglobinuria and a biosimilar to treat adults with moderately-to severely-active Crohn’s disease, plaque psoriasis, pediatric plaque psoriasis, and psoriatic arthritis (3).

EMA. First Nasal Adrenaline Spray for Emergency Treatment Against Allergic Reactions. Press Release. June 28, 2024. 

https://www.ema.europa.eu/en/news/first-nasal-adrenaline-spray-emergency-treatment-against-allergic-reactions

EMA. Positive CHMP Opinion on First-in-Class Medicine to Treat Pulmonary Arterial Hypertension. Press Release. June 28, 2024. 

https://www.ema.europa.eu/en/news/positive-chmp-opinion-first-class-medicine-treat-pulmonary-arterial-hypertension

EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 24–27 June 2024. Press Release. June 28, 2024.

EMA’s CHMP gave positive opinions on a nasal delivery for epinephrine and for a first-in-class medicine to treat pulmonary arterial hypertension, among others, including a biosimilar for treatment of autoimmune diseases.

First Nasal Adrenaline Spray Among EMA Approvals in June

FDA has chosen seven companies to participate in its Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. START was created to advance development of novel drugs and biologics for rare diseases. The pilot will gather information on how to best facilitate efficient development of therapies for rare diseases and assist sponsors to generate high-quality data to support new drug or biologics license applications.

The Center for Drug Evaluation and Research (CDER) chose the following companies to participate in START for the development of rare neurodegenerative conditions:

Larimar Therapeutics to treat Friedreich’s ataxia through its Nomlabofusp product

Calico Life Sciences to treat vanishing white matter disease with its ABBV-CLS-7262 product

Denali Therapeutics for its DNL 126 product to treat Mucopolysaccharidosis Type IIIA (Sanfilippo syndrome).

The Center for Biologics Evaluation and Research (CBER) chose the following companies for their gene or cellular therapies to treat rare diseases:

Grace Science for their GS-100 (AAV0-rhNGLY1) product to treat NGLY1 deficiency

Moderna TX for their mRNA-3705 product to treat isolated methylmalonic acidemia due to complete or partial methylmalonyl-coenzyme A mutase deficiency

Myrtelle to treat Canavan disease with their product, rAAV-Olig001-ASPA

Neurogene for the treatment of Rett syndrome with NGN-401.

“Although there were a number of excellent and qualified applicants, there was only availability for a limited number of programs within the START Pilot Program. In making these selections, we considered the strength of the development programs, and the unmet medical need represented by the indicated conditions. To help aid our evaluation of the program, we also attempted to include a spectrum of entities in the pilot ranging from companies initially established to produce a single product to established biotechnology companies,” CDER Director, Patrizia Cavazzoni and CBER Director, Peter Marks stated (1).

Participants in START will receive advice from FDA regarding product-specific development issues such as clinical study design, control groups, and patient populations. Early development problems will be addressed to avoid potential delays or prevention of trial progression. Access to FDA programs, such as the Advancing Real-World Evidence Program, Complex Innovative Trial Design program, Translational Science Team, and Rare Disease Endpoint Advancement Pilot, will be given to those participating in START.

Eligibility requirements to participate in START per FDA include (2):

“For both CBER and CDER, the program is open to sponsors of products currently in clinical trials under an active investigational new drug application (IND) and IND has been submitted in or converted to Electronic Common Technical Document (eCTD) format, unless the IND is of a type granted a waiver from eCTD format.”

“For both CBER and CDER, the program is open to sponsors who have demonstrated substantial effort to ensure that Chemistry, Manufacturing, and Controls (CMC) development aligns with clinical development.”

“For CBER, eligible products must be a gene or cellular therapy intended to address an unmet medical need as a treatment for a serious rare disease or condition, which is likely to lead to significant disability or death within the first decade of life.”

“For CDER, products must be intended to treat rare neurodegenerative conditions, including those of rare genetic metabolic etiology.”

“CBER and CDER look forward to actively working together to fulfill our shared vision of bringing better treatment options to patients and their families. Through the START Pilot Program, the opportunity for increased engagement with the selected sponsors should facilitate more rapid achievement of regulatory milestones, if supported by the data and the science,” Cavazzoni and Marks stated (1).

FDA. FDA Opens Doors for More Treatments for Rare Diseases through the New START Pilot Program. 

https://www.fda.gov/drugs/our-perspective/fda-opens-doors-more-treatments-rare-diseases-through-new-start-pilot-program

FDA. Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. 

https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/support-clinical-trials-advancing-rare-disease-therapeutics-start-pilot-program

The seven chosen sponsors will help accelerate development of novel drugs and biologics for rare diseases.