Drug Authorizations: ADUHELM for Alzheimer’s, AMONDYS 45 for DMD, TEMBEXA for Smallpox, WEGOVY for weight management, TRUSELTIQ for cholangiocarcinoma, KLOXXADO for opioid overdose – Drug and Device Digest



INDICATION: Treatment of Alzheimer’s disease

  • Accelerated approval based on reduction in amyloid beta plaques
  • Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s)

ADDRESSSING UNMET NEED: First novel therapy approved for Alzheimer’s disease since 2003; first to be directed at the underlying pathophysiology of Alzheimer’s disease, the presence of amyloid beta plaques in the brain. Potential to address the gradual and cumulative devastation that Alzheimer’s disease causes, as patients lose their memory and cognitive functioning over time.

MECHANISM OF ACTION: Immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta; accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease,


  • Clinical trials for Aduhelm were the first to show that a reduction in beta amyloid plaques, a hallmark finding in the brain of patients with Alzheimer’s, and is expected to lead to a reduction in the clinical decline of dementia
  • Three double-blind, randomized, placebo-controlled dose-ranging studies, n-3,482 patients with Alzheimer’s disease
  • Significant dose-and time-dependent reduction of amyloid beta plaque with treatment


  • Warning: Amyloid-related imaging abnormalities, risk of hypersensitivity reactions, including angioedema and urticaria
  • Most common side effects: Headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation

REG PATHWAY: BLA, Accelerated approval

  • Based on surrogate endpoint (plaque reduction) that is expected to lead to a meaningful clinical benefit; required to conduct post-approval confirmatory studies to verify the anticipated clinical benefit
  • FDA offers perspective on the controversial approval; granted despite a negatve Advisory Committee vote



Sarepta Therapeutics

INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping

  • Approved under accelerated approval based on an increase in dystrophin production in skeletal muscle
  • Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials

ADDRESSING UNMET NEED: First targeted treatment for patients with this type of mutation; ~ 8% of DMD patients have a mutation that is amenable to exon 45 skipping

MECHANISM OF ACTION: Binds to exon 45 of dystrophin; allows production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 45 skipping


  • Double-blind, placebo-controlled study, n=43 patients with genetically confirmed mutation of the DMD gene that is amenable to exon 45 skipping.
  • Significantly greater increase in dystrophin protein levels from baseline to week 48 with treatment vs placebo
  • Demonstration of increase in dystrophin production is reasonably likely to predict clinical benefit


  • Potential for kidney toxicity -observed in the nonclinical studies
  • Most common side effects: Upper respiratory tract infections, cough, fever, headache, joint pain and throat pain

REG PATHWAY: BLA, Accelerated approval


TEMBEXA (brincidofovir)


INDICATION FOR USE: Treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates

ADDRESSIGN UNMET NEED: Although naturally occurring smallpox no longer exists, concerns about potential uses of variola virus as a bioweapon has made smallpox drug development an important component of the U.S. medical countermeasures response.

MECHANISM OF ACTION: Antiviral drug against variola (smallpox) virus


  • Not been determined in humans because trials not feasible and inducing smallpox disease in humans is not ethical
  • Adequate and well-controlled animal efficacy studies of infected rabbits and mice
  • Statistically significant improvement in survival relative to placebo


  • Information clinical trials for a non-smallpox indication, primarily from patients who received hematopoietic stem cell transplants
  • Increased risk of death was seen in another disease (Cytomegalovirus disease – a viral infection) when Tembexa was used for a longer-than-recommended duration (longer than once a week for two weeks on days 1 and 8). Tembexa is only approved for the treatment of smallpox  
  • Most common side effects when using Tembexa are diarrhea, nausea, vomiting, and abdominal pain


  •  Approved under Animal Rule; allows findings from adequate and well-controlled animal efficacy studies to serve as the basis of an approval when it is not feasible or ethical to conduct efficacy trials in humans 
  • Priority ReviewFast Track and Orphan drug designations 
  • Developed in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA)


FDA Smallpox preparedness

Wegovy (semaglutide)

Novo Nordisk

INDICATION : An adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of : 30 kg/m2 or greater (obesity) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)

Limitations of Use:
• Should not be coadministered with other semaglutide-containing products/ GLP-1 receptor agonist
• Safety and effectiveness in combination with other products intended for weight loss have not been established
• Not been studied in patients with a history of pancreatitis

ADDRESSING UNMET NEED: New drug treatment for chronic weight management, first since 2014

MECHANISM OF ACTION: GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, physiological regulator of appetite and caloric intake


  • Four randomized, double-blind, placebo-controlled trials, 68-week, n>2,600 on Wegovy vs n> 1,500 on placebo, average body weight 231 pounds (105 kg) and average BMI 38 kg/m2., 76% female
  • Average loss of initial body weight: 12.4% (no diabetes) and 6.2% (with diabetes) 


  • Boxed warning: Potential risk of thyroid C-cell tumors,
  • Should not be used in patients with a personal or family history of medullary thyroid carcinoma or in patients with a rare condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
  • Most common side effects: Nausea, diarrhea, vomiting, constipation, abdominal (stomach) pain, headache, fatigue, dyspepsia (indigestion), dizziness, abdominal distension, eructation (belching), hypoglycemia (low blood sugar) in patients with type 2 diabetes, flatulence (gas buildup), gastroenteritis (an intestinal infection) and gastroesophageal reflux disease (a type of digestive disorder).  


  • Required pediatric assessments and Post-marketing commitments


TRUSELTIQ (infigratinib)

QED Therapeutics

FoundationOne® CDx

Foundation Medicine

INDICATION: Treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test
This indication is approved under accelerated approval based on overall response rate and duration of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

ADDRESSING UNMET NEED: Treatment option for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma 

MECHNISM OF ACTION: Small molecule kinase inhibitor of FGFR that supports proliferation and survival of malignant cells


  • Multicenter open-label single-arm trial, n=108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion determined by testing
  • Overall response rate (ORR) was 23% with 1 complete response and 24 partial responses
  • Median Duration of Response (DoR) was 5 months; 8 patients maintained response for 6 mo. or more    


  • Serious risks; Hyperphosphatemia and retinal pigment epithelial detachment
  • Most common adverse reactions: Hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting

REGULATORY PATHWAY: NDA, Accelerated Approval

  • Review conducted under Project Orbis, for concurrent submission and review of oncology drugs among international partners
  • FDA collaboration with the Australian Therapeutic Goods Administration (TGA) and Health Canada
  • Used the Real-Time Oncology Review (RTOR) pilot program for streamlined data submission and Assessment Aid and Product Quality Assessment Aid (PQAA)
  • Granted priority review, fast-track designation, and orphan drug designation


KLOXXADO (naloxone hydrochloride)


INDICATION: For the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and /or central nervous system depression, for adult and pediatric patients
-Is intended for immediate administration as emergency therapy in settings where opioids may be present
-Is not a substitute for emergency medical care

ADDRESSIBNG UNMET NEED:  Higher dose naloxone hydrochloride nasal spray for combatting opioid overdose

MECHANISM OF ACTION: Antagonizes opioid effects by competing for the same receptor sites; reverses effects of opioids, including respiratory depression, sedation and hypotension


  • Scientific justification based on FDA’s finding of safety and effectiveness for naloxone hydrochloride (NARCAN injection)
  • Specific pharmacokinetic data to establish the drug’s safety and efficacy for its approved use


  •  New product delivers 8 mg naloxone into nasal cavity; FDA had previously approved 2 mg and 4 mg naloxone nasal spray products



Image credits: Biogen, Sarepta, Chimerix, Novo Nordisk, QED, Hikma

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