SHH Pathway Inhibitor

Metastatic Basal Cell Cancer (not amenable to surgery)
1. Vismodegib (Erivedge)
2. Sonidegib (Odomzo)
Acute Myeloid Leukemia (new onset, or age >75 years and not candidate for induction Chemotherapy)
1. Glasdegib (Daurismo)

Sonic Hedgehog (Shh) Signaling Pathway
1. Hedgehog (Hh) family of signaling Proteins
  1. Key role in human development (as well as many other species, including Drosophila)
  2. Regulates tissue and organ morphogenesis, as well as stem cell proliferation in adults
  3. Many cancers involve aberrant activation of the Hh pathway
2. Components
  1. Fused (Serine/Threonine Protein kinase)
  2. Coastal 2 or COS2 (kinesin motor Protein)
  3. Gli (zinc finger transcription factor )
3. Signal cascade
  1. Sonic Hedgehog (SHh) family factors bind PTC (patched)
  2. PTC binding releases SMO (smoothened) as a signal
  3. SMO activates transcription of target genes via the GLI family of Proteins
SHH Pathway Inhibitor
1. Shh Inhibitors block patch Protein (PTC) and smoothened Protein (SMO)

Vismodegib (Erivedge)
1. Highly Teratogenic (see below)
2. Risk of myalgias, severe cutaneous reactions, prematurely fuses Growth Plates (children)
Sonidegib (Odomzo)
1. Highly Teratogenic (see below)
2. Risk of myalgias, prematurely fuses Growth Plates (children)
3. Avoid with moderate to strong CYP3A Inhibitors and Inducers
Glasdegib (Daurismo)
1. Highly Teratogenic (see below)
2. Risk of Prolonged QTc
3. Avoid with moderate to strong CYP3A Inhibitors and Inducers

Teratogenic (Vismodegib, Sonidegib)
1. See safety below
Premature Growth Plate closure in children (Vismodegib, Sonidegib)
1. Not approved for use in children
Severe Cutaneous Reactions (Vismodegib)
QTc Prolongation (Glasdegib)
Other common adverse effects
1. Arthralgias, myalgias and Muscle spasms, and Fatigue
2. Weight loss, decreased appetite, Dysgeusia, Nausea, Vomiting and Constipation

Avoid in Lactation
Avoid in pregnancy (all trimesters, pregnancy category X and )
1. Use reliable Contraception
Boxed Warning for Vismodegib, Sonidegib and
1. Highly Teratogenic (severe midline defects, irreversible malformations and missing digits)
2. Continue reliable Contraception for at least 1 month Glasdegib, 20 months Sonidegib, 24 months after Vismodegib
3. Men should use Condoms to prevent transmission of agent via semen
  1. Do not donate semen for 1 month after Glasdegib, 3 months after Vismodegib and 8 months after Sonidegib
4. Avoid donation of blood or Blood Products for 24 months after Vismodegib, 20 months after Sonidegib

Avoid in pregnancy (all trimesters)
1. Use reliable Contraception
2. Shh Pathway is key to Embryo Development
Monitoring
1. Serum Creatinine
2. Serum Creatine Kinase
3. Electrocardiogram (Glasdegib)

CYP3A Inhibitors
1. Avoid Sonidegib, Glasdegib with strong CYP3A Inhibitors overall
2. Avoid Sonidegib with moderate CYP3A Inhibitors for >14 days
CYP3A Inducers
1. Avoid Sonidegib, Glasdegib with moderate to strong CYP3A Inducers
Medication Causes of QTc Prolongation
1. Avoid with Glasdegib