Drug Development Flashcards
what are the phases of chronic myelogenous leukemia (CML)?
- Chronic phase
- accelerated phase (develops in 3 to 4 years)
- acute leukemia (blast phase)
what used to be first-line therapy for CML?
Hydroxyurea (HU) + interferon alpha (IFN-a) or IFN-a + stem cell transplantation.
Responses to IFN-a were rarely durable and treatment was associated with substantial toxicity.
What causes CML?
- CML is caused by a translocation between c-Src and c-Abl1b that removes the amino-terminus of Abl, making Bcr-abl
- Myristoylization (myr-), which is located at the amino-terminus, creates an intramolecular bound to the kinase domain and this stabilizes ABL in an inactive form.
- The the N terminal BCR coiled-coil domain facilitates dimerization and constitutive autophosphorylation of the ABL1 tyrosine kinase domain
- this leads to an increase kinase activity
What are the steps in drug development?
- preclinical work
- submit investigational new drug (IND) application in order to be able to conduct clinical trials
- phase 1 clinical trial
- phase 2 clinical trial
- phase 3 clinical trial
- submit a new drug application
- phase 4 after it goes in the market
what rules have to be followed when performing a clinical trial?
- conduct the clinical study in accordance with the IRB approved protocol
- inform potential subjects that the drugs are being used for investigational purposes
- report to the sponsor adverse events that occur in the course of the investigation
what is the purpse of a phase 1 clinical trial?
- determine toxicity of drug
- pharmacokinetics
- pharmacodynamics
How is a phase 1 clinical trial conducted?
- take a small number of patients (often people who failed standard therapies) often 20 to 80
- dose escalation (start at ~10% of dose that cause toxicity in animals)
- peripheral blood is taken to monitor drug uptake/clearance
- if possible take tumor sample to see if the drug is hitting the target
it is not blinded
what was the outcome of the phase 1 clinical trial for the RTK inhibitor for CML?
Saw that 53 of 54 patients had a complete response with only 1 replaspe over a year (this was seen in the 300-1000mg dose.
also no maximum tolerated dose could be found
what is the purpse of a phase 2 clinical trial?
to determine if there is any efficay with a specific patient population (often lasts 2 to 3 years)
how is a phase 2 clinical trail conducted?
- take a greater number of patients that have the intended disease (50-300 people)
- this is intended for dose refinement, where we have an idea of the dose that works but want to know which dose is best
- unblinded studies
what was the outcome of phase 2 clinical trials for the RTK inhibitor for CML?
the drug was approved (gleevec or imatinib), which never happens normally
drugs are approved after phase 3 clinical trial
what is the purpose of phase 3 clinical trials?
to determine the efficay within a larger patient population with a specific indication and to learn more about drug safety. Also, get additional data directly comparing to existing therapies.
how is a phase 3 clinical trial conducted?
- a double blinded, placebo controlled, and multi-center trial
- greater numbers of patients (100s-1000s of people) of many ethnicities, genders, and in many countries/hospitals
- randomized between investigational drug and standard of care
what was the outcome of the phase 3 clinical trial for gleevec in CML?
saw very high complete clinical response with low intolerance BUT some patients relapsed and/or progressed to accelerated phase or blast crisis
how did the IC50 change in patients who relapsed? why?
10-70X higher, the relapse tumors are resistant to Gleevec.
Over 40 mutations have been identified that
confer Imatinib (Gleevec) resistance: contact mutants or conformation mutants (ATP still able to bind but reated a clash with Gleevec)
what was a common mutatation seen CML relapse?
T315I (tyrosine to isoleucine)
what is Dasatinib?
inhibitors that are capable of inhibiting the “escapers” (those resistant to Gleevec, against T315I mutant)
How could we double drug CML?
TKI combinations or a TKI and Asciminib (myr-site inhibitor,)
what happens when you take a patient off Gleevec?
half of the people have relapse, but that also means that half are basically cured
what are limitations of a phase 3 clinical trials?
- Too few - very seldom more than 3000 people
- Too simple –patients with complicated medical conditions excluded (including pregnancy)
- Too narrow – patients receiving concurrent meds are excluded
- Too median-aged –pediatric and elderly populations excluded
- Too brief – trials often are no longer than necessary to see a difference (<36months); precluding identification of reactions due to long term use or latent effects
what is th purpse of phase 4 clinical trials?
To determine how well approved drugs work over longer periods of time and in more people.
- are there rare side effects
- does the drug have any effects in the long term?
- does it increase longevity? (often approval is “disease free survival” and not “overall survival”)
how are phase 4 clinical trials conducted?
- greater numbers of patients (10,000-50,000 people)
- not blinded
- These studies may also look at other aspects of the treatment, such as quality of life or cost effectiveness.
are the off-target effects of Gleevec?
inhibits c-abl, PDGF-R and KIT
could we use gleevec for other cancers than CML?
~85% of GISTs contain activating c-Kit mutations (RTK) and ~3-5% have PDGFR activating, putting the twoyear survival way up
gastrointestinal stromal tumors
