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Genome-Based Therapeutics Targeted Drug Discovery and Development: Workshop Summary (2012) / Chapter Skim
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3 Case Studies
Pages 17-28

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From page 17...
... · Small-sample randomized clinical trials can generate valuable data that can be aggregated to generate information similar to that from a large clinical trial. · Drug and diagnostic development can proceed quickly if the appropriate patient populations can be identified.
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From page 18...
... that is anaplastic lymphoma kinase (ALK) -positive as detected by an FDA-approved test." The related diagnostic device, which was simultaneously approved for use with crizotinib, is the Abbott Vysis ALK Break Apart FISH Probe Kit, which is described in the package insert as "a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH)
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From page 19...
... The results indicated that the drug was active against gastric, esophageal, and lung cancer cell lines that exhibited c-MET amplification; in fact, the drug was originally developed with c-MET as the primary kinase target. It also was found to be active against neuroblastoma with ALK mutation or amplifications, anaplastic large-cell lymphoma with an NPM-ALK fusion, and NSCLC with ALK and ROS alterations.
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From page 20...
... . The development of the diagnostic proceeded in parallel with the clinical trials, so that the data package brought forward to support efficacy included data from patients identified by the final diagnostic test.
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From page 21...
... Food and Drug Administration; FISH, fluorescence in situ hybridization; IDE, investigational device exemption; IUO, investigational use only; LDT, laboratory developed test; MGH CTA, Massachusetts General Hospital clinical trial assay; NDA, new drug application; NEJM, New England Journal of Medicine; PMA, premarket approval. SOURCE: Ho, workshop presentation, March 21, 2012.
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From page 22...
... Thus, instead of using knowledge of the molecular genetics of the disease, as has been done with cancer, Eli Lilly and Company researchers used knowledge of drug mechanisms to formulate a strategy for the discovery of drug-response markers. The drug currently being developed for the treatment of schizophrenia by Eli Lilly and Company is called pomaglumetad methionil (hereafter referred to as pomaglumetad)
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From page 23...
... "You'll have to stay tuned to see how the story plays out," Nisenbaum said.1 "But we are very excited at the prospect of potentially being able to help tailor something in the psychiatric space where we know that the response rate for these types of drugs is modest." As genetic markers related to the serotonin 2A receptor are considered for further use in clinical trials, it is necessary to understand additional factors regarding receptor expression, Nisenbaum said. The serotonin variants identified in the proof-of-concept study are all located within a large intron of the serotonin 2A receptor, and the variants do not have an obvi 1 Eli Lilly and Company announced results from the first of these studies, H8Y-MC-HBBM, subsequent to the workshop on July 11, 2012.
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From page 24...
... Also, as was the case with crizotinib, if Phase III results support the need for a companion diagnostic, the development of that diagnostic will need to be timed appropriately so that it does not become the ratelimiting factor for the drug approval. A GENETIC APPROACH TO THE TREATMENT OF CYSTIC FIBROSIS Cystic fibrosis is an orphan disease, which differentiates it from cancer and schizophrenia, said Peter Mueller of Vertex Pharmaceuticals.
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From page 25...
... Accordingly, Vertex investigated both potentiators that increase channel activity and correctors that increase the delivery, or trafficking, of CFTR protein to the cell surface. A search of about 10,000 molecules turned up a particular molecule, ivacaftor, that restored function and removed mucus in patient cells with a particular mutation known as G551D.
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From page 26...
... NOTE: CFTR, cystic fibrosis transmembrane conductance regulator. SOURCE: Mueller, workshop presentation, March 21, 2012; data derived from the Cystic Fibrosis Foundation Annual Figure 3-4.eps Patient Registry Report, 2009.
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From page 27...
... Michelle Penny of Eli Lilly and Company added that during the development of pomaglumetad m ethionil, the company made the collection of DNA samples mandatory where local regulations and IRB approval allowed, with consents ranging from candidate gene study to whole-genome sequencing. Only by having these
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From page 28...
... Small-sample randomized clinical trials known as N-of-1 trials could be a way of generating valuable data (Lillie et al., 2011)
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Key Terms

  • clinical trials
  • diagnostic test
  • clinical trial
  • lung cancer
  • eli lilly

  • cftr function
  • phase iii
  • cell lines
  • drug development
  • randomized clinical

  • alk gene
  • drug discovery
  • drug application
  • alk fusion
  • iii diagnostic

  • tumor cell
  • cell surface
  • residual cftr
  • cftr gating
  • cftr channel

  • companion diagnostic
  • alk translocation
  • class iii
  • gene association
  • candidate gene

  • fibrosis transmembrane
  • patients taking
  • genetic markers
  • dna samples
  • abbott molecular


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