NCI Developmental Therapeutics Program
Hi all, regarding toxicity testing, I went back and listened to the radio interview with Robert McInnis from Aug 6th again. Human trials are likely 12-18 months away he says. If the NCI-60 dose response tests come back externally validating the compound which I think they should given the excellent single dose response results and they have an active pharmaceutical ingredient (API) then it will be toxicity testing which will be needed to move this forward. Robert says that this can cost money but that these further tests before human trials will add value and it will be worth more for future deals.
https://www.cfra.com/chum_audio/biz@nite.bob.mcinnis.aug.6.mp3
If the upcoming NCI results are very good, a Screening Data and Review Committee, a group of biologists and chemists from DTP, reviews the screening data from the tumor cell lines and recommends which candidate drugs should be tested in animals. It looks like with promising agents, the NCI could perform the in vivo, pharmacology, formulation and toxicology studies.
"Drugs that reach this stage of development are under serious consideration for testing in humans so that substantial resources may eventually be committed to their development".
"If a drug progresses to the next level, NCI commits substantial resources, approximately $250,000 to $500,000, to further development. A large-scale production plan for the compound may be developed if needed. In addition, toxicology evaluations are done in two species of animals using the same material under consideration for human trials. If the drug has no serious problems, scientists recommend the initial dose, route and schedule for patients in early trials (phase I clinical trials)".
https://www.cancer.gov/newscenter/benchmarks-vol2-issue3/page2
It would make sense if the next results are really good for a licensing deal to follow shortly but if pharma is waiting for more validation prior to doing a deal then as more and more positive results and progress towards human trials occurs the company will have more and more value. It also sounds like NCI may fund further investigations if the compound is a promising agent and makes it to the next step so that may also assist with financial considerations the company may have with doing toxicity testing.
See below for some excerpts for drug discovery at NCI
GLTA,
Andy
The National Cancer Institute (NCI) has played an active role in the development of drugs for cancer treatment for over 40 years. This is reflected in the fact that approximately one half of the chemotherapeutic drugs currently used by oncologists for cancer treatment were discovered and/or developed at NCI. The Developmental Therapeutics Program (DTP) promotes all aspects of drug discovery and development before testing in humans (preclinical development), and is a part of the Division of Cancer Treatment and Diagnosis (DCTD). NCI also funds an extensive clinical (human) trials network to ensure that promising agents are tested in humans. NCI's Cancer Therapy Evaluation Program (CTEP), also a part of DCTD, administers clinical drug development.
What are the specific stages of testing in DTP once a drug has been chosen to be evaluated?
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Preliminary in vitro screening: New drugs are first evaluated in a pre-screen consisting of three human tumor cell lines. Cells are exposed to each drug at a single concentration for 48 hours. If growth of one or more cell lines is inhibited, the drug is automatically evaluated against the full panel of 60 human tumors.
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In vitro screen in human tumors: Each drug is exposed to 60 human tumor cell lines, including lung, colon, melanoma, prostate, ovarian, breast and kidney cancers at five different doses for 48 hours. Approximately 2,500 compounds are ested on a yearly basis. If the drug is unique in some way - kills preferentially one or more of the tumor cell lines, has a unique mechanism of action, or can kill tumors at a very small concentration - testing will proceed to the next stage. About 2 percent of those screened will be recommended for the next stage of testing in mice.
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In vivo testing using hollow-fiber technique: Small hollow fibers (tubes 1 millimeter in diameter and 2 centimeters long made of a plastic, polyvinylidene fluoride), containing cells from human tumors are inserted underneath the skin and in the body cavity of the mouse. Each candidate drug is administered at two dosages and is tested against 12 target tumor cells in different hollow fibers. A total of about 150-200 compounds/year is screened by this method. Compounds that retard the growth of the cells are recommended for the next level of testing. The average length of this test is about four days.
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In vivo testing using xenografts: Human tumors are injected directly below the skin of mice. Candidate drugs which have shown evidence of activity in the hollow fibers may be selected for testing in xenografts. The drugs are administered to the mice at various dosages, and those compounds that kill or slow down the growth of specific tumors with minimal toxicity to the animal will proceed to the next stage of testing. The average length of this test is about 30 days.
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Pharmacology, formulation and toxicology studies: Drugs that reach this stage of development are under serious consideration for testing in humans so that substantial resources may eventually be committed to their development. There are two levels of development at this stage.
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At the first level of development, scientists determine the basic pharmacology of the compound in animals to see where the drug is metabolized. The best chemical formulation for administering the drug, how much of the drug to give, how often and whether the drug should be taken orally or by injection is also established.
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If a drug progresses to the next level, NCI commits substantial resources, approximately $250,000 to $500,000, to further development. A large-scale production plan for the compound may be developed if needed. In addition, toxicology evaluations are done in two species of animals using the same material under consideration for human trials. If the drug has no serious problems, scientists recommend the initial dose, route and schedule for patients in early trials (phase I clinical trials).