Surrogate markers
The invention provides a method to analyze an effect of a biological insult such as exposure to ionizing radiation comprising (a) exposing one or more groups of subjects to a biological insult of at least about an LD 10 to obtain one or more groups of exposed subjects; and (b) measuring one, two, three or more surrogate markers in one or more of the groups of exposed subjects, wherein one, two, three or more of the surrogate markers correlate with death at a P≦0.1.
1 . A method to analyze an effect of a biological insult comprising
(a) exposing one or more groups of subjects to a biological insult of at least about an LD 10 to obtain one or more groups of exposed subjects;
(b) measuring one, two, three or more surrogate markers in one or more of the groups of exposed subjects, wherein one, two, three or more of the surrogate markers correlate with death at a P≦0.1; and
(c) optionally repeating steps (a) and (b) 1, 2, 3, 4 times or more; and/or
(d) optionally measuring survival of the individuals in the one or more groups of exposed subjects, wherein the surrogate markers are associated with or caused by the biological insult.
2 . The method of claim 1 wherein the subjects are non-human primates and the biological insult is exposure of the non-human primates to ionizing radiation and the surrogate markers are selected from the group consisting of (i) the duration of febrile severe neutropenia or the duration of severe neutropenia, (ii) duration of severe thrombocytopenia, (iii) time, e.g., delay, of onset of febrile severe neutropenia or severe neutropenia, (iv) delay of onset of severe thrombocytopenia or early recovery from severe thrombocytopenia, (v) degree of severity of febrile severe neutropenia, severe neutropenia or severe thrombocytopenia, and (vi) degree of severity of severe neutropenia.
3 . The method of claim 2 wherein the biological insult is about an LD 20 to about an LD 70 .
4 . The method of claim 3 wherein steps (a) and (b) are repeated 1, 2, 3, 4, 5, 6, 7, 8 or more times and the coefficient of determination is obtained (R 2 trial ) and the coefficient of determination obtained from individuals (R 2 individual ) is obtained, wherein R 2 trial or R 2 individual is at least about 0.65.
5 . The method of claim 3 wherein one of the groups of exposed subjects is treated with a formula 1 compound and one or more surrogates for efficacy or toxicity of the formula 1 compound treatment are determined.
6 . The method of claim 5 wherein the one or more surrogates for efficacy of the formula 1 compound treatment is selected from the group consisting of (i) the duration of febrile severe neutropenia or the duration of severe neutropenia, (ii) duration of severe thrombocytopenia, (iii) time, e.g., delay, of onset of febrile severe neutropenia or severe neutropenia, (iv) time, e.g., delay, of onset of severe thrombocytopenia, (v) degree of severity of febrile severe neutropenia or severe neutropenia and (vi) degree of severity of severe neutropenia.
7 . The method of claim 5 wherein the one or more surrogates for toxicity of the formula 1 compound treatment is selected from the group consisting of (i) the incidence, severity or duration of damage, loss or impairment to a tissue optionally selected from the group consisting of eye, liver, kidney, muscle, CNS, peripheral nerves, lung, bone, bone marrow or integument (ii) the incidence, severity or duration of pain, hyperthermia, hypothermia, emesis, diarrhea, fatigue, edema, insomnia or weight loss, (iii) the incidence, severity or duration of weakness or impaired motor coordination and (iv) the incidence, severity or duration of anemia or unwanted hormonal side-effects optionally selected from the group consisting of unwanted androgen side-effects, unwanted estrogen side-effects and unwanted progestin or progesterone side-effects.
8 . The method of claim 2 further comprising
(e) treating one or more groups of exposed subjects with a drug candidate to obtain one or more groups of exposed treated subjects;
(f) measuring the one, two, three or more surrogate markers in the one or more groups of exposed treated subjects; and
(g) optionally repeating steps (a), (b), (d) and (e) 1, 2, 3, 4 times or more; and/or
(h) optionally measuring survival of the individuals in the one or more groups of exposed treated subjects, whereby the effect, if any, of the drug candidate on the one, two, three or more surrogate markers is determined.
9 . The method of claim 8 wherein the drug candidate is a compound having the structure
wherein the dotted lines are optional double bonds and 0, 1, 2, 3, 4 or 5 double bonds are present in the four compound rings;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 independently or together are —H, —OH, —OR PR , SR PR , —SH, —N(R PR ) 2 , —NHR PR , —NH 2 , —O—Si—(R 13 ) 3 , —CHO, —CHS, —CN, —SCN, —NO 2 , —N 3 , —COOH, —COOR PR , —OSO 3 H, —OSO 2 H, —OPO 3 H 2 , ═O, ═S, ═N—OH, ═N—OCH 3 , ═CH 2 , ═CH—CH 3 , ═CH-optionally substituted alkyl, =N-optionally substituted alkyl, ═N—O-optionally substituted alkyl, —NH—S(O)(O)-optionally substituted alkyl, —S—S-optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonate, phosphonate ester, thiophosphonate, thiophosphonate ester, phosphiniester, sulfite ester, sulfate ester, sulfamate, sulfonate, sulfonamide, amide, amino acid, peptide, ether, thioether, acyl, thioacyl, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, polymer, spiro ring, epoxide, acetal, thioacetal, ketal or a thioketal, ═N—O-optionally substituted alkyl, ═N-optionally substituted alkyl, —NH-optionally substituted alkyl, —N(optionally substituted alkyl) 2 where each optionally substituted alkyl is independently selected, or, one or more of two adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 10 comprise an independently selected epoxide or optionally substituted, saturated or unsaturated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring any of which rings optionally contain one or two independently selected —O—, —S—, —S(O)(O)—, —NH— —N(optionally substituted alkyl)- or ═N-heteroatoms;
R 7 is —O—, —S—, —NR PR —, —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —C(R 10 ) 2 —, —C(R 10 ) 2 —O—C(R 10 ) 2 —, —C(R 10 ) 2 —S—C(R 10 ) 2 —, —C(R 10 ) 2 —NR PR —C(R 10 ) 2 —, —O—C(R 10 ) 2 —, —S—C(R 10 ) 2 — or —NR PR —C(R 10 ) 2 —, where each R 10 is independently selected;
R 8 and R 9 independently are —C(R 10 ) 2 —, —C(R 10 ) 2 —C(R 10 ) 2 —, —O—, —O—C(R 10 ) 2 —, —S—, —S—C(R 10 ) 2 —, —NR PR — or —NR PR —C(R 10 ) 2 —, or one or both of R 8 or R 9 independently are absent, leaving a 5-membered ring, where each R 10 is independently selected;
R 11 is —O—, —S—, —S(O)(O)-, —NR PR —, —CH 2 —, —CHR 10 —, —C(R 10 ) 2 —, —C(R 10 ) 2 —O—C(R 10 ) 2 —, —C(R 10 ) 2 —S—C(R 10 ) 2 —, —C(R 10 ) 2 —S(O)(O)—C(R 10 ) 2 —, —C(R 10 ) 2 —NR PR —C(R 10 ) 2 —, —O—C(R 10 ) 2 —, —S—C(R 10 ) 2 —, —S(O)(O)—C(R 10 ) 2 — or —NR PR —C(R 10 ) 2 —, where each R 10 is independently selected;
R 13 independently is C 1-6 alkyl; and
R PR independently are —H or a protecting group, wherein one or two independently selected R 10 moieties are present at the 1-, 6- and 12-positions, optionally wherein the compound is administered daily or every other day for 1 to about 14 days, and optionally wherein the first compound dose is administered to the non-human primate within about 0.5 hour after to about 72 hours after exposure of the non-human primate to the whole body radiation dose.
10 . A drug product for treating an actual or potential radiation exposure in a human or for treating acute radiation syndrome in a human comprising,
(a) a drug in a dosage form; and
(b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, toxicity or mechanism of action wherein such information was obtained at least in part from a method that comprises (i) exposing one or more groups of subjects to a biological insult of at least about an LD 10 to obtain one or more groups of exposed subjects, wherein the subjects are not humans; (ii) measuring one, two, three or more surrogate markers in one or more of the groups of exposed subjects, wherein one, two, three or more of the surrogate markers correlate with death at a P≦0.1; and (iii) optionally repeating steps (i) and (ii) 1, 2, 3, 4 times or more; and/or (iv) optionally measuring survival of the individuals in the one or more groups of exposed subjects, wherein the surrogate markers are associated with or caused by the biological insult, whereby at least some of the information in the package insert or label about the drug's efficacy, toxicity or mechanism of action was obtained.
11 . The drug product of claim 10 wherein the subjects are non-human primates and the surrogate markers are selected from the group consisting of (i) the duration of febrile severe neutropenia or the duration of severe neutropenia, (ii) duration of severe thrombocytopenia, (iii) time, e.g., delay, of onset of febrile severe neutropenia or severe neutropenia, (iv) delay of onset of severe thrombocytopenia or early recovery from severe thrombocytopenia, (v) degree of severity of febrile severe neutropenia, severe neutropenia or severe thrombocytopenia, and (vi) degree of severity of severe neutropenia.
12 . The drug product of claim 11 wherein the biological insult is about an LD 20 to about an LD 70 .
13 . The drug product of claim 12 wherein one, two, three or more of the surrogate markers correlate with death or survival at a P≦0.05.
14 . A drug product for treating radiation exposure or acute radiation syndrome comprising,
(a) a drug in a dosage form; and
(b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, wherein the efficacy information was obtained at least in part from a method that comprises (i) exposing mammals, wherein the mammals are not humans or rodents, to a whole body radiation dose of at least about an LD 30 to obtain exposed subjects; (ii) obtaining exposed treated subjects by administering the drug to at least some of the exposed subjects and obtaining exposed placebo subjects by administering a suitable placebo to at least some of the exposed subjects, wherein neither the exposed treated subjects nor the exposed placebo subjects are provided with any other ameliorative treatment other than analgesics to treat pain if needed; and (iii) measuring the survival rate of the exposed treated subjects to obtain a treatment survival rate and measuring the survival rate of the exposed placebo subjects to obtain a placebo survival rate, whereby at least some of the information in the package insert or label about the drug's efficacy, toxicity or mechanism of action was obtained.
15 . The drug product of claim 14 wherein the radiation dose is about an LD 40 to about an LD 60 and wherein the ameliorative treatment is (i) a transfusion, optionally a whole blood transfusion or a platelet transfusion, (ii) an antimicrobial treatment to treat or prevent an infection, (iii) assisted feeding such as feeding by parenteral or catheter feeding or by tube feeding to the digestive system or stomach of the exposed subjects, or (iv) intravenous administration of fluids, electrolytes or nutrition.
16 . The drug product of claim 15 wherein the drug is androst-5-ene-3β,17β-diol, optionally wherein drug product is for treating, ameliorating or preventing (i) acute radiation syndrome or a hematopoietic component or aspect thereof, optionally neutropenia, thrombocytopenia, anemia, hemorrhage, bone marrow hypocellularity or deficiency of stem cells in blood or bone marrow, optionally CD34 + stem cells, or (ii) bacterial infection, bacteremia, systemic inflammatory response syndrome, sepsis or a symptom thereof, optionally fever, organ failure, hypoperfusion or inflammation.
17 . The drug product of claim 16 wherein the mammals are non-human primates or canines.
18 . The drug product of claim 17 wherein the non-human primates are rhesus monkeys or cynomolgus monkeys and the information about the drug's efficacy is information about increased survival, an improved surrogate for lethality indicating a decreased probability of death, decreased morbidity, optionally infections, fever, pain, bleeding, bacteremia or sepsis, or a decreased need for any ameliorative treatment for the exposed treated subjects compared to the exposed placebo subjects.
19 . The method of claim 18 wherein the package insert or label indicates that the dosage of the androst-5-ene-3β,17β-diol is 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day or 400 mg/day.
20 . A method to use a drug product comprising obtaining the drug product of claim 10 and offering to sell the drug product or selling the drug product, optionally wherein the drug product is delivered to a buyer to obtain a drug product delivery, wherein the offer to sell, the selling or the drug product delivery is lawful or authorized under any applicable rules, laws and/or private party contracts.