WO2003020286A1 - The diagnosis and treatment of airways disease - Google Patents

The diagnosis and treatment of airways disease Download PDF

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Publication number
WO2003020286A1
WO2003020286A1 PCT/GB2002/004009 GB0204009W WO03020286A1 WO 2003020286 A1 WO2003020286 A1 WO 2003020286A1 GB 0204009 W GB0204009 W GB 0204009W WO 03020286 A1 WO03020286 A1 WO 03020286A1
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WIPO (PCT)
Prior art keywords
mmp
group
subject
level
treatment
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PCT/GB2002/004009
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French (fr)
Inventor
Robin Mark Bannister
Andrew John Mcglashan Richards
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Arakis Ltd.
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Publication of WO2003020286A1 publication Critical patent/WO2003020286A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines

Definitions

  • This invention relates to the diagnosis and treatment of airways disease.
  • Background of the Invention Many studies have shown that tetracyclines can influence the matrix metalioproteinase system. During long-term treatment, this makes the use of such compounds an extremely attractive approach, and provides potential patient benefit by reducing the rate of long-term decline in lung function.
  • WO-A-01/62261 and the corresponding, pending US Patent Application derived from PCT/GB01/00814 disclose the use of tetracycline antibiotics, such as doxycycline, in the treatment of airways disease such as COPD.
  • the specification (incorporated herein by reference) includes discussion of appropriate active agents, conditions, routes of administration, dosages etc. Vignola et al, Am. J. Respir. Crit. Care Med. 158(6): 1945-50 (1998), reports that the MMP-9/TIMP-1 ratio in sputum correlates with airflow obstruction in asthma and chronic bronchitis. Summary of the Invention
  • a further aspect of the invention lies in the realisation that these characteristics can be used as markers of airway disease, in patients who would benefit from therapy, e.g. with tetracycline antibiotics. Such patients may be suffering from or susceptible or predisposed to such disease. It is likely that these patients will show a common genotype, and this may also be a suitable marker.
  • the discoveries and results reported here support the utility of the inventions described in WO-A-01/62261 , i.e. using low or high dose therapy.
  • they indicate further utility, for example in patients exhibiting high MMP-9 and/or TIMP-1 levels. These patients may benefit from prophylactic treatment; they will typically have breathing difficulties and/or a compromised lung function.
  • the present invention is based at least in part on the results of studies carried out using doxycycline in the treatment of COPD. These studies will now be described. Assays for MMP-9 and TIMP-1 are described in WO-A-01 /62262. Results of the studies are given below. Table 1 shows that all patients exhibited a high MMP-9 level, i.e. of at least 25 and usually higher than the normal level, i.e. 50 or up to 120. It was also found that all but one patient exhibited a TIMP-1 level higher than 500, which is normally below 200. These results imply that patients exhibiting high MMP-9 levels, especially 400 to 10,000 ng/mL, are most likely to benefit from treatment.
  • results indicate that there are two distinct groups of people.
  • MMP-9 levels are relatively high, and in a second group (“non-responders”) they are relatively low.
  • These groupings may have a genetic determinant.
  • SD standrd deviation
  • N neutrophils
  • Figure 1 administration of doxycycline to subjects diagnosed as having COPD causes, in the first group, a time-dependent reduction in the MMP-9 level. This indicates that this group is especially suitable for and sensitive to treatment with a tetracycline antibiotic, and/or that the dosage of such a compound, especially by the inhaled route, can be reduced. It also assists determination of a strategy for non-responders, who may benefit from treatment with an increased dosage or, possibly, alternative or complementary medication.
  • the level of MMP-9 is also an indication that a subject who is non-clinical for COPD is at a high risk of developing such a problem.
  • Such subjects are susceptible to or exhibiting symptoms of an airway disease, and at risk of developing associated tissue destruction, as in COPD.
  • treatment strategies can be determined on the basis of a simple assay.
  • subjects in this category are active smokers; others at risk are passive smokers and those who work in dusty conditions, e.g. coal mines.
  • the present invention shows that patients may benefit from prophylactic treatment.
  • TIMP-1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 average sem median

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Treatment of a patient who exhibits an airway disease associated with tissue destruction, may be assessed by analysing the MMP-9 level in a sample taken from the subject, and thereby determining whether the subject belongs to a first group, of 'responders', or to a second group, of 'non-responders', which are respectively characterised by high and low levels of MMP-9. Further, the risk that a subject susceptible to or exhibiting symptoms of an airway disease is likely to develop associated tissue destruction, may be assessed by analysing the MMP-9 level in a sample taken from the subject, and thereby determining whether the subject belongs to a first, 'high risk' group or to a second, 'low risk' group which are respectively characterised by high and low levels of MMP-9.

Description

THE DIAGNOSIS AND TREATMENT OF AIRWAYS DISEASE Field of the Invention
This invention relates to the diagnosis and treatment of airways disease. Background of the Invention Many studies have shown that tetracyclines can influence the matrix metalioproteinase system. During long-term treatment, this makes the use of such compounds an extremely attractive approach, and provides potential patient benefit by reducing the rate of long-term decline in lung function.
WO-A-01/62261 and the corresponding, pending US Patent Application derived from PCT/GB01/00814 disclose the use of tetracycline antibiotics, such as doxycycline, in the treatment of airways disease such as COPD. The specification (incorporated herein by reference) includes discussion of appropriate active agents, conditions, routes of administration, dosages etc. Vignola et al, Am. J. Respir. Crit. Care Med. 158(6): 1945-50 (1998), reports that the MMP-9/TIMP-1 ratio in sputum correlates with airflow obstruction in asthma and chronic bronchitis. Summary of the Invention
Surprisingly, it has now been found that doxycycline has additional benefits in lung disease. Most interestingly, these effects may manifest themselves in the acute aspects of disease.
Most interestingly, it has been found that patients characterised by high MMP-9 expression in sputum, and possibly also high overall proteolytic potential (as exemplified by high MMP-9/TIMP-1 ratio), have the most dramatic response to this treatment. This is the first time that beneficial acute responses have been identified, in what may be termed a "responder" population, for the tetracycline class of drugs. Accordingly, such drugs, and in particular doxycycline, are useful for the treatment of acute airway disease that is characterised by a high MMP-9 level. The existence of a "responder" population, and also a "non-responder" population, is surprising.
A further aspect of the invention lies in the realisation that these characteristics can be used as markers of airway disease, in patients who would benefit from therapy, e.g. with tetracycline antibiotics. Such patients may be suffering from or susceptible or predisposed to such disease. It is likely that these patients will show a common genotype, and this may also be a suitable marker. On the one hand, the discoveries and results reported here support the utility of the inventions described in WO-A-01/62261 , i.e. using low or high dose therapy. On the other hand, they indicate further utility, for example in patients exhibiting high MMP-9 and/or TIMP-1 levels. These patients may benefit from prophylactic treatment; they will typically have breathing difficulties and/or a compromised lung function. Description of the Invention
The present invention is based at least in part on the results of studies carried out using doxycycline in the treatment of COPD. These studies will now be described. Assays for MMP-9 and TIMP-1 are described in WO-A-01 /62262. Results of the studies are given below. Table 1 shows that all patients exhibited a high MMP-9 level, i.e. of at least 25 and usually higher than the normal level, i.e. 50 or up to 120. It was also found that all but one patient exhibited a TIMP-1 level higher than 500, which is normally below 200. These results imply that patients exhibiting high MMP-9 levels, especially 400 to 10,000 ng/mL, are most likely to benefit from treatment.
In particular, the results indicate that there are two distinct groups of people. In a first group ("responders"), MMP-9 levels are relatively high, and in a second group ("non-responders") they are relatively low. These groupings may have a genetic determinant. As illustrated by the results reported in Table 2 (SD = standrd deviation,
N = neutrophils) and graphically in the accompanying drawing (Figure 1), administration of doxycycline to subjects diagnosed as having COPD causes, in the first group, a time-dependent reduction in the MMP-9 level. This indicates that this group is especially suitable for and sensitive to treatment with a tetracycline antibiotic, and/or that the dosage of such a compound, especially by the inhaled route, can be reduced. It also assists determination of a strategy for non-responders, who may benefit from treatment with an increased dosage or, possibly, alternative or complementary medication.
Based on the data, the level of MMP-9 is also an indication that a subject who is non-clinical for COPD is at a high risk of developing such a problem. Such subjects are susceptible to or exhibiting symptoms of an airway disease, and at risk of developing associated tissue destruction, as in COPD. There are essentially a first, "high risk" group, and a second, "low risk" group. Again, treatment strategies can be determined on the basis of a simple assay. Typically, subjects in this category are active smokers; others at risk are passive smokers and those who work in dusty conditions, e.g. coal mines. The present invention shows that patients may benefit from prophylactic treatment.
Table 1
TIMP-1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 average sem median
Day 1 727.27 4829.91 3486.40 2037.53 383.53 720.65 3215.25 2341.11 3451.64 6235.61 2742.89 598.24 2778.18
Day 4 845.36 3921.07 1062.83 1378.95 2902.28 4886.275 9686.50 4535.36 916.57 2735.54 3287.07 856.95 2818.91
Day 8 8007.46 4816.74 1576.52 1049.66 3840.03 1964.525 9415.25 4408.99 644.69 3175.92 3889.98 923.65 3507.97
Day 11 11116.28 2696.11 2959.54 1076.00 1146.90 1949.025 66067.75 5665.03 725.10 3903.51 9730.52 6334.95 2827.82
Day 15 7085.36 5646.55 6990.05 1497.49 3119.28 4587.9 28092.75 3455.47 472.36 2655.12 6360.23 2511.88 4021.68
Day 18 8533.53 7253.48 4421.59 1629.21 344.78 3223.9 4300.25 2088.37 349.82 3049.55 3519.45 859.99 3136.72
Day 31 5560.53 7075.65 5657.4 550.15 1023.80 2333.45 3436.32 3662.47 947.41 3436.32
MMP-9
Day 1 735.70 3698.00 34.42 2685.64 100.36 231.63 110.31 962.60 155.55 4139.65 1285.39 506.31 483.67
Day 4 353.03 5390.44 24.17 1803.71 150.21 296.52 64.50 1774.10 137.62 1746.52 1174.08 526.86 324.77
Day 8 279.73 2614.22 63.30 1856.50 1732.24 278.47 470.39 1437.29 66.12 1882.43 1068.07 295.68 953.84
Day 11 282.88 1536.64 31.00 1719.86 87.40 1057.95 425.29 2089.24 166.97 2441.81 983.90 286.40 741.62
Day 15 288.21 2344.05 69.82 1558.38 1342.47 1975.13 444.95 1531.83 302.68 1380.17 1123.77 250.04 1361.32
Day 18 300.29 1927.92 29.14 1359.64 24.60 2428.52 157.15 982.30 227.04 1057.14 849.37 268.72 641.29
Day 31 263.21 108.57 64.04 274.51 161.85 97.05 161.54 36.32 135.21
Table 2
Responders
Study Day
Patient 1 4 8 11 15 18 31
2 8470.451 11675.3 2614.217 1536.643 2344.047 1927.924 4067.491
4 2685.641 1803,708 1856.5 1719.862 1558.381 1359.636 64.04132
8 962.5997 1774.096 1437.285 2089.24 1531.829 982.2962 870.6529
10 4139.645 1746.52 1882.426 2441.807 474.4011 1057.143 1589.057
11 2134.459 39.65783 1062.975 50.00274 211.4559 292.2313
Mean 3678.559 3407.855 1770.681 1946.888 1191.732 1107.691 1376.695
SD 2912.104 4682.356 579.5268 402.0987 921.417 624.0541 1615.602
N 5 5 5 4 5 5 5
Non-Responders
Study Day
Patient 1 4 8 11 15 18 31
1 709.27 279.66 91.13 206.88 158.94 205.91 1654.77
3 34.42 24.17 63.30 31.00 69.82 29.14 107.57
5 75.60 105.58 1732.24 87.40 1342.47 24.60 274.51
6 154.64 314.25 277.24 1057.95 1975.13 2428.52 161.85
7 110.31 64.50 470.39 425.29 444.95 157.15 97.05
9 155.55 137.62 68.08 166.97 302.68 227.04 80.73
12 102.83 118.64 178.48 138.07 34.24 45.08
Mean 191.80 149.20 411.55 329.25 633.15 443.80 345.94
SD 232.1284 108.0421 600.2741 381.8301 734.3926 879.4183 581.9022
N 7 7 7 6 7 7 7

Claims

1. A method for assessing treatment of a patient who exhibits an airway disease associated with tissue destruction, which comprises: analysing the MMP-9 level in a sample taken from the subject, and thereby determining whether the subject belongs to a first group, of "responders", orto a second group, of "non-responders", which are respectively characterised by high and low levels of MMP-9.
2. A method for assessing the risk that a subject susceptible to or exhibiting symptoms of an airway disease is likely to develop associated tissue destruction, which comprises: analysing the MMP-9 level in a sample taken from the subject, and thereby determining whether the subject belongs to a first, "high risk" group or to a second, "low risk" group which are respectively characterised by high and low levels of MMP-9.
3. A method according to claim 2, wherein the subject is a smoker.
4. A method according to claim 1 , wherein the analysing is conducted after administration to the subject of a tetracycline antibiotic, and includes observation of a time-dependent reduction in the MMP-9 level for the first group and the substantial absence of such a change for the second group.
5. A method according to claim 4, wherein the antibiotic is doxycycline.
6. A method according to any preceding claim, wherein the disease is COPD, CF, asthma, emphysema or chronic bronchitis.
7. A method according to any preceding claim, wherein the disease associated with tissue destruction is COPD.
8. A method according to any preceding claim, wherein the sample is of sputum.
9. A method according to any preceding claim, wherein the first group exhibits a MMP-9 level of above 120 ng/mL
10. A method according to claim 9, wherein the MMP-9 level is 0.4 to 10 mg/mL
11. A method according to any preceding claim, which comprises subsequent treatment of the subject with a tetracycline antibiotic.
12. A method according to claim 11 , wherein the antibiotic is doxycycline.
13. Use of a tetracycline antibiotic for the manufacture of a medicament for the treatment of airway disease in a subject exhibiting MMP-9 levels characteristic of the first group defined in claim 1.
14. Use of a tetracycline antibiotic for the manufacture of a medicament for the prevention of airway disease associated with tissue destruction in a subject exhibiting MMP-9 levels characteristic of the first group defined in claim 1.
15. Use according to claim 13 or claim 14, wherein the antibiotic is doxycycline.
16. Use according to any of claimsl 3 to 15, wherein the first group exhibits a MMP-9 level of above 120 ng/mL.
17. Use according to claim 16, wherein the MMP-9 level is 0.4 to 10 mg/mL
PCT/GB2002/004009 2001-08-30 2002-08-30 The diagnosis and treatment of airways disease WO2003020286A1 (en)

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GB0121046.7 2001-08-30

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062261A1 (en) * 2000-02-25 2001-08-30 Arakis Ltd. Metalloproteinase inhibitors for the treatment of respiratory diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062261A1 (en) * 2000-02-25 2001-08-30 Arakis Ltd. Metalloproteinase inhibitors for the treatment of respiratory diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VIGNOLA, A. M. ET AL.: "Sputum Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 Ratio Correlates with Airflow Obstruction in Asthma and Chronic Bronchitis", AMERICAN JOURNAL OF RESPIRATORY CRITICAL CARE MEDICINE, vol. 158, no. 6, 1998, pages 1945 - 1950, XP002223183 *

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