Title:  Methods for treating HIV-Infected Patients by the Administration of GM-CSF and a protease inhibitor

United States Patent:  6,576,231

Issued:  June 10, 2003

Inventors:  Echols; Roger M. (Monroe, CT)

Assignee:  Schering AG (Berlin, DE)

Appl. No.:  928279

Filed:  September 12, 1997

Provided are methods for inducing an increase in the number of CD4⁺ T-lymphocytes in HIV-infected patients by administering human GM-CSF. The GM-CSF may be administered concurrently with at least one antiretroviral agent.

SUMMARY OF THE INVENTION

The present invention provides methods for increasing CD4⁺ lymphocyte counts in HIV-infected patients by the therapeutic administration of GM-CSF. This method of treatment has been demonstrated to induce an increase in the absolute number of circulating CD4⁺ T-lymphocyte cells in patients concurrently receiving antiretroviral drugs, with no significant increase in viral load.

This invention is based on the results of a double-blinded, placebo-controlled study that enrolled HIV-infected patients at two study sites. In this study, patients receiving anti-retroviral agents for a minimum of eight weeks prior to study received therapeutically effective amounts of recombinant human GM-CSF or placebo. Viral load and CD4⁺ T-lymphocyte counts were determined twice prior to the start of the study (baseline), then two weeks, four weeks, and eight weeks after the start of the study, and twice approximately four weeks after the treatment phase was completed. Results indicated that within the placebo arm of the study, there was no significant change in the median values for CD4⁺ T-cell counts relative to the baseline. Within the GM-CSF arm of the study, a trend towards an increase in the median value for CD4⁺ T-lymphocyte counts was observed between the baseline and all evaluations during the course of the study.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention provides methods for inducing an increase in the number of CD4⁺ T lymphocytes in an HIV-infected patient by administering therapeutically effective amounts of granulocyte-macrophage stimulating factor (GM-CSF).

In accordance with the present invention, GM-CSF is administered to HIV-infected patients in amounts and for a time sufficient to induce a clinically significant increase in the patient's CD4⁺ T-lymphocyte count. A "CD4⁺ T-lymphocyte count" means the number of circulating CD4⁺ T-lymphocytes in the patient's blood, expressed as CD4⁺ T-lymphocyte cells per unit volume. Generally, CD4⁺ lymphocyte counts are expressed as cells/mm³ of whole blood. An increase in the CD4⁺ T-lymphocyte count is defined as a rise relative to the baseline (i.e., before administration of GM-CSF) value. For the purposes of the present invention, a "clinically significant" increase in CD4⁺ T-lymphocyte cells is an increase of greater than or equal to about 30% of the baseline value.

GM-CSF used in the practice of the invention includes any pharmaceutically safe and effective human GM-CSF, or any derivative thereof having the biological activity of human GM-CSF. In a presently preferred embodiment, the GM-CSF used in the practice of the subject methods is recombinant human GM-CSF (rhu GM-CSF), such as LEUKINE.RTM. (Immunex Corporation, Seattle, Wash.). LEUKINE.RTM. is a biosynthetic, yeast-derived, recombinant human GM-CSF, consisting of a single 127 amino acid glycoprotein that differs from endogenous human GM-CSF by having a leucine instead of a proline at position 23. Other natural and synthetic GM-CSFs, and derivatives thereof having the biological activity of natural human GM-CSF, will of course be equally useful in the practice of the invention.

As the degree of glycosylation of biosynthetic GM-CSFs appears to influence half-life, distribution, and elimination, the most effective dose of GM-CSF for the subject methods may vary depending on the source used (Lieschke and Burgess, N. Engl. J. Med. 327:28-35, 1992; Dorr, R. T., Clin. Ther. 15:19-29, 1993; Horgaard et al., Eur. J. Hematol. 50:32-36, 1993). The optimal dose of GM-CSF used for LEUKINE.RTM. may be adjusted if a GM-CSF other than LEUKINE.RTM. is used to induce CD4⁺ T-lymphocyte cells in HIV-infected patients.

LEUKINE.RTM. has been shown to exhibit the same hematopoietic effects as those induced by endogenous GM-CSF, namely, the stimulation of progenitor cells committed along the granulocyte-macrophage pathway to form neutrophils, monocytes, macrophages, and eosinophils (Technical Product Report: LEUKINE.RTM. Liquid, Immunex Corp., Seattle, Wash., 1997, which is herein incorporated by reference). LEUKINE.RTM., like endogenous GM-CSF, also promotes the differentiation of progenitor cells giving rise to erythrocytes and megakaryocytes (Ibid.) In addition to stimulating hematopoiesis, LEUKINE.RTM. enhances many of the functional activities of mature neutrophils, monocytes and macrophages, such as chemotaxis, growth factor secretion, anti-tumor activity, antibacterial and antifungal activities, and so on (Ibid.).

Various embodiments of the subject invention are disclosed herein. In one preferred embodiment, GM-CSF may be administered concurrently with antiretroviral agents, including, but not limited to, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors. The term "antiretroviral agent", as used herein, includes any pharmacological, biological or cellular agent that has demonstrated the ability to inhibit HIV replication. Specific examples of nucleoside reverse transcriptase inhibitors include zidovudine (AZT), didanosine (ddI), lamivudine (3TC), stavudine (d4T), and dalcitabine (ddC). Specific examples of non-nucleoside reverse transcriptase inhibitors include nevirapine and delavirdine. Specific examples of protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Patients treated in accordance with the present invention may be treated concurrently with one or more anti-retroviral agents. Additional antiretroviral agents not yet approved by the Food and Drug Administration may also be effective.

The optimal dose, frequency of administration, and duration of treatment with GM-CSF which is effective to induce a clinically significant increase in CD4⁺ T-lymphocyte counts may vary from patient to patient. Generally, however, therapeutically effective doses of GM-CSF sufficient to induce an increase in the patient's CD4⁺ T-lymphocyte count will be greater than or equal to about 100 micrograms (mcg). Preferably, doses of GM-CSF will be greater than or equal to about 150 mcg, and more preferably, doses of GM-CSF will be greater than or equal to about 250 mcg.

In preferred embodiments of the present invention, GM-CSF is administered for a period of time greater than about three weeks, and more preferably greater than about four weeks, at a frequency of at least two times per week, more preferably at least three times per week, and most preferably once per day or more. However, it should be understood that the optimal dose and length of treatment may vary from patient to patient, depending on the individual patient's condition and response to the treatment, and is best determined by monitoring the patient's response during the course of the treatment. It should further be understood that administration of higher doses may permit less frequent administration, and lower doses may require more frequent administration in order to achieve clinically significant increases of CD4⁺ T-lymphocyte counts. A treatment regimen (dosage amount, frequency and duration) is therapeutically effective if it results in a clinically significant increase in CD4⁺ T-lymphocyte counts.

The methods of the subject invention thus include inducing an increase in the CD4⁺ T-cell count in an HIV-infected patient who may also be treated with an antiretroviral agent in which the patient is administered an amount of GM-CSF sufficient to induce an increase in the patient's CD4⁺ T-lymphocyte count.

Claim 1 of 6 Claims

We claim:

1. A method for treating an HLV-infected patient consisting of administering a combination of one protease inhibitor selected from the group consisting of indinavir, nelfinavir, ritonavir and saquinavir, at least one additional antiretroviral agent that is selected from the group consisting of didanosine, lamivudine, stavudine, dalcitabine and a non-nucleoside reverse transcriptase inhibitor, and human recombinant GM-CSF, wherein said combination is administered for a time sufficient to induce an increase of at least 30% in the patient's CD4⁺ T-lymphocyte count, and further wherein said patient has received indinavir, nelfinavir, ritonavir or saquinavir for a minimum of eight weeks prior to receiving a first dose of GM-CSF.

 

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