CA2199154A1 - The use of medicaments containing interferon-beta - Google Patents

Abstract

The invention concerns the use of .beta.-interferon in the preparation of adjuvant drugs for the low-dose systemic intramuscular or subcutaneous therapy of ailments induced by papilloma viruses pathogenic to humans.

Description

~ t 2 1 ~9 1 54 The u~e o~ Medicaments Cont~;n;ng Interferon-~

Description The present invention relates to the use of inter-feron-~ for the preparation of medicaments for the ad-juvant systemic intramuscular or subcutaneous therapy in low dosage of diseases induced by humanopathogenic papilloma virus.

Interferons (IFNs) belong to the group of regulatory proteins of the immunological system, the cytokins, and have an antiviral, antiproliferative, cell-differen-tiating and immunomodulating effect. Based on their an-tigenic properties, we differentiate between 3 IFN
families: IFN-~, IFN-$ and IFN-~. Among the three IFN
families, IFN-y displays a number of peculiarities. For this reason, it is also called Type II IFN as opposed to the other two Type I IFNs. While the development of Type I IFNs is initiated by virus and two-stranded RNA, mitogens and specific antigens are the inductors for IFN-X. Accordingly, the main biological activity of the Type I IFNs is antiviral, whereas IFN-X primarily acts as an immunoregulatory substance. In addition, there are a number of other differences between the two IFN
types, e.g. with regard to acid stability, gene local-isation and receptor binding (Came and Carter, 1984;
Baron et al., 1991; Hundgen and von Eick, 1991).

In addition to IFNs obtained from human cells (natural IFNs), IFNs produced by genetic engineering with the aid of host cells (recombinant IFNs) have been used in-creasingly for the therapy of human diseases since the beginning of the 1980s. Methods for obt~'nlng natural and recombinant IFNs are described in various publica-tions, among those many patent applications (surveys in ~t 2~99~54 Came and Carter, 1984; Finter and Oldham, 1985; Tabor, 1986).

Due to the fact that recombinant IFNs are produced in host cells, they must be present in high purity (c99 ~) when used for human therapy so as to ensure that the medicaments contain no substances which originate from other species and may therefore be toxic. Natural IFN
preparations which, as a rule, are not subjected to se-vere purification usually also contain other cytokins (Came and Carter, 1984; Finter and Oldham, 198~) With regard to pharmacokinetics, IFN-~ has special properties. While intramuscular (i.m.) or subcutaneous (s.c.) administrations of IFN-a or INF-~ can still be measured in the serum at a dosage of 1 x 106 interna-tional units (I.U.), IFN-~ when administered the same way is not detectable in the serum below a dosage of 3 - 9 x 106 I.U. From this fact, one can conclude a high tissue affinity of IFN-$ to its application site (Koyama, 1983; Finter and Oldham, 1985; Hundgen and von Eick, 1991; Wills, 1990, Fierlbeck (not published)).
Therefore, IFN-$ is highly suitable for local therapy (Hundgen and von Eick, 1991). Systemic treatment with IFN-~ is thus often carried out intravenously (i.v ) (instructions for use of Fiblaferon~ of Rentschler, Laupheim, Germany; instructions for u-se of Feron~ of Toray, Tokyo, Japan). In case o~ systemic i.m. applica-tion, natural IFN-~ for therapeutic purposes is gener-ally used in dosages of 2 2 x 106 I.U (instructions for use of Frone~ of Serono, Rome, Italy). Treatment with natural IFN-~ administered by the systemic s.c.
route has so far been carried out in individual cases only; therefore, no general therapy recommendations can be given for this type of a~plication.

~ 2~99~5~

In the studies carried out so far with the objective of determining the dosage to be used, recombinant IFN-~was administered by the i.v., i.m. and s.c. routes. In case of multiple sclerosis, the recommended and thera-peutically effective daily dosage is 8 x 105 I.U. i.m.
or 6 x 106 I.U. s.c., respectively (instructions for use of Betaseron~ of Berlex, Richmond, CA., information to the press of Biogen, Cambridge, Mass.). In case o~
the systemic i.m. or s.c. application for treating various other diseases such as chronic myeloid leukae-mia (Aulitzky et al., 1993), hepatitis B and C (Irving Fox, Biogen, Cambridge, Mass., personal information) and condylomata acuminata (Gerd Gross, Dermatology De-partment of the Hamburg University, personal informa-tion; Robert Gerety, Biogen, Cambridge, Mass, personal in~ormation), the lowest daily dosage was 3 x lo6 I.U.
Accordingly, there have been no therapy recommendations for either natural or recombinant IFN-~ to use smaller daily dosages than 2 x 106 I.U. in case of systemic i.m. or s.c. application.

Humanopathogenic papilloma virus (HPV) represent a he-terogeneous group of DNA virus which may cause a number of epithelial tumours (warts and papillomae). At pres-ent, over 70 HPV types are ~nown. Among the most widely known clinical appearances are common warts ( verrucae vulgares), thorn warts (verrucae plantares) and level juvenile warts (verrucae planae juveniles), the pointed condylomae ( condylomata acuminata) and HP.V associated dysplasia of the cervix (cervicale intraepitheliale neoplasia, condylomata plana) in the genital area (Kirby and Corey, 1987; Cobb, 1990; Gross et al., 1990;
Lowy et al., 1994. Genital HPV diseases are generally spread through sexual intercourse. In the U. K., condy-lomata acuminata (CA) is the most ~requent virus dis-ease spread by sexual activity (Lancet editorial, 1991). According to statistical surveys of the American 4 2l 99l54 Center for Disease Control (CDC), CA occurs three times more frequently than genital herpes~ Thus, approx. one million patients suf~ering ~rom CA sought treatment with local practitioners in the United States in 1983 (Kirby and Corey, 1987).

Deficiencies in cell-communicated immunity promote HPV
infections and are often found in patients with recur-ring HPV diseases (Kirby and Corey, 1987; Cobb, 1990;
Lancet editorial, 1991). In otherwise healthy persons, the spontaneous rate o~ remission o~ HPV diseases dur-ing the first year after infection is 20 to 50 ~. It is therefore not surprising that placebo effects play an important role in the therapy of HPV diseases (Kirby, 1988, Cobb, 1990). Therefore, an unambiguous scientific proof of effectiveness for a certain method of treat-ment is only possible by randomised, placebo-controlled studies.

Therapy o~ HPV diseases mainly comprises surgical meas-ures such as curettage, electrocauterisation, cryogenic and laser surgery as well as touching the sites with keratolytic and caustic substances such as salicylic acid, podophyllin, trichloroacetic acid and 5-fluoro-uracil (Kirby and Corey, 1987; Cobb, 1990; Gross et al., 1990; Cirelli and Tyring, 1994). On the whole, however, the results of these therapies are not very satisfactory, since HPV diseases often recur. In case of primary CA, a recidivation rate of 20 to 40 ~ must be expected within a period of three months (Jensen, 1985). As a rule, the rate o~ recidivation even exceeds 50 ~ for patients with prolonged and/or recurring CA
(Cirelli and Tyring, 1994).

Based on their antiviral, antiproliferative and immuno-modulating properties, the IFNs seem to be suitable substances for the therapy of HPV diseases (Cobb, _ _ . .. , . . , _ . . . .. . .

~ 2199~54 1990). Therefore, it is not surprising that IFNs have been used for treating such diseases as early as the 1970s. They were administered systemically, topically on an ointment basis or locally by intralesional injec-tion. Surveys about the numerous studies conducted since are given by Kirby and Corey, 1987; Gross et al., 1990; Cirelli and Tyring, 1994.

Even though the effectiveness of IFNs for the local therapy of CA is undisputed, it is of little signifi-cance for practical application, since this form of treatment does not have any advantages in comparison with other conventional therapy methods. Untreated warts either do not respond at all or only marginally.
In addition, intralesional injections are very painful (Kirby, 1988; Gross et al., 1990). Only small warts re-spond to topical IFN preparations (Brzoska, 1994). How-ever, this form of application is not suitable for CA
in the anal area or large-scale lesions of the skin or mucous membranes.

The investigations conducted so far on the systemic monotherapy of CA produced inconsistent results. Pla-cebo-controlled double-blind studies with s.c. applied recombinant IFN-a in a dosage of 1.5, 3 and 9 x 106 I.U. did not confirm the positive results of open stud-ies (Condylomata International Collaborative Study Group 1991, 1993). So far, only a few studies of which two had a placebo-controlled design were conducted with natural IFN-$. In both studies, a daily dosage of 2 x 106 I.U. i.m. was used. The side effects of this ther-apy were negligible. In the verum-groups, a healing of CA was confirmed in noticeably more patients than in the placebo groups (Schonfeld et al., 1984; Costa et al., 1988). When viewing these positive results, how-ever, it should be noted that only patients who were suffering from primary CA from three weeks to six 6 2~ 991 54 months were included in the study, but not patients with recurring older CA who, as experience has shown, respond less well to the treatment with IFNs (Gross et al, 1990; Fierlbeck et al. 1991; Cirelli and Tyring, 1994). In an open study on patients with old CA, for example, complete remission was not achieved in a sin-gle case (Piccoli et al., 1989). So far, results on re-combinant IFN-~ are not available. As far as IFN-~ is concerned, two placebo-controlled studies confirmed ef-fectiveness against CA ~Gross et al., 1991). One of the disadvantages of a systemic monotherapy with IFNs, how-ever, is the sometimes long duration o~ the treatment and the considerable time lapse until the symptoms on the skin disappear. In addition, this form of therapy is successful in only half of the patients. The major-ity of dermatologists, therefore, consider the systemic application of IFNs for the treatment of CA unsuitable (Kirby, 1988).

In our own double-blind, placebo-controlled study we have adjuvantly used recombinant IFN-$ in the systemic therapy of CA in order to reduce the rate of recidiva-tion. Treatment with IFN-$ started within one week of surgical removal of the CA. As opposed to previous treatment methods, the daily dosage was only 1 x 106 I . U . ~m; n; stration was carried out s.c. under the ab-dominal skin on five consecutive days and repeated af-ter an intermission of three weeks (total dosage 10 x 106 I.U.). Only patients with recurring CA were ac-cepted. Within three months after surgical removal of the CA, the rate of recidivation was determlned for both groups. Even an intermediate evaluation of the study after the e~m;n~tion of 25 patients suitable for analysis showed a statistically significant difference between the two groups, i.e. the recidivation rate of CA could be reduced noticeably by the ad~uvant therapy with IFN-$ administered system-ically s.c. On the basis ~ ' 7 2~99154 of the previous assumption that the effect of 1 x 106 I.U. o~ IFN-~ after s.c application is by no means sufficient, this result could not be expected. It was particularly surprising that patients with recurring CA
responded to this low dosage.
-In addition to the therapeutic regimen described above,other treatment schemes may also be used for the adju-vant systemic therapy of HPV diseases with IFN-~. In such cases, the details may be as follows:

dosage 0.5 - 1.5 x 106 I.U., applied i.m. or s.c., application ~requency 1 - 7 times per week, and duration of therapy 1 day - 3 months.

The formulations for i.m. or s.c. injection are pre-pared in the form of sterile, aqueous preparations o~
the active ingredient which are preferably isotonic with the blood of the recipient. The dosage units pre-pared for injection may be provided in individual small sterile bottles, e.g. as lyophilisate in a quantity of, for example, 0.5 x 106, 1.0 x 106 or 1.5 x 106 I.U.
based on the pure active ingredient IFN-$ as individual dosage, the active ingredient being prepared for appli-cation immediately before use by solving it in aqua ad injectabilia. Physiologically compatible buffers are considered as formulation buffer, e.g. 0.1 M sodium phosphate with 0.05 M sodium chloride. A suitable car-rier substance for the lyophilisate, for example, is 0.5 - 30 mg/ml human serum albumin based on the recon-stituted solution ~ 219915~

Literatu3: e Aulitzky WE, Peschel C, Desprès D, Aman J, Trautman P, Tilg ~i, Rudolf G, Hutt-mann H, Obermeier J, Herold M, Huber C (1993~: Divergent In vivo and in vitro antileukemic activity of recombinant interferon beta in patients with chronic-phase chronic myelogenous leukemia. Ann Hematol 67: 205-211 Baron S, Tyring SK, Fleischmann WR, Coppenhaver DH, Niesel DW, Klimpel GR, Stanton GJ, Hughes TK (1991): The interferons. Mechanisms o~ action and clinicalapplications. JAMA 266: 1375-1383 Brzoska J (1984) Topische Interferonpraparationen bei dermatologischen Erkran-kungen. In: Gross G, Brocker EB (eds~ (1994): Interferon-Therapie in der Derma-tologie. W Zuckschwerdt Verlag: Munchen, Bern, Wien, New York, pp 1-9 Came PE, Carter WA ~eds) (1984): Interferons and their applications. Springer Verlag: Berlin, Heidelberg, New York, Tokyo Cirelli R, Tyring SK (1994): Interferons in human papillomavirus infections. Antiviral Res 24: 191-204 Cobb MW ~1990). Human papillomavirus infection. ~J Am Acad Dermatol 22: 547-Condylomata International Colloborative Study Group (1991): Recurrent condy-lomata acumina.a treated with recombinant interfeton alfa-2a. A mullicenter double-blind placebo-controlled clinical trial. JAMA 265: 2684-2687 Condylomata International Collobarative Study Group (1993): Recurrent condy-lomata acuminata treated with recombinant interferon alpha-2a. A multicenter double-blind placebo-controlled clinical trial: Acta Derm.Venereol 73: 223-226 Costa S, Poggi MG, Palmisano L, Syrjanen S, Yliskosky M, Syrjanen K (1988):
Intramuscolar i'3-interferon treatment of human papillomavirus lesions in the iower female genital tract. Cervix & I.f.g.t 6: 203-212 Editorial (1991): Persistent anogenital warts. Lancet 338: 1114-1116 Fierlbeck G, Breuninger H, Fierlbeck i3, Rassner Ci (1991): Condyiomata acuminata - lokale und systemische Interferontherapie. Hautarzt 42: 39-43 ~ ' 2199154 Finter NB, Oidham RK (eds) (1985): Interferon. In vivo and clinical studies. Elsevier:
Amsterdam, New York, Oxford Gross G, Jablonska S, Pfister H, Stegner HE (eds) (1990): Genital papillomavirusinfections. Modern diagnosis and treatment. Springer: Berlin, Heidelberg, New York, London, Paris, Tokyo, Hong Kong, Barcelona Gross G (1991) Recombinant interferon gamma in condylomata acuminata. JAMA
266: 2706 Hunden M, Eick H von (1991): Interferone. Grundlagen und Anwendung in Klinik und Praxis. Med Mo Pharm 14: 164-173 Jensen SL (1985): Comparison of podophyllin application with simple surgicat excision in clearance and recurrence of perianal condylomata acuminata. ~ancet ii:

Kirby P (1988): Interferon and genital warts: much potential, modest progress.
JAMA 259: 570-572 Kirby P, Corey L (1987): Genital human papillomvirus infections. Infect Dis ClinNorth America 1: 123-143 Koyama Y (1983): Pharmacokinetics and clinica1 trials of HulFN-~ in malignant tumors. In: Kishida T (ed) Interferons. Proceedings of the International Symposium on Interferons. ISIFN: Kyoto, Japan, pp 189-195 Lowy DR, Kirnbauer R, Schiller JT (1994): Genital human papillomavirus infection.
Proc Natl Acad Sci 91: 2436-2440 Piccoli R, Santoro MG, Nappi C, Capodanno M, De Santis V, La Torre PC, Costa S, Montemagno U (1989): Vulvo-vagimal condylomatosis and relapse: combined treatment with electrocauterization and beta-interferon. Clin Exp Obst Gyn 16: 31-Schonfeld A, Nitke S, Schattner A, Wallach D, Crespi M, Hahn T, Levavi H, YardenO, Shoham J, Doerner T, Revel M l1984): Intramuscular human interferon-~injections ;n treatment of condylomata acuminata. Lancet i: 1038-1042 Tabor JM (1986): Production-purification of interferons: recombinant technology.In: Stringfellow DA (ed) Clinical application of interferons and their inducers. Marcel Dekker, Inc: New York, Basel, pp 61-82 Wills RJ, (1990): Clinical pharmacokinetics of interferons. Clin Pharmacokinetic 19:

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Claims (13)

1. The use of interferon beta produced by genetic engineering (recombinant interferon beta) for the preparation of medicaments for the adjuvant systemic intramuscular (i.m.) or subcutaneous (s.c.) treatment of diseases induced by humanopathogenic papilloma virus (PC), comprising 0.5 to 1.5 million international units as a daily dosage, based on an adult patient of about 60 kg bodyweight.

2. The use of interferon beta according to claim 1, characterised in that the medicaments for treatment are intended for subcutaneous application.

3. The use of interferon beta according to claim 1, characterised in that the medicaments used for treatment comprise 1 million international units as a daily dosage.

4. The use of interferon beta according to claim 1 for the preparation of medicaments for treating genital HPV diseases.

5. The use of interferon beta according to claim 4 for the preparation of medicaments for treating condylomata acuminata.

6. The use of interferon beta according to claim 5 for the preparation of medicaments for treating recurrent condylomata acuminata.

7. The use of interferon beta according to any of the claims 1 - 6, characterised in that the adjuvant systemic i.m. or s.c. treatment is carried out after surgical removal.

8. The use of interferon beta according to claim 7, characterised in that said surgical removal is carried out by measures such as curettage, electrocauterisation, cryogenic and/or laser surgery.

9. The use according to any of the claims 1 - 6, characterised in that the adjuvant systemic i.m.
or s.c. treatment is carried out after touching the sites with keratolytic and caustic substances such as salicylic acid, podophyllin, trichloroacetic acid and 5-fluorouracil.

10. The use of interferon beta according to any of the claims 1 - 9, characterised in that the application frequency of the daily dosage is one to seven times a week.

11. The use of interferon beta according to claim 10, characterised in that the s.c. application of 1 x 10 6 international units each takes place on five consecutive days.

12. The use of interferon beta according to claim 11, characterised in that the application is repeated on five consecutive days after an intermission of three weeks.

13. The use of interferon beta according to any of the claims 1 - 12, characterised in that the injection solution for i m. or s.c. administration contains a pharmaceutically customary level of sodium phosphate buffer and human serum albumin in addition to NaCl.