NZ712273B2 - Method for reducing flu-like symptoms associated with intramuscular administration of interferon using a fast titration escalating dosing regimen - Google Patents

Abstract

titration package for enabling compliance with a regimen of changing dosage of an interferon over a period of time, the package comprising interferon-?-1a, delivery devices for said interferon-?-1a, and instructions for intramuscular administration of said interferon-?-1a to a patient during a titration period, wherein the interferon is administered at a dosage of 7.5 micrograms in week one, a dosage of 15 micrograms in week two, a dosage of 22.5 micrograms in week 3, and a dosage of 30 micrograms in week 4. ration period, wherein the interferon is administered at a dosage of 7.5 micrograms in week one, a dosage of 15 micrograms in week two, a dosage of 22.5 micrograms in week 3, and a dosage of 30 micrograms in week 4.

Description

PCT/U82012/02920] TITLE OF THE INVENTION: METHOD FOR REDUCING FLU—LIKE SYMPTOMS ASSOCIATED WITH INTRAMUSCULAR ADMINISTRATION OF INTERFERON USING A FAST TITRATION ESCALATING DOSING REGIMEN BACKGROUND OF THE INVENTION Field of the Invention The present invention relates generally to a method for treating multiple sclerosis (MS), and for reducing flu-like ms generally associated with administration of interferons. In particular, the method uses a fast-titration escalating dosing n of uscularly administered interferon. The invention also relates to titration packaging to e compliance with the dosage titration.

Description of Related Art Multiple sclerosis (MS) is a chronic neurological and inflammatory disorder of the central nervous system, marked by focal autoreactive T-cell and macrophage infiltration through the blood brain barrier that lead to demyelination, and axonal and al loss. In people affected by MS, patches of damage called plaques or lesions appear in seemingly random areas of the CNS white matter. At the site of a , a nerve insulating material, myelin, is lost in demyelination. Inflammation, demyelination, oligodendrocyte death, membrane damage and axonal death all contribute to the symptoms of MS.

PCT/U52012/029201 Although MS has an unknown etiology, the classical hypothesis is that MS is a T helper 1 (THU-cell mediated autoimmune disease. Development of lesions is characterized by lation of activated microglia and macrophages. Acute plaques are terized by blood brain r damage, infiltration by activated CD4+ T cells and clonotypic CD8+ T cells that recognize CNS autoantigens, and the presence of reactive astrocytes and proliferating oligodendrocytes. Pro—inflammatory cytokines, e.g. interleukin 12 ) and tumour-necrosis factor-a (TNF-a), are also present. There is further evidence that other adaptive immune cells (e.g. TH17 cells and peripheral B lymphocytes) and innate immune cells (dendritic cells, natural killer T cells and resident microglia) play a role in MS pathogenesis.

Relapse-remitting MS, the most common form of the disease, is characterized by multiple bations over time. Exacerbations are attacks on vision, motor, sensory, and sphincter control and cognitive processes. Patients with relapse-remitting MS do not completely recover from these exacerbations and accrue neurologic disability with each subsequent exacerbation.

Natural human fibroblast interferon-beta (IFN—B) was the first drug to treat relapse-remitting MS. lFN-B has immunomodulatory effects, which include ting cytokine levels (e.g., ng Th1 per 1) related cytokines and Th2 related cytokines), inhibiting T-cell activation and eration, inhibiting transmigration of autoreactive T cells into the CNS, increasing T cell apoptosis, and reducing expression of molecules required for antigen presentation. IFN-B has well-established clinical effects PCT/U52012/029201 and studies evidence that IFN—B works against multiple sclerosis through immunomodulation.

There are currently two different recombinant interferon-beta treatments for MS: interferon beta-1a (IFN-Bla) and interferon b (IFN-Brb). IFN-Bia and b are two distinct molecules with different recommended s, routes of administration and dosing intervals. IFN-Bla is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human eron beta gene has been introduced. The amino acid sequence is identical to that of natural human interferon beta. IFN-Blbhas 165 amino acids and an approximate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material. IFN—Bn, is manufactured by bacterial tation of a strain of ichia coli that bears a genetically engineered d ning the gene for human interferon betasem. The specific activity of IFN-Bla and IFN-Blb are different and based on different World Health Organization (WHO) reference standards of recombinant interferon beta and different assays used to measure ty.

Current IFN-Bla treatments include Avonex®, CinnoVexTM, Rebif®, and Resigene. Current IFN-[Slb treatments include Betaseron® in the US and Betaferon® in Europe, and Extavia®. Avonex® and CinnoVexTM are administered intramuscularly, while the other interferon treatments for MS are administered subcutaneously.

PCT/U52012/029201 Although there is a difference in specific activity between the two types of erons, IFN-[Sia and , share similar side effect profiles. For example, a common adverse event associated with interferon therapies are flu-like symptoms that develop within a few hours after stration and subside within 24 hours. Flu-like symptoms associated with administration of interferons include fever, muscle aches (myalgia), chills, ng, fatigue, headache, and malaise. The exact mechanism for the development of flu-like symptoms is not well understood but occurs among patients taking interferons ective of disease state. It has been postulated that interferons stimulate the sub-thalamic nucleus, thus affecting temperature, as well as local cytokines resulting in other symptoms.

Generally, the flu-like symptoms will significantly decrease after 2-3 months.

However, flu-like symptoms associated with interferon stration at the beginning of treatment can be a significant barrier to the initiation or maintenance of MS therapy, even before the onset of any therapeutic benefit. Use of an escalating dosing regimen (also known as dose titration) has become a routine practice for the stration of eron therapies to manage side s at the initiation of therapy. The goal of dose titration is to improve the acceptance and adherence of therapy and, thus, impact long-term health benefits for patients with le sclerosis. Currently, there are only two interferon-beta products, Betaseron® and Rebif®, that provide dose titration instructions in their labels.

Both Betaseron® and Rebif® are administered subcutaneously.

PCT/U52012/029201 The Betaseron® (10/07) label includes titration instructions for subcutaneous administration of lFN—Bn, over a six-week period, with full dose beginning in week 7: Weeks 1 — 2 - 1/: of a dose (0.0625mg/0.25ml) Weeks 3 -4 - V2 of a dose (O.125mg/0.5ml) Weeks 5 — 6 - 3/4 of a dose (0.1875mg/0.75ml) Week 7 - full dose (0.25mg/lml) The Betaseron® label tes dose titration may reduce e symptoms. The European Betaferon® label (124) includes ion instructions for subcutaneous administration over a three week period, with full dose beginning in week 4: Week 1 - 1/: of a dose (0.0625mg/0.25ml) Week 2 — 1/2 of a dose mg/0.5m1) Week 3 — 1% of a dose (0.1875mg/0.75ml) Week 4 — full dose (0.25mg/lml) Although the European Betaferon® label has a three week titration period with 1A dose increments, the label recommends dose titration at the start of treatment in order to increase tolerability and to reduce side effects, only generally, at the start of therapy.

Unlike the US Betaseron® label which indicates a 6 week titration period and the possibility of a reduction in flu-like symptoms, the 3 week titration period of the European Betaferon® label is silent with t to treating flu—like symptoms. Two clinical studies reveal that 1A dose increments over a three-week period do not provide a significant reduction in flu-like symptoms in comparison to slow titration ns.

] Rice et a1 (Rice GPA, Ebers GC, Lublin FD, Knobler RL. Ibuprofen Treatment versus Gradual Introduction of Interferon beta—1b in Patients with MS.

Neurology 1999;52:1893—1895) evaluated the iveness of dose titration in combination with ibuprofen in reducing the flu-like side effects of Betaseron® PCT/U52012/029201 administered subcutaneously in 49 patients with Relapsing-Remittmg and Secondary Progressive Multiple sis (RR and SPMS). This was a randomized, open-label, study that compared patients who did not titrate Betaseron® but took ibuprofen prophylaxis (Group A), to those who titrated Betaseron® with (Group B) and without Ibuprofen treatment (Group C). Group A received 8 n IU (MIU) of Betaseron® every second day (the standard dose) during weeks 0-4. Groups B and C each received Betaseron® ing to the titration schedule starting at 2 MIU (25% of the rd dose) and increased at increments of 2 MIU (25% of the standard dose) during weeks 0-4.

During weeks 0-4, 11% (2 out of 18) of Group A patients developed flu-like symptoms, 6% (1 out of 6) of Group B patients developed flu-like symptoms, and 40% of Group C patients developed flu-like symptoms (Table l of Rice et al.). The ences in incidence of flu-like symptoms between the group receiving ibuprofen treatment alone (Group A) and the group receiving dosage escalation and ibuprofen treatment (Group B) does not appear to be significant.

Moreover, Rice et al. reported that 5 (three from Group A, one from Group B, and one from Group C) of the 49 patients (10%) in the study experienced difficulty while escalating the dose of IFN—Blb, and these patients required either dosage ion or a delay in the ting le.

This was common practice according to Bayas et a1. (Bayas A and Rieckmann P. Managing the Adverse Effects of Interferon-B Therapy in Multiple Sclerosis. Drug Safety 2000 Feb: 22(2): 9). Bayas et al. described dose titration for administration PCT/U52012/029201 of IFN-Bu, (which is only administered subcutaneously) where treatment began at 20 to % dose for 1 week, increased to 50% dose the second week, and if treatment was tolerated, increased to full dose. According to Bayas et al., interferon—[3 dosage should be reduced or kept at the same level for a longer time until improved drug tolerability allows an increase. Walther et a1. (Walther EU, Hohlfeld R. Multiple Sclerosis Side Effects of Interferon beta Therapy and their Management. Neurology 1999; 53: 1622-1627) ended one dose reduction (between 25-50%) that should be maintained, rather than escalated, for 4-6 weeks. Thus, it was common practice to err on the side of an extended titration le.

Wroe (Wroe SJ. Effects of dose titration on bility and efficacy of interferon beta-1b in people with multiple sclerosis. J Int Med Res 2005; -18) evaluated whether a slower, four-stage, 4 week titration to a final dose of 250 pg subcutaneous IFN-[inJ might improve tolerability over a more rapid two-stage, 2 week titration in patients with ing-remitting MS over a 3-month period. In the slow— titration group, IFN-Bn, was subcutaneously stered, initially at 62.5 pg (M: dose) every other day for 9 days, and then at 1%: dose increments (125 pg and 187.5 pg, respectively) on days 11 and 21, and a full dose (250 pg) beginning on day 31 (i.e. in the middle of week 5) for the remainder of the 3-month treatment. See Figure 1 of Wroe et al. In the fast-titration group, IFN-Bu, was subcutaneously administered, initially at 125 pg (V2 dose) every other day for 2 weeks and then at full dose for the remainder of the 3- month treatment. One of the primary adverse events assessed was flu—like symptoms.

Wroe ed no noticeable differences with t to the occurrence of adverse events WO 25809 PCT/U52012/029201 between the two treatment groups, e.g., the nce rates of flu-like symptoms were similar in the slow- ) and rapid titration (41.9%) groups (Figure 3 of Wroe et al).

Wroe concluded that a rapid-titration regimen (V2 dose increments, with a full dose ing in week 3) results in a quicker onset of clinical benefit and slow titration (M: dose increments, with a full dose beginning in the middle of week 5) showed a non- significant reduction in flu—like ms compared to the rapid-titration regimen.

The Rebif® label includes titration instructions for subcutaneous administration of IFN-Bla three times per week over a 4-week period, with full dose administered in week 5: Weeks 1 — 2 -1/5 of a dose— subcutaneous injection 3X/week (titration dose for 33 pg = 4.4 pg) (titration dose for 44 pg = 8.8 pg) Week 3 — 4 - 1/2 of a dose - subcutaneous injection 3X/week (titration dose for 33 pg = 11 pg) tion dose for 44 pg = 22 pg) Week 5 — full dose — subcutaneous injection 3X/week The European Rebif® label recommends a gradual increase during a 4 week period to reduce adverse reactions. The 1/5 dose during the first two weeks serves the purpose of allowing tachyphylaxis to p, thus reducing side s. Both the US and European labels are silent with respect to treating flu-like symptoms associated with administration of interferon-beta. All of the products and clinical studies discussed thus far relate to subcutaneous administration of IFN—Bla or lFN-Blb.

PCT/U52012/029201 ] Brandes et a1. (Brandes DW, Bigley K, Hornstein W, Cohen H, Au W, Shubin R. Alleviating Flulike Symptoms with Dose Titration and Analgesics in MS Patients on Intramuscular Interferon beta—1a Therapy: a pilot study. Curr Med Research and Opinions 2007; 23:7: 1667-1672), appears to be the first to investigate dose titration of intramuscular administration (IM) of IFN-Bla. Brandes et a1. evaluated the effectiveness of dose titration in combination with inophen or ibuprofen in reducing the flu-like side effects of ® (IFN-Bla) in 47 patients with relapsing-remitting multiple sclerosis.

The Brandes et al. study was a multi-site, randomized, open-label, 12-week study. Group 1 patients received (IM) 1a at a dose of 30 ug once weekly with no titration. Groups 2 and 3 ed (IM) IFN-Bla at ‘A dose during weeks 1 and 2, V2 dose for weeks 3 and 4, 3/: dose at weeks 5 and 6, and a full dose (30 u g) for weeks 7-12.

Groups 1 and 2 received acetaminophen 650mg 1 hour before each (IM) 13 ion, then every 4 hours as needed. Group 3 received ibuprofen 400 mg 1 hour before each (IM) IFN—Bla injection, again at 6 hours ing injection, then every 6 hours as needed. Flu-like symptoms were recorded at three time points: baseline (first dose of analgesic, 1 hour pre-injection); Time A (second dose of analgesic, 4 hours post- injection); and Time B (12-15 hours post-injection).

Brandes et al. found that one-quarter titration (Groups 2 and 3) significantly reduced the proportion of patients with a mean se of 22 from baseline in flu-like symptom score compared with no titration only at 4 hours post-injection during the first PCT/U52012/029201 two weeks (Figure 1A of Brandes et al., p=0.015 indicated with *). There was no significant difference between the one-quarter titration s 2 and 3) and no titration (Group 1) at 4 hours during weeks 3-12 as the dose was increased. These data suggested that a 1/: dose escalation does not reduce flu—like symptoms, suggesting that further prolonged titration, i.e., an even slower titration, would be necessary.

Also, there was no significant difference between the one—quarter titration (Groups 2 and 3) and no ion (Group 1) at 12-15 hours during any week, including the first two weeks. These data suggested that initiating (IM) IFN-Bla injection with a 1/1 dose had d effects in reducing flu-like symptoms because the ‘A dose only delayed the onset of flu-like symptoms and only did so during the first two weeks.

Frohman et al (Frohman E et a1. Disease-Modifying Therapy in Multiple Sclerosis: Strategies for Optimizing Management. Neurologist 2002;8z227-236) in a comprehensive review of MS therapy management, recommends initiating treatment during the tapering phase of a steroid regimen and applying a fractionated dosing scheme in patients treated with either Avonex®, Rebif® or Betaseron® in combination with a nonsteroidal anti-inflammatory agent. In particular, patients were started at 25% of the ended dose and s were sed by 25% increments weekly to every other week. Frohman et al. bes the 25% dose as “a dose usually ated with minimal to no side effects” given that interferon-related side effects are dose—response related.

Significantly, Frohman et al. states, “If patients ence severe and ng side effects as the dose is increased, we will generally prolong titration, escalating by the same 304148005 KAE511214NZPR increment every 2 to 4 weeks. With this approach, we have had very few patients fail drug initiation.” Thus, Frohman teaches to err on the side of an extended titration It is therefore desirable to provide a method for r reducing flu-like symptoms associated with intramuscular interferon administration, which will promote compliance and continuation of interferon therapy for MS. [00021A] It is an object of the t ion to provide a titration package for reducing the severity of flu-like symptoms in a patient having le sclerosis treated with intramuscularly stered interferon-ȕ-1a over an eight week period and/or a method of preparing said titration package. It is an alternative object of the invention to at least provide the public with a useful choice.

SUMMARY OF THE INVENTION The inventors have surprisingly found that by decreasing the time period of the dose titration le for the intramuscular administration of interferon (“fast titration”), the appearance of flu-like symptoms is significantly reduced as compared to a longer dose titration schedule (“slow titration”).

KAE511214NZPR As such, the present invention provides a method for treating multiple sclerosis, which includes intramuscularly administering an interferon to a patient once per week, and ically includes an initial titration period wherein the interferon is administered in an escalating dose regimen (a “titration period”). In particular, the titration period es a one-quarter dose in week one, a one-half dose in week two, a three-quarter dose in week 3, and a full therapeutically ive dose in week 4 and thereafter.

The present invention also provides a method for reducing flu-like symptoms associated with the administration of an interferon to a patient with multiple sclerosis, including (a) intramuscularly administering the interferon to the patient ing to an escalating dosing regimen in weeks 1 to 3; and (b) intramuscularly administering a full therapeutically effective dose of interferon in week 4.

The invention also relates to a titration package for enabling compliance with these s, wherein the dosage of interferon changes over a period of time. The titration package includes interferon delivery devices containing an interferon, and instructions for the t to administer the interferon in an escalating dose n during a titration period.

KAE511214NZPR 304159160 [00025A] In a particular aspect, the ion provides a titration package for reducing the severity of flu-like symptoms in a patient having multiple sclerosis treated with intramuscularly administered interferon-β-1a over an eight week period, wherein the titration package comprises interferon-β-1a and delivery devices for once a week intramuscular administration to a patient having multiple sclerosis according to a first schedule comprising a first delivery device including 7.5 μg of interferon-β-1a for intramuscular administration to the patient in week one, a second delivery device ing 15 μg of eron-β-1a for uscular administration to the t in week two, and a third delivery device ing 22.5 μg of interferon-β-1a for intramuscular administration to the patient in week three, wherein the severity of the ke symptoms is reduced at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-β-1a throughout an eight week period which includes once a week intramuscular administration of 30 μg of interferon-β-1a to the t in weeks four through eight when compared to the severity of the flu-like symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-β-1a to the patient according to (i) a second schedule comprising once a week intramuscular administration of μg of interferon-β-1a to a patient having multiple sclerosis for eight weeks and (ii) a third schedule comprising intramuscular administration of 7.5 μg of interferon-β-1a to the patient in weeks one and two, intramuscular administration of 15 μg of interferon-β-1a to the t in weeks three and four, intramuscular KAE511214NZPR 304159160 administration of 22.5 μg of eron-β-1a to the patient in weeks five and six and intramuscular administration of 30 μg of interferon-β-1a to the patient in week seven and eight. [00025B] In a ular aspect, the invention provides a method of preparing a titration package ing to the previous aspect, the method including providing: a first delivery device capable of including 7.5 μg of interferon-β-1a for intramuscular administration to the patient in week one, a second delivery device capable of including 15 μg of interferon-β-1a for intramuscular administration to the patient in week two, and a third delivery device capable of including 22.5 μg of interferon-β-1a for intramuscular administration to the patient in week three, and sufficient interferon to be included in the ry devices.

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the ion.

BRIEF DESCRIPTION OF THE FIGURES The accompanying Figures, which are incorporated herein and form part of the ication, illustrate embodiments of the present invention and, together with the description, further serve to explain the principles of the invention.

Figure 1 is a flow chart g the design of a “fast vs. slow” titration trial.

Note that in the Example below, additional ts were investigated. 2012/029201 Figure 2 is a table with the titration schedules in a clinical study. Patients in Treatment Group 1 ed a full intramuscular dose of Avonex® each week for 8 weeks. Patients in Treatment Group 2 received intramuscular doses of Avonex® according to a fast ion schedule (1/: dose in week 1, 1/2 dose in week 2, 3%: dose in week 3, and full dose in weeks 4-8). Patients in Treatment Group 3 received intramuscular doses of Avonex® according to a slow titration schedule (M: dose in weeks 1-2, 1/2 dose in weeks 3-4, 3A dose in weeks 5-6, and full dose in weeks 7-8). All patient groups received prophylactic medication.

Figure 3 describes a method of scoring flu-like symptoms (FLS) in accordance with the invention.

Figure 4 is a line graph of the primary outcome variable and shows the change in total flu-like symptom (FLS) score from pre—injection to 4 to 6 hours after ion over 8 weeks.

Figure 5 is a line graph of the ary outcomes variable and shows the change in total flu-like symptom (FLS) score from pre—inj ection to 12 to 15 hours after injection over 8 weeks.

PCT/U52012/029201 ] Figure 6 is a table of the secondary outcome variable and provides the odds ratio of incidence of flu—like symptom (FLS) score at 4 to 6 hours and at 12 to 15 hours after injection over 8 weeks.

] Figure 7 provides data comparing the effect on flu-like symptoms of no titration, fast titration and slow titration.

Figure 8 is a bar graph comparing the change in flu-like symptoms (FLS) at 4- 6 hours, comparing no titration to fast titration.

Figure 9 provides data comparing the effect on flu-like symptoms of no ion to slow titration.

DETAILED DESCRIPTION OF THE INVENTION The invention es a method for treating a subject with le sclerosis, by intramuscularly stering an interferon using an initial escalating dosage regimen or titration period. Treatment is preferably once a week. The escalating dosage regimen typically involves administration of a one—quarter dose in week one, a one—half dose in week two, a three-quarter dose in week 3, and a full therapeutically effective dose in week 4 and thereafter.

PCT/U52012/029201 In a preferred embodiment, the week one dose is about 7.5 micrograms, the week two dose is about 15 micrograms, the week three dose is about 22.5 micrograms, and the week four dose is about 30 micrograms.

In a preferred embodiment, the interferon is interferon B. In a more red embodiment, the interferon is an interferon [31. In a most preferred ment, the interferon is interferon [31,.

] The invention also provides a method for reducing the flu-like ms which can accompany the intramuscular administration of an interferon. In particular, the invention provides a method involving the intramuscularly administration of interferon to the patient according to an escalating dosing regimen in weeks 1 to 3; and then the administration of a full therapeutically effective dose of interferon in week 4.

Reducing flu-like symptoms can be measured in reduction of severity of symptoms, and/or ion in incidence of flu-like symptoms. The reduction can be measured at various timepoints post-injection, for example 4 to 6 hours post-injection and 12 to 15 hours post-injection. ably, the reduction in ty of flu-like symptoms at 4 to 6 hours is at least 40%, more preferably at least 50%, even more preferably at least 60%, and most preferably at least 70%. The reduction in ty of flu-like symptoms at 12 to 15 hours PCT/U52012/029201 is preferably at least 10%, more preferably at least 20%, even more preferably at least %, and most preferably at least 30%.

The reduction in incidence of flu-like symptoms at 4 to 6 hours is preferably at least 5%, more preferably at least 10%, even more preferably at least 15%, and most preferably about 20%. ably, the reduction in incidence of flu-like symptoms at 12 to 15 hours is at least 10%, more preferably at least 15%, even more preferably at least %, and most preferably about 25%.

In a preferred embodiment, the invention includes administering one quarter of the eutically effective dose in week 1, half of the eutically effective dose in week 2, and three-quarters of the full therapeutically effective dose in week 3.

In a most preferred embodiment, the full therapeutically effective dose is 30 rams.

Flu-like symptoms can include, for example, fever, muscle aches (myalgia), chills, sweating, fatigue, headache, and malaise, and can be scored in ance with the method of Figure 3.

] The methods of the invention can further include the administration of an analgesic or anti-inflammatory drug, or a mixture thereof. The drug may be a steroid or a PCT/U52012/029201 non—steroidal anti-inflammatory drug. Preferred drugs include acetaminophen and ibuprofen.

The invention also provides titration packages, wherein the interferon is presented in a way to promote compliance with the escalating dosage regimen, and ultimately the long-term treatment using the eron.

In a preferred embodiment, the package includes interferon and delivery devices for the interferon. The interferon may be in lyophilized form, and thus packaged in a jar or vial. In this case, the e also preferably contains a device, such as a syringe, which is pre-filled with a diluent for lyophilized interferon.

Alternatively, the interferon may in liquid form. In this case, the interferon may be provided in lled syringes. The syringes may be provided with the exact dosage for weeks 1-4 and thereafter. Alternatively, an accessory to the ry device may also be provided, which when used in ation with the syringe, is capable of titrating the correct volume or dosage for the particular week of the escalating dosage regimen (titration period).

Where the interferon is provided in a syringe, the syringe may also be ed with a needle stick prevention device. Such a prevention device can e a needle shield, which may be automated. The shield may be completely automatic (i.e., without any action by the patient), or may be activated by the patient.

] The eron may also be provided in other delivery devices, such as a pen.

The titration package also preferably contains instructions for uscular administration of the interferon by a patient during a titration period, wherein the interferon is preferably stered at a one-quarter dose in week one, a one-half dose in week two, a three—quarter dose in week 3, and a full therapeutically effective dose in week 4.

The following terms are used herein: Interferon--An "interferon" (also referred to as "IFN") is a small, s- specific, single chain polypeptide, produced by ian cells in response to exposure to a variety of inducers such as viruses, polypeptides, mitogens and the like. The most preferred interferon used in the invention is ylated, human, interferon- B that is glycosylated at residue 80 (Asn 80) and that is preferably derived via recombinant DNA technologies. This preferred glycosylated interferon—[3 is called "interferon- [31a ". The " is also intended to term "interferon- Bla encompass all mutant forms (i.e., Example 1) provided that the mutants are also glycosylated at the Asn 8O residue.

Recombinant DNA methods for producing proteins are known.

Preferred interferon- [313 cleotides that may be used in the present methods of the invention are derived from the wild-type interferon B gene sequences of various vertebrates, preferably s and are obtained using methods that are well- known to those having ordinary skill in the art such as the methods described in the following US. Patents: US. Pat. No. 5,641,656 (issued Jun. 24, 1997: DNA encoding avian type I interferon proprotein and mature avian type I interferon), US. Pat. No. ,605,688 (Feb. 25, 1997-recombinant dog and horse type I interferons); US. Pat. No. ,231,176 (Jul. 27, 1993, DNA molecule encoding a human leukocyte interferon);); US.

Pat. No. 5,071,761 (Dec. 10, 1991, DNA sequence coding for subfsequences of human lymphoblastoid interferons LylFN-alpha-2 and LyIFN-alpha—3); US. Pat. No. 4,970,161 (Nov. 13, 1990, DNA ce coding for human interferon-gamma); US. Pat. No. 4,738,931 (Apr. 19, 1988, DNA containing a human interferon beta gene); US. Pat. No. 4,695,543 (Sep. 22, 1987, human alpha-interferon Gx—l gene and US. Pat. No. 4,456,748 (Jun. 26, 1984, DNA encoding sub-sequences of different, naturally, occurring leukocyte interferons). s of interferon- [31a may be used in accordance with this invention.

Mutations are developed using conventional s of ed mutagenesis, known to those of ordinary skill in the art. Moreover, the invention provides for functionally lent interferon-[31a polynucleotides that encode for functionally equivalent interferon-beta- 1 a polypeptides.

PCT/U52012/029201 In summary, the term "interferon" includes, but is not limited to, the agents listed above as well as their onal equivalents. As used herein, the term ional equivalent" therefore refers to an interferon- [313 protein or a polynucleotide encoding the interferon-beta-la protein that has the same or an improved beneficial effect on the ian recipient as the interferon of which it is deemed a functional lent. As will be appreciated by one of ordinary skill in the art, a functionally equivalent protein can be produced by recombinant techniques, e.g., by expressing a "functionally equivalent DN Accordingly, the instant invention es interferon- [31a ns encoded by naturally-occurring DNAs, as well as by non-naturally-occurring DNAs which encode the same protein as d by the naturally-occurring DNA. Due to the degeneracy of the nucleotide coding sequences, other polynucleotides may be used to encode interferon- Bra. These include all, or portions of the above sequences which are altered by the substitution of different codons that encode the same amino acid residue within the sequence, thus producing a silent change. Such altered sequences are regarded as equivalents of these ces. For example, Phe (F) is coded for by two codons, TTC or TTT, Tyr (Y) is coded for by TAC or TAT and His (H) is coded for by CAC or CAT.

On the other hand, Trp (W) is coded for by a single codon, TGG. Accordingly, it will be appreciated that for a given DNA sequence encoding a particular interferon there will be many DNA degenerate sequences that will code for it.

The eron may be administered per se as well as in the form of pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. In such pharmaceutical and medicament formulations, the interferon preferably PCT/U52012/029201 is utilized together with one or more pharrnaceutically able carrier(s) and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient f. The eron is provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.

The formulations include those suitable for intramuscular administration.

The formulations may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the active ingredient(s) into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are ed by uniformly and intimately bringing the active ingredient(s) into ation with a liquid carrier.

The formulations may be presented in unit-dose or dose form.

In addition to the aforementioned ingredients, the ations may further include one or more accessory ingredient(s) selected from diluents, buffers, disintegrants, surface active agents, thickeners, lubricants, preservatives ding antioxidants), and the like.

PCT/U52012/029201 In yet more detail, the present invention is described by the following items which represent additional embodiments hereof. 1. A method for treating le sclerosis, including intramuscularly administering an interferon to a patient once per week, wherein treatment begins with a ion period wherein the interferon is administered at a one-quarter dose in week one, a one—half dose in week two, a three-quarter dose in week 3, and a full therapeutically effective dose in week 4 and thereafter. 2. The method of item 1, wherein the week one dose is about 7.5 micrograms, the week two dose is about 15 micrograms, the week three dose is about 22.5 micrograms, and the week four dose is about 30 micrograms. 3. The method of item 1, wherein the interferon is interferon B13. 4. A method for reducing e ms associated with administration of an interferon to a patient with le sclerosis, including: (a) intramuscularly administering the interferon to the patient according to an escalating dosing regimen in weeks 1 to 3; and (b) intramuscularly administering a full therapeutically effective dose of interferon in week 4.

PCT/U52012/029201 5. The method of item 4, wherein the escalating dosing regimen comprises administering one quarter of the therapeutically effective dose in week 1, half of the therapeutically effective dose in week 2, and quarters of the therapeutically effective dose in week 3. 6. The method of item 4, wherein the interferon is interferon [31,. 7. The method of item 4, n the full therapeutically ive dose is 30 micrograms. 8. The method of item 4, wherein the flu-like symptoms include fever, muscle aches, chills, sweating, fatigue, he, and malaise. 9. A titration package for enabling compliance with a n of changing dosage of an interferon over a period of time, the package including interferon delivery devices containing an eron and instructions for administration by a patient during a titration period, wherein the interferon is administered at a one—quarter dose in week one, a one—half dose in week two, a three-quarter dose in week 3, and a full eutically effective dose in week 4. 10. The titration package of item 9, wherein the instructions indicate a week one dosage of about 7.5 micrograms, a week two dose of about 15 micrograms, a week three dosage of about 22.5 micrograms, and a week four dosage of about 30 micrograms. 2012/029201 1 1. The titration e of item 9, n the interferon is provided in a vial in lyophilized form. 12. The titration package of item 11, further comprising a vial adapter and a syringe pre-filled with a diluent for said lyophilized interferon. 13. The titration package of item 9, wherein the interferon is provided in a liquid formulation. 14. The titration package of item 13, wherein the liquid interferon formulation is provided in lled es. 15. The titration package of item 14, wherein the pre—filled syringes are filled with a correct dosage for weeks one to four. 16. The titration package of item 9, wherein the delivery device comprises an njector. 17. The titration package of item 9, wherein the delivery device is needle- free. 18. The titration package of item 9, wherein the deliver device is a pen.

WO 25809 PCT/U52012/029201 19. The titration package of item 9, further comprising a needle stick prevention device. 20. The titration package of item 19, wherein the needle-stick prevention device includes a needle shield. 21. The titration e of item 20, wherein the shield is activated manually by the patient. 22. The titration package of item 20, wherein the shield is automated. 23. The titration package of item 22, wherein the automated shield is activated by the patient. 24. The titration e of item 22, wherein the needle is automatically shielded without any action by the patient. 25. The titration e of item 22, wherein the needle is shielded without any action by the patient. 26. The ion package of item 9, wherein the package further es a dose-limiting titration device.

PCT/U52012/029201 27. The method of any of items 1-8, further comprising administration of an analgesic or anti-inflammatory drug, or a e thereof. 28. The method of item 27, wherein the drug is a d. 29, The method of item 27, wherein the drug is a non—steroidal anti- inflammatory agent. 30. The method of item 27, wherein the drug is acetaminophen. 31. The method of item 27, wherein the drug is fen.

EXAMPLES: The compositions and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such s and modifications including, without limitation, those ng to the processes, formulations and/or methods of the invention may be made without departing from the spirit of the ion and the scope of the appended claims.

PCT/U52012/029201 Avonex® was d in a randomized, three-arm, dose-blinded, parallel- group study to ine the effect of Avonex® dose titration, administered intramuscularly, on the severity and incidence of lFN-Bla—related flu-like symptoms in healthy volunteers. The approved therapeutic dose of ® is 30 pg weekly by IM administration.

In this blinded, parallel-group study, subjects were randomized to 1 of 3 treatment arms: Group 1 - no titration (weekly IM IFN-B;a 30 pg for 8 weeks); Group 2 - fast dose titration (quarter—dose increments every week up to 30 pg over 3 weeks, full dose to Week 8); and Group 3 - slow dose titration (quarter-dose increments every 2 weeks up to 30 pg over 6 weeks, full dose to Week 8). See Figure 1. In order to evaluate flu-like symptoms (FLS) in a controlled condition and to avoid bias, all subjects, regardless of symptoms, were administered prophylactic medication minophen 650 milligrams (mg) orally within 1 hour prior to Avonex® ion, and at 4 to 6 hours, 8 to hours, and 12 to 15 hours following injection.) Each week, the presence and intensity of fever, muscle aches (myalgia), chills, and fatigue symptoms were recorded at pre-injection, 4 to 6 hours and 12 to 15 hours post injection. Each FLS was assigned a score from O to 3 by the investigator as follows: 0=absent; 1: mild, did not interfere with daily activities; 2 = te, sufficient to interfere with daily activities; 3=severe, bed rest required. Body temperature was recorded to determine the presence of fever using the following scale: 0 (<99.1°F); 1- (Z99.1°F but °F); 2 (2100.1°F but <101.1°F); 3 (2101.1°F). The total score (sum PCT/U52012/029201 of the 3 symptom scores and fever score) for each of the 3 timepoints njection, 4 to 6 hours, and 12 to 15 hours) was be calculated during data analysis. For each timepoint, the m total score was 12 and the minimum total score was 0. A total score of 2 points or greater above the pre-injection score was considered positive for the presence of FLS.

A total of 234 subjects were enrolled, 78 per arm, and 195 (83%) ted the study. The majority of subjects were female (62%) and the mean age was 32.9 years.

Subjects in the fast and slow titration arms had significantly less severe FLS over 8 weeks than subjects in full-dose arm at 4-6 hours post injection (0.132 [P<0.001] and 0.267 [P<0.001] vs 0.539) (see Figure 2) and 12 to 15 hours post injection (0.475 [P<0.001] and 0.515 [P=0.002] vs 0.753) (see Figure 3). When compared to the no ion group at 4—6 hours post injection, the incidence of FLS was significantly less for the fast titration group (odds ratio [OR]: 0.179 [0.075, 0.429], 1) and the slow titration group (OR: 0.414 , 0.994], P=0.023) (see Figure 4). Similar results were demonstrated at 12-15 hours post injection (fast titration OR: 0.469 , 0.907], P=0.006; slow titration OR: 0.562 [0.338, 0.936], P=0.027) (see Figure 4).

The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby KAE511214NZPR 303921210 incorporated by reference. All other published references, documents, ripts and scientific literature cited herein are hereby incorporated by nce.

While this ion has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”. 6] The reference to any prior art in the specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in New Zealand. 214NZPR

Claims (15)

1. A titration package for reducing the severity of flu-like symptoms in a patient having multiple sclerosis treated with intramuscularly administered interferon-β-1a over an eight week period, wherein the titration package ses interferon-β-1a and delivery devices for once a week intramuscular administration to a patient having multiple sclerosis according to a first schedule comprising a first delivery device including 7.5 μg of interferon-β-1a for intramuscular administration to the patient in week one, a second delivery device ing 15 μg of interferon-β-1a for uscular administration to the patient in week two, and a third delivery device ing 22.5 μg of eron-β-1a for intramuscular administration to the patient in week three, wherein the severity of the flu-like symptoms is reduced at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-β-1a throughout an eight week period which includes once a week intramuscular administration of 30 μg of interferon-β- 1a to the patient in weeks four through eight when compared to the severity of the flu-like symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-β-1a to the patient according to (i) a second schedule comprising once a week intramuscular administration of 30 μg of interferon-β-1a to a patient having multiple sclerosis for eight weeks and (ii) a third schedule comprising intramuscular administration of 7.5 μg of interferon-β-1a to the t in weeks one and two, intramuscular administration of 15 KAE511214NZPR 304159160 μg of interferon-β-1a to the patient in weeks three and four, intramuscular administration of 22.5 μg of interferon-β-1a to the patient in weeks five and six and intramuscular administration of 30 μg of eron-β-1a to the patient in week seven and eight.

2. The titration e of claim 1, wherein the delivery devices comprises vials containing the interferon-β-1a in lyophilized form, a viral adapter and syringes pre-filled with a diluent for the lyophilized interferon-β-1a.

3. The titration package of claim 1, wherein the delivery devices are pre-filled syringes containing correct dosages of interferon-β-1a in liquid form.

4. The titration package of any one of claims 1 to 3, n the delivery device comprises an njector.

5. The ion package of claim 1, wherein the delivery device is needle-free.

6. The titration e of claim 1, wherein the delivery device is a pen.

7. The titration package of claim 1, further comprising a needle stick prevention device.

8. The titration package of claim 7, wherein the needle stick prevention device is a needle shield. KAE511214NZPR 304159160

9. The titration package of claim 8, wherein the shield is activated ly.

10. The titration package of claim 8, wherein the shield is automated.

11. The titration package of claim 10, wherein the automated shield is activated by the patient.

12. The titration package of claim 10, n the needle is automatically shielded without any action by the patient.

13. The titration package of claim 10, wherein the needle is shielded t any action by the patient.

14. A method of preparing a titration package according to claim 1, the method including providing: a first delivery device capable of including 7.5 μg of eron-β-1a for intramuscular administration to the patient in week one, a second delivery device capable of including 15 μg of interferon-β-1a for intramuscular administration to the patient in week two, and a third delivery device e of including 22.5 μg of interferon-β-1a for intramuscular administration to the patient in week three, and sufficient interferon to be included in the delivery devices. KAE511214NZPR 304159160

15. The titration package of claim 1, substantially as hereinbefore described with particular reference to any one or more of the es and/or figures. PCT/U