NZ616536B2 - Method for reducing flu-like symptoms associated with intramuscular administration of interferon using a fast titration escalating dosing regimen - Google Patents

Abstract

Discloses use of interferon-?-1a in the manufacture of a medicament for reducing the severity of flu-like symptoms associated with treating a patient with multiple sclerosis with intramuscularly administered interferon-?-1a over an eight week period, wherein the medicament is formulated for administration intramuscularly according to a dosage regime providing interferon-?-1a to a patient once per week, wherein the medicament is formulated to provide treatment according to a first schedule to provide: interferon-?-1a at 7.5 micrograms in week one, interferon-?-1a at 15 micrograms in week two, interferon-?-1a at 22.5 micrograms in week 3, and interferon-?-1a at 30 micrograms in week 4 and each week thereafter; 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-?-1a to the patient throughout the eight week period when compared to the severity of flulike symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-?-1a to a patient having multiple sclerosis according to: (i) a second schedule comprising once a week intramuscular administration of 30 micrograms interferon- ?-1a to the patient having multiple sclerosis for eight weeks and; (ii) a third schedule comprising intramuscular administration of 7.5 micrograms of interferon-?-1a to the patient in weeks one and two, intramuscular administration of 15 micrograms of interferon-?-1a to the patient in weeks three and four, intramuscular administration of 22.5 micrograms of interferon-?-1a to the patient in weeks five and six and intramuscular administration of 30 micrograms of interferon-?-1a to the patient in weeks seven and each week thereafter. ration intramuscularly according to a dosage regime providing interferon-?-1a to a patient once per week, wherein the medicament is formulated to provide treatment according to a first schedule to provide: interferon-?-1a at 7.5 micrograms in week one, interferon-?-1a at 15 micrograms in week two, interferon-?-1a at 22.5 micrograms in week 3, and interferon-?-1a at 30 micrograms in week 4 and each week thereafter; 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-?-1a to the patient throughout the eight week period when compared to the severity of flulike symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon-?-1a to a patient having multiple sclerosis according to: (i) a second schedule comprising once a week intramuscular administration of 30 micrograms interferon- ?-1a to the patient having multiple sclerosis for eight weeks and; (ii) a third schedule comprising intramuscular administration of 7.5 micrograms of interferon-?-1a to the patient in weeks one and two, intramuscular administration of 15 micrograms of interferon-?-1a to the patient in weeks three and four, intramuscular administration of 22.5 micrograms of interferon-?-1a to the patient in weeks five and six and intramuscular administration of 30 micrograms of interferon-?-1a to the patient in weeks seven and each week thereafter.

Description

TITLE OF THE INVENTION: METHOD FOR REDUCING FLU—LIKE MS 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 regimen of intramuscularly administered interferon. The invention also relates to titration packaging to promote compliance With the dosage titration. ption of Related Art Multiple sis (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 neuronal 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 bute to the symptoms of MS.

W0 2012/125809 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 accumulation of activated microglia and macrophages. Acute s are terized by blood brain barrier damage, infiltration by activated CD4+ T cells and clonotypic CD8+ T cells that recognize CNS autoantigens, and the presence of reactive astrocytes and erating oligodendrocytes. Pro-inflammatory cytokines, e.g. interleukin 12 ) and tumour—necrosis factor—a (TNF-a), are also present. There is further evidence that other ve 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 enesis.

Relapse—remitting MS, the most common form of the disease, is characterized by multiple exacerbations over time. bations are s 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. l human fibroblast interferon-beta (IFN—B) was the first drug to treat relapse-remitting MS. IFN—B has imrnunomodulatory effects, which include modulating cytokine levels (e.g., inducing Th1 (T-helper 1) related cytokines and Th2 related nes), inhibiting T-cell activation and proliferation, 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 W0 2012/125809 and studies ce that IFN—B works against multiple sclerosis h imrnunomodulation.

There are currently two different recombinant interferon-beta treatments for MS: interferon a (IFN-Bla) and interferon b (IFN-B 1b). IFN-B]a and IFN-Blb are two distinct molecules with different recommended dosages, routes of administration and dosing intervals. IFN-l?)1a is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 daltons. It is produced by inant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence is identical to that of natural human interferon beta. IFN—Blb has 165 amino acids and an imate molecular weight of 18,500 daltons. It does not include the carbohydrate side chains found in the natural material. IFN—Blb is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon betasem. The specific activity of IFN-[31a and IFN—Blb are different and based on different World Health Organization (WHO) reference rds of recombinant interferon beta and different assays used to measure ty. t IFN-Bia treatments include Avonex®, CinnoVexTM, , and Resigene. Current IFN-Blb 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.

W0 2012/125809 Although there is a difference in specific activity between the two types of interferons, lFN-[31a and b 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 administration and subside within 24 hours. Flu-like symptoms associated with administration of erons include fever, muscle aches (myalgia), chills, sweating, fatigue, headache, and malaise. The exact mechanism for the development of flu—like symptoms is not well understood but occurs among ts taking interferons irrespective 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 ated with interferon administration 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 n (also known as dose ion) has become a routine ce for the administration of eron therapies to manage side effects 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 multiple sis. tly, 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.

W0 2012/125809 ] The Betaseron® (10/07) label includes titration instructions for subcutaneous stration of IFN—Blb over a six—week period, with full dose beginning in week 7: Weeks 1 — 2 - 1/1 of a dose (0.0625mg/0.25ml) Weeks 3 — 4 - 1/2 of a dose (0.125mg/0.5ml) Weeks 5 3%: of a dose (0.1875mg/0.75m1) Week 7 - full dose g/1m1) The Betaseron® label indicates dose titration may reduce flu-like symptoms. The European Betaferon® label (1-8—24) es titration instructions for subcutaneous administration over a three week period, with full dose beginning in week 4: Week 1 — 1A4 of a dose (0.0625mg/0.25ml) Week 2 —— 1/2 of a dose (0.125mg/0.5m1) Week 3 —— % of a dose (0.1875mg/0.75m1) Week 4 — full dose (0.25mg/1ml) Although the European ron® 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 ms, the 3 week titration period of the European Betaferon® label is silent with respect to ng flu—like symptoms. Two clinical s 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 regimens.

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 effectiveness of dose titration in combination with ibuprofen in reducing the flu-like side s of Betaseron® W0 2012/125809 administered subcutaneously in 49 patients With Relapsing-Remitting and Secondary Progressive Multiple sis (RR and SPMS). This was a ized, open-label, study that compared patients who did not e 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 million IU (MIU) of Betaseron® every second day (the standard dose) during weeks 0—4. Groups B and C each received Betaseron® according to the titration schedule starting at 2 MIU (25% of the standard dose) and sed 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 1 of Rice et al.). The differences in incidence of flu—like symptoms n the group receiving ibuprofen ent 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 ts (10%) in the study experienced difficulty while escalating the dose of IFN—Blb, and these patients required either dosage reduction or a delay in the escalating schedule.

] This was common practice according to Bayas et al. (Bayas A and Rieckmann P. Managing the Adverse Effects of Interferon-B Therapy in Multiple Sclerosis. Drug Safety 2000 Feb: 22(2):149—159). Bayas et al. described dose titration for administration W0 2012/125809 of IFN-Blb (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—B dosage should be reduced or kept at the same level for a longer time until improved drug tolerability allows an increase. Walther et a1. er EU, Hohlfeld R. Multiple Sclerosis Side Effects of Interferon beta Therapy and their Management. Neurology 1999; 53:1622—1627) recommended 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 ed titration schedule.

] Wroe (Wroe SJ. Effects of dose titration on tolerability and efficacy of interferon beta—1b in people with multiple sclerosis. J Int Med Res 2005; 33:309-18) evaluated whether a slower, four—stage, 4 week titration to a final dose of 250 pg subcutaneous IFN-Blb might improve tolerability over a more rapid two—stage, 2 week titration in patients with relapsing—remitting MS over a 3-month period. In the slow— titration group, IFN4311, was subcutaneously administered, initially at 62.5 pg (Mi dose) every other day for 9 days, and then at Mt 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 h treatment. See Figure 1 of Wroe et al. In the fast-titration group, b was subcutaneously stered, initially at 125 pg (1/2 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 reported no noticeable differences with t to the ence of adverse events W0 2012/125809 between the two treatment , e.g., the nce rates of flu—like symptoms were similar in the slow- (32.4%) and rapid titration (41.9%) groups (Figure 3 of Wroe et al).

Wroe concluded that a rapid—titration regimen (1/2 dose increments, with a full dose beginning in week 3) results in a quicker onset of clinical benefit and slow titration (% dose increments, with a full dose beginning in the middle of week 5) showed a non- significant reduction in flu-like symptoms compared to the rapid-titration regimen.

The Rebif® label includes titration instructions for subcutaneous administration of IFN—Blz,1 three times per week over a 4-week , with full dose administered in week 5: Weeks 1 — 2 —l/5 of a dose— aneous injection 3X/week (titration dose for 33 pg = 4.4 pg) tion 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) (titration 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 develop, thus ng side effects. Both the US and European labels are silent with respect to treating flu-like symptoms ated with administration of interferon-beta. All of the products and clinical studies discussed thus far relate to subcutaneous administration of IFN-fila or IFN—Blb.

W0 2012/125809 Brandes et al. (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 acetaminophen or ibuprofen in ng the flu-like side effects of Avonex® (LPN—01a) in 47 patients with relapsing—remitting le sis.

The s et 31. study was a multi—site, randomized, open-label, 12—week study. Group 1 patients received (IM) IFN-Bla at a dose of 30 ug once weekly with no ion. Groups 2 and 3 received (IM) IFN—[31a at 1A dose during weeks 1 and 2, 1/2 dose for weeks 3 and 4, 3%: dose at weeks 5 and 6, and a full dose (30 ug) for weeks 7—12.

Groups 1 and 2 ed acetaminophen 650mg 1 hour before each (IM) IFN-[31a injection, then every 4 hours as needed. Group 3 received ibuprofen 400 mg 1 hour before each (IM) IFN—Bla injection, again at 6 hours following injection, then every 6 hours as needed. ke symptoms were recorded at three time points: baseline (first dose of analgesic, 1 hour pre-inj ection); 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 s 2 and 3) significantly reduced the proportion of patients with a mean increase of 22 from baseline in flu-like symptom score compared with no titration only at 4 hours post-injection during the first W0 2012/125809 two weeks (Figure 1A of Brandes et al., p=0.015 indicated with *). There was no significant difference between the one—quarter titration (Groups 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 ged titration, i.e., an even slower titration, would be necessary.

Also, there was no significant ence n the arter titration (Groups 2 and 3) and no titration (Group 1) at 12—15 hours during any week, including the first two weeks. These data ted that initiating (IM) IFN—Bla injection with a 1A. dose had limited effects in reducing e symptoms because the Mt dose only delayed the onset of flu—like symptoms and only did so during the first two weeks.

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

Significantly, Frohman et a1. states, “If patients experience severe and limiting side effects as the dose is increased, we will lly prolong titration, escalating by the same increment every 2 to 4 weeks. With this approach, we have had very few patients fail drug initiation.” Thus, Frohman s to err on the side of an extended titration schedule.

It is therefore desirable to e a method for further reducing ke symptoms associated with intramuscular interferon administration, which will promote compliance and continuation of interferon therapy for MS. [00021A] It is an object of the present invention to provide use of interferon-β-1a in the manufacture of a medicament for ng the severity of flu-like symptoms associated with ng a patient with multiple sclerosis with intramuscularly administered interferon- β-1a over an eight week period. It is an alternative object of the invention to at least provide the public with a useful choice.

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

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 specifically includes an initial titration period wherein the interferon is administered in an escalating dose regimen (a “titration period”). In particular, the titration period includes 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 and thereafter.

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

The invention also relates to a titration package for enabling compliance with these methods, 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 patient to administer the interferon in an escalating dose regimen during a titration period. [00025A] In one aspect the invention provides use of interferon-β-1a in the manufacture of a medicament for reducing the severity of ke symptoms associated with treating a patient with multiple sis with intramuscularly administered interferon- β-1a over an eight week period, wherein the medicament is formulated for administration intramuscularly according to a dosage regime providing interferon- β-1a to a patient once per week, wherein the medicament is formulated to e treatment according to a first schedule to provide: interferon- β-1a at 7.5 micrograms in week one, interferon- β-1a at 15 rams in week two, interferon- β-1a at 22.5 micrograms in week 3, and interferon- β-1a at 30 micrograms in week 4 and each week thereafter; 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 to the patient throughout the eight week period when compared to the severity of flu-like symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon- β-1a to a patient having le sis according to: (i) a second schedule comprising once a week intramuscular administration of 30 micrograms interferon- β-1a to the t having le sclerosis for eight weeks and; (ii) a third schedule comprising intramuscular administration of 7.5 micrograms of interferon- β-1a to the patient in weeks one and two, intramuscular stration of 15 micrograms of interferon- β-1a to the patient in weeks three and four, intramuscular administration of 22.5 micrograms of interferon- β-1a to the patient in weeks five and six and intramuscular administration of 30 micrograms of interferon- β-1a to the patient in weeks seven and each week thereafter.

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

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

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

Note that in the Example below, additional subjects were investigated.

W0 2012/125809 Figure 2 is a table with the titration schedules in a al study. Patients in Treatment Group 1 received 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 titration le (1A 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 le (Mi dose in weeks 1—2, 1/2 dose in weeks 3-4, % 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 le and shows the change in total flu—like symptom (FLS) score from j ection to 4 to 6 hours after injection over 8 weeks.

Figure 5 is a line graph of the secondary 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.

W0 2012/125809 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 e 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, ing no titration to fast titration.

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

DETAILED PTION OF THE INVENTION The invention provides a method for treating a t with multiple sclerosis, by uscularly 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.

W0 2012/125809 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 red embodiment, the interferon is interferon [3‘ In a more preferred embodiment, the interferon is an interferon Bl. In a most preferred embodiment, the interferon is interferon Bla.

The invention also provides a method for reducing the flu-like symptoms which can accompany the intramuscular administration of an interferon. In ular, 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 e symptoms can be measured in reduction of severity of symptoms, and/or reduction in incidence of ke symptoms. The reduction can be measured at various timepoints post-injection, for example 4 to 6 hours post-injection and 12 to 15 hours njection.

] Preferably, the reduction in severity 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 severity of flu—like symptoms at 12 to 15 hours W0 2012/125809 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 ably at least %, and most preferably about 25%.

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

In a most red embodiment, the full therapeutically effective dose is 30 micrograms.

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

The methods of the invention can further include the stration of an analgesic or anti-inflammatory drug, or a mixture thereof. The drug may be a steroid or a W0 2012/125809 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 ting dosage regimen, and ultimately the long-term treatment using the interferon.

In a preferred embodiment, the package includes interferon and delivery s for the interferon. The interferon may be in lyophilized form, and thus ed in a jar or vial. In this case, the package also ably contains a , 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 pre-filled syringes. The syringes may be provided with the exact dosage for weeks 1-4 and thereafter. Alternatively, an accessory to the delivery device may also be provided, which when used in combination with the syringe, is capable of titrating the correct volume or dosage for the particular week of the escalating dosage regimen tion ).

Where the interferon is provided in a syringe, the syringe may also be provided with a needle stick prevention device. Such a prevention device can include 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 interferon may also be provided in other delivery devices, such as a pen.

The ion package also preferably ns instructions for intramuscular administration of the interferon by a patient during a titration period, wherein the interferon is preferably 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.

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

W0 2012/125809 Preferred interferon- [31a polynucleotides that may be used in the present methods of the invention are derived from the Wild—type interferon B gene sequences of s vertebrates, preferably mammals and are ed 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 eron), US. Pat. No. ,605,688 (Feb. 25, ecombinant dog and horse type I interferons); US. Pat. No. ,231,176 (Jul. 27, 1993, DNA molecule encoding a human leukocyte eron);); US.

Pat. No. 5,071,761 (Dec. 10, 1991, DNA sequence coding for subrsequences of human lymphoblastoid interferons LyIFN—alpha—2 and LyIFN-alpha—3); US. Pat. No. 4,970,161 (Nov. 13, 1990, DNA sequence 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 ng sub—sequences of different, naturally, occurring leukocyte interferons).

] Mutants of interferon- [31a may be used in accordance with this invention.

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

W0 25809 In summary, the term "interferon" includes, but is not limited to, the agents listed above as well as their functional equivalents. As used herein, the term "functional equivalent" therefore refers to an interferon— B13 protein or a polynucleotide encoding the interferon-beta-la n that has the same or an improved beneficial effect on the mammalian recipient as the interferon of which it is deemed a functional lent. As will be iated by one of ordinary skill in the art, a functionally equivalent protein can be produced by recombinant techniques, e.g., by expressing a ionally equivalent DNA". Accordingly, the instant invention embraces interferon— [31a proteins encoded by naturally—occurring DNAs, as well as by turally—occurring DNAs which encode the same protein as encoded by the naturally-occurring DNA. Due to the degeneracy of the nucleotide coding sequences, other polynucleotides may be used to encode interferon- [313. 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 sequences. For example, Phe (F) is coded for by two , 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 ular interferon there will be many DNA degenerate sequences that will code for it.

The interferon 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 W0 2012/125809 is utilized together with one or more aceutically acceptable 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 thereof. The interferon is ed in an amount ive 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 ng the active ingredient(s) into association with a carrier which tutes one or more accessory ingredients. lly, the formulations are prepared by mly and intimately bringing the active ingredient(s) into association with a liquid carrier.

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

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

W0 2012/125809 In yet more detail, the present invention is described by the following items which represent additional embodiments hereof. ] 1. A method for treating multiple sclerosis, including intramuscularly administering an interferon to a patient once per week, wherein treatment begins with 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 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 eron Bla. 4. A method for reducing flu-like symptoms associated with administration of an interferon to a patient with multiple sclerosis, including: (a) intramuscularly administering the interferon to the patient according to an escalating dosing regimen in weeks 1 to 3; and (b) intramuscularly stering a full eutically ive dose of interferon in week 4.

W0 2012/125809 5. The method of item 4, wherein the ting dosing regimen comprises administering one quarter of the eutically effective dose in week 1, half of the therapeutically effective dose in week 2, and three—quarters of the therapeutically effective dose in week 3. 6. The method of item 4, wherein the interferon is interferon Bla- 7. The method of item 4, wherein the full therapeutically effective dose is 30 micrograms. 8. The method of item 4, wherein the flu-like symptoms include fever, muscle aches, chills, sweating, fatigue, headache, and malaise. ] 9. A ion package for ng compliance with a regimen of changing dosage of an eron over a period of time, the package including interferon delivery devices containing an interferon 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 quarter dose in week 3, and a full therapeutically 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.

W0 2012/125809 11. The titration package of item 9, wherein 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 ation. 14. The titration e of item 13, wherein the liquid interferon formulation is provided in pre-filled syringes. 15. The titration package of item 14, n 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 ses an nj ector. 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.

W0 2012/125809 19. The titration package of item 9, r sing a needle stick prevention device. 20. The titration package of item 19, wherein the -stick prevention device includes a needle shield. 21. The ion package 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 ted shield is activated by the patient. 24. The titration package of item 22, n the needle is automatically shielded without any action by the patient. 25. The titration package of item 22, wherein the needle is shielded without any action by the patient. 26. The titration package of item 9, wherein the package further includes a dose-limiting titration device.

W0 25809 27. The method of any of items 1—8, further comprising administration of an sic or anti—inflammatory drug, or a mixture thereof. 28. The method of item 27, wherein the drug is a steroid. 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 inophen. ] 31. The method of item 27, wherein the drug is ibuprofen.

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 s and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the processes, ations and/0r methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

W0 2012/125809 ] Avonex® was studied in a ized, three—arm, dose—blinded, parallel— group study to determine the effect of Avonex® dose titration, administered intramuscularly, on the severity and incidence of a—related flu-like symptoms in healthy volunteers. The approved therapeutic dose of Avonex® is 30 ug weekly by IM administration. 0] In this d, parallel—group study, ts were randomized to 1 of 3 treatment arms: Group 1 — no titration (weekly IM IFN—[31a 30 ug for 8 ; Group 2 — fast dose titration (quarter—dose ents every week up to 30 ug over 3 weeks, full dose to Week 8); and Group 3 - slow dose titration (quarter-dose increments every 2 weeks up to 30 ug 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 lactic medication (acetaminophen 650 milligrams (mg) orally within 1 hour prior to Avonex® injection, 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 0 to 3 by the investigator as follows: O=absent; 1: mild, did not interfere with daily activities; 2 = moderate, 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' (299.1°F but <100.1°F); 2 (2100.1°F but <101.1°F); 3 (2101.1°F). The total score (sum W0 2012/125809 of the 3 symptom scores and fever score) for each of the 3 timepoints (pre—injection, 4 to 6 hours, and 12 to 15 hours) was be calculated during data analysis. For each timepoint, the maximum total score was 12 and the minimum total score was 0. A total score of 2 points or greater above the pre—inj ection score was considered positive for the presence of FLS .

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

Subjects in the fast and slow ion 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 titration group at 4—6 hours post ion, the incidence of FLS was significantly less for the fast titration group (odds ratio [OR]: 0.179 [0.075, 0.429], P<0.001) and the slow titration group (OR: 0.414 [0.194, 0.994], P=0.023) (see Figure 4). Similar s were trated at 12-15 hours post injection (fast titration OR: 0.469 [0.272, 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 hed or unpublished United States patent applications cited herein are incorporated by nce. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by nce.

While this invention 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 ption and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or tive sense, that is to say, in the sense of “including, but not limited to”.

The nce to any prior art in the specification is not, and should not be taken as, an ledgement or any form of suggestion that the prior art forms part of the common general knowledge in New Zealand.

Claims (10)

1. Use of interferon-β-1a in the cture of a medicament for reducing the severity of flu-like symptoms associated with treating a patient with multiple sclerosis with intramuscularly administered interferon- β-1a over an eight week , wherein the medicament is formulated for administration intramuscularly ing to a dosage regime providing interferon- β-1a to a patient once per week, wherein the medicament is ated to provide treatment according to a first schedule to provide: interferon- β-1a at 7.5 micrograms in week one, interferon- β-1a at 15 micrograms in week two, interferon- β-1a at 22.5 micrograms in week 3, and interferon- β-1a at 30 micrograms in week 4 and each week thereafter; wherein the ty of the ke symptoms is reduced at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon- β-1a to the patient throughout the eight week period when compared to the severity of flulike symptoms at 4-6 hours and at 12-15 hours after each intramuscular administration of interferon- β-1a to a patient having multiple sclerosis according (i) a second schedule comprising once a week intramuscular administration of 30 micrograms interferon- β-1a to the patient having multiple sclerosis for eight weeks and; (ii) a third schedule comprising intramuscular administration of 7.5 micrograms of interferon- β-1a to the patient in weeks one and two, intramuscular administration of 15 micrograms of eron- β-1a to the patient in weeks three and four, intramuscular administration of 22.5 micrograms of interferon- β-1a to the patient in weeks five and six and intramuscular administration of 30 micrograms of interferon- β-1a to the patient in weeks seven and each week thereafter.

2. The use of Claim 1, wherein the flu-like symptoms include fever, muscle aches, chills, sweating, fatigue, headache, and malaise.

3. The use of Claims 1 or 2, n the medicament further ses an analgesic or anti-inflammatory drug, or a mixture thereof.

4. The use of Claim 3, wherein the drug is a steroid.

5. The use of Claim 3, wherein the drug is a non-steroidal nflammatory agent.

6. The use of Claim 3, wherein the drug is acetaminophen.

7. The use of Claim 3, wherein the drug is ibuprofen.

8. The use of any one of Claims 1 to 7, wherein the flu-like symptoms are d by at least 40% at 4-6 hours post-injection

9. The use of any one of Claims 1 to 8, wherein the flu-like symptoms are reduced by at least 10% at 12-15 hours post injection.

10. The use of Claim 1, substantially as hereinbefore described with particular reference to any one of the Examples and/or