NOVEL DOSING AND USES OF OFATUMUMAB

FIELD OF INVENTION The present invention relates to a novel dosing regimen for ofatumumab to treat pemphigus diseases.

BACKGROUND OF THE INVENTION

Pemphigus is a group of rare autoimmune diseases that cause blistering of the skin arid mucous membranes (mouth, nose, throat, eyes, and genitals). More specifically, pemphigus vulgaris (PV) is a chronic, debilitating, and potentially life-threatening autoimmune vesiculobullous disorder that is characterized by mucocutaneous blisters. Without treatment, such blistering eventually leads to erosions in the skin, resulting in significant morbidity and mortality.

Pemphigus affects people across racial and ethnic lines. Research has shown that certain ethnic groups (such as the eastern European Jewish community and people of

Mediterranean descent) are more susceptible to pemphigus. A particular type of pemphigus (endemic pemphigus foiiaceus) occurs more frequently in people who live in specific geographic regions in Central- and South America.

Men and women are approximately equally affected. Research studies suggest a genetic predisposition to the disease. Although the onset usually occurs in middle-aged and older adults, all forms of the disease may occur in young adults and children.

There are several types of pemphigus and other similar autoimmune blistering disorders. The type of disease depends on what layer in the skin the blisters form and where they are located on the body. Blisters always occur on or near the surface of the skin, which is called the epidermis. People with pemphigus vulgaris, for example, have blisters that occur within the lower layer of the epidermis, while people with pemphigus foiiaceus have blisters that form in the topmost layer. The type of antibody that is attacking the skin typically defines the type of disease present.

_* Pemphigus vulgaris is the most common type of pemphigus in the United States and Europe. Soft and limp blisters appear on healthy -looking skin and mucous membranes. The sores almost alwa s start in the mouth. The blisters of pemphigus vulgaris form within the deep layer of the epidermis, and are often painful. Blistered skin becomes so fragile that it may peel off by rubbing a finger on it. The blisters normally heal without scarring, but pigmented spots (spots where skin appears darker than the surrounding skin) may remain for a number of months.

Pemphigus vegetans is a. form of pemphigus with thick sores in the groin and under the arms.

Pemphigus foliaceiis involves crusted sores or fragile blisters that often appear first on the face and scalp and later on the chest and other parts of the body. Unlike pemphigus vulgaris, blisters do not form in the mouth. The sores are superficial and often itchy, and are rarely as painful as pemphigus vulgaris blisters. There may also be loose, moist scales on the skin.

IgA pemphigus is a. blistering disorder in which a different type of antibody binds to the cell surface of epidermal ceils. This disease is different, from other forms of pemphigus because it involves a different type of antibody (called IgA) than other types. The disease may result in blisters similar to those seen in pemphigus foliaceiis, or it may involve many smal l bumps containing pus. This is the most, benign, or least harmful, form of pemphigus.

Paraneoplastic pemphigus is distinct from pemphigus, but shares some features of it. It occurs in people with certain types of cancer, including some lymphomas and leukemias. it often involves severe ulcers of the mouth and lips, cuts and scarring of the lining of the eye and eyelids, and skin blisters. Because the antibodies also target the membranes lining the airways, patients may develop life-threatening problems in the lungs. This disease is different from other types of pemphigus, and the antibodies in the blood are different. Special tests may be needed to identit paraneoplastic pemphigus.

Pemphigoid is also an autoimmune blistering disorder, characterized by splitting where the epidermis and the dermis (the layer below the epidermis) meet, causing deep, tense (taut or rigid) blisters that do not break easily. Pemphigus, on the other hand, causes a separation within the epidermis, and the blisters are soft, limp, and easily broken. This is because the antibodies attack cells where the epidermis and dermis (the layer below the epidermis) meet.

Pemphigoid is seen most often in the elderly and may be fatal. Usually, both

pemphigus and pemphigoid are treated with similar medications. Severe cases may require different treatment. Treatment for pemphigus in general and specifically pemphigus vulgaris involves using one or more drugs. High-dose oral corticosteroids, such as prednisone or prednisolone, are the main treatment for pemphigus. High doses are often required to bring pemphigus under control. To minimize the side effects, corticosteroid levels are reduced slowly to the lowest level required to prevent new blisters or sores from appearing. Many patients will go into complete remission with treatment, although this may take a number of years. Other patients will need to continue to take small doses of medication to keep the disease under control. Prednisone is usually taken by mouth, but can also be injected into a vein, muscle, or directly into a blister. The route administered depends on the type and severity of disease. For pemphigoid, a corticosteroid cream will typically be used directly on the blisters.

To keep the levels of corticosteroid use to a minimum, immunosuppressive drugs are often added to a patient's treatment. These are drugs that stop or slow down the immune system's response to what it sees as an attack on the body. They include, but are not limited to the immunosuppresants: Mycophenolate (mofetil and sodium salts),

Azathioprine, Cyclophosphamide, Methotrexate, and Cyclosporine. Other drugs that may be used include, but are not limited to Diamino diphenyi sulfone (Dapsone), and other antibiotics such as tetracycline, and intravenous immunoglobulin.

The use of immunosuppressive drugs to treat pemphigus can also increase the chances of developing an infection and may cause neutropenia (a decrease in the white blood cells in the blood) inflammation of the liver, nausea, vomiting, or allergic reactions. People with severe pemphigus that cannot be control led with corticosteroids may undergo plasmapheresis, a treatment in which the blood containing the damaging antibodies is removed and replaced with blood that is free of antibodies. Such patients can also be treated with IVIg (or IVIG), or intravenous im unoglobulin, which is given daily for 3 to 5 days, every 2 to 4 weeks for 1 to several months. Plasmapheresis and IVIg are both very expensive treatments, and require large amounts of donated and specially processed blood. Some success has been reported in treating difficult cases of pemphigus vulgaris with a combination of IVIg and rituximab (Rituxan/MabThera™), a non-approved indication for rituximab. In general the treatment prescribed will depend on the type of pemphigus and the severity of the disease. It may take several months to years for the ulcers and blisters of pemphigus vulgaris to disappear after treatment has begun because circulating antibodies can remain in the body for a long time.

However, use of systemic glucocorticoids has shown to reduce mortality to approximately 5% to 10% [Robinson JC, et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod.

1997;84(4):349-355]. In the United States (US), various steroid preparations are approved for treatment of pemphigus. In Europe, both steroids and azathioprine are approved for pemphigus or PV. Unfortunately, chronic treatment with high-dose corticosteroids causes significant morbidity. A recent Cochrane report [Martin LK, et al., J Am Acad Dermatol. 2011;64(5):903-908] identified only 11 randomized controlled studies assessing pemphigus interventions, and concluded that the optimal therapeutic strategy remains unclear.

Rituximab (Rituxan/MabThera™) is a chimeric monoclonal antibody (comprised of human and mouse components) that selectively depletes B cells bearing cluster of differentiation 20 (CD20 ⁺ B cells). Humanized or fully human monoclonal antibodies may have more favorable pharmacokinetics, better efficacy and lower immunogenicity than chimeric antibodies. Intravenous (IV) rituximab, has been reported to successfully treat PV in case-series reports in severe or refractory disease [Ahmed AR, et al., N Engl J Med. 2006;355: 1772- 1779; Cianchini et al., Arch Dermatol. 2007; 143(8): 1033-1038; Joly et al., N Engl J Med. 2007;357(6):545-552; Eming et al., J Invest Dermatol. 2008; 128(l):2850-2858; Kim et al., Br J Dermatol. 2011; 165(3):646-651. doi: 10.1111/j .1365-2133.2011.10411.x;

Kasperkiewics et al., Br J Dermatol. 2012; 166: 154-160; Leshem et al., J Am Acad

Dermatol. 2013;68:404-411; Lunardon et al., Arch Dermatol. 2012; 148(9): 1031-1036. doi: 10.1001/archdermatol.2012.1522], and in a single case report as a first-line therapy [Craythorne et al., J Am Acad Dermatol. 2011;65(5): 1064-1065]. The reduction of pathogenic antibodies via targeted B-cell depletion forms the basis for the use of rituximab in the treatment of PV, and clinical response to rituximab has correlated with B-cell depletion [Mouquet et al., J Invest Dermatol. 2008; 128(12):2859-2869; Eming, supra]. Use of rituximab for PV treatment remains limited by the need for infusion suites for drug administration and the lack of any randomized prospective clinical studies evaluating its efficacy and safety. Rituximab is not an approved treatment for PV.

Ofatumumab (OF A) is a fully human anti-CD20 monoclonal antibody. More specifically, ofatumumab is a novel human IgGlk lytic monoclonal antibody that specifically binds to the human CD20 antigen, which is expressed only in B lymphocytes from the pre-B-cell stage to the plasmacytoid immunoblast stage. This antibody has previously been studied by GlaxoSmithKline/Genmab in a placebo-controlled trial using an intravenous (IV) formulation (GEN414). It is approved as Arzerra®, as an intravenous injection, for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

Accordingly, novel treatments are still needed for the treatment of pemphigus. Thus, in addition to providing a new treatment for pemphigus, it is additionally highly desirable to also minimise the risk of undesirable side effects and other opportunistic infections in the course of treating patients with pemphigus. The present invention fulfils both of these needs.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a method of treating, or arresting pemphigus in a patient suffering therefrom, comprising administering to the patient a novel dosing regimen of ofatumumab. In one embodiment, the pemphigus disease is pemphigus vulgaris.

One aspect of the invention is a method of treating, or arresting pemphigus in a patient suffering therefrom requiring administration of a dose suppressing amount of ofatumumab sufficient to suppress B cells between a dosing interval. In one embodiment, the dosing interval is every 4 weeks for up to a year. Suitably, the dose suppressing amount of ofatumumab sufficient to suppress B cells is a depleting or fully-depleting dosage amount.

The method of treating, or arresting Pemphigus in a patient suffering therefrom comprises administration to the patient a plurality of doses over a course of treatment time period. The course of treatment time period includes dosing intervals. In one aspect of the invention, a loading dose is given at week zero (day 1), and then a dosage is administered at each dosing interval thereafter. In another embodiment, a loading dose is given at week zero (day 1), and then at the next dosage interval an additional loading dose is also administered, followed subsequently with a lower dose at each dosing interval thereafter. Suitably, the dosing interval is a 4 week doing time period. In another embodiment, the course of treatment time period is up to 56 weeks. Maintenance therapy may be the same dose suppressing amount administered at the same or at reduced dosing intervals. Another aspect of the invention is a method of treating, or arresting a pemphigus disease in a patient suffering therefrom, comprising administering to said patient a dose depleting or dose suppresing amount of ofatumumab at week 1, followed by subsequent administration of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals.

Another aspect of the invention is ofatumumab for use in treating, or arresting a pemphigus disease in a patient suffering therefrom, comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent administration of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals. Another aspect of the invention is a method for controlling the flare or relapse of a pemphigus disease in a patient suffering therefrom comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent administration dosing of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals.

Another aspect of the invention, is ofatumumab for use in controlling the flare or relapse of a pemphigus disease in a patient suffering therefrom comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent administration dosing of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals.

Another aspect of the invention is a method of reducing steroid therapy in a patient with pemphigus disease, comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent administration dosing of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals. Yet another aspect of the invention is ofatumumab for use in reducing steroid therapy in a patient with pemphigus disease, comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent dosing administration of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals Another aspect of the invention is a method of reducing immunosuppressive therapy in a patient receiving an immunosuppressive therapeutic agent with pemphigus disease, comprising administering to said patient a dose suppressing amount of ofatumumab at week 1, followed by subsequent dosing administration of a dose suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals, and reducing the dose or eliminating the dose of the immunosuppressive therapeutic agent over the course of treatment.

Yet another aspect of the invention is ofatumumab for use in reducing immunosuppressive therapy in a patient receiving an immunosuppressive therapeutic agent with pemphigus disease, comprising administering to said patient a dose suppressing amount of

ofatumumab at week 1, followed by subsequent dosing administration of a dose

suppressing amount of ofatumumab at 4 week intervals, and wherein the dose suppressing amount of ofatumumab is sufficient to suppress B cells between dosing intervals, and reducing the dose or eliminating the dose of the immunosuppressive therapeutic agent over the course of treatment.

DETAILED DESCRIPTION

The present invention provides for a method of treating, or arresting Pemphigus in a patient suffering therefrom, comprising administering to the patient a novel dosing regimen of ofatumumab. In one embodiment the Pemphigus disease is pemphigus vulgaris.

One aspect of the invention is a method of treating, or arresting Pemphigus in a patient suffering therefrom requires administration of a dose suppressing amount of ofatumumab sufficient to suppress B cells between a dosing interval.

In one embodiment, the dosing interval is every 4 weeks for up to a year. In another embodiment the dosing interval is every 8 weeks, for up to a year. Suitably, the dose suppressing amount of ofatumumab sufficient to suppress B cells is a depleting or fully-depleting dosage amount. Another embodiment of the present invention is the use of ofatumumab for treatment or arrestation of pemphigus in a patient suffering therefrom by administering to the patient an improved dosing regimen of ofatumumab wherein the dosing regimen is a dose

suppressing amount of ofatumumab sufficient to suppress B cells between dosing intervals, and the dosing interval is every 4 weeks for up to a year.

In an embodiment of the invention, administration of ofatumumab for any of the uses herein is preferably by the subcutaneous (SC) route. The method of treating, or arresting pemphigus in a patient suffering therefrom comprises administration to the patient a plurality of doses over a course of treatment time period. In one aspect of the invention, a loading dose is given at week zero (day 1), and then a dosage is administered at each dosing interval thereafter. In another embodiment, a loading dose is given at week zero (day 1), and then at the next dosage interval an additional loading dose is also administered, followed subsequently with a lower dose at each dosing interval thereafter.

In another embodiment a first dose of 20 mg is given with an additional dose of 20mg to equal a loading dose of 40mg; at the second dosing interval at 4 weeks, a second dose of 20mg is also given with another 20mg (e.g., a second loading dose) to equal 40mg administered, subsequently at the remaining dosing intervals of 4 weeks time,

administration of 20mg is given, e.g. at 8 weeks, 12 weeks, 16 weeks etc. out to either 48 weeks or a full year of treatment, e.g. 56 weeks. In another embodiment, ofatumumab is administered subcutaneously at week zero (day 1) followed by a dosing interval of every 4 weeks. In another embodiment the first dose of 20 mg is given with an additional loading dose to equal 40mg, and then subsequent doses of 20mg are administered over the course of 4 week intervals, such as at 4 weeks, 8 weeks, 12 weeks, etc. out to either 48 weeks or a full year of treatment, e.g. 56 weeks.

Another aspect of the invention is a method of controlling the flare or relapse of pemphigus in a patient suffering therefrom comprising administering to the patient at least one dose suppressing and/or fully-depleting dose of ofatumumab. One aspect of controlling the flare or relapse of Pemphigus in a patient suffering therefrom requires the administration of a dose suppressing amount of ofatumumab sufficient to suppress B cells between the dosing intervals. In one embodiment, the dosing interval is every 4 weeks for up to a year. In another embodiment the dosing interval is every 8 weeks, for up to a year. Suitably, the dose suppressing amount of ofatumumab sufficient to suppress B cells for this method is a depleting or fully-depleting dosage.

Suitably, the dose suppressing amount of ofatumumab is 20mg, 30mg, 40mg or 60mg. In one embodiment, the method of controlling the flare or relapse of pemphigus will be a similar treatment as indicated above with a 40mg loading dose, followed by either a 20mg or 40mg second dose at 4 weeks, and then a 20mg dose every 4 weeks thereafter for up to 1 year of treatment. In one embodiment, for the method of controlling the flare or relapse, the pemphigus disease is pemphigus vulgaris.

One embodiment of the present invention is the use of ofatumumab for controlling the flare or relapse of Pemphigus in a patient suffering therefrom by administering to the patient an improved dosing regimen of ofatumumab wherein the dosing regimen is a dose suppressing amount of ofatumumab sufficient to suppress B cells between dosing intervals, and the dosing interval is every 4 weeks for up to a year.

In another embodiment, is provided a method for treating pemphigus in a patient suffering therefrom while concomitantly reducing the use of steroids, comprising administering to the patient a plurality of doses over a course of treatment time period. In one embodiment, the patient is requiring use of more than 20mg of steroid or 1.5mg/kg of steroid usage (which ever is higher) for disease control prior to administration of ofatumumab. In one embodiment, the steroid is oral prednisone.

Similar to above, a method for treating pemphigus in a patient suffering therefrom while concomitantly reducing the use of steroids during said treatment will also require administration of a dose suppressing amount of ofatumumab sufficient to suppress B cells between the dosing intervals.

Suitably, the dose of ofatumumab is 20mg, 30mg, 40mg or 60mg. In one embodiment, for treating pemphigus in a patient suffering therefrom while concomitantly reducing the use of steroids there will be a similar treatment regimen, with a 40mg loading dose, followed by either a 20mg or 40mg second dose at 4 weeks, and then a 20mg dose every 4 weeks thereafter for up to 1 year of treatment. In one embodiment, the pemphigus disease is pemphigus vulgaris.

One embodiment of the present invention is the use of ofatumumab for treating Pemphigus in a patient while concomitantly reducing the use of steroids in said patient by administering to the patient an improved dosing regimen of ofatumumab wherein the dosing regimen is a dose depleting and/or dose suppressing amount of ofatumumab sufficient to suppress B cells between dosing intervals, and the dosing interval is every 4 weeks for up to a year.

Another aspect of this invention is a method of reducing immunosuppressive therapy in a patient with Pemphigus disease, comprising administering to said patient will be a similar treatment as indicated above with a 40mg loading dose, followed by either a 20mg or 40mg second dose at 4 weeks, and then a 20mg dose every 4 weeks thereafter for up to 1 year of treatment, and reducing the dose or eliminating the dose of the immunosuppressive therapeutic agent over the course of treatment.

Similar to above, the method of reducing immunosuppressive therapy in a patient with pemphigus disease will also require the administration of a dose depleting or dose suppressing amount of ofatumumab sufficient to suppress B cells between the dosing intervals. Suitably, the dose suppressing amount of ofatumumab is an amount sufficient to be a depleting or fully depleting dose.

Suitably, the dose of ofatumumab is 20mg, 30mg, 40mg or 60mg. In one embodiment, for a method of reducing immunosuppressive therapy in a patient with Pemphigus disease, there will be a similar treatment as indicated above with a 40mg loading dose, followed by either a 20mg or 40mg second dose at 4 weeks, and then a 20mg dose every 4 weeks thereafter for up to 1 year of treatment. In one embodiment, the Pemphigus disease is pemphigus vulgaris.

One embodiment of the present invention is the use of ofatumumab for reducing immunosuppressive therapy in a patient with Pemphigus disease by administering to the patient an improved dosing regimen of ofatumumab wherein the dosing regimen is a dose suppressing amount of ofatumumab sufficient to suppress B cells between dosing intervals, and the dosing interval is every 4 weeks for up to a year.

It is recognized that for a method of treating a patient suffering from pemphigus; and for a method for controlling the flare or relapse of pemphigus in a patient suffering therefrom; and for a method of treating pemphigus in a patient suffering therefrom while

concomitantly reducing the use of steroids; and for a method of reducing

immunosuppressive therapy in a patient with pemphigus disease that the dose of ofatumumab administered could vary as well as the course of cycles of treatment administered. The loading dose followed at 4 week intervals may end after a 5 cycle treatment, e.g. at week 16. The treatment may end after a 6 cycle administration of drug, e.g. week 20. Similarly the treatment may end after a 7 cycle administration, e.g. week 24, etc. It is also an embodiment of the invention that the 4 week dosing interval may be extended to dosing every 2 cycles, e.g. at 8 week intervals or even 3 cycles intervals, e.g. every 12 weeks with the dose of ofatumumab being administered as 20mg, 30mg, 40mg or 60mg. It is also possible that at week 8 an additional loading dose may be necessary followed by the lower dosage throughout the remainder of the dosing intervals. In a related aspect of the invention, the invention provides for an anti-CD20 antibody, preferably ofatumumab or rituximab, for use in the treatment or arrest of pemphigus in a patient suffering therefrom, wherein the antibody is administered at a dose suppressing amount sufficient to suppress B cells between a dosing interval. In another related aspect of the invention, the invention provides an anti-CD20 antibody, suitably ofatumumab or rituximab, for use in the treatment of pemphigus by prevention of flare or relapse in a patient suffering therefrom, wherein the antibody is administered at a dose suppressing amount sufficient to suppress B cells between a dosing interval. In one embodiment the anti-CD20 antibody is ofatumumab.

For treatment with an anti-CD20 antibody, the course of treatment time period includes dosing intervals. In one aspect of the invention, a loading dose is given at week zero (day 1), and then a dosage is administered at each dosing interval thereafter. In another embodiment, a loading dose is given at week zero (day 1), and then at the next dosage interval an additional loading dose is also administered, followed subsequently with a lower dose at each dosing interval thereafter. Suitably, the dosing interval is a 4 week doing time period. In another embodiment, the course of treatment time period is up to 56 weeks. Maintenance therapy may be the same dose suppressing amount administered at the same or at reduced dosing intervals.

Pemphigus vulgaris is an acquired, rare, chronic, debilitating, and potentially life- threatening autoimmune vesiculobullous disorder, characterized by mucocutaneous erosions or blisters. The disease is caused by pathogenic antibodies directed against desmoglein 1 and 3, which are members of the desmosomal cadherin family. The in vivo binding of these anti-desmoglein autoantibodies (mainly IgG4 and IgGl) leads to the loss of adhesion between keratinocytes resulting in the formation of intra-epidermal blisters [Amagai M, et a\. J Invest Dermatol. 1995 Aug; 105(2):243-7]. These blisters eventually lead to erosions in the skin which, prior to steroid therapy, resulted in significant mortality.

The more general term "pemphigus" represents a group of rare autoimmune blistering diseases caused by anti-desmoglein antibodies (including pemphigus vulgaris (PV), pemphigus folicaeus, and paraneoplastic pemphigus), of which pemphigus vulgaris is the most common.

Pemphigus vulgaris presents with peak frequency generally occurring at 30 to 60 years of age and older, with an incidence of approximately 5-6 per million worldwide and a mortality rate of <10%. The disease, caused by pathogenic antibodies directed against desmoglein (Dsg) 1 and 3, are members of the desmosomal cadherin family. The in vivo binding of these anti-Dsg autoantibodies (mainly IgG4 and IgGl) causes a loss of adhesion between keratinocytes, and the resultant formation of intra-epidermal blisters [Amagai M, et al. J Invest Dermatol. 1995 Aug; 105(2):243-7]. These blisters eventually lead to erosions in the skin which, prior to the corticosteroid era, frequently resulted in mortality.

The PV Dsg3-/-mouse model demonstrated telogen hair loss, providing the first cutaneous manifestation of Dsg3 dysfunction in adult mice [Koch et al., J Cell Sci 1998, 111 :2529- 2537]. These findings also suggested that anti-Dsg3 autoantibodies directly interfered with the adhesive function of Dsg3 to cause blisters. Another PV mouse model has been developed by the adoptive transfer of splenocytes from recombinant Dsg3 -immunized Dsg3-/- mice to Rag2-/-immunodeficient mice that expressed Dsg3. A deposition of IgG on keratinocyte cell surfaces in stratified squamous epithelia is noted in this PV mouse model as well as circulating anti-Dsg3 IgG antibodies [Ohyama M, et al., J Invest

Dermatol. 2002, 118: 199-204]. Taken together the models suggest that generation of anti- Dsg3 by autoreactive B-cells play a central role in PV.

The reduction of pathogenic antibodies via targeted B-cell depletion forms the basis for the use of rituximab in the treatment of PV, and clinical response to rituximab has correlated with B-cell depletion [Mouquet H, et al. Journal of Investigative Dermatology 2008, 128: 2859-2869; Eming et al., Journal of Investigative Dermatology 2008: 128: 2850-2858] The initial clinical improvement is attributed to the elimination of autoreactive B-cells resulting in a reduction of anti-desmoglein antibodies, and long-term remission observed in several patients may be due to the reappearance of naive B-cells characterized by a normal repertoire. The actions of ofatumumab on B-cells are similar to rituximab; however, ofatumumab binds to a different epitope on the CD20 molecule and has demonstrated superior in vitro Fc effector functions (complement-dependent and antibody-dependent cellular cytotoxicity). B-cell depletion has been documented with IV administration of ofatumumab in subjects with rheumatoid arthritis and multiple sclerosis, and with subcutaneous (SC) administration of ofatumumab in subjects with rheumatoid arthritis (Study OF Al l 0867).

Study, OFA110867, established that the duration of peripheral B cell depletion increases with dose of subcutaneous ofatumumab, an anti-CD20 antibody. Thus, therapeutic efficacy with anti-CD20 antibody therapy could be maintained and controlled, while also reducing the incidence of infections (including JC virus variants) that may trigger relapse by opening the blood brain barrier or by activating pathogenic immune cells expressing Toll-Like Receptor 9 (TLR9), even if partial B-cell depletion is achieved (i.e. by delivering "a sub-depleting dose"). Depleting the CD20 ⁺ B-cell subset may reduce the supply of mature B-cells (including pathogenic B-cells) for migration across the blood brain barrier, clonal expansion, and differentiation into plasma or memory cells.

Therefore, it is believed that when a dosage of ofatumumab which is depleting, fully depleting or is a suppressing dosage amount is administered, suitably by subcutaneous injection, (ofatumumab SC) it has the potential to reduce disease activity in patients with PV, a potentially life-threatening condition.

As used herein a "dose depleting" or "dose suppressing amount" of ofatumumab is that which is expected to suppress B-cells to below the limit of quantification (LLQ). While it is possible to have "depletion to 0 cells/ul" occurring, a surrogate endpoint, such as suppression to 32 cells/ul is within the range of clinical effect. Thus a "dose suppressing" amount is a clinical effect of 32cells/ul and a "depleting" or "fully depleting dose" would be to the limit of quantification, such as -5-7 cells/ul. Both terminologies, e.g. dose suppressing and dose depleting are used interchangeably herein within the context of this invention as are the terminologies, e.g. depleting and fully depleting.

Although no cure is currently available for pemphigus vulgaris, the efficacy of systemic corticosteroids (often administered at high doses and concomitantly with other immunosuppressive treatment) in managing pemphigus vulgaris has been well demonstrated. While systemic corticosteroids are currently the most commonly utilized therapy for the management of pemphigus vulgaris, multiple side-effects associated with high-dose corticosteroids are seen. This can increase morbidity and may necessitate the use of other adjuvant steroid-sparing therapies.

For subjects failing pemphigus vulgaris treatment due to adverse events associated with high-dose steroid treatment or other immunosuppressants, or due to dosing inconvenience (as in the case of rituximab and the attendant need for infusion suites), additional therapeutic approaches are needed to appropriately treat pemphigus vulgaris. This is believed to be one such needed therapy. It is anticipated that with sustained B-cell depletion in the presence of ofatumumab SC, and the resultant reduction of pathogenic anti-Dsg autoantibodies in pemphigus vulgaris, clinical remission of the disease will result.

"Week one", as used herein, may refer to, the 8 ^th day of treatment (wherein the initial dose is administered to the patient on day 1 of treatment), "week 4" as used herein may refer to the 29 ^th day of treatment, e.g. administration of ofatumumab, "week 12" as used herein may refer to the 85 ^th day of treatment, e.g. administration of ofatumumab, etc. It will be understood that the exact timing of the administration - i.e. the exact day of delivery - may not be critical. Thus, for instance, delivery may be within +/-7 days of the stated day, +/-5days of the stated day, +/- 3 days of the stated day, +/-2days of the stated days or +/- lday of the stated day. For example, in one embodiment, delivery could be on day 1, day 8 (+/- 3 days), day 85 (+/- 3 days).

While not wishing to be limited, the method may also comprise the administration to the patient of a tolerizing dose, wherein the tolerizing dose is administered to the patient prior to the delivery of the at least one sub-depleting dose. In one embodiment, the tolerizing dose may be administered about 1 week prior to the delivery of the (first) at least one sub- depleting dose. In an embodiment, the tolerizing dose is between about 0.3mg and 3mg of ofatumumab. In another embodiment, the tolerizing dose is about 3mg of ofatumumab.

It is desirable to suppress B cells during the inter-dosing intervals of ofatumumab administration. When dosed every 4 weeks, B cell suppression is improved. Achieving adequate B cell depletion is believed to be essential for maintenance of efficacy in pemphigus treatment although no threshold for B cell depletion has been demonstrated. It is believed that dividing the dose of drug to administer 20mg every 4 weeks, rather than 60mg every 12 weeks will achieve this goal. By administration of the higher loading dose and the subsequent additional higher dosage at week 4 a more rapid depletion of B-cells is believed to occur. It is expected to maintain a desired level of suppression during the inter-dosing intervals and which can be achieved with a non-loading dose of ofatumumab, such as 20mg, administrated approximately every 4 weeks.

When a patient presents with a high steroid intake and steroid tapering is needed, suppression of B cells during a multiple of cycles may be needed. Thus, additional loading doses, such as 20mg of ofatumumab may be administered at the first dose, at the second dose (week 4) and even at the third dose (week 8) or longer if believed necessary. This would be followed thereafter by 20mg throughout the remaining 4 week cycles of treatment.

For any of the uses indicated herein, additional loading doses of ofatumumab, such as 20mg may be administered at any of the dosing intervals, e.g. as presently indicated for the first dose, and the second dose (week 4) but also at the third dose (week 8) or the forth dose (week 12) or longer if believed necessary. This would be followed thereafter by 20mg throughout the remaining 4 week cycles of treatment.

In one aspect, the present invention relates to a method for treating pemphigus in a human patient comprising administering ofatumumab at an:

(a) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; followed by a 20 mg dose, a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every 4 weeks a dose of 20mg for a multiple of cycles out to 56 weeks, e.g. weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 weeks.; or

(b) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; followed by a 20 mg dose at week 4; and then every 4 weeks a dose of 20mg for a multiple of cycles out to 56 weeks, e.g. weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 weeks.; or

(c) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; followed by a 20 mg dose at week 4; and then every 8 weeks a dose of 20 mg for a multiple of cycles out to 56 weeks, e.g. weeks 12, 20, 28, 36, 44, and 52 weeks; or (d) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; a 20mg dose followed with a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every 8 weeks a dose of 20 mg for a multiple of cycles out to 56 weeks, e.g. weeks 12, 20, 28, 36, 44, and 52 weeks; or

(e) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; a 20mg dose followed with a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every 4 weeks a dose of 30mg for a multiple of cycles out to 56 weeks, e.g. weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 weeks.; or

(f) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; a 20mg dose followed with a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every 4 weeks a dose of 40mg for a multiple of cycles out to 56 weeks, e.g. weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 56 weeks.; or

(g) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; a 20mg dose followed with a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every twelve weeks thereafter for a multiple of cycles administration of a 60mg dose at weeks 16, 28, 40, and 52 weeks; or

(h) initial 20 mg dose, followed with a second 20mg dose (e.g. a 40mg loading dose) administered at week one; a 20mg dose followed with a second 20mg dose (e.g. a second 40mg loading dose) at week 4; and then every 8 weeks a dose of 40 mg for a multiple of cycles out to 56 weeks, e.g. weeks 12, 20, 28, 36, 44, and 52 weeks; or

(i) any of the above dosing regimens followed by a 20mg, 30mg, 40mg or 60mg dosage of ofatumumab for maintenance therapy, administered as needed.

For all of the above dosing regimens described herein including but not limited to (a) to (g) above, it is recognized that the regimen may in fact be less than the full 48 -56 weeks of dosing. Time to remission or sustained remission may be present after less than 10 doses, or less than 9 doses, or less than 8 doses, or less than 7 doses. Alternatively, time to remission or sustained remission may be present after less than 6 doses. Alternatively, time to remission or sustained remission may be present after less than 6 doses. In another embodiment, time to remission or sustained remission may be present after less than 4 doses. In all cases, maintenance therapy may be initiated at a lower dose than the one used in the regimen, or it may be administered at more infrequent scheduling. s used herein, the following definitions shall mean: Did not flare/relapse Achieved remission on minimal steroid therapy and did not subsequently have a flare/relapse of disease by Week 60

Disease control No new lesions for >2 weeks

Disease flare/relapse Appearance of >3 new lesions within 1 month that do not heal spontaneously within 1 week, or when there is an extension (worsening) of lesions that were present at the randomization visit (Note: the appearance of 1 or 2 new lesions is not considered a flare/relapse)

Duration of remission on Sum of all periods of remission on minimal steroid therapy up minimal steroid therapy to Week 60

Eliminated use of systemic An oral prednisone/prednisolone dose of 0 mg/day for steroids >2 weeks

Minimal steroid therapy An oral prednisone/prednisolone dose of <10 mg/day

Remission Absence of new or nonhealing (established) lesions for

>8 weeks (Note: Subjects with existing, healing lesions may be considered in remission if other criteria are met.)

Remission on minimal Absence of new or nonhealing (established) lesions while on steroid therapy an oral prednisone/prednisolone dose of <10 mg/day for

>8 weeks

Sustained remission (SR) The absence of new or nonhealing (established) lesions for

>8 weeks that is sustained until Week 60

Time to remission off Time from randomization to the time the subject initially steroid therapy tapered off all steroids for >8 weeks with an absence of new or nonhealing (established) lesions by Week 60

Time to remission on Time from randomization to the time the subject initially minimal steroid therapy tapered his/her oral prednisone/prednisolone dose to

<10 mg/day and maintained dose at <10 mg/day with no new or nonhealing (established) lesions for >8 weeks by Week 60

Time to initial Time from randomization to the time of appearance of flare/relapse >3 new lesions within 1 month that do not heal spontaneously within 1 week, or to the time when there is an extension of lesions that were present at the randomization visit

Time to sustained Time from randomization to the time the subject initially remission on minimal tapered his/her oral prednisone/prednisolone dose to steroid therapy <10 mg/day and maintained a dose <10 mg/day with no new or nonhealing (established) lesions for >8 weeks AND maintained that status until Week 60 The term "patient", as used herein, refers to a human patient.

Ofatumumab may be administered via any suitable route, such as nasal, inhalable, intrabronchial, intraalveolar, topical (including buccal, transdermal and sublingual), rectal, vaginal and/or parenteral route. In one embodiment, a pharmaceutical

composition of the present invention is administered subcutaneously (SC), optionally intramuscularly, typically by injection. As used herein, the term, "carrier", refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.

As used herein, the term, "pharmaceutically acceptable", means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

In one embodiment of the invention, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration or subcutaneous administration to human beings. Typically, compositions for these administrations are solutions in sterile isotonic aqueous buffer. Where suitable, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder, or water-free concentrate, in a hermetically sealed container, such as an ampoule or sachette, indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion. In one embodiment, ofatumumab can be formulated according to the disclosure of

WO2009/009407. In another embodiment, ofatumumab may be formulated as described in WO2012/096924. In another embodiment, ofatumumab may be formulated as the commercially available product, Azerra®, which although formulated for intravenous injection may be used subcutaneously.

As noted, ofatumumab is presently available as a parenteral injection to be prepared for administration as a 300mg or a 2000mg dose. To prepare a solution of the parental product, the label indicates that for a 300mg dose 3 single use vials of lOOmg are diluted with 0.9% sodium Chloride Injection, USP. Similarly, for a 2000mg dose, 2 single use lOOOmg vials are diluted with 50ml of 0.9% sodium Chloride Injection, USP. The IV vials include as inactive ingredients include: lOmg/mL arginine, diluted hydrochloric acid, 0.019mg/mL edetate disodium, 0.2 mg/mL polysorbate 80, 6.8 mg/mL sodium acetate, 2.8 mg/mL sodium chloride, and Water for Injection, USP. The vials contain no preservatives.

Suitably, the commercial product may be used and diluted accordingly from a lOOmg/vial to deliver a 20mg, 30 mg, 40mg or 60mg dose. Alternatively, prefilled syringes may be used having the appropriate concentration and dosage may be used for SC administration. In one aspect of the invention, Ofatumumab is supplied as a liquid concentrate in 3-mL glass vials containing 1 mL of concentration 100 mg/mL drug product, or in 1-mL prefilled glass syringes with stake needles containing 0.6 mL of concentration 100 mg/mL drug product.

If using a dilution method for administration of the desired dose is needed, the contents of prefilled (0.6 mL) syringes of ofatumumab 60-mg syringe can be injected into a sterile vial and 0.4 mL of the resulting solution will be drawn into a new syringe to achieve a 20-mg ofatumumab (concentration 50 mg/mL) dose.

Suitably, Ofatumumab may also be supplied in prefilled glass syringes containing 0.4 mL (20 mg) of concentration 50 mg/mL drug product.

Other pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, antioxidants and absorption delaying agents, and the like that are physiologically compatible with a compound of the present invention. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the present invention is contemplated.

Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Pharmaceutical compositions containing ofatumumab may also comprise pharmaceutically acceptable antioxidants for instance (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid

(EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Pharmaceutical compositions containing ofatumumab may also comprise isotonicity agents, such as sugars, polyalcohols such as mannitol, sorbitol, glycerol or sodium chloride in the compositions.

Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.

The pharmaceutical compositions containing ofatumumab may also contain one or more adjuvants appropriate for the chosen route of administration, such as preservatives, wetting agents, emulsifying agents, dispersing agents, preservatives or buffers, which may enhance the shelf life or effectiveness of the pharmaceutical composition. An anti- CD20 antibody the present invention may for instance be admixed with lactose, sucrose, powders (e.g., starch powder), cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol. Other examples of adjuvants are QS21, GM-CSF, SRL-172, histamine

dihydrochloride, thymocartin, Tio-TEPA, monophosphoryl-lipid A/microbacteria compositions, alum, incomplete Freund's adjuvant, montanide ISA, ribi adjuvant system, TiterMax adjuvant, syntex adjuvant formulations, immune-stimulating complexes (ISCOMs), gerbu adjuvant, CpG oligodeoxynucleotides, lipopolysaccharide, and polyinosinic:polycytidylic acid.

Prevention of presence of microorganisms may be ensured both by sterilization procedures and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminium monostearate and gelatin. To administer the pharmaceutical compositions containing ofatumumab by certain routes of administration according to the invention, it may be necessary to coat the ofatumumab antibody with, or co-administer the antibody with, a material to prevent its inactivation. Depending on the route of administration, ofatumumab may be coated in a material to protect the antibody from the action of acids and other natural conditions that may inactivate the compound. For example, ofatumumab may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J. Neuroimmunol. 7, 27 (1984)). Pharmaceutically acceptable carriers for parenteral administration include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical

compositions of the present invention is contemplated. Supplementary active compounds may also be incorporated into the compositions.

Pharmaceutical compositions for injection must typically be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier may be a aqueous or nonaqueous solvent or dispersion medium containing for instance water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. The proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as glycerol, mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients e.g. as enumerated above, as required, followed by sterilization microfiltration.

Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients e.g. from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, examples of methods of preparation are vacuum drying and freeze- drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, examples of methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The method according to the invention may also comprise the step of administering additional pharmaceutically active agents with Ofatumumab. Suitable additional pharmaceutically active agents include, but are not limited to, firategrast, fingolimod, natalizumab, methotrexate, interferon-gamma, cyclophosphamide, cyclosporine, corticosteroids such as prednisone and prednisolone, non-steroidal anti-inflammatory drugs (NSAIDs), such as paracetamol, and anti-histamines, such as ceterazine, or diphenhydramine.

It is postulated that drugs such as firategrast and natalizumab may sequester B-cells by blocking migration or egress of such cells from germinal centres, and thus, combining such therapies with ofatumumab therapy may result in an enhancement of the cell-killing effect of the ofatumumab. Accordingly, in one aspect, the invention provides a method of treating, or arresting pemphigus in a patient suffering therefrom, comprising administering to the patient an anti-CD 20 antibody, preferably ofatumumab, and one or more of a second pharmaceutical active agent. In one embodiment the second pharmaceutical active agent is firategrast, fingolimod or natalizumab.

Prior use in autoimmune disease settings such as pemphigus typically involves treatment with corticosteroids. In an embodiment of the invention, patients treated with the dosage regimen of the present invention may be a steroid niave patient who does not receive treatment with corticosteroids, or they may be patients who wish to reduce or limit their concurrent usage of steroids with a dosage regimen of the present invention.

The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

Example 1 - Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of

Subcutaneously administering Ofatumumab in patients with Pemphigus. This study will, based on disease remission, determine the efficacy of ofatumumab administered SC at a dose of 40 mg administered at week 1, a 40mg dose administered at week 4, and then a 20mg dose administered every 4 weeks for up to 56 weeks. Patients will be evaluated to determine disease flare and/or relapse during treatment with ofatumumab SC. Patients will be evaluated to see if there are reductions in co- administered steroids while maintaining disease control.

Study Design

Study OPV116910 is a global, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy, safety, and tolerability of ofatumumab SC in subjects with active PV, who have failed a previous attempt to taper steroid dosing

(i.e., had a disease flare during the taper attempt). The study includes a Screening Period, a 48-week Treatment Period, and a 12-week Follow-up Period. Subjects will visit the clinic during Screening; at Baseline (Week 0); at Weeks 2, 4, 6, and 8; and then every 4 weeks from Week 8 through Week 60. Subjects will also have structured phone visits between each of the clinic visits from Week 10 through Week 22. It is anticipated that total duration of participation in this study will be approximately 72 weeks. A Screening Period of 2 to 12 weeks will occur prior to randomization to allow subjects to achieve disease control (no new lesions for >2 weeks) using a stable oral dose of prednisone/prednisolone (20 mg/day up to 120 mg/day or 1.5 mg/kg/day [whichever is higher] for >2 weeks). Multiple visits to the clinic are permitted during this Screening Period to assess disease status and to adjust the oral prednisone/prednisolone dose. Once disease control is achieved, subjects who continue to satisfy the eligibility criteria may be randomized.

At the Baseline Visit (Day 0), approximately 136 eligible subjects will be centrally randomized 1 : 1 across 2 strata (disease duration [<1 year, >1 year] and baseline prednisone dose [<60 mg, >60 mg]) to receive SC administration of ofatumumab 40 mg or placebo once every 12 weeks for a total of 56 weeks (with the first dose occurring on Day 0 subsequent to enrollment and randomization). Two weeks after the first dose of ofatumumab SC or placebo (i.e., Week 2), the oral steroid dose will be gradually reduced according to a fixed dose-taper schedule with a goal of reducing (i.e., to <10 mg/day) or eliminating the dose of prednisone/prednisolone.

After the last dose of ofatumumab SC or placebo at Week 56, subjects will be followed-up at Week 60. Subjects completing the study and meeting all entry criteria will be offered the option to participate in an open-label extension (OLE) study (OPV117059), which will start after completion of the Week 60 visit. If B-cell counts have not recovered by the Week 60 visit, subjects not entering the OLE study will remain in an Individualized Follow-up Period until either the CD 19+ B-cell counts or circulating IgG levels are >LLN or baseline levels (if <LLN) or until 2 years after the last dose of investigational product (whichever comes first). Individualized Follow-up visits will be scheduled every

12 weeks. Subjects who withdraw from treatment will also enter the Individualized Follow-up Period.

A Screening Period of up to 12 weeks will allow subjects who have active lesions at the initial Screening Visit to achieve disease control using a stable dose of 20 mg/day up to 120 mg/day (or 1.5 mg/kg/day, whichever is higher) of oral prednisone/prednisolone for >2 weeks. Once disease control has been attained, subjects may be randomized to treatment, provided they continue to fully satisfy the eligibility criteria. Subjects are co-administered acetaminophen/paracetamol and an antihistamine (such as cetirizine or an equivalent). Subjects will remain on the stable daily oral steroid dose achieved during the Screening Period until Week 2, when they will begin steroid tapering; with the goal of reducing or eliminating the daily use of steroids, subjects will have their oral steroid dose reduced by 1 dose level every 2 weeks (as illustrated in Table 1 below). Subjects will remain on the standardized steroid taper schedule until the onset of disease flare/relapse (appearance of >3 new lesions within 1 month that do not heal spontaneously within 1 week, or when there is an extension of lesions that were present at the randomization visit). If a subject experiences disease flare/relapse, the prednisone/prednisolone dose will be increased by

1 to 4 levels per week until disease control is achieved (i.e., no new lesions for >2 weeks. The prednisone/prednisolone taper will then be reinitiated after a 2-week period of disease control. Once the dose is reduced to 10 mg, an attempt at reducing the steroids further need only be made until the first flare/relapse. Following the first flare/relapse at or below 10 mg prednisone/prednisolone, further steroid tapering attempts will be made at the investigator's discretion based on the subject's clinical status.

The design of this study takes into account the low incidence and chronic relapsing nature of PV, and the fact that therapy with corticosteroids— albeit associated with significant side effects— represents the standard of care for management of PV. The study is designed to evaluate the efficacy of ofatumumab SC in an environment where a subject requiring corticosteroids is undergoing a taper to minimal treatment or, ideally, no treatment with systemic steroids. For this reason, the study has been designed with 1 study group receiving ofatumumab SC and the other group receiving placebo, over a background of tapering steroids for both treatment arms. The dosing duration of 1 year will allow adequate time to assess time to remission in both study groups. Historical data indicate that remission can be expected in approximately 54% of subjects in the placebo group (with steroid dose adjustment), and in about 80% of subjects in the ofatumumab SC group. When administered via IV infusion, ofatumumab has been associated with infusion reactions that have occasionally led to temporary interruption or withdrawal of treatment. To reduce such reactions, premedication with acetaminophen/paracetamol, oral or IV antihistamine, and oral and/or IV glucocorticoids has been used in clinical studies involving oncology and rheumatoid arthritis populations. In the current study, to lessen the likelihood of localized reactions with administration of ofatumumab SC, oral doses of acetaminophen/paracetamol and antihistamine will be administered as premedication, 1 to

2 hours prior to the administration of investigational product. All subjects (ofatumumab SC and placebo groups) will be premedicated in order to maintain blinding and to minimize confounding variables on dosing days.

Two co-primary efficacy endpoints include but are not limited to the evaluation of:

· Time to sustained remission (SR) on minimal steroid therapy (defined as time from randomization to the time the subject initially tapered his/her oral

prednisone/prednisolone dose to <10 mg/day and maintained <10 mg/day of oral prednisone/prednisolone with no new or nonhealing lesions for >8 weeks AND maintained that status until Week 60).

· Duration of remission on minimal steroid therapy (defined as total time of all periods during the 60 week period, from when the subject initially tapered his/her oral prednisone/prednisolone dose to <10 mg/day and had remission, until initial flare/relapse or Week 60, whichever comes first). Secondary Efficacy Endpoints include, but are not limited to:

• Proportion of subjects achieving remission on minimal steroid therapy (defined as subjects who had an absence of new or nonhealing lesions while on a

prednisone/prednisolone dose of <10 mg/day for >8 weeks) at Week 60.

• Time to remission while on minimal steroid therapy (defined as time from

randomization to the time the subject initially tapered his/her oral

prednisone/prednisolone dose to <10 mg/day and maintained <10 mg/day of oral prednisone/prednisolone with no new or nonhealing lesions for >8 weeks) by Week 60.

• Time to initial flare/relapse (defined as the time from randomization to the time that >3 new lesions within 1 month appear and do not heal spontaneously within 1 week, or to the time when there is an extension of lesions that were present at the randomization visit) by Week 60.

• Proportion of subjects who did not flare/relapse (defined as subjects who achieved remission on minimal steroid therapy and did not subsequently have a flare of disease) by Week 60. A flare/relapse is defined as new lesions that do not heal spontaneously within 1 week, or when there is an extension of lesions that were present at the randomization visit.

• Time to remission off steroid therapy by Week 60 (defined as the time from

randomization to the time the subject initially tapered off all steroids for >8 weeks with an absence of new or nonhealing lesions).

· Proportion of subjects achieving remission while off steroid therapy by Week 60. Number of days a subject maintained minimal steroid therapy (an oral prednisone/prednisolone dose of <10 mg/day in the absence of new or nonhealing lesions) by Week 60.

Table 1 Oral Prednisone/Prednisolone Dose-ta er Schedule

a. Prednisone/prednisolone is reduced by 1 dose level every 2 weeks, with the goal being elimination of prednisone/prednisolone. For subjects at a starting dose >160 mg, taper dose by 20 mg every 2 weeks until the dose is 160 mg, at which point the decrements shown on the table above should be used.

b. Subjects will remain on the standardized oral prednisone/prednisolone taper schedule until disease flare/relapse (appearance of >3 new lesions within 1 month that do not heal spontaneously within 1 week, or when there is an extension of lesions that were present at the randomization visit). In the event of disease flare/relapse, oral

prednisone/prednisolone will be increased by a rate of 1 to 4 levels per week until disease control is re-established. The oral prednisone/prednisolone taper will then be reinitiated after disease control is maintained for 2 weeks.

c. Once the dose is reduced to 10 mg, an attempt at reducing the steroid doses further need only be attempted until the first flare/relapse. Following the first flare/relapse at or below 10 mg oral prednisone/prednisolone, further steroid tapering attempts will be at the investigator's discretion based on the subject's clinical status.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the Examples herein are to be construed as merely illustrative and not a limitation of the scope o f the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.