BACKGROUND

Plasma kallikrein is a serine protease component of the contact system and a potential drug target for different inflammatory, cardiovascular, infectious (sepsis) and oncology diseases (Sainz I. M. et al.,Thromb Haemost98, 77-83, 2007). The contact system is activated by either factor XIIa upon exposure to foreign or negatively charged surfaces or on endothelial cell surfaces by prolylcarboxypeptidases (Sainz I. M. et al.,Thromb Haemost98, 77-83, 2007). Activation of the plasma kallikrein amplifies intrinsic coagulation via its feedback activation of factor XII and enhances inflammation via the production of the proinflammatory nonapeptide bradykinin. As the primary kininogenase in the circulation, plasma kallikrein is largely responsible for the generation of bradykinin in the vasculature. A genetic deficiency in the C1-inhibitor protein (C1-INH), the major natural inhibitor of plasma kallikrein, leads to hereditary angioedema (HAE). Patients with HAE suffer from acute attacks of painful edema often precipitated by unknown triggers (Zuraw B. L. et al.,N Engl J Med359, 1027-1036, 2008).

SUMMARY

Provided herein are regimens for treating hereditary angioedema (HAE) attack, reducing the rate of HAE attack, or blocking HAE attack using antibodies capable of binding and inhibiting human plasma kallikrein (pKal) in active form, for example, antibodies that bind to the same epitope as DX-2930 (a.k.a. SHP643) or competes against DX-2930 for binding to active human pKal.

In some aspects, the present disclosure provides methods for treating hereditary angioedema (HAE) attack or reducing the rate of HAE attack, comprising administering (e.g., subcutaneously) to a subject in need thereof any of the anti-pKal antibodies described herein (e.g., DX-2930) in single and/or multiple doses. In some embodiments, the antibody is administered to a subject (e.g., a human patient) at multiple doses in a first treatment period, e.g., 26 weeks. For example, the antibody can be administered at about 300 mg every two weeks, about 300 mg every four weeks, or about 150 mg every four weeks in the first treatment period.

Any of the methods described herein may further comprise administering to the subject the antibody for a second treatment period (e.g., 26 weeks) after the first treatment period. In some embodiments, the first dose of the second treatment period is about two weeks after the last dose of the first treatment period. In some embodiments, the second treatment period comprises multiple doses of the antibody at about 300 mg every two weeks for, e.g., 26 weeks.

Alternatively, the methods may further comprise administering to the subject a single dose of the antibody (e.g., about 300 mg) after the first treatment period. The single dose may be followed up with one or more doses of the antibody (e.g., about 300 mg every 2 weeks) of the antibody if an HAE attack occurs after the single dose. The first dose of the follow-on treatment can be within one week after the HAE attack. In some embodiments, the single dose and the first dose of the follow-on treatment are at least 10 days apart.

Other aspects of the present disclosure provide methods for treating hereditary angioedema (HAE) attack or reducing the rate of HAE attack in a subject that has undergone a prior treatment of HAE, comprising (i) administering (e.g., subcutaneously) to a subject in need thereof any of the anti-pKal antibodies described herein (e.g., DX-2930) antibody at a single dose of about 300 mg; and (ii) further administering to the subject the antibody at multiple doses of about 300 mg every two weeks, if the subject experiences an HAE attack after (i). The subject may have undergone a first HAE treatment as described herein. For example, the first HAE treatment can be a treatment involving the same antibody (e.g., DX-2930). In some examples, the first HAE treatment involves administering the antibody in multiple doses of about 150 mg or 300 mg every four weeks or administering the antibody in multiple doses of about 300 mg every two weeks. Alternatively or in addition, the first dose of the multiple doses is given to the subject within one week after the HAE attack.

In any of the treatment methods described herein, the subject can be a human patient having, suspected of having, or at risk for HAE. In some embodiments, the subject is a human patient having HAE type I or type II. For example, the subject may have at least one HAE attack in the four weeks prior to the first dose of the first treatment period or at least two HAE attacks in the eight weeks prior to the first dose of the first treatment period. In other examples, the subject can be a human patient who had experienced at least two HAE attacks per year prior to the treatment. Alternatively or in addition, the subject is a human patient who is free of prior treatment, for example, at least two weeks before the first dose of the first treatment period.

In some embodiments, the subject to be treated by any of the methods described herein, which involve the use of any of the anti-pKal antibody as also described herein (e.g., DX-2930) have received one or more HAE treatment before the first dose of the anti-pKal antibody. Such prior HAE treatments may involve an C1-inhibitor (e.g., C1-INH), a plasma kallikrein inhibitor (e.g., ecallantide), a bradykinin receptor antagonist (e.g., icatibant), an attenuated androgen (e.g., danazol), an anti-fibrinolytic agent (e.g., tranexamic acid) or a combination thereof. Such a subject may undergo a taper period to gradually transit from the prior HAE treatment to the anti-pKal antibody treatment described herein. In some examples, the tapering period may range from 2-4 weeks. The prior HAE treatment may terminate either before the first dose of the anti-pKal antibody or within three weeks after the first dose of the anti-pKal antibody is given to the subject. Alternatively, the subject may be directly transitioned from any of the prior HAE treatment to the anti-pKal antibody treatment as described herein.

In some embodiments, the subject is free of a long-term prophylaxis for HAE, or an HAE treatment involving an angiotensin-converting enzyme (ACE) inhibitor, an estrogen-containing medication, or an androgen prior to the first treatment period, during the first treatment period, and/or during the second treatment period.

The anti-pKal antibody for use in the treatment regimens described herein may be a full length antibody or an antigen-binding fragment thereof. In some embodiments, the antibody may comprise the same CDRs as DX-2930. In one example, the antibody is DX-2930.

In any of the methods described herein, the antibody can be formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically composition comprises sodium phosphate, citric acid, histidine, sodium chloride, and Tween 80. In one example, the sodium phosphate is at a concentration of about 30 mM, the citric acid is at a concentration of about 19 mM, the histidine is at a concentration of about 50 mM, the sodium chloride is at a concentration of about 90 mM, and/or the polysorbate 80 is at about 0.01%.

The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawing and detailed description of several embodiments, and also from the appended claims.

