Composition and method of treating human t cell lymphotropic virus associated disease

Abstract

Disclosed herein is a composition of a compound that has superior pharmacokinetics and pharmacodynamics as compared to conventional interferon. In addition, a method to use such composition to treat human T-cell leukemia virus type 1 (HTLV-1) associated diseases are also disclosed.

Description

COMPOSITION AND METHOD OF TREATING HUMAN T CELL LYMPHOTROPIC VIRUS ASSOCIATED DISEASETechnical Field of the Invention

[0001] The present disclosure relates in general to the field of cancer therapy. More specifically, a treatment of various types of diseases associated with infection of human T cell lymphotropic virus in a subject.Background Art

[0002] Human T-cell leukemia virus type 1 (HTLV-1) is transmitted by cell contact with infected lymphocytes, exposure to which may occur by ingesting breast milk, through condomless sexual intercourse, blood transfusions, organ transplantation, intravenous drug use or other means. No directly acting antiviral agents specific to HTLV-1 have been developed and current antiretroviral agents are ineffective in treating chronic HTLV-1 infection.

[0003] HTLV-1 is a replication-competent human retrovirus which is associated with two types of oncology diseases: a malignancy of mature CD4+ T cells called adult T-cell leukemialymphoma or adult T-cell leukemia / lymphoma (ATLL or ATL, used interchangeably in the art) and a chronic inflammatory central nervous system disease HTLV-1 -associated myelopathy / tropical spastic paraparesis (HAM / TSP). It was the first human retrovirus ever associated with human cancer. Although most HTLV-1 -infected individuals remain asymptomatic for life, a population develops ATL or HAM / TSP.

[0004] Other HTLV-1 associated diseases, include but not limited to: oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases, endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder.

[0005] Human T-cell leukemia virus type 1 (HTLV-1) belongs to the genus Deltaretrovirus of the Orthoretrovirinae subfamily and infects approximately 5-10 million individuals worldwide. HTLV-1 is a causative agent of adult T-cell leukemia (ATL), an aggressive form of T-cell malignancy. Some HTLV-1 carriers develop ATL during their lifetime. HTLV-1 also causes HTLV-1 -associated myelopathy / tropical spastic paraparesis (HAM / TSP) in some patient infections. In HAM / TSP, the corticospinal (pyramidal) tracts of the spinal cord are severely affected by inflammatory reactions. This inflammatory disease results in irreversible paraparesis of the lower limbs. The majority of infected individuals remain lifelong asymptomatic carriers (ACs).

[0006] In the context of virus induced adult T-cell leukemia / lymphoma, at the time of this disclosure, it is known to be endemic in southern Japan, the Caribbean, intertropical Africa, and Brazil. Recently northeast Iran, particularly the region of Mashhad, has also been recognized as a new endemic region. Adult T-cell leukemia / lymphoma is an aggressive proliferation of mature activated CD4+ CD25+ T cells associated with the human T-cell lymphotropic virus type I (HTLV-I). ATL is resistant to chemotherapy and carries a dismal prognosis particularly for the acute and lymphoma subtypes. Leukemia develops after a very long latency period and is preceded by oligocl onal expansions of HTLV-I infected activated T cells.

[0007] In the context of ATL, the diversity in clinical features and prognosis of ATL patients has led to its subclassification into smoldering, chronic, lymphoma, and acute subtypes. Patients with aggressive ATL (acute and lymphoma subtypes) generally have a very poor prognosis because of intrinsic chemoresistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and / or frequent infectious complications due to a profound T-cell immune deficiency. The median survival time for acute and lymphoma (aggressive) subtypes is less than one year. In addition, an atypical aggressive, primary cutaneous tumoral form (PCT) of ATL with a shorter survival has been described in the medical community.

[0008] Patients with indolent ATL (e.g., chronic or smoldering subtypes) with data in the medical community, have shown poor long-term survival results when these patients are managed with a watchful-waiting policy until disease progression or with chemotherapy.

[0009] Most current subjects are being treated using chemotherapy, zidovudine (AZT), granulocyte colony-stimulating factor (G-CSF), Arsenic Trioxide, chemotherapy, histone deacetylase inhibitors, specific monoclonal antibodies, Anti-CC Chemokine Receptor 4 drugs, or other therapy / drugs known in the art. However, the prognosis for subjects who received any of the known treatments are still not bright. For example, in its more common aggressive forms, ATL carries one of the poorest prognoses of the non-Hodgkin lymphomas.

[0010] Therefore, there is an unmet medical need for the treatment of various types of disease associated with infection of human T cell lymphotropic type 1 virus in a subject. One of many aims of this disclosure is to serve the public for such unmet needs, for example, patients with ATL (of any sub-type). The present disclosure presents a unique new way to alleviate / treat / assist / prevent one or more of the above medical issues and / or symptoms with subjects or subject in need infected with HTVL-1.Disclosure of the Invention

[0011] In one aspect the present disclosure relates in general to a method of treating, preventing, slowing the progression, inhibiting and / or ameliorating one or more symptoms / diseases in a subject or subject in need infected with HTLV-1, comprising administering to said subject in need thereof an effective amount of ropeginterferon alfa-2b including the structure of Formula I, which is also known as Pl 101.(Formula I)

[0012] In another aspect, wherein said one or more symptoms / diseases as a result of HTLV-1 infection comprises oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases, endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder. Oncological diseases can comprise ATL (including all sub-types and / or relapse / refractory types), cervical cancer, and / or non-Hodgkin lymphoma,

[0013] Yet in another aspect, the cardiovascular diseases can comprise damage to the heart valve, atherosclerosis, and / or hypertension, wherein said respiratory diseases can comprise pulmonary inflammation, interstitial pneumonias, bronchiolitis and alveolitis, diffuse panbronchiolitis or bronchiectasis, and / or interstitial pneumonia, wherein said skin diseases can comprise infectious dermatitis, chronic recurrent infected eczema, lymphadenopathy, persistent hyperreflexia, and / or gait disturbances, wherein said disease of the musculoskeletal system can comprise tenosynovitis, wherein said neurological diseases can comprise HTLV-l-associated myelopathy / tropical spastic paraparesis (HAM / TSP), acute myelopathy, encephalopathy, and / or myositis, wherein said rheumatic diseases can comprise rheumatoid arthritis (RA), Sjogren’s syndrome, and / or polymyositis, wherein said endocrinological diseases can comprise hypothyroidism and / or hyperthyroidism, wherein said eye inflammation can comprise HTLV-l- associated Uveitis (HU), wherein said ophthalmic diseases can comprise keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, and / or ophthalmological manifestations associated with ATLL in adults, wherein said diseases of the genitourinary system can comprise urinary dysfunction, or wherein said mental disorder can comprise depression.

[0014] In an aspect, the present disclosure relates in general to a method of treating, preventing, slowing the progression, inhibiting and / or ameliorating one or more symptoms of adult T-cell leukemia / lymphoma (ATL) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) in a subject comprising administering to said subject in need thereof an effective amount of ropeginterferon alfa-2b including the structure of formula I, which is also known as Pl 101.(Formula I)

[0015] In an aspect, said ATL comprises acute, lymphoma, chronic, and / or smoldering ATL subtype, and / or relapsed and / or refractory ATL and / or unfavorable chronic ATL.

[0016] In another aspect, Formula I includes two mPEGs each having mPEG size between about 19 to about 23 KDa. In a different aspect the total mPEG size is between about 38 to 42 KDa. In an aspect the total mPEG size is between about 38 to 46 KDa.

[0017] Yet in another aspect, the Formula I disclosed above further comprises a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, a pharmaceutically acceptable adjuvant, a diluent, and / or or carrier.

[0018] In an aspect, the ropeginterferon alfa-2b also known as depicted in Formula I, is administered subcutaneously to a subject.

[0019] Yet in another aspect, the ropeginterferon alfa-2b is administered using a first dosage, a second dosage, and a third dosage of ropeginterferon alfa-2b, wherein the 3rddosage can be constant or variable (up or down as compared to the second dosage) for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes). In an aspect, the first and second dosage can be incremental, constant, or in a decrease fashion, for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL and / or myelopathy / tropical spastic paraparesis (HAM / TSP). In another aspect, during any treatment period, the Pl 101 can be administered at a constant dose, which includes meaning that the same dose is administered each time or only minimally different doses are administered (e.g., dose variation or deviation of less than 10%, less than 5%, and / or less than 1 %).

[0020] In an aspect, the first dosage of ropeginterferon alfa-2b can include administering of about 250 pg, the second dosage comprises about 350 pg, and the third dosage comprises about 500 pg of ropeginterferon alfa-2b for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP).

[0021] Alternatively, or additionally, the first dosage is between about 400 pg to about 500 pg of ropeginterferon alfa-2b for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP).

[0022] Yet in another aspect, the first, second or third dosage is maintained at a constant dosage during a treatment period for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP).

[0023] In another aspect, the first dose is about 450 pg for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes).

[0024] In an aspect, the subject is administered with a third dose of the ropeginterferon alfa-2b at between about 2 to 16 weeks, between about 2 to 24 weeks, after a second dose without an intervening dose, wherein the third dose being between about 50 pg to 200 pg higher than the second dose for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP).

[0025] Yet in an aspect, for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), ropeginterferon alfa-2b is administered for a period of about between 2 to 16 weeks, between about 2 to 24 weeks, or longer. In another aspect, the ropeginterferon alfa- 2b is administered for a period of about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 52, 60, 72, 96, 130, 156 weeks, or longer period.

[0026] In an aspect, method of the present disclosure increases said patient’s OS, CR, CRu, PFS, DFS, PR, TTF, DCR and / or remission rate who has any types or subtypes of ATL. Alternatively or additionally, the method decreases said patient’s tumor size and / or AE rate for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP).

[0027] In another aspect, for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), ropeginterferon alfa-2b can be administrated along with chemotherapy, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Tucidinostat, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine plus interferon-alfa, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530.

[0028] In an aspect, the present disclosure includes use of the substantially homogenous composition or pharmaceutical formulation including ropeginterferon alfa-2b having the structure of formula I.

[0029] for the preparation of a medicament for the treatment of one or more conditions including a subject having adult T-cell leukemia / lymphoma (ATL, including any subtypes). Alternatively, or additionally, the subject has relapsed and / or refractory ATL, and / or unfavorable chronic ATL.

[0030] Yet in an aspect, a substantially homogenous composition or pharmaceutical formulation including ropeginterferon alfa-2b having the structure of formula I characterized in that it is used to treating one or more of condition including a subject having adult T-cell leukemia / lymphoma (ATL) is disclosed herein. In one aspect, the treatment of ATL includes subjects having acute, lymphoma, chronic, and / or smoldering ATL, relapsed, refractory ATL, and / or unfavorable chronic ATL.

[0031] In an aspect, the present disclosure relates to a composition comprising ropeginterferon alfa-2b having the structure of formula I for treatment of adult T-cell leukemia / lymphoma (ATL) in a subject. Such subject can have different types of ATL, including, but not limited to acute, chronic, smoldering, relapsed, refractory ATL and / or unfavorable chronic ATL.

[0032] In an aspect, for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), the administration of the ropeginterferon alfa-2b includes a first dosage of about 250 pg, a second dosage including between about 400 pg to 500 pg, and optionally additional dosages at a constant or variable amount of ropeginterferon alfa-2b. Alternatively or additionally, the second dosage comprises about 500 pg of ropeginterferon alfa-2b. Yet alternatively or additionally, the administration includes an intermediate dosage of about 350 pg of ropeginterferon alfa-2b between the first dose and the second dose.

[0033] In an aspect, the present disclosure denotes using ropeginterferon alfa-2b to treat a subject having HTLV-1 infected related diseases or symptoms, for example, ATL (of any sub-type) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) patients, which results in PR, CR, SD, and / or CRu. In another aspect, the present disclosure denotes using ropeginterferon alfa-2b to prevent ATL relapse.Description of the Drawings

[0034] For a more complete understanding of the features and advantages of the present disclosure, reference is now made to the detailed description of the disclosure along with the accompanying figures and in which:Figure 1 denotes the chemical structure of Pl 101, also known as ropeginterferon alfa-2b. Each mPEG has a molecular weight range from about 10 KD to 30 KD, and / or between about 19-23 kD. IFN denotes interferon alpha 2b.Figure 2 denotes an example of clinical design to use Pl 101 to treat subjects having ATL.Figure 3 denotes clinical treatment progress of one of the clinical trials being conducted.Description of the Invention

[0035] While the making and using of various embodiments of the present disclosure are discussed in detail below, it should be appreciated that the present disclosure provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the disclosure and do not delimit the scope of the disclosure.

[0036] To facilitate the understanding of this disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present disclosure. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which one or more examples may be used for illustration. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not delimit the disclosure, except as outlined in the claims.

[0037] The following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0038] As used herein, “administering,” means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. Administration is by any route including parenteral, and transmucosal (e.g.,oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Moreover, where injection is to treat a tumor, e.g., induce apoptosis, administration may be directly to the tumor and / or into tissues surrounding the tumor. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0039] As used herein, the term “isolated molecule” as referring to a molecule (where the molecule is, for example, a polypeptide, a polynucleotide, or an antibody) that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is substantially free of other molecules from the same source, e.g., species, cell from which it is expressed, library, etc., (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a molecule that is chemically synthesized, or expressed in a cellular system different from the system from which it naturally originates, will be “isolated” from its naturally associated components. A molecule also can be rendered substantially free of naturally associated components by isolation, using purification techniques well known in the art. Molecule purity or homogeneity may be assayed by a number of methods known in the art. For example, the purity of a polypeptide sample may be assayed using polyacrylamide gel electrophoresis and staining of the gel to visualize the polypeptide using techniques known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means known in the art for purification.

[0040] As used herein, the terms “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” all refer to (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and / or (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully “treated” according to the methods and molecules of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of disorder, while keeping subject within a regulatory approved range of safety parameters.

[0041] Non-limiting examples of treating include clinical results with abbreviation of “CR”, which denotes disappearance of lesions; “CRu”, which denotes stable residual in bulky lesions mass; “PR”, which denotes regression of disease, or “SD”, which denotes non-CR / PR but no progressive the disease. Alternatively, or additionally, non-limiting examples of “treating” include increasing disease-free survival (DFS) and / or OS (overall survival) rates.

[0042] The term “subject” refers to a living organism (including primate or non-primate) which includes both humans and animals.

[0043] The terms “subject in need” and “patient” are used interchangeably and refer to a living organism (including primate or non-primate) which includes both humans and animals having one or more disorder as denoted in the present disclosure.

[0044] By “refractory” in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent. A cancer is refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (i.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.

[0045] As used herein, a subject at “high risk of cancer recurrence or relapse” is one who has a greater chance of experiencing recurrence of cancer. A subject's risk level can be determined by a physician.

[0046] As used herein, “extending survival” or “increasing the likelihood of survival” refers to increasing disease free survival (DFS) and / or OS (overall survival) or increasing the probability of remaining alive and / or disease-free at a given point in time in a patient treated with a drug relative to an untreated patient (i.e. relative to a patient not treated with the drug being administered), or relative to a control treatment, such as treatment only with the chemotherapeutic agent or other agent). Non-limited survival monitoring can be monitored for at least about 16 weeks, at least about 24 weeks, at least about two months, at least about four months, at least about six months, at least about nine months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years, etc., following the initiation of drug treatment.

[0047] As used herein, “branched” in reference to the geometry or overall structure of a polymer, can refer to a polymer having 2 or more arms.

[0048] A “host cell” includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this disclosure. One example is E. Coli.

[0049] As used herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer as indicated per se, as well as within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0050] As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial, safe (e.g., within a given regulatory agency’s tolerance level), and / or desired results. In more specific aspects, an effective amount prevents, alleviates, ameliorates symptoms of disease, and / or prolongs the survival of the subject being treated. For prophylactic use, beneficial or desired results include, but not limited to eliminating or reducing the risk, lessening the severity, or delaying the outset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include, but not limited to safe clinical results such as reducing one or more symptoms of a disease such as cancer.

[0051] Non-limiting cancers include, for example, ATL, different subtypes of ATL, and / or relapse, recurrent, and / or refractory ATL patients, decreasing the dose of other medications required to treat ATL, enhancing the effect of another medication, and / or delaying the progression of ATL in patients. An effective dosage can be administered in one or more administrations.

[0052] For purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly in a safe manner within a given regulatory agency’s parameter. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” or “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result along with safety may be or is achieved.

[0053] As used herein, the term “per dose”, “dosage”, or “dose” means administering a given numeric amount of drug to a subject. Per dose can be administered in separate injections or tablet at about the same time and / or different time, so long as a subject receives the denoted drug amount.

[0054] As used herein, the term “stabilizer” can include a pharmaceutical acceptable excipient, which assist, and / or inhibits the active pharmaceutical ingredient and / or the formulation from chemical and / or physical degradation during manufacturing, storage and application. Chemical and physical degradation pathways of protein pharmaceuticals are known in the art, for example, reviewed by Cleland et al., Crit. Rev. Ther. Drug Carrier Syst., 70(4):307-77 (1993); Wang, Int. J. Pharm., 7S5(2): 129-88 (1999); Wang, Int. J. Pharm., 203(1-2): 1-60 (2000); and Chi et al., Pharm. Res., 20(9): 1325-36 (2003). Stabilizers can include, but are not limited to sugars, amino acids, polyols, cyclodextrines, e.g. hydroxypropyl-beta-cyclodextrine, sulfobutylethyl-beta- cyclodextrin, beta-cyclodextrin, polyethylenglycols, e.g. PEG 3000, PEG 3350, PEG 4000, PEG 6000, albumine, human serum albumin (HSA), bovine serum albumin (BSA), salts, e.g. sodium chloride, magnesium chloride, calcium chloride, chelators, e.g. EDTA.

[0055] As used herein, the term “per injection” means administering the entire denoted amount of drug to a subject for a given dose in a single injection or tablet.

[0056] The term “PEG” generally refers to a polyalkylene glycol compound or derivative thereof, with or without linkers or activating moieties. The term PEG as used herein includes, but is not limited to, polyethylene glycol homopolymers, copolymers of ethylene glycol with propylene glycol and derivatives and equivalents thereof, wherein said homopolymers and copolymers are unsubstituted or substituted, for example, at one end with an alkyl group. The PEG polymers for use with the present disclosure can be linear, branched, comb, and / or starshaped with a wide range of molecular weights. The term “mPEG” refers to the methoxy version of any of the above wherein PEG is capped with a methoxy group at the end. The average molecular weight of the mPEG for use with embodiments of the present disclosure can range from between about 5 to about 100 kDa, between about 10 to about 50 KD, between about 10 to about 30 KD, and / or at between about 19-23 KD.

[0057] The term “preventing” or “prevent” refers to (a) keeping a disorder from occurring or (b) delaying the onset of a disorder or onset of symptoms of a disorder. None-limiting examples include “preventing” tumor progression for subjects diagnosed with ATL, any type or subtype of ATL, and / or myelopathy / tropical spastic paraparesis (ELAM / TSP).

[0058] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutical acceptable excipient” includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity or stability and does not cause adverse effect to a subject. Examples include, but are not limited to, any of the pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil / water emulsion, and various types ofwetting agents. Example diluents such as for aerosol or parenteral administration can be phosphate buffered saline (PBS) or normal (0.9%) saline.

[0059] The term “intradermal administration”, “i.d ”, or “administered intradermally,” in the context of administering a substance to a mammal including a human, refers to the delivery of the substance into the dermis layer of the skin of the mammal. The skin of a mammal is composed of an epidermis layer, a dermis layer, and a subcutaneous layer. The epidermis is the outer layer of the skin. The dermis, which is the middle layer of the skin, contains nerve endings, sweat glands and oil (sebaceous) glands, hair follicles, and blood vessels. The subcutaneous layer is made up of fat and connective tissue that houses larger blood vessels and nerves. In contrast in intradermal administration, “s.c ”, or “subcutaneous administration”, refers to the administration of a substance into the subcutaneous layer and “topical administration” refers to the administration of a substance onto the surface of the skin.

[0060] As used herein, “about” mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, “about” can mean a range of up to 5%, 7.5%, 10%, 12.5%, 15%, 17.55, 20%, 22.5% 25%, 27.5%, or 30%of difference in either direction (positive or negative) compared to a reference value. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 1, 2, or 3 -folds of a value. When particular values are provided in the application and claims, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. Numeric ranges are inclusive of the numbers defining the range.

[0061] As used herein, the term “constant” dose refers to, during any treatment period, a drug can be administered at a constant dose, meaning that the same dose is administered each time or only minimally different doses are administered (e.g., dose variation or deviation of less than 10%, less than 5%, and / or less than 1 %).

[0062] As used herein, the terms “Pl 101”, “Ropeg”, “ropeginterferon alfa-2b-njft”, or “ropeginterferon alfa-2b” are used interchangeably. Pl 101 is known in the art, for example, see U.S. Patent Numbers: US 8,143,214, US 8,273,343, US 8,617,532, and / or US 8,106,160, the content of all of which are incorporate herein in their entirety. Also see U.S. Patent Application Numbers: US 20170326206, US 20220152156, US 20220362343, and / or US 20230057788, thecontent of all of which are incorporate herein in their entirety. Briefly, for example, the chemical formula, method of manufacturing, and its uses are disclosed therein. For convenience, its structure is briefly denoted in Figures 1. More specifically, the interferon (IFN) is the version that is functional in human subjects. The term “mPl lOl” denotes the mouse version of IFN that has the same PEGylation and PEGylation structure.

[0063] With respect to Pl 101 characterization, pharmacokinetics, pharmacodynamics etc., they are also known in the art. For example, see European Medicinal Agency’s published BESREMi (trademarked) Assessment report, with all of the contents incorporated herein by reference in their entirety.

[0064] Briefly, ropeginterferon alfa-2b is produced by covalent attachment of about 40 kDa mPEG molecules to the N-terminal proline residue of a Proline-Interferon alfa-2b (Pro-IFN alfa- 2b) wherein it comprises two mPEG with each mPEG having between about 19-23KD. Prolineinterferon alfa-2b is generated by recombinant DNA technology introducing an extra proline residue to a human interferon alpha-2b at N-terminus, giving a polypeptide of total 166 amino acids in length. Pro-IFN alfa-2b has a molecular weight of about 19 kDa and has the amino acid sequence identical to the theoretical sequence predicted excluding the additional N-terminal proline. It is then PEGylated with an about 40 kDa mPEG moiety forming an about 60 kDa PEGylated proline-interferon alfa-2b or ropeginterferon alfa-2b.

[0065] The ropeginterferon alfa-2b conjugate denoted in Figure 1 is also described in detail in W02009 / 023826A1. In particular, W02009 / 023826A1 disclosed a method of making Pl 101, and the content of which are incorporated herein by reference in their entirety.

[0066] At the time of the filing of this disclosure, Pl 101 is approved and being marketed in multiple countries, including the United States, for treatment of a type of myeloproliferative neoplasms (MPNs) called PV (polycythemia vera). PV is considered as an orphan disease in the U.S. The National Comprehensive Cancer Network (NCCN) has recommended ropeginterferon alfa-2b as a first line cytoreductive therapy for patients with PV in the NCCN Clinical Practice Guidelines in Oncology for MPNs. Pl 101 is not approved by a regulatory agency for another non-MPN disease at the time of the initial filing of this application.

[0067] In an embodiment, the present disclosure also relates to using Pl 101 to treat HTLV-1 associated disease, including but not limited to oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases,endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder.

[0068] In another embodiment, in the context of oncological diseases, Pl 101 can treat a subject or subject in need having HTLV-1 associated oncological diseases, such as ATL, ATL of any subtypes, cervical cancer, and / or non-Hodgkin lymphoma.

[0069] In other embodiments, in the context of oncological diseases, Pl 101 can treat a subject or subject in need having HTLV-1 associated myelopathy and / or tropical spastic paraparesis (HAM / TSP).

[0070] In an embodiment, in the context of cardiovascular diseases, Pl 101 can treat a subject or subject in need having HTLV-1 associated cardiovascular diseases such as damage to the heart valve, atherosclerosis, and / or hypertension,

[0071] In another embodiment, in the context of respiratory diseases, Pl 101 can treat a subject or subject in need having HTLV-1 associated respiratory diseases. In this context, HTLV-1 mediated inflammation. Pulmonary inflammation associated with HTLV-1 infection involves the interstitium, airways and alveoli, resulting in several clinical entities including interstitial pneumonias, bronchiolitis and alveolitis, depending on which structures are most affected, parenchymal damage, which may progress to bronchiectasis where this involves the airways.

[0072] Other HTLV-1 associated respiratory diseases, which Pl 10 can treat, include bronchioloalveolar disease associated with HTLV-1 infection typically has a chronic, progressive form. Diffuse panbronchiolitis or bronchiectasis is usually revealed in patients using computed tomography (CT), while interstitial pneumonia is sometimes detected. High levels of polyclonal CD4+ and CD25+ lymphocytes were observed in the bronchoalveolar fluid of the patients, reflecting the infiltration of HTLV-1 -infected T cells in the lungs.

[0073] Further, Pl 101 can treat subjects with HTLV-1 associated respiratory diseases include diffuse pan-bronchiolitis (DPB) and idiopathic, and interstitial pneumonia (IIP),

[0074] Yet in an embodiment, in the context of skin diseases, Pl 101 can treat a subject or subject in need having HTLV-1 associated skin diseases such as HTLV-1 associated non-tumor skin diseases, For example, infectious dermatitis associated with HTLV-1 (IDH), which a chronic recurrent infected eczema which was reported to relate to erythematous-squamous, exudative, and crusty lesions of the scalp, retroauricular areas, neck, axillae, groin, paranasal and perioral skin, ears, chest, abdomen, and other areas of the body in juvenile IDH, as well as the formation of crusts in the nostrils. Other skin related diseases include infectious dermatitis, persistent hyperreflexia, and / or gait disturbances,

[0075] In an embodiment, Pl 101 can treat a subject or subject in need having HTLV-1 associated lymphadenopathy

[0076] Yet in another embodiment, in the context of musculoskeletal system, Pl 101 can treat a subject or subject in need having HTLV-1 associated tenosynovitis.

[0077] In another embodiment, in the context of neurological system, Pl 101 can treat a subject or subject in need having HTLV-l-associated myelopathy / tropical spastic paraparesis (HAM / TSP), acute myelopathy, encephalopathy, and / or myositis.

[0078] In an embodiment, in the context of rheumatic diseases, Pl 101 can treat a subject or subject in need having HTLV-l-associated rheumatoid arthritis (RA), Sjogren’s syndrome, and / or polymyositis.

[0079] In an embodiment, in the context of endocrinological diseases, Pl 101 can treat a subject or subject in need having HTLV-l-associated hypo- and hyperthyroidism.

[0080] Yet in an embodiment, Pl 101 can treat a subject or subject in need having HTLV-l- associated inflammation and tumorigenesis.

[0081] In an embodiment, Pl 101 can treat a subject or subject in need having HTLV-l- associated eye inflammation such as uveitis (HU)

[0082] In another embodiment, in the context of ophthalmic diseases, Pl 101 can treat a subject or subject in need having HTLV-l-associated keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, and / or ophthalmological manifestations associated with ATLL in adults.

[0083] Yet in another embodiment, Pl 101 can treat a subject or subject in need having HTLV-l- associated urinary dysfunction

[0084] In an embodiment, in the context of mental disorders, Pl 101 can treat a subject or subject in need having HTLV-l-associated depression, as cerebral changes occur in individuals with HTLV-1- associated myelopathy and appear to predominate in the subcortical regions

[0085] In an embodiment, the present disclosure relates to using Pl 101 to treat subject or subject in need having ATL. Adult T-cell leukemia-lymphoma (ATL), is a distinct, non-MPN related mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains an extremely challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and / or frequent opportunistic infection. The prognosis of aggressive ATL remains dismal with nontransplantation treatments. There is no standard treatment for relapsed or refractory (r / r) ATL, and clinical outcomes are poor. Relapsed or refractory (r / r) ATL hasextremely poor prognosis, with a median overall survival (OS) of less than 4 months after the first salvage therapy with conventional chemotherapy and an OS 9 months in patients with intensive chemotherapy.

[0086] The clinical features of ATL vary by disease type. Acute-type ATL is typically associated with a large number of circulating leukemia cells, generalized lymphadenopathy, hepatosplenomegaly, lytic bone lesions, visceral lesions, skin involvement, and systemic symptoms resulting from organ involvement, hypercalcemia, or opportunistic infection. The lymphoma type presents with lymphadenopathy in the absence of circulating leukemic cells in the peripheral blood. Patients may present with skin lesions, lung lesions, hepatomegaly, splenomegaly, and hypercalcemia, but these manifestations may be less frequent compared with the acute type. Chronic-type ATL is typically associated with chronic peripheral lymphocytosis for several years and may occasionally be associated with skin and lung involvement, lymphadenopathy, and hepatosplenomegaly. Typically, no associated hypercalcemia or infiltration of the CNS, gastrointestinal tract, or bones are seen, and lactate dehydrogenase levels are normal or only slightly increased. Chronic type ATL may further be subdivided into favorable and unfavorable subtypes, based on clinical parameters (e.g., serum albumin, blood urea nitrogen (BUN), and lactate dehydrogenase (LDH) levels). The smoldering type characteristically shows skin or lung infiltration with no other visceral involvement, a normal lymphocyte count, and at least 5% abnormal lymphocytes in the peripheral blood. Aggressive ATL types are associated with a particularly poor prognosis (median OS approximately 6-10 months); indolent types generally have a median OS of at least 2 years. In addition to ATL disease type, several other prognostic factors have been identified. Factors that predict poor prognosis include examples such as poor performance status, elevated LDH level, at least four total involved lesions, hypercalcemia, age at least 40 years, thrombocytopenia, eosinophilia, bone marrow involvement, high interleukin-5 serum level, C-C chemokine receptor 4 (CCR4) expression, lung resistance-related protein, p53 mutation, and pl6 deletion.

[0087] Chemotherapy and targeted agents have been attempted as therapies for relapsed / refractory ATL. Although certain clinical efficacy has been demonstrated in terms of response rate, it still remains a disease with adverse / poor prognosis, and new therapeutic drug are being investigated. In addition, IFN (interferon, along or in combination with other agents) was attempted as a treatment but is never approved to treat ATL at the time of the initial filing of this disclosure.

[0088] In another embodiment, diagnosis of ATL is determined by a combination of clinical presentation and morphologic / immunophenotypic features of the malignant cells, along withconfirmation of HTLV-1 infection. Abnormal T cells characteristic of ATL have markedly polylobated nuclei with homogeneous and condensed chromatin, small or absent nucleoli, and agranular and basophilic cytoplasm. The cells have a flower petal-like appearance and often express a CD3+ CD4+ CD5+ CD7- CD8- CD25+ immunophenotype. ATL tumor cells are detected in peripheral blood or biopsy of affected organs. At least 5% of circulating abnormal T lymphocytes are required for a diagnosis of ATL in patients without histologically proven tumor lesions.

[0089] In an embodiment, the clinical features of ATL can vary by disease type. Acute-type ATL presents with a large number of circulating leukemia cells, generalized lymphadenopathy, hepatosplenomegaly, lytic bone lesions, visceral lesions, skin involvement, and systemic symptoms resulting from organ involvement, hypercalcemia, or opportunistic infection. The lymphoma type presents with lymphadenopathy in the absence of circulating leukemic cells in the peripheral blood. Patients may present with skin lesions, lung lesions, hepatomegaly, splenomegaly, and hypercalcemia, but these manifestations may be less frequent compared with the acute type. Chronic-type ATL is associated with chronic peripheral lymphocytosis for several years and may occasionally be associated with skin and lung involvement, lymphadenopathy, and hepatosplenomegaly; no associated hypercalcemia or infiltration of the CNS, gastrointestinal tract, or bones are typically seen, and lactate dehydrogenase levels are typically normal or only slightly increased. Chronic-type ATL may further be subdivided into favorable and unfavorable subtypes, based on clinical parameters (serum albumin, blood urea nitrogen (BUN), and lactate dehydrogenase (LDH) levels). The smoldering type characteristically shows skin or lung infiltration with no other visceral involvement, a normal lymphocyte count, and at least 5% abnormal lymphocytes in the peripheral blood. Aggressive ATL types are associated with a particularly poor prognosis (median overall survival approximately 6-10 months); indolent types generally have a median overall survival (OS) of at least about 2 years.

[0090] For patients who have relapsed or refractory (r / r) ATL, they have extremely poor prognosis, with a median overall survival (OS) of less than about 4 months after the first salvage therapy with conventional chemotherapy and an OS of about 9 months in patients with intensive chemotherapy.

[0091] Given the lack of an effective treatment strategy for patients HTLV-1 associated diseases in the present disclosure, and for example with ATL, (aggressive, and / or r / r ATL), alternative options of using Pl 101 are disclosed herein. In an embodiment, different types of HTLV-1 associated diseases such as ATL (smoldering, chronic, lymphoma, acute, and / or r / r) can be treated by administering an effective amount of Pl 101 to a subject.

[0092] In an embodiment, adverse events (“AE”) with respect to ATL can include, but not limited to: hematologic, non-hematologic, or biochemical adverse events. Hematologic adverse events can include anemia, neutropenia, lymphopenia, thrombocytopenia, and pancytopenia. Non-hematologic adverse events can include infections, psychiatric disorders (e.g., depression), asthenia, fatigue, musculoskeletal pain, muscle cramps, abdominal pain, edema, dizziness, rash, headache, nausea, thrombosis, weight gain, weight loss, seizures, hemorrhage, diarrhea, and vomiting. Biochemical events can include, but are not limited to: elevated aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase levels. Adverse events can be graded based on standards accepted in the field (e.g., National Cancer Institute Common Terminology Criteria for Adverse Events) such as grade 4 neutropenia, grade 4 thrombocytopenia. Other AE can include, but are not limited to: death, requirement of transfusions of red cells, transient elevations in liver enzymes, peripheral neuropathy, anorexia, infectious complications, transient episodes of syncope, large number of circulating leukemia cells, generalized lymphadenopathy, hepatosplenomegaly, lytic bone lesions, visceral lesions, skin involvement, systemic symptoms resulting from organ involvement, hypercalcemia, lymphadenopathy in the absence of circulating leukemic cells in the peripheral blood, skin lesions, lung lesions, hepatomegaly, splenomegaly, hypercalcemia, chronic peripheral lymphocytosis, lymphadenopathy, and / or hepatosplenomegaly.

[0093] In another embodiment, in the context of ATL, complete response (CR) can mean, for example, disappearance or significant reduction of measurable tumor lesions (which may include, but not limited to normalization of lymph node size) and / or normalization of absolute lymphocyte (which may include, but not limited to flower cells less than about 5%) count such as below about 4 x 109 / L. Complete response unconfirmed (CRu) for ATL can mean a reduction such as about 75% of the tumor size and normalization of absolute lymphocyte (which may include, but not limited to flower cells) count such as below about 4 x 109 / L. Partial response (PR) for ATL can mean reduction such as about 50% of tumor size and absolute lymphocyte count.

[0094] In another embodiment, the different types of ATL can be determined using the following clinical properties as listed in Table 1.

[0095] Table 1A blank indicates that there are no restrictions other than the conditions specified in other disease types.

[0096] N: Upper limit of normal value

[0097] 1. Chronic form with poor prognostic factors: BUN > Upper limit of reference value (ULN), LDH > ULN, serum albumin < If even one of the lower limit of the reference value is satisfied

[0098] 2. HTLV-1 antibody semi-quantitative (PA) assay, enzyme-linked immune-sorbent assay (ELISA), Western blot assay, be positive in any of the line plot (LIA) methods. It is desirable that a positive reaction has been confirmed by the immunofluorescence method, Western blot method, or LIA method.

[0099] 3. Sum of the real number of lymphocyte-like cells, including normal lymphocytes and abnormal lymphocytes

[0100] 4. Morphologically distinct ATL cells

[0101] 5. Flower cells characteristic of ATL may be recognized.

[0102] 6. The corrected Ca value is obtained by the following equation.

[0103] For serum albumin level = 4.0 (g / dL): corrected Ca value (mg / dL) = total Ca value (mg / dL)

[0104] For serum albumin level < 4.0 (g / dL): Corrected Ca value (mg / dL) = total Ca value (mg / dL) -0.8 [albumin / dL-4]

[0105] 7. In order to diagnose smoldering type with less than 5% of abnormal lymphocytes in peripheral blood, it is necessary to identify tumor lesions histologically in the skin or lungs.

[0106] 8. Diagnoses of a chronic acute subtype requires histology-proven malignant lesion in case abnormal lymphocytes is less than 5% in peripheral blood.

[0107] The composition used in the present disclosure, whether Pl 101 alone, or with any combinations of other active ingredients for treating HTLV-1 associated diseases, can further comprise pharmaceutically acceptable carriers, excipients, or stabilizers, in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers, excipients, or stabilizers can be nontoxic to recipients at the dosages and concentrations, and can comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN (trademarked), PLURONICS (trademarked) polyethylene glycol (PEG), or methoxy polyethylene glycol (mPEG).

[0108] The term “interval” as used herein refers to the time between administration of two consecutive doses. In any of the methods described herein, the Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks, or longer. An interval that is defined in days or months is also disclosed. A regular interval of about every 10 to 60 days (e.g., about every 7, 14, 21, 25, 26, 27, 28, 29, 30, 31, 35, 42, 49, and / or 56 days), one month, or two months can also be used. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks, or longer.

[0109] In an aspect, a treatment period to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 42, 48, 54, 60, 66, 72, 78, 84 or more months. In some embodiments, the treatment period is about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 or more years. In some embodiments, the treatment period is at least about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 12, 14, 15, 16, 17, 18, 19, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60 weeks, or longer. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0110] In another embodiment, Pl 101 can be administered to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0111] In another embodiment, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every week. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500pg, up to about 540 pg, or up to about 650 pg every week. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every week. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0112] In another embodiment, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every 2 weeks. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 2 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 2 weeks.

[0113] In another embodiment, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routes every 3 weeks. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 3 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 3 weeks.

[0114] In another embodiment, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered using between about 50 to 540 pg per dose or per injection subcutaneously, via i.d., or other routesevery 4 weeks. Alternatively, or additionally, a dose or injection of Pl 101 can be administered during the treatment period ranges from about 250 to about 650 pg. The dose / inj ection can also be up to about 250 pg, up to about 255 pg, up to about 260 pg, up to about 265 pg, up to about 270 pg, up to about 275 pg, up to about 280 pg, up to about 285 pg, up to about 290 pg, up to about 295 pg, up to about 300 pg, up to about 305 pg, up to about 310 pg, up to about 315 pg, up to about 320 pg, up to about 325 pg, up to about 330 pg, up to about 335 pg, up to about 340 pg, up to about 345 pg, up to about 350 pg, up to about 400 pg, up to about 450 pg, up to about 500 pg, up to about 540 pg, or up to about 650 pg every 4 weeks. Alternatively, or additionally, a dose or injection of 135 pg or 180 pg of Pl 101 can be administered every 4 weeks.

[0115] In some embodiments, an initial (starting) dose to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be about 250 to about 500 pg (e.g., about 250 pg, about 300 pg, about 350, about 400 pg, about 450 pg, or about 500 pg) of Pl 101 administered to the subject. The initial dose / inj ection can be maintained or varied during the treatment period depending on patient’s need and / or physician’s recommendation.

[0116] In any of the methods or treatment periods described herein, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be titrated. As non-limiting example, a subject can be treated with a lower starting dose / inj ection (e.g., about 50 pg, about 100 pg, about 150 pg, about 200 pg, or about 250 to about 500 pg) of the Pl 101. If the subject responds well (e.g., lack of significant drug-related adverse events, significant self-reported discomfort, abnormal hematological responses, or other symptoms) after a time (e.g., between about 1 to 16 weeks or between about 1 to 24 weeks), the dose / inj ection given to the subject can be increased incrementally (e.g., by between about 50 to 250 pg, such as at about 50 pg, about 75 pg, about 100 pg, about 125 pg, about 150 pg, about 200 pg, about 250 pg or a combination thereof) every 2 to 16 weeks (e.g., every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 24 weeks, or any combination thereof) until the dose reaches a target dose (e.g., at least about 400 pg, at least about 425 pg, at least about 450 pg, at least about 475 pg, at least about 500 pg, at least about 525 pg, at least about 550 pg, or at least about 650 pg). After that, a target dose can be maintained during the treatment period, increased, and / or decreased depending on subject’s condition. The dose / inj ection can also be increased successively until the desired target dose is reached. For example, if the Pl 101 is administered once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, the dose / inj ection can be increased every 1, 2, 3, 4, 5, 6,7 or 8 weeks, respectively. In some embodiments, a subject can be given a starting dose / inj ection of 250 pg (i.e., at week 0). If the subject responds well to the initial dose / inj ection, the dose / inj ection can be increased by about 100 to about 150 pg every 2 to 8 weeks until it reaches a target dose of about 500 pg, about 550 pg, and / or 600 pg. For example, a 250-350-500 pg dosing schedule can be implemented (i.e., about 250 pg at week 0, about 350 pg between about week 2 to 8, and about 500 pg at the third administration 2 to 8 weeks after the initial second dose, without other intervening doses). Alternative, a subject can be given a starting dose / inj ection of about 350 pg and a second dose of about 500 pg between about 2 to 16 weeks, between about 2 to 24 weeks thereafter without an intervening dose (i.e., 350-500). Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0117] Exemplary dosing schedules can be abbreviated, nonetheless, each number is approximated. For example, 250-350-500 includes 1stdose / inj ection to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (ELAM / TSP), administered at about 250 pg, 2nddose / inj ection administered at about 350 pg, and 3rddose / inj ection administered at about 500 pg. Other embodiments include, but are not limited to: 250-400-500, 250-400, 250-500, 250-400-500, 250-450, 250-350-400-500, 250-300-400-500, 250-350-450-500, 250-350-450, 250-250-350-500, 250-250-250-350-500, 250-350-350-500, 250-500-500-500 (and remain at 500 afterwards), 350-500, 350-400-500, 350-400-450-500, 350- 450-500, 350-400, 350-450, 350-350-500, 350-350-350-500, 400-450-500, 400-500, 400-400- 500, 450-500 pg. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks. In some embodiments, the target dose and / or desirable effect is reached between about 1 to 16 weeks or between about 1 to 24 weeks from the initial administration. During the titration process, any dose, prior to reaching the target dose, may be maintained for a time period (e.g., between about 4 to 16 weeks or between about 4 to 24 weeks) or a number of successive doses dose / inj ection (e.g., between 2 to 8 successive doses dose / inj ection, e.g., 250-350-350-500 pg) or reduced depending on the subject's response. In some embodiments, the target dose is reached within about 2 to 8 successive doses. In further embodiments, once the subject is clinically stable, the dose / inj ection for the treatment of a subject having HTLV-1 infected related diseases or symptoms, for example ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) can be maintained at a constant level for a given treatment period, which can be at least about 1, 2, 3, 4, 5, 6, 7, 8, 12, 14, 15, 16, 17, 18, 19, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60 weeks, or longer. Pl 101 canbe administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0118] In an aspect, an initial dose / inj ection or starting dose / inj ection of Pl 101 refers to the first dose administered to a subject during a treatment period (i.e., week 0), wherein, prior to the treatment period, the subject is interferon-treatment naive or has not been administered the same active ingredient as Pl 101. A subject who is interferon-treatment naive is a subject who has not been treated with any form of interferon, whether pegylated or non-pegylated (e.g., recombinant interferon, or peginterferon alfa-2b that is not Pl 101, or peginterferon alfa-2a approved to be administered weekly).

[0119] In another embodiment, all of the above recited dosages to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be administered per dose, and / or per injection. Non-limiting example include administering about 250-350-500 pg of drug using about 50pg per about 5 injections at about the same time and / or different times, so long as the subject receives a total of about 250pg dose, or about 100 pg per injection about 5 times at about the same time and / or different times for a total of about 500 pg dose. The combination can be picked and choose depending on patient or subject convenience and / or medical need. In another non-limiting example, the entire about 250pg can be all administered in a single injection (per injection) at a single time point for the desired 250 pg dose.

[0120] In an embodiment, any of the above-mentioned dosage, or dosage scheme can be use, and / or in a mix-and-match fashion, depending on the subject’s tolerance and a physician’s assessment (e.g., based on number and / or types of AE).

[0121] In an embodiment, Pl 101 can be administered by any means known in the art, e.g., via subcutaneous or intravenous route. Pl 101 can be formulated as an injectable formulation. For example, it can be in the form of a ready-to-use prefilled syringe and / or injectable pen, containing, e.g., between about 0.2 to about 2 mL of solution, that can be for selfinjection. Each prefilled syringe can contain a labeled amount of the drug product including, for example, sodium chloride, sodium acetate anhydrous, acetic acid, benzyl alcohol, TWEEN (trademarked) and / or polysorbate 80. The vehicle for the drug product can be sterile water for injection and the drug product solution can have a pH of about 6, 6.5, 7, 7.5, or 8.

[0122] In an embodiment, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypesthereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), can be used for subcutaneous injection to a subject. Alternative, or additionally, Pl 101 can be administered via topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Other administration is by any route including parenteral, and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intraarteriole, intradermal, intraperitoneal, intraventricular, and / or intracranial. Moreover, where injection is to treat a tumor, e.g., induce apoptosis, administration may be directly to the tumor and / or into tissues surrounding the tumor. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches.

[0123] In certain embodiments, Pl 101 to treat and / or alleviate a subject or subject in need having HTLV-1 infected related diseases and / or symptoms, such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP), is administered once daily, about once weekly, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, or about once every three months. Pl 101 can be administered within about twenty-four hours of a dose of chemotherapy and / or radiation therapy. In certain embodiments, Pl 101 is administered at least once about 3, once about 7, once about 10, once about 14, once about 17 or once about 21 days before or after a dose of chemotherapy and / or radiation therapy. In an embodiment, Pl 101 can be administered to a patient immediately after, at about the same time, and / or any time during chemo and / or radiation therapy. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0124] In one embodiment, Pl 101 of present disclosure can be used to treat, slow the progression, increase OS, change or improve the categorization of ATL (including any subtypes thereof) disease (CR / Cru / PR / PFS / DFS), and / or prevent ATL in a subject. In addition, decrease AE on subjects who has ATL which can include but not limited to the following four classifications or subtypes of ATL based on the Shimoyama criteria: 1. acute subtypes, 2. lymphoma subtypes. These two are considered aggressive forms. 3. chronic subtypes, and 4. smoldering ATL. The aggressive disease types typically comprise the majority of ATL cases. For example, in Japan and Brazil, the acute type accounts for 55-60% of cases, lymphoma 20-25%, chronic 10-20%, and smoldering 5-10%. However, data from the International Peripheral T-cell Lymphoma Project showed that 87% of aggressive ATL cases were the lymphoma type (13% were acute type).

[0125] In another embodiment, Pl 101 can be used to treat, slow the progression, increase OS, change or improve the categorization of ATL (including any subtypes thereof) disease (CR / Cru / PR / PFS / DFS), and / or prevent ATL, and / or decrease AE on a subject having relapsed and / or refractory (r / r) ATL. Additionally or alternatively, the Pl 101 can be used to treat, slow the progression, increase OS, change or improve the categorization of ATL disease (CR / Cru / PR / PFS / DFS), and / or prevent ATL, and / or decrease AE on a subject having acute, lymphoma, chronic subtypes, and / or smoldering ATL.

[0126] In an embodiment, the present disclosure’s composition can be formulated by methods known in order to treat ATL (including any subtypes thereof). For example, a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a Solvent or Suspending medium (e.g., synthetic mono- or di glycerides). Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.

[0127] In another aspect, the present disclosure’s composition can be formulated for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets, carriers include lactose and corn starch, lubricating agents such as magnesium stearate, can also be added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[0128] Alternative, or additionally, a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. A composition having one or more of theabove-described compounds can also be administered in the form of suppositories for rectal administration.

[0129] Other pharmaceutically acceptable carrier can be used with one or more active above-mentioned compounds. The carrier in the pharmaceutical compositions is “acceptable1in the sense that it is compatible with the active ingredient of the composition (and for example, capable of stabilizing the active ingredient) and not deleterious to the patient to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an above- mentioned compound. Examples of other carriers include, but not limited to colloidal silicon oxide, magnesium Stearate, cellulose, sodium laurylsulfate, and D&C Yellow #10.

[0130] Surprising Efficacy, Advantages and Improvement

[0131] There is current no approved cure for HTLV-1 associated diseases, in particular, ATL (including any subtypes thereof).

[0132] As for ATL, known experimental treatment for ATL (regardless of subtypes, or whether or not approved by a given regulatory authority), can include but not limited to one or more of the below: chemotherapy, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine plus interferon- alfa, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530. Some of the above-mentioned therapies have failed clinical trials and / or subjects have poor tolerance, e.g, unmodified interferon (INF) alone or in combination with another drug, all of which have shown poor efficacy and none have been approved by any regulatory authority in any jurisdiction at the time of the initial filing of this disclosure.

[0133] On the contrary, in an embodiment, the present disclosure describes Pl 101 having surprising and unexpected improved in vitro, in vivo, ex vivo and / or actual in human clinical performance over one or more of the known experimental treatments mentioned in this disclosure or known in the art. A non-limiting example is that Pl 101 was able to treat a r / r ATL patient and achieving PR for at least two or more patients, with one ATL subject showing a partial response (PR) at Week 24. As a result, this clearly indicates that Pl 101 is effective in ATL.

[0134] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, atleast about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of OS (overall survival rate) and / or median OS. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0135] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having CR (complete response), median CR, or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0136] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL(including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having Cru (complete response unconfirmed), median Cru, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0137] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having increase number of PFS (progression-free survival), median PFS, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0138] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome (regression of disease) as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having increase number of PR (partial response), median PR, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0139] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having ATL remission, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0140] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of time to treatment failure (TTF), and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0141] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of disease control rate (DCR), and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0142] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having fewer number of adverse event(s) and / or decrease one or more AE such as those listed in the present disclosure. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0143] In another embodiment, the present disclosure describes using Pl 101 to treat subjects infected with HTLV-1 and associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP) having surprising and unexpected improved clinical outcome as compared to known treatment by reducing cancer symptoms by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold for subjects, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0144] In another embodiment, the present disclosure describes using Pl 101 to treat ATL subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of OS (overall survival rate) and / or median OS. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0145] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having CR (complete response), median CR, or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0146] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having Cru (complete response unconfirmed), median Cru, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0147] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having increase number of PFS (progression-free survival), median PFS, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0148] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having increase number of PR (partial response), median PR, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0149] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having ATL remission, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0150] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least aboutone fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of time to treatment failure (TTF), and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0151] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold of subjects having increase number of disease control rate (DCR), and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0152] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment at least about 5%, at least about 10%, by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, and / or at least about 5 fold of subjects having fewer number of adverse event(s) and / or decrease one or more AE such as those listed in the present disclosure. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0153] In another embodiment, the present disclosure describes using Pl 101 to treat ATL subjects (including any subtypes thereof) having surprising and unexpected improved clinical outcome as compared to known treatment by reducing lesion size by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold for subjects, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0154] In another embodiment, the present disclosure describes using Pl 101 to treat ATL (including any subtypes thereof) subjects having surprising and unexpected improved clinical outcome as compared to known treatment by reducing cancer symptom by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about one fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold for subjects, and / or improve disease category as listed in Table 1 and / or Table 4. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0155] In an embodiment, Pl 101 can be combined with one or more of the following experimental or known treatment chemotherapy, zidovudine (AZT), granulocyte colonystimulating factor (G-CSF), Arsenic Trioxide, chemotherapy, histone deacetylase inhibitors, specific monoclonal antibodies, Anti-CC Chemokine Receptor 4 drugs, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine plus interferon-alfa, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530 for treating subjects with HTLV-1 associated disease such as ATL (including any subtypes thereof) and / or myelopathy / tropical spastic paraparesis (HAM / TSP). The combination with Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks. In an embodiment, Pl 101 can be combined with one or more of the following experimental or known treatment chemotherapy, zidovudine (AZT), granulocyte colony-stimulating factor (G-CSF), Arsenic Trioxide, chemotherapy, histone deacetylase inhibitors, specific monoclonal antibodies, Anti-CC Chemokine Receptor 4 drugs, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine plus interferon-alfa, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530 for treating subjects with ATL (of any type). The combination with Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0156] Surprising Efficacy, Advantages and / or Improvement

[0157] In an embodiment, the present disclosure describes Pl 101 having surprising and unexpected improved clinical performance, as there is no current treatment available to HTLV-1 viral infection related diseases or condition known in the art at the time of the initial filing of this disclosure. One example this present disclosure demonstrated is to achieve clinical difference in the HTLV-1 infected disease in the oncology as shown in the below examples. Which showed clinical effect of Pl 101 treating ATL (including any subtypes thereof). This presents surprising and unexpected results for one ordinary skilled in the art as no treatment of drug has yet shown any disease regression known by the applicant at the initial disclosure of this application. Pl 101 can be administered at an interval of between about every 1 to about every 8 weeks, e.g., about every 1, 2, 3, 4, 5, 6, 7, 8 weeks.

[0158] Examples

[0159] Example 1. Ropeginterferon alfa-2b structure and method of making is known in the art. Briefly, Ropeginterferon alfa-2b has a total molecular mass of approximately 60 kilodaltons (kDa). Ropeginterferon alfa-2b is a covalent conjugate of a recombinant prolineinterferon alfa-2b and a two-arm methoxypolyethylene glycol (mPEG) moiety Pro-IFN alfa-2b, produced in Escherichia coli, is an approximately 19 kDa non-glycosylated polypeptide of 166 amino acids, with an approximately 40 kDa two-arm mPEG moiety attaches to its N-terminal proline.

[0160] Detailed method of making Pl 101 is known in the art and were disclosed, for example, in U.S. Patent Numbers: US 8,143,214, US 8,273,343, US 8,617,532, and / or US 8,106,160, the content of all of which are incorporate herein in their entirety. Briefly, the making of Pl 101 process typically starts with fermentation in E. coli. The initial cell expressing protein was expressed as an intracellular protein in the form of inclusion bodies. The product was extracted by lysing the cells followed by washing with buffers, and then solubilizing the inclusion bodies that contain the product. Downstream processing steps include protein refolding and chromatography and ultrafiltration / diafiltration purification steps to produce prolineinterferon alfa-2b intermediate.

[0161] Proline-interferon alfa-2b was then PEGylated by attaching an approximately 40 kDa two-arm branched mPEG intermediate to the N-terminal proline. It is then further purified via chromatography to produce the formulated active substance.

[0162] More specifically, the generation of the cell substrate used a cell substrate for expression of the recombinant protein based on E. coli strain BLR (DE3). Construction of theexpression plasmid was documented and the gene encoding Pro-IFN alfa-2b was cloned by polymerase chain reaction (PCR).

[0163] A two-tiered cell bank system master cell bank (MCB) and working cell bank (WCB) were established; characterization of the cell banks including testing for identity, purity, viability and genetic characterization. Extensive testing demonstrated genetic stability has been performed at the end of production cells (EPC) derived from the MCB and WCB.

[0164] The route of synthesis as well as the process parameters and in-process controls of the intermediate are known in the art as described in various patents and patent applications as described in the present disclosure.

[0165] Example 2. Pl 101 Characterization. Ropeginterferon alfa-2b is a PEGylated recombinant human IFN alpha-2b with addition of an extra amino acid (proline) at the N- terminus. It is a long-acting interferon with only one major isoform in contrast to the 8-14 isomers of other PEGylated interferon products.

[0166] Characterization studies for the intermediate as well as for the active substance (AS) were performed with batches manufactured.

[0167] Interferon alfa-2 is a non-glycosylated polypeptide chain of 165 amino acid residues. Different types of alfa-2 interferon exist, varying in the amino acid residue at position 23. The selected one for this product is interferon alpha-2b, with arginine at position 23. Prolineinterferon alfa-2b contains an identical amino acid sequence to interferon alpha-2b plus an extra proline at the N-terminus (166 amino acid residues). Ropeginterferon alfa-2b is a PEGylated proline-interferon alfa-2b synthesized by conjugating a single approximately 40 kDa PEGylation molecule including two mPEG molecules, each having between about 19-23KD, to the N- terminal proline residue.

[0168] The structures of the intermediate and the active substance were elucidated using a variety of physico-chemical (e.g. peptide mapping, N- and C-terminal sequencing, electrophoretic and liquid chromatography-mass spectrometry analysis (LC-MS), SE-HPLC, RP- HPLC, IEX-HPLC, etc.), biophysical, and biological (cytopathic effect (CPE)-based potency assay and surface plasmon resonance (SPR) binding assay) techniques to provide a comprehensive understanding of their structure and functional properties and impurity profile.

[0169] The primary amino acid sequences were confirmed using peptide map and other known techniques. Molecular mass of the intact protein, extinction coefficient, and presence of disulfide bridges as well as secondary and tertiary structure profiles of sample and respectivereference batches were confirmed to be superimposable. Only one main PEGylation site was determined.

[0170] The primary sequence of was confirmed using peptide map / RP-HPLC / LC- MS / MS. Molecular mass of the intact protein, extinction coefficient, and presence of disulfide bridges as well as secondary and tertiary structure profiles of the sample and respective reference batches were confirmed to be superimposable. Only one main PEGylation site was determined; positional isomers, i.e. mono-PEGylated products with different PEGylation sites, were virtually non-existent.

[0171] Active substance’s (“AS”) biological characterization includes cytopathic effectbased potency assay (antiviral assay) and ligand / receptor binding assay. The antiviral bioassay was used while the ligand / receptor binding assay, intended for characterization use, monitors the binding affinity of AS intermediate active substance toward both chains (IFNAR1 and IFNAR2) of the Type I IFN receptor.

[0172] Example 3. Efficacy and Safety of Ropeginterferon alfa-2b (Pl 101) in Subjects with Recurrent / Refractory Adult T-cell Leukemia.

[0173] This example denotes the protocols, efficacy and safety of Pl 101 as a therapy for recurrent or refractory ATL of acute type, lymphoma type, or chronic type with poor prognostic factors.

[0174] A single-arm, open label, multicenter, uncontrolled example to evaluate the efficacy and safety of Pl 101 in subjects with relapsed / refractory ATL of acute, lymphoma, and chronic subtype with adverse prognostic factors are demonstrated. The example includes 2 parts: Part 1 and Part 2. When the achievement of primary endpoint and tolerability is confirmed in one or more subjects in Part 1, the subject proceeds to Part 2. If the patients in Part 1 respond and enter Part 2, a procedure can be established to withhold Part 2 when an event occurs that raises safety concerns and detects a significant signal for safety risks to ensure the safety of the subjects. Recruitment of subjects could continue until Part 1 reaches a maximum of 7 subjects and Part 2 reaches a total of 20 subjects together with Part 1. The primary endpoint are assessed at 4, 8, 12, 16, 24 weeks (or longer) after the first study treatment (Weeks 4, 8, 12, 16, and 24). The duration of study treatment varies from subject to subject because treatment continues until any of the discontinuation criteria described below.

[0175] This example comprises of a screening period, a dosing period, and a safety follow-up period for about 14 days from end of treatment. The initial evaluation period can be attimes between week 4-16 (or longer, such as 24 week, or longer) post initial Pl 101 administration. Administration can continue until any of the criteria for discontinuation occurs.

[0176] In this example, patients include subjects having ATL of acute, lymphoma, and chronic subtype with adverse prognostic factors according to the ATL diagnostic category who received at least one standard chemotherapy regimen after being diagnosed with ATL but refractory without achieving complete or a partial remission, recurred after achieving a complete remission / unconfirmed or a complete remission, or relapse after achieving a partial remission.

[0177] The inclusion and exclusion criteria for this example are established to exclude patients who may interfere with the efficacy and / or safety evaluation of Pl 101. Patients with complications and a history thereof, such as autoimmune diseases, neuropsychiatric diseases, ophthalmic diseases, diabetes mellitus and cancer, are excluded because Pl 101 treatment may exacerbate them. Patients with concerns about liver and kidney function are also excluded from this study. In addition, there have been reports of interstitial pneumonia due to the combination of IFN a preparations such as IFN a-2a and IFN a-2b with Xiao Chai Hu Yu (an herbal supplement), and from the viewpoint of safety, patients taking Xiao Chai Hu Yu at the time of screening are excluded. Furthermore, since hemoglobin levels and neutrophil counts are expected to decrease due to the cytoreductive effect of the investigational drug, anemia and susceptibility problems can be expected to occur if they are low at the time of screening, so they are excluded.

[0178] In order to participate, all of the following criteria must be met:1) Patients aged 18 years or older at the time with informed consent obtained.2) Patients with a diagnosis of peripheral lymphoid neoplasm by hematology or histopathology and proven to be T-cell derived from surface trait.3) Patients with positive anti-HTLV-1 antibodies.4) Patients with acute, lymphoma, and chronic subtype with adverse prognostic factors [ATL subtype can be diagnosed by using the Japanese Society of Hematology Practical Guidelines for Hematological Malignancies, 2023],5) Patients with at least one measurable lesion, either peripheral blood or skin lesion in the assessment performed within 28 days before the start of treatment.6) Patients diagnosed with ATL followed by at least one standard chemotherapy regimen but refractory without achieving a complete or a partial remission, recurred after achieving a complete remission / unconfirmed or a complete remission, or relapse after achieving a partial remission. Recurrence, Relapse, and Refractory are defined as follows:Recurrence: Reappearance of lesions after a complete remission or a complete remission / unconfirmed was achieved as a result of the most recent treatment.Relapse: Re-exacerbation of lesions after response to the most recent treatment and a partial remission was achieved.Refractory: Change of current treatment is required or exacerbation of lesions is observed after the stable condition was achieved as a result of the most recent treatment.7) Patients with ECOG PS of 0 to 2.8) Patients who have completed the previous treatment and at least 4 weeks (28 days) has passed since the completion of the previous treatment before the start day of Pl 101 treatment for ATL.9) Patients who meet the following criteria confirmed by the laboratory test at screening: a. Neutrophils >1 x 109 / L (not applicable in case of organ infiltration by ATL cells). b. Platelets >50 x 109 / L (not applicable in case of organ infiltration by ATL cells). c. Hemoglobin: >10 g / dL in female or >1 Ig / dL in male. d. AST and ALT: <3.0 x ULN (not applicable in case of organ infiltration by ATL cells). e. Total bilirubin: <1.5 x ULN (not applicable in case of organ infiltration by ATL cells). f. Serum creatinine: <1.5 x ULN.10) Males, females of childbearing potential, as well as all females <2 years from the onset of menopause, must agree to use an acceptable method of birth control during the treatment period and until 14 days following the last dose of the study drug. Also, females must agree not to breastfeed during the study.11) Patients who are expected to survive at least 3 months at the time informed consent is obtained.12) Patients who have received sufficient information on the contents of the study using the informed consent form and who have given written consent to participate in the study at their own discretion.

[0179] ECOG denoted in item 7 above are shown in Table 2 below.Table 2

[0180] Exclusion Criteria. Subjects who do not meet all of the inclusion criteria and who violate any of the exclusion criteria are not be allowed to participate.1) Patients with a history of treatment with IFN.2) Pregnant or lactating women. Women who may be pregnant or who may become pregnant who are unable or unwilling to use adequate contraception during the duration of administration of Pl 101 and for 14 days after the end of administration. Also, if a lactating woman is not willing to stop breastfeeding during the trial period.3) Patients with active concurrent overlapping carcinoma or metachronous overlapping carcinoma within 5 years (excluding cutaneous basal cell carcinoma, squamous cell carcinoma, carcinoma in situ carcinoma in situ judged to have been cured by topical treatment, and lesions equivalent to carcinoma in the mucosa).4) Self-owned hematopoietic stem cell transplant patients.5) Patients taking Xiao Chai Hu Yu, Xiao Chai Hu Yu plus Kakikyo Gypsum, Shiba Hu Katsura Bath, Shiba Yuan Bath, Shiba Pak Bath, or Shiba Tang Bath (all of which are herbal supplements) at the time of screening.6) Patients with central nervous system infiltration or clinical findings that make it suspicious.7) Patients with severe drug sensitivity or a history of hypersensitivity to P 1101.8) Patients participating in other investigational / clinical studies with treatment within 4 weeks prior to initiation of study drug administration or receiving another investigational drug.9) Patients with the following medical history or complications:a. Patients with or a history of autoimmune thyroid dysfunction. However, patients whose symptoms are stabilized with oral thyroid hormone replacement therapy who are not considered to cause additional harm to the patient may be included. b. Patients with a history or comorbidity of autoimmune disease (e.g., hepatitis, idiopathic thrombocytopenic purpura, scleroderma, psoriasis, or autoimmune arthritis).10) Patients with clinically significant pulmonary infiltrates, infectious pneumonitis, and non- infectious pneumonitis at screening, or patients with a history of interstitial pneumonitis11) Patients with active infections that cannot be controlled with antibiotics or antifungals. HIV antibody positive patients with gender, HBsAg positive, HBs antibody positive, HBc antibody positive, and HCV antibody positive. HBs antibody positive or Patients who are HBc antibody positive and whose HBV-DNA quantitative test results are below the detection sensitivity may be eligible for registration.12) Patients with severe retinopathy (cytomegaloviral retinitis, macular degeneration, etc.) or clinically significant ophthalmic disease (due to diabetes or hypertension) based on the evaluation of an ophthalmologist.13) Patients who are judged by the investigator to have uncontrolled depression.14) Patients with a history of suicide attempts or at risk of suicide at screening.15) Patients with uncontrolled diabetes mellitus (HbAlc >7% at screening).16) Patients with a history of alcohol or drug abuse within the past 1 year from the time of obtaining consent.17) Other patients who are judged by the investigator to be inappropriate for the safe conduct of this clinical trial.

[0181] In this example, OS is measured as the period from the date of initiation of Pl 101 administration to the date of death from any cause; TTF is the date of determination of recurrence (RD) / disease progression (PD) from the date of start of study drug administration, date of death due to any cause, or the period until the date of discontinuation of Pl 101, whichever is earlier; DCR is "Best Overall Response" obtainable at 16 weeks (or longer, such as 20 weeks, 24 weeks, or longer) after initiation of Pl 101 administration and can be expressed as CR, CRu, PR as the proportion of patients with stable medical condition (SD).

[0182] The proportion of patients (who responded) is calculated by disease type (acute type, lymphoma type, chronic type with poor prognostic factors). Administration of the Pl 101 drug is continued until one of the discontinuation criteria is met or as determined by a physician.

[0183] Two subcutaneous administrations every week at a starting dose of 250 pg (Day 1) and at a dose of 500 pg from week 2 onwards can be administered. Any concern about safety or tolerability, the dose is adjusted up or down as determined by a physician or according to the dosage adjustment shown below.

[0184] The study period consists of a screening period, a dosing period, and a safety follow-up period. The screening period can be up to 28 days. The primary evaluation period can be at Week 4, Week 8, Week 12, and / or Week 16 (or longer, such as week 20, week 24, or longer) from the date of initiation of drug administration. The safety follow-up period can be at the end of Pl 101 administration. Evaluation includes the following as listed in Table 3 below.Table 3*The assessment at the points marked with (X) are performed only when the investigators judge it clinically necessary.1. Vital signs: body temperature, blood pressure, pulse rate and respiratory rate.2. In re-staging, the same methods as prior study treatment (screening or baseline) should be used for assessment. Plain CT is acceptable if the contrast medium cannot be used due to a history of allergy to the contrast medium or if the lesion can be assessed by non-contrast CT. If other imaging is deemed necessary for evaluation due to the type of lesion or other factors, other imaging may be additionally performed (e g., MRI, FDG-PET / CT).3. To be performed every 8 weeks or when RD / PD is suspected during the continuation period.4. If infiltration is suspected under the endoscope (ulcerative lesions, elevated lesions, etc.), the presence of lymph node cell infiltration by biopsy should be confirmed if necessary.5. To avoid inter-evaluator variation, the evaluation of lesion in each subject is, in principle, performed consistently by the same physician.6. To be performed when tumor lesions are observed on the skin. A pathological diagnosis by biopsy should be performed when necessary in case tumor lesions are observed on the skin or when it is difficult to make a diagnosis by visual examination.7. To be performed in the subjects who were “positive” or “uncertain” of bone marrow infiltration as the result of bone marrow examination (bone marrow aspiration or bone marrow biopsy) prior to study treatment only when the subject may have achieved CR or CRu as an overall response based on the other assessment [contrast-enhanced CT, upper endoscopy (lower endoscopy as needed), assessment of peripheral blood lesion, skin lesions] except bone marrow examination. To be also assessed when bone marrow infiltration is suspected, such as cytopenia inconsistent with the clinical course or appearance of abnormal cells suggestive of lymphoma cells in peripheral blood. Flow cytometry findings alone cannot conclude positive result, but it should be positioned as an aid to diagnosis in cellular form.8. Not required to repeat the test on Day 1 if it is performed within 7 days prior to Day 1.9. Blood samples will be collected from subjects who agree to participate in the exploratory research of this study.10. Urine pregnancy test should be performed for all females of childbearing potential or have been <2 years post-menopausal. A blood pregnancy test is acceptable if a urine pregnancy test cannot be performed.11. Ophthalmological examination: visual acuity assessment, slit lamp examination, tonometry and fundus examination. When the fundus examination is performed after screening or baseline, measurements should be taken under the same conditions throughout the study period. In addition to the specified tests, ophthalmologist will interview all subjects who complain of deterioration in visual acuity or dark spots in the visual field.12. The study drug should be administered every 2 weeks at an initial dose of 250 pg (Day 1) and 500 gg after Week 2. All assessments at each visit should be completed prior to administration of study drug.

[0185] Pl 101 are delivered in a prefilled syringe filled with 500 gg Pl 101. The prefilled syringe consists of a 1 mL capacity Type I glass syringe consisting of a luer tip cap (with adapter) and a plunger stopper. Included with a disposable safety injection needle. Each prefilled syringe has a 1.1 mL of Pl 101 formulation solution is filled to ensure the volume of 1.0 mL.

[0186] Patients in whom the "best overall response" obtained during the 12, 16, 20, or 24 weeks after the start of treatment is CR, CRu, or PR are determined as responders, and the response proportion (RP) are determined.

[0187] Overall survival (OS), time to treatment failure (TTF), disease control rate (DCR), response rate by disease type, and incidence and severity of adverse events are also determined.

[0188] The duration of administration is defined as the period from the date of commencement of study drug administration to the end of study drug administration (discontinuation).

[0189] Dose and Dose Adjustments. Pl 101 are administered subcutaneously every 2 weeks at an initial dose of 250 pg (Day 1) and the dose will be increased to 500 gg after Week 2.

[0190] Dose reduction to 350 gg of Pl 101 can occur when there are concerns about the safety and tolerability for a patient. The dose can be further reduced to 250 gg. When Pl 101 related AE occurs at the dose of 500 gg and it is difficult to ensure the safety or tolerability, the dose of the study drug can be reduced or discontinued according to the procedure denoted in this example. If the subject recovers, dosage can be increased to 500 gg. When subject does not recover from the AE even after the dose reduction or treatment interruption, the treatment for the subject can be suspended and / or terminated.

[0191] For a subject experiencing a severe (Grade 3 or 4 based on CTCAE v5.0) AE or absolute neutrophil count (ANC) decrease to <0.5 x 109 / L, treatment are temporarily suspended / interrupted until recovery to a condition that allows resumption of the treatment (e.g., Grade 1 mild), treatments can restart / resume with a dose of 350 gg. The resume dose of 350 gg can be reduced to 250 gg if relapse occurs. If relapse occurs even at the dose of 250 gg, the treatment for the subject can be discontinued.

[0192] A dose reduction without interruption are considered if a subject experiences Grade 2 AE or a decrease in ANC to <0.75 x 109 / L (but >0.5 x 109 / L). For Grade 1 AE, dose reduction or treatment interruption should not occur.

[0193] Prohibited Drugs / Concomitant Therapy. During the period from the time of obtaining consent to the time of EoT, the following combinations are prohibited: other anticancer drugs, IFNs, reverse transcriptase inhibitors (e.g., zidovudine), corticosteroids (Treatment for hypersensitivity, topical or inhaled corticosteroids, or topical agents used for skin lesions before obtaining informed consent are acceptable), radiation therapy, UV radiation therapy for skin lesions, investigational products other than the study drug used in this clinical (for other clinical trials), (At screening visit) Sho-saiko-to (herbal supplement), Sho-saiko-to-kakyo-sekko (herbal supplement), Saiko-keishi-to (herbal supplement, Sairei-to (herbal supplement), Saiboku-to (herbal supplement), and Saiboku-to (herbal supplement).

[0194] Drugs other than prohibited drugs / prohibited therapies are acceptable. In this example, the following combinations are allowed: Fluconazole, etc.: for prevention against fungal infections. ST combination (sulfamethoxazole and trimethoprim preparations): for prevention of pneumocystis pneumonia. Paracetamol (acetaminophen) or non-steroidal antiinflammatory drugs (NSAIDs): for prophylaxis against influenza-like symptoms (8~10 hours after the start of study drug administration, 24 hours and 48 hours). Chlorphenamine (chlorpheniramine) and other antihistamines (used as a single agent or combination): for the prevention and treatment of injection site reactions associated with PEGylated IFN.

[0195] Treatment Discontinuation. The treatments are discontinued when any of the following criteria are met: Pl 101 related adverse events (e.g., AE of Grade 3 or 4, or decrease of ANC to <0.5 x 109 / L) develop but do not resolve from AE even after treatment suspension / interruption; AEs meeting the discontinuation criteria occur despite dose reduction of the study drug ; elevation of liver enzymes (ALT, AST, GGT) considered clinically significant despite dose reduction of Pl 101 or accompanied by elevation of total bilirubin; in the event that persistent or unexplained pulmonary infiltration or pulmonary dysfunction occurs during the treatment period; severe retinopathy (cytomegalovirus retinitis, macular degeneration, etc.) or clinically significant ophthalmic disorder (due to diabetes mellitus or hypertension) occurred during the treatment period; it is judged that the subject's underlying disease has deteriorated; the subject requests to discontinue the study treatment; significant protocol violations are identified, or it is judge that the difficultly to continue the treatment defined by the protocol is high.

[0196] Pl 101 treatment cannot be resumed after the treatment interruption period exceeds 8 weeks because of the onset of adverse events specified in the interruption criteria (Grade 3 or 4severe toxicity or a drop in ANC to below 0.5* 109 / L), or an adverse event that meets the interruption criteria occurs despite dose reduction, or the primary disease is exacerbated, or the investigator determines that the continuation of the protocol treatment is difficult due to adverse events, or the subject requests to discontinue treatment or withdraws consent, or the investigator judges it difficult to continue the protocol treatment for other reasons.

[0197] Efficacy Determination. The primary efficacy endpoint is RP obtained up to 16, 20, 24, 28 or longer weeks after initiation of study drug. RP is defined as having a "Best Overall Response" of CR, CRu, defined as the proportion of patients with PR (respondents). The primary assessment were conducted at weeks 4, 8, 12, 16, 20, 24 and 28 (Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, and Week 28, or longer).

[0198] The overall effectiveness are measured or determined as follows as shown in Table 4 below.Table 4

[0199] 1. Provided that <5% of flow cell remains, it is considered to be normal if the absolute lymphocyte count, including flower cells, is <4 x 109 / L.

[0200] 2. Calculated by the sum (cm2) of the products of the longest and shortest diameters (cm) of measurable disease on CT image.

[0201] 3. Defined by >50% increase from nadir in the sum of the product measurable disease.

[0202] 4. Defined by >50% increase from nadir in the sum of flower cells and an absolute lymphocyte count, including flower cells, of >4 x 109 / L.

[0203] In this example, biomarkers are also examined for the relationship between the safety and efficacy endpoints of Pl 101 using patient background information and blood samples. Participation with the following known biomarkers is mandatory, and blood samples are collected from subjects who have consented to participate in the trial. Known biomarkers: Soluble IL-2 receptors, Abnormal lymphocyte count, Serum albumin, LDH, and / or BUN (Blood urea nitrogen).

[0204] Immunogenicity assessment. Immunogenicity assessment specimens are collected for the purpose of evaluating ADA for Pl 101. Blood samples for ADA analysis in serum for Pl 101 are collected from all subjects who have received Pl 101 and are measured at a central laboratory. Table 5 denotes the blood assessments.Table 51. HbAlc is measured only at screening.2. A multi-tiered test that consists of Pl 101 binding antibody assay and confirmatory test, antibody titer test, and Pl 101 neutralizing antibody test will be used.3. HBV-DNA quantitative tests will be performed for a subject with HBs antibody-positive or HBc antibody-positive.4. Blood pregnancy test is acceptable if urinary pregnancy test cannot be performed.

[0205] Statistical methods are applied to the primary and secondary endpoints. The analysis of categorical values is summarized in frequency, percentage, and 95% confidence intervals. Continuous variables display the total number (n), mean, standard deviation, median, minimum and maximum values.

[0206] Statistical analysis is performed using SAS software or other valid statistical software, as appropriate. The details of the statistical analysis are described in a separate statistical analysis plan (SAP) and signed before the first database lock.Example 4. Clinical Efficacy.

[0207] Subjects are enrolled using protocol and criteria as described in Example 3.

[0208] The primary efficacy endpoint is RP obtained by 16 weeks, week 20, and / or week 24, after initiation of study treatment. The RP is defined as proportion of patients (responders) who achieved CR, CRu, or PR as the "Best Overall Response" during the first 16-24 weeks (or longer) of study treatment. The evaluation occurr at 4, 8, 12, 16, 20, 24 weeks after the first treatment (Weeks 4, 8, 12, 16, 20, and 24).

[0209] A method based on the binomial distribution are were used to calculate RP and its two-sided 90% confidence interval (which is equivalent to a one-sided 95% confidence interval) in the FAS population.

[0210] The accurate test based on a binomial distribution is used to determine if the response rate is greater than 5% by significance level of a one-sided 5%.

[0211] Results show that at least one or more subjects demonstrated Pl 101 can be used to treat, slow the progression, increase OS, change or improve the categorization of ATL disease (CR / Cru / PR / PFS / DFS), and / or prevent ATL, and / or decrease AE on a subject having relapsed and / or refractory (r / r) ATL. Additionally or alternatively, the Pl 101 can be used to treat, slow the progression, increase OS, change or improve the categorization of ATL disease (CR / Cru / PR / PFS / DFS), and / or prevent ATL, and / or decrease AE on a subject having acute, lymphoma, chronic subtypes, and / or smoldering ATL.Example 5 Additional Clinical Efficacy.

[0212] A clinical trial was conducted with patients using the same protocol illustrated in the present disclosure, such as enrollment, screening, discontinuation, safety, hematology, AE...etc. criteria. With 4 patients initially enrolled, 1 failed initial screening and 1 patient was discontinued as shown in Figure 3. The Efficacy / Safety assessments incidents for 3 patients (including the later discontinued one) were listed in Table 6 below.Table 6

[0213] Two subject who was diagnosed with having Recurrence or Relap se / Refractory of Aggressive acute ATL was administered with Pl 101 at initial baseline, week 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 with 250 ug at initial baseline, a second dosage of 350ug , followed by subsequent multiple dosages of constant 500 ug of Pl 101 injection every two weeks for the remaining duration.

[0214] The overall response of the anti-rumor effects of one patient was listed in Table 7 below. The data were thoroughly reviewed by IDMC, which stands for Independent Data Monitoring Committee, and the final determination from IDMC was that anti-tumor overall response was confirmed to be PR, as defined above in the present disclosure. Details are shown below in Table 7.Table 7

[0215] In addition, a second patient also exhibited PR against ATL at week 24 post initial Pl 101 administration following the 250-350-500 administration scheme every 2 weeks, with continuous constant 500ug dose after the 3rdadministration also at every two weeks.

[0216] These real-life examples and treating ATL patients demonstrated with solid data such as from Table 7 which clearly showed that Pl 101 is effective in human clinical trial and has anti-rumor effects against ATL, which can be reached PR as soon as week 4, 16, and / or 24.

[0217] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure.

[0218] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the disclosure. The principal features of this disclosure can be employed in various embodiments without departing from the scope of the disclosure. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein.

[0219] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0220] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives onlyor the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0221] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0222] The term “or combinations thereof’ as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof’ is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0223] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure.

Claims

What is claimed is:

1. A method of treating, preventing, slowing the progression, inhibiting and / or ameliorating a subject or subject in need who has one or more diseases as a result of human T cell lymphotropic virus I infection (HTLV-1) , the method comprising administering to said subject or subject in need thereof an effective amount of a composition including ropeginterferon alfa-2b with the structure:wherein each mPEG includes between about 19 to about 23 KDa, or a pharmaceutical formulation thereof.

2. The method according to claim 1, wherein said one or more diseases as a result of HTLV- 1 infection comprises oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases, endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder.

3. The method according to claim 1, wherein said oncological diseases comprises adult T- cell leukemia / lymphoma (ATL), cervical cancer, and / or non-Hodgkin lymphoma, wherein said cardiovascular diseases comprise damage to the heart valve, atherosclerosis, and / or hypertension, wherein said respiratory diseases comprise pulmonary inflammation, interstitial pneumonias, bronchiolitis and alveolitis, diffuse panbronchiolitis or bronchiectasis, and / or interstitial pneumonia, wherein said skin diseases comprise infectious dermatitis, chronic recurrent infected eczema, lymphadenopathy, persistent hyperreflexia, and / or gait disturbances, wherein said disease of the musculoskeletal system comprises tenosynovitis, wherein said neurological diseases comprise HTLV-1 -associated myelopathy / tropical spastic paraparesis (HAM / TSP), acute myelopathy, encephalopathy, and / or myositis,wherein said rheumatic diseases comprise rheumatoid arthritis (RA), Sjogren’s syndrome, and / or polymyositis, wherein said endocrinological diseases comprise hypothyroidism and / or hyperthyroidism, wherein said eye inflammation comprises HTLV-1 -associated Uveitis (HU), wherein said ophthalmic diseases comprise keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, and / or ophthalmological manifestations associated with ATL in adults, wherein said diseases of the genitourinary system comprise urinary dysfunction, and wherein said mental disorder comprises depression.

4. The method according to claim 1, wherein said one or more diseases as a result of human T cell lymphotropic virus infection comprises adult T-cell leukemia / lymphoma (ATL).

5. The method according to claim 4, wherein said ATL comprises acute, lymphoma, chronic, and / or smoldering ATL subtype.

6. The method according to claim 4, wherein said subject has relapsed and / or refractory ATL and / or unfavorable chronic ATL.

7. The method according to claim 1, wherein said ropeginterferon alfa-2b is formulated into a pharmaceutical composition comprising a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, a pharmaceutically acceptable adjuvant, a diluent, and / or or carrier.

8. The method according to claim 7, wherein said ropeginterferon alfa-2b pharmaceutical composition is administered via an injection to said subject or subject in need.

9. The method according to claim 8, wherein said injection is administered subcutaneously.

10. The method according to any of the claims 1-9, wherein the effective amount of said ropeginterferon alfa-2b or said pharmaceutical composition comprises between about 50 to 540 ug of ropeginterferon alfa-2b administered every 1, 2, 3, 4, 5, or 6 weeks.

11. The method according to any of the claim 1-9, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical composition comprises a first initial dosage, a second dosage, a third dosage, and / or one or more subsequent dosages of ropeginterferon alfa-2b administered every 1, 2, 3, 4, 5, or 6 weeks.

12. The method according to claim 11, wherein the first initial dosage of said ropeginterferon alfa-2b or pharmaceutical composition comprises about 250 pg, the second dosage comprises between about 250 pg to 500 pg, and the third dosage and / or the one or more subsequent dosage comprises between about 350 pg to 500 pg of ropeginterferon alfa-2b or pharmaceutical composition thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

13. The method according to any of the claims 1-9, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical composition comprises a first initial dosage of between about 250 pg to about 500 pg of said ropeginterferon alfa-2b or pharmaceutical composition thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

14. The method according to claim 11, wherein the second, the third dosage and the one or more subsequent dosage is maintained about at the same amount or constant amount administered every 1, 2, 3, 4, 5, or 6 weeks during a treatment period.

15. The method according to any of the claims 1-9 and 14, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical composition comprises the subject being administered a first initial dosage comprises between about 50 to 250 pg administered every 1, 2, 3, 4, 5, or 6 weeks; and a third dose or subsequent dose of the ropeginterferon alfa-2b or pharmaceutical composition at between about 2 to 16 weeks, at between about 2 to 24 weeks, or longer, administered every 1, 2, 3, 4, 5, or 6 weeks, after a second dose without an intervening dose, wherein the third dose being between about 50 pg to 300 pg higher than the second dose.

16. The method according to any of the claims 1-9, 12 and 14, wherein the effective amount of the ropeginterferon alfa-2b or pharmaceutical composition comprises a first initial dosage including about 250 pg, a second dosage including between about 250 pg to 500 pg, and optionally one or more subsequent dosages at a constant or variable amount of ropeginterferon alfa-2b or pharmaceutical composition administered every 1, 2, 3, 4, 5, or 6 weeks.

17. The method according to any of the claims 1-9, 12 and 14, wherein said ropeginterferon alfa-2b or pharmaceutical composition is administered for a period of between about 0 to 8 weeks, between about 0 to 16 weeks, between about 0 to 24 weeks, between about 0 to 32 weeks, between about 0 to 52 weeks, or longer than 52 weeks, wherein the frequency is administered every 1, 2, 3, 4, 5, or 6 weeks.

18. The method according to any of the claims 3-6 , wherein said method’s therapeutic effect to said subject exhibits slowing the progression, increase OS, change or improve the categorization of ATL disease (CR / Cru / PR / PFS / DFS / TTF / DCR), and / or decrease in ATL remission / relapse rate.19 The method according to any of the claims 1-9, wherein said method decreases said subject’s progression of HTLV-1 infection associated disease, decrease in tumor size and / or AE rate.

20. The method according to any of the claims 1-9, 12 and 14, wherein said ropeginterferon alfa-2b is administrated along with: chemotherapy, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine, zidovudine plus interferon-alfa, Tucodonosat, Everolimus, Parsaclisib, Palbociclib, Alvocidib, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530.

21. A use of the substantially homogenous composition or pharmaceutical formulation thereof comprises ropeginterferon alfa-2b having the structure of formula I(Formula I) for the preparation of a medicament for the treatment of one or more conditions as a result of human T cell lymphotropic virus I (HTLV-1) infection in a subject, wherein each mPEG includes between about 19 to about 23 KDa.

22. The use of claim 21, wherein said one or more conditions as a result of HTLV-1 infection comprises oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases, endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder.23 The use of claim 21, wherein said one or more conditions as a result of human T cell lymphotropic virus infection comprises ATL.

24. The use of claim 21, wherein said subject has relapsed and / or refractory ATL, and / or unfavorable chronic ATL.

25. The use of claim 22, wherein said oncological diseases comprises ATL, cervical cancer, and / or non-Hodgkin lymphoma,wherein said cardiovascular diseases comprise damage to the heart valve, atherosclerosis, and / or hypertension, wherein said respiratory diseases comprise pulmonary inflammation, interstitial pneumonias, bronchiolitis and alveolitis, diffuse panbronchiolitis or bronchiectasis, and / or interstitial pneumonia, wherein said skin diseases comprise infectious dermatitis, chronic recurrent infected eczema, lymphadenopathy, persistent hyperreflexia, and / or gait disturbances, wherein said disease of the musculoskeletal system comprises tenosynovitis, wherein said neurological diseases comprise HTLV-1 -associated myelopathy / tropical spastic paraparesis (HAM / TSP), acute myelopathy, encephalopathy, and / or myositis, wherein said rheumatic diseases comprise rheumatoid arthritis (RA), Sjogren’s syndrome, and / or polymyositis, wherein said endocrinological diseases comprise hypothyroidism and / or hyperthyroidism, wherein said eye inflammation comprises HTLV-1 -associated Uveitis (HU), wherein said ophthalmic diseases comprise keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, and / or ophthalmological manifestations associated with ATLL in adults, wherein said diseases of the genitourinary system comprise urinary dysfunction, and wherein said mental disorder comprises depression.

26. The use according to claim 21, wherein said substantially homogenous composition or pharmaceutical formulation comprises a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, a pharmaceutically acceptable adjuvant, a diluent, and / or or carrier.

27. The use according to claim 21, wherein said substantially homogenous composition or pharmaceutical formulation is administered via an injection to said subject or subject in need.

28. The use according to claim 27, wherein said injection is administered subcutaneously.

29. The use according to any of the claims 21-28, wherein the effective amount of said ropeginterferon alfa-2b or said pharmaceutical formulation comprises between about 50 to 540 ug of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

30. The use according to any of the claims 21-28, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical formulation thereof comprises a first initial dosage, a second dosage, a third dosage, and / or subsequent dosage of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

31. The use according to claim 30, wherein the first initial dosage of said ropeginterferon alfa-2b or pharmaceutical formulation thereof comprises about 250 pg, the second dosage comprises between about 250 pg to 500 pg, and the third dosage and / or the subsequent dosage comprises between about 350 pg to 500 pg of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

32. The use according to any of the claims 21-28, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical formulation thereof comprises a first initial dosage of between about 250 pg to about 500 pg of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

33. The use according to claim 30, wherein the second, third dosage and subsequent dosage is maintained constant during a treatment period administered every 1, 2, 3, 4, 5, or 6 weeks.

34. The use according to any of the claims 21-28 and 33, wherein the effective amount of said ropeginterferon alfa-2b or pharmaceutical formulation thereof comprises the subject being administered a first initial dosage comprises between about 50 to 250 pg administered every 1, 2, 3, 4, 5, or 6 weeks; and a third dose or subsequent dose of the ropeginterferon alfa-2b or pharmaceutical formulation thereof at between about 2 to 16 weeks, between about 2 to 24 weeks, or longer, after a second dose without an intervening dose, wherein the third dose being between about 50 pg to 300 pg higher than the second dose administered every 1, 2, 3, 4, 5, or 6 weeks.

35. The use according to any of the claims 21-28, 31 and 33, wherein the effective amount of the ropeginterferon alfa-2b or pharmaceutical formulation thereof comprises a first initial dosage including about 250 pg, a second dosage including between about 250 pg to 500 pg, and optionally subsequent dosages at a constant or variable amount of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

36. The use according to any of the claims 21-28, 31 and 33, wherein said ropeginterferon alfa-2b or pharmaceutical formulation thereof is administered for a period of between about 0 to 8 weeks, between about 0 to 16 weeks, between about 0 to 24 weeks, between about 0 to 32 weeks, between about 0 to 52 weeks or longer than 52 weeks with administration frequency of every 1, 2, 3, 4, 5, or 6 weeks.

37. The use according to any of the claims 23-25, wherein said use’s therapeutic effect to said subject exhibits slowing the progression, increase OS, change or improve the categorization of ATL disease (CR / Cru / PR / PFS / DFS / TTF / DCR), and / or decrease in ATL remi s si on / rel apse rate.

38. The use according to any of the claims 21-28, 31 and 33, wherein said use decreases said subject’s progression of HTLV-1 infection associated disease, decrease in tumor size and / or AE rate.

39. The use according to any of the claims 21-28, 31 and 33, wherein said ropeginterferon alfa-2b or pharmaceutical formulation thereof is administrated along with: chemotherapy, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine, zidovudine plus interferon-alfa, Tucodonosat, Everolimus, Parsaclisib, Palbociclib, Alvocidib, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530.

40. A pharmaceutical composition for the treatment of one or more conditions as a result of human T cell lymphotropic virus I (HTLV-1) infection in a subject comprising ropeginterferon alfa-2b having the structure of formula I(Formula I) or a pharmaceutical formulation thereof, wherein each mPEG includes between about 19 to about 23 KDa.

41. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 40, wherein said one or more diseases as a result of HTLV-1 infection comprises oncological diseases, myelopathy / tropical spastic paraparesis, cardiovascular diseases, respiratory diseases, skin diseases, lymphadenopathy, diseases of the musculoskeletal system, neurological diseases, rheumatic diseases, endocrinological diseases, inflammation and tumorigenesis, eye inflammation, ophthalmic diseases, diseases of the genitourinary system and / or mental disorder.

42. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 41, wherein said oncological diseases comprises ATL, cervical cancer, and / or nonHodgkin lymphoma,wherein said cardiovascular diseases comprise damage to the heart valve, atherosclerosis, and / or hypertension, wherein said respiratory diseases comprise pulmonary inflammation, interstitial pneumonias, bronchiolitis and alveolitis, diffuse panbronchiolitis or bronchiectasis, and / or interstitial pneumonia, wherein said skin diseases comprise infectious dermatitis, chronic recurrent infected eczema, lymphadenopathy, persistent hyperreflexia, and / or gait disturbances, wherein said disease of the musculoskeletal system comprises tenosynovitis, wherein said neurological diseases comprise HTLV-1 -associated myelopathy / tropical spastic paraparesis (HAM / TSP), acute myelopathy, encephalopathy, and / or myositis, wherein said rheumatic diseases comprise rheumatoid arthritis (RA), Sjogren’s syndrome, and / or polymyositis, wherein said endocrinological diseases comprise hypothyroidism and / or hyperthyroidism, wherein said eye inflammation comprises HTLV-1 -associated Uveitis (HU), wherein said ophthalmic diseases comprise keratoconjunctivitis sicca, interstitial keratitis, optic neuritis, and / or ophthalmological manifestations associated with ATLL in adults, wherein said diseases of the genitourinary system comprise urinary dysfunction, and wherein said mental disorder comprises depression.

43. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 40, wherein said one or more diseases as a result of human T cell lymphotropic virus infection comprises adult T-cell leukemia / lymphoma (ATL).

44. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 43, wherein said ATL comprises acute, lymphoma, chronic, and / or smoldering ATL subtype.

45. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 43, wherein said subject has relapsed and / or refractory ATL and / or unfavorable chronic ATL.

46. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 40, wherein said pharmaceutical composition or pharmaceutical formulation comprises a pharmaceutically acceptable carrier, salt, a solvate or prodrug thereof, a pharmaceutically acceptable adjuvant, a diluent, and / or or carrier.

47. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 40, wherein said pharmaceutical composition or pharmaceutical formulation is administered via an injection to said subject or subject in need.

48. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 47, wherein said injection is administered subcutaneously.

49. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, wherein the effective amount of said pharmaceutical composition or said pharmaceutical formulation comprises between about 50 to 540 ug of ropeginterferon alfa-2b administered every 1, 2, 3, 4, 5, or 6 weeks.

50. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, wherein the effective amount of said pharmaceutical composition or pharmaceutical formulation thereof comprises a first initial dosage, a second dosage, a third dosage, and / or subsequent dosage of ropeginterferon alfa-2b administered every 1, 2, 3, 4, 5, or 6 weeks.

51. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 50, wherein the first initial dosage of said pharmaceutical composition or pharmaceutical formulation thereof comprises about 250 pg, the second dosage comprises between about 250 pg to 500 pg administered every 1, 2, 3, 4, 5, or 6 weeks, and the third dosage and / or the subsequent dosage comprises between about 350 pg to 500 pg of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

52. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, wherein the effective amount of said pharmaceutical composition or pharmaceutical formulation thereof comprises a first initial dosage of between about 250 pg to about 500 pg of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

53. The pharmaceutical composition or pharmaceutical formulation thereof according to claim 50, wherein the second, third dosage and subsequent dosage is maintained constant during a treatment period administered every 1, 2, 3, 4, 5, or 6 weeks.

54. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48 and 53, wherein the effective amount of said pharmaceutical composition or pharmaceutical formulation thereof comprises the subject being administered a first initial dosage comprises between about 50 to 250 pg; anda third dose or subsequent dose of the pharmaceutical composition or pharmaceutical formulation thereof at between about 2 to 16 weeks, between about 2 to 24 weeks, or longer, administered every 1, 2, 3, 4, 5, or 6 weeks, after a second dose without an intervening dose, wherein the third dose being between about 50 pg to 300 pg higher than the second dose administered every 1, 2, 3, 4, 5, or 6 weeks.

55. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, 51 and 53, wherein the effective amount of the pharmaceutical composition or pharmaceutical formulation thereof comprises a first initial dosage including about 250 pg, a second dosage including between about 250 pg to 500 pg administered every 1, 2, 3, 4, 5, or 6 weeks, and optionally subsequent dosages at a constant or variable amount of ropeginterferon alfa-2b or pharmaceutical formulation thereof administered every 1, 2, 3, 4, 5, or 6 weeks.

56. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, 51 and 53, wherein said pharmaceutical composition or pharmaceutical formulation thereof is administered for a period of between about 0 to 8 weeks, between about 0 to 16 weeks, between 0 to 24 weeks, between about 0 to 32 weeks, between about 0 to 52 weeks or longer than 52 weeks administered every 1, 2, 3, 4, 5, or 6 weeks.

57. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 42-48, wherein said pharmaceutical composition or pharmaceutical formulation’s therapeutic effect to said subject exhibits slowing the progression, increase OS, change or improves the categorization of ATL disease (CR / Cru / PR / PFS / DFS / TTF / DCR), and / or decrease in ATL remission / relapse rate.

58. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, 51 and 53, wherein said pharmaceutical composition or pharmaceutical formulation decreases said subject’s progression of HTLV-1 infection associated disease decrease in tumor size and / or AE rate.

59. The pharmaceutical composition or pharmaceutical formulation thereof according to any of the claims 40-48, wherein said pharmaceutical composition or pharmaceutical formulation is administrated along with: chemotherapy, Tobinai, Clofarabine, Pralatrexate + Romidepsin, Mogamulizumab, Daclizumab, Brentuximab, Alemtuzumab, Bortezomib, Bortezomib + EPOCH and raltegravir, Carfilzomib, Alisertib, Alisertib + Vorinostat, Lenalidomide, TAX DC vaccine, THV-02, IMTOX-25, LMB-2 + Fludarabine and cyclophosphamide, zidovudine, zidovudine plus interferon-alfa, Tucodonosat, Everolimus, Parsaclisib, Palbociclib, Alvocidib, Ruxolitinib, Panobinostat, Pembrolizumab, and / or RP6530.

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