Classifications

• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q10/00—Administration; Management
  • G06Q10/10—Office automation; Time management
• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q40/00—Finance; Insurance; Tax strategies; Processing of corporate or income taxes
  • G06Q40/08—Insurance
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
  • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
  • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

• Specialty drugs are widely administered to treat a wide variety of diseases and disorders including, e.g., oncology indications, autoimmune diseases, inflammatory disorders, microbial infections, rare diseases, and ultra-rare diseases.
• Achieving excellent clinical outcome, i.e., excellent therapeutic response or clinical remission of the disease, in a subject treated with a specialty drug leads to significantly better economic outcomes for payers, employers, pension funds, and patients.
• An effective and practical treatment model which could provide information as to whether an individual patient will or will not be responsive to a specialty drug therapy would be desirable for several reasons, including avoidance of delays in alternative treatments, elimination of exposure to adverse effects, and reduction of unnecessary treatment expenses.
• achieving efficiency in the healthcare delivery process of a specialty drug will result in significant reduction of overall healthcare spending.
• the methods, processes, reagents, and kits presented herein address these inefficiencies.
• Methods and processes of healthcare delivery and treatment are provided, particularly for achieving better economic outcomes in patients treated with specialty drugs.
• Methods, processes, and kits provide several uses, e.g., for providing therapeutic guidance, for providing therapeutic efficacy assurance, for providing product differentiation of a specialty drug, for delivering drugs from a pharmaceutical company to patient through a novel healthcare delivery platform, etc.
• the present invention is based, in part, upon the observation that achieving better clinical outcomes to specialty drug treatment in mechanistically stratified or targeted subset(s) of patient(s) can lead to better economic outcomes for payers, employers, pension funds, patients, dependents, and families.
• Theragnostic guidance can be a key factor in providing therapeutic efficacy assurance to stakeholders.
• the present invention is based upon the additional observation that major inefficiencies in healthcare supply chain and delivery model can be addressed by integrating and streamlining key processes pertaining to healthcare delivery and treatment.
• the present inventions provide several novel aspects of healthcare delivery, treatment, and payment model for specialty drugs.
• the first is a method providing assurance for a specialty drug treatment, comprising selecting a specialty drug by a theragnostic evaluation of a patient for treatment of a chronic disease or disorder; and providing efficacy assurance or financial assurance.
• the method provides both efficacy assurance and financial assurance; or the chronic disease or disorder is subject to theragnostic evaluation, specialty drug treatment, and efficacy assurance.
• the method further comprises: selecting the specialty drug from a panel of available drugs in a drug formulary; treating the patient with an appropriate specialty drug; and/or achieving better than about 70%, e.g., 80, 90, or 95%, patient therapeutic adherence.
• the method is applied to a plurality of individual patients, including a disease population or subset(s) of patients.
• the theragnostic evaluation provides, typically prospectively: therapeutic appropriateness in the patient or group of patients; therapeutic guidance in the patient or group of patients; and/or therapeutic effectiveness in the patient or group of patients; often also with selection of an alternative therapeutic strategy, e.g., if there are contraindications (e.g., pharmacological or mechanism problems in the patient) or the first strategy fails.
• the theragnostic will further be directed to further provide efficacy assurance, financial assurance, prior authorization or payment approval, and/or providing guidelines in developing a disease specific drug formulary.
• the disease or disorder is an oncology indication, an autoimmune disease, an inflammatory disorder, a rare disease, or a microbial infection
• the oncology indication is B-cell non-Hodgkin's lymphoma (B-NHL)
• B-NHL B-cell non-Hodgkin's lymphoma
• the autoimmune disease is rheumatoid arthritis
• the inflammatory disorder is relapsing-remitting multiple sclerosis
• the microbial infection is hepatitis C viral infection.
• the theragnostic evaluation further: stratifies a disease population into one or more distinct subsets based on immunological subtype(s); stratifies a disease population into one or more distinct subsets based on disease severity or some other relevant feature; achieves significant therapeutic response in one or more subtypes of disease by administering a specialty drug; achieves significant therapeutic response in a subject categorized according to a set of immunological subtypes by administering a specialty drug; achieves significant therapeutic response in multiple subset(s) of the disease population; and/or includes evaluation of responsiveness to drug during treatment.
• the efficacy assurance may be provided: for a specialty drug for the treatment of a disease, disorder, or cancer; and/or by using a theragnostic evaluation comprising use of a biomarker, diagnostic procedure, companion diagnostic procedure, or combination thereof.
• the efficacy assurance is provided to: an eligible patient selected from a disease population; an eligible subset of patients selected from a disease population; or all eligible patients selected from a disease population.
• the therapeutic efficacy assurance is provided to an eligible patient, payer, or employer, e.g., where the payer is a private payer or government payer.
• the financial assurance may be provided to the eligible patient, payer, or employer; and/or the financial assurance may involve: full or partial money-back guarantee of coinsurance to the eligible patient; or full or partial money-back guarantee to the payer or the employer who pays for the specialty drug.
• the specialty drug is: approved by a disease specialist; intended for treating a chronic disease or disorder, autoimmune disease, inflammatory disorder, a rare disease, a cancer indication, or microbial infection; further delivered or dispensed for administration to the patient; a biotech product or biologic; an oral or injectable formulation; or subject to post approval surveillance, e.g., risk evaluation and mitigation strategies, from drug manufacturer(s).
• the invention further encompasses an entity, e.g., a pharmacy, which may be a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic company, which directly or indirectly uses or pays for these described methods.
• a pharmacy which may be a specialty pharmacy
• a pharmacy benefits management entity including a health insurer, a commercial health insurer, or a public/government health insurer
• a healthcare provider entity including a clinic, hospital, outpatient facility, specialty clinic, or physician's office
• a pharmaceutical or drug manufacturing company e.g., a diagnostic company, which directly or indirectly uses or pays for these described methods.
• a method which allows assurance- based prior authorization of a specialty drug, comprising using a theragnostic evaluation of a patient for treatment of a chronic disease or disorder; and making a decision on prior authorization for payment for the specialty drug.
• the method further comprises: selecting the specialty drug from a panel of available drugs in a drug formulary; dispensing the specialty drug by a specialty pharmacy to the patient, and/or delivering the specialty drug to the patient.
• the theragnostic evaluation provides, typically prospectively: therapeutic appropriateness; therapeutic guidance; and/or therapeutic effectiveness; often also with selection of an alternative therapeutic strategy, e.g., if there are contraindications (e.g., pharmacological or mechanism problems in the patient) or the first strategy fails; and/or support for an assurance-based prior authorization decision, e.g., based on efficacy assurance or financial assurance.
• the theragnostic will further be directed to further provide efficacy assurance, financial assurance, prior authorization or payment approval, and/or providing guidelines in developing a disease specific drug formulary.
• the assurance-based prior authorization is provided: for a specialty drug for the treatment of a disease, disorder, or cancer; by using a theragnostic evaluation comprising use of a biomarker, diagnostic procedure, companion diagnostic procedure, or combination thereof; for bundles of like patients having similar, or functionally equivalent, theragnostic measures, such that such bundles of patients are subject to a like decision; for a bundle of like patients numbering at least about 2000, e.g., 4000, or 8000 individual patients; or where the prior authorization covers at least about 40%, e.g., 60% or 80%, of the specialty drug cost as compared to the Medicare non-negotiated cost .
• the prior authorization may involve: approval of the specialty drug that was originally prescribed by a disease specialist of the patient; or substitution of the specialty drug that was originally prescribed by a disease specialist of the patient with an alternate specialty drug or non-specialty drug by a Disease and Therapy Management specialist.
• this aspect of the invention also provides an entity, e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or related healthcare service company; which directly or indirectly uses or pays for these described methods.
• a method is provided generating a specialty drug formulary for treating a specific disease, comprising identifying specialty drugs that are highly efficacious in distinct subsets of patients based on a set of theragnostic evaluation(s).
• the methods further comprise: including the specialty drugs in the formulary; treating a patient or subset of patients with an appropriately-matched specialty drug to achieve excellent therapeutic efficacy; and/or providing efficacy assurance for a specialty drug that is chosen for treatment from the formulary.
• Another embodiment of the invention is the resulting formulary.
• the drug formulary is generated: to include a specialty drug for the treatment of a disease, disorder, or cancer; or by using a theragnostic evaluation comprising use of a biomarker, diagnostic procedure, companion diagnostic procedure, or combination thereof, including assignment by genotypic evaluation.
• This aspect of the invention further provides an entity, e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or related healthcare service company; which directly or indirectly uses the drug formulary, or pays for the specialty drug that is chosen for treatment from the formulary.
• an entity e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or related healthcare service company; which directly or indirectly uses the drug formulary, or pays for the specialty drug that is chosen for treatment from the formulary.
• Another aspect of the invention provides a method delivering a specialty drug and/or treating a patient with a specialty drug, the method achieving an improvement derived from a theragnostic evaluation, patient therapeutic adherence, or pricing change (e.g., ability to negotiate and reduce drug price with a biopharmaceutical company), the improvement in: distribution and/or delivery efficiency; a priori matching of appropriate specialty drug to the individual patient; treatment efficiency; patient therapeutic adherence efficiency; product differentiation for a specialty drug in a disease indication; or market enrichment for a specialty drug in a disease indication.
• a theragnostic evaluation e.g., ability to negotiate and reduce drug price with a biopharmaceutical company
• components of the distribution and/or treatment method include: a prescription drug plan; a specialty drug formulary; a specialty pharmacy; a theragnostic facility providing disease-specific theragnostic evaluation; or a disease and therapy management care specializing in a specific disease.
• the disease and/or therapy management care is through telehealth architecture, and: the care is provided by disease-specific specialty doctor or specialty nurse; the disease is an oncology indication, autoimmune disease, inflammatory disorder, or microbial infection; the oncology indication is B-cell non-Hodgkin's lymphoma (B-NHL); the autoimmune disease is rheumatoid arthritis; the inflammatory disorder is relapsing-remitting multiple sclerosis; or the microbial infection is hepatitis C viral infection.
• B-NHL B-cell non-Hodgkin's lymphoma
• the disease and/or therapy management care involves: approval of the specialty drug that was originally prescribed by the disease specialist of the patient; or substitution of the specialty drug that was originally prescribed by a disease specialist of the patient with an alternate specialty drug or non-specialty drug, e.g., properly approved with assistance, by a Disease and Therapy Management specialist.
• This aspect of the invention also provides an entity, e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or related healthcare service company; which directly or indirectly uses or pays for these methods.
• entity e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or related healthcare service company; which directly or indirectly uses or pays for these methods.
• Another aspect of the invention provides a method providing assurance based on theragnostic evaluation of a patient for specialty drug distribution and/or treatment, wherein the patient is subjected to theragnostic evaluation to select and administer an appropriate specialty drug.
• the method is applied to a plurality of patients.
• the methods further comprise: selecting an appropriate specialty drug matched for the patient or subset of patients to achieve better treatment outcomes; evaluating a disease population by theragnostic evaluation to stratify into distinct subsets, and administering an appropriate specialty drug in that subset to achieve better treatment outcomes; using theragnostic evaluation in guiding therapeutic dosing and/or scheduling during treatment; using theragnostic indications for evaluating therapeutic outcome(s) during treatment cycle; or selecting an alternate specialty drug for the patient at the end of the treatment cycle, if the patient failed to respond to the treatment.
• the distribution and/or treatment are provided: for a specialty drug for the treatment of a disease, disorder, or cancer; or by using a theragnostic evaluation comprising use of a biomarker, diagnostic procedure, companion diagnostic procedure, or combination thereof.
• an entity e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a
• a healthcare provider entity including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug
• methods achieving patient therapeutic adherence for a specialty drug treatment comprising: selecting a specialty drug by a theragnostic evaluation of a patient for treatment of a specific disease or disorder; and/or providing efficacy assurance, e.g., therapeutic or financial assurance. Either or both promote patient adherence, or compliance, with treatment protocols by improving treatment outcomes and/or decreasing downside risk. These may be combined with additional aspects of patient education, among other factors affecting patient adherence.
• the methods further comprise steps incorporating a telehealth architecture, e.g., in disease and therapy management team or monitoring, telepharmacy, financial approval and payment exchange, or patient therapy adherence monitoring.
• the methods further comprise location-based authentication or certification; or time-dependent authentication or certification, e.g., of compliance with therapy instructions, typically time logs of drug administration or dosing.
• an entity e.g., a pharmacy, including a specialty pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, a commercial health insurer, or a public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical or drug manufacturing company; or a diagnostic or healthcare services company; which directly or indirectly uses or pays for these methods.
• a pharmacy including a specialty pharmacy
• a pharmacy benefits management entity including a health insurer, a commercial health insurer, or a public/government health insurer
• a healthcare provider entity including a clinic, hospital, outpatient facility, specialty clinic, or physician's office
• a pharmaceutical or drug manufacturing company e.g., a diagnostic or healthcare services company
• the integrated model herein referred to as KlaritosTM platform, includes a specialty drug formulary, specialty pharmacy, theragnostic laboratories, disease and therapy management care.
• all the components of the healthcare supply chain and delivery model operate as one integrated system.
• all the components of the healthcare supply chain and delivery model use telehealth medium.
• the specialty pharmacy is a telepharmacy through which a patient can interact with a specialty pharmacist.
• an in-house, disease-specific, specialty physician(s) and specialty nurse(s) operate the disease and therapy management care.
• the specialty physician(s) and specialty nurse(s) perform the roles of a healthcare provider.
• examples of such specialty disease include rheumatoid arthritis, multiple sclerosis, cancers such as breast cancer, colorectal cancer, etc.
• these functions are integrated to theragnostic laboratories in regards to selection of a therapy, selection of a patient for treatment with an appropriate therapy, methods of treatment, differential dosing, differential dosing schedule, differential dosing frequency, etc.
• the healthcare delivery and treatment model is a platform through which all stakeholders are efficiently connected to achieve maximum efficiency in regards to: delivery, care, clinical and economic outcomes, and payments.
• external pharmacy benefit management companies PBMs
• specialty pharmacies distributors, hospitals, specialty clinics or the specialty physicians are not involved in fixing the drug price.
• the stakeholders of the platform include: pharmaceutical companies, theragnostic providers, diagnostic providers, healthcare providers, patients, and payers (FIG-1 ).
• this platform is an essential cog in the delivery and treatment model by providing significant proprietary advantages to stakeholders.
• the platform provides an efficient market place for pharma companies and diagnostic companies to offer their products and services to payers and patients.
• payers are insurance companies, employers, government payers.
• patients are payers.
• the healthcare delivery and treatment platform specializes in specific diseases.
• the disease or disorder is selected from the group consisting of oncology indications, autoimmune diseases, inflammatory disorders, microbial infections, rare diseases, and ultra-rare diseases.
• the disease is rheumatoid arthritis.
• it is relapsing-remitting multiple sclerosis.
• it is breast cancer.
• B-CLL B-cell chronic lymphocytic leukemia
• the platform can provide therapeutic guidance by identifying and selecting a priori several of the marketed specialty drugs for the entire disease population.
• the platform can provide therapeutic guidance by identifying and selecting a priori several of the marketed specialty drugs for 50- 70% or more of the disease population. In other embodiments, the platform can provide therapeutic guidance by identifying and selecting a priori only one or two of the marketed specialty drugs targeting 10-20% or 20-40% of the disease population.
• the disease is rheumatoid arthritis. In another embodiment, the disease is relapsing- remitting multiple sclerosis.
• the specialty drug is an antibody therapy. In certain embodiments, the anti-CD20 antibody is rituximab. In other
• the specialty drug is a small molecule therapy. In yet other embodiments, the specialty drug is an intravenous chemotherapy.
• the healthcare delivery and treatment platform adopts different kinds of diagnostic, biomarker tests and stratification platforms as part of its proprietary theragnostic guidance.
• the specialty drug has an existing companion diagnostic product, approved by regulatory agencies such as FDA and EMEA.
• the specialty drug does not have a companion diagnostic product but has an independent diagnostic product approved by a regulatory agency for that drug in a particular indication.
• the specialty drug has an existing CLIA- certified diagnostic or biomarker product.
• the specialty drug is a targeted therapy, e.g., an antibody therapy, e.g., anti-CD52 antibody, but does not have any approved biomarker tests.
• ⁇ all the financial transactions KlariPayTM occur electronically.
• KlariPay is a two-way exchange of assets and such assets include specialty drug, theragnostic guidance, and money.
• KlariPay is considered a securities lending and repurchase agreement.
• the financial transaction is instant between a payer and an assurance company through KlariPay.
• An external entity, e.g., re-insurance (assurance) company may provide just the financial assurance whereas the therapeutic efficacy assurance is provided by KlariPay.
• re-insurance (assurance) company may provide just the financial assurance whereas the therapeutic efficacy assurance is provided by KlariPay.
• both efficacy and financial assurances are provided by KlariPay.
• a pharmaceutical company and (or) a financial risk assurance (reinsurance) company may involve as stakeholders in this transaction.
• a proprietary therapeutic efficacy assurance is the assurance platform that provides both efficacy and financial assurances to payers.
• KlariPay platform is part of the telehealth platform, e.g., Klaritos platform.
• this solution integrates the benefits of (a) theragnostics, (b) specialty pharmacy operations, (c) pharmacy benefit management, (d) disease and therapy management care (FIG-1 ).
• payment for the specialty drug is performance-based and tied to the therapeutic efficacy in a patient.
• the payment is ensured once pre-defined clinical or therapeutic response criteria are achieved.
• the payment is made on a provisional basis by the payer immediately upon dispensing the drug.
• payers mean government or private payers, employers, pension funds, and patients.
• the specialty drug company agrees to pay back the payment received from payers via KlariPay, minus the applicable costs for goods and services rendered by the specialty drug company, and the theragnostic provider/specialty pharmacy provider, if the patient does not achieve the intended clinical response; e.g., remission or excellent response or such pre-defined criteria; depending on the disease and stage of the disease (FIG-4).
• the specialty drug company e.g., pharmaceutical company
• the specialty drug company is not involved in providing such assurance, and it is exclusively provided by an assurance company to payers.
• the KlariPay provider may split this 30% payment, e.g., in two equal halves.
• the payer will pay an additional two-thirds of the drug cost to KlariPay.
• Specialty drug manufacturer and the theragnostic guidance provider and the specialty pharmacy provider may split this payment, e.g., in two equal halves;
• theragnostic guidance provider and the specialty pharmacy provider may form components of one entity, e.g., a prescription drug plan, an assurance company, a PBM company, a payer.
• the additional payment is for the significant avoidance of medical and pharmacy cost(s) the payer might have accrued otherwise.
• such a commercialized drug is expected to differentiate itself from other commercially available IP-protected drugs, and other biosimilars and small molecule generic drugs in regards to efficacy, safety and toxicity profiles.
• this delivery model can conceivably increase net sales of the drug, possibly 2-fold, and in some instances 3-5 fold, by bringing more patients who are eligible from within this stratified segment.
• payers will approve this specialty drug because of the therapeutic efficacy assurance provided by KlariPay.
• the methods may comprise, e.g., genotyping or phenotyping the individual for one or more genotypic polymorphisms to obtain a result; genotyping point mutations or gene deletions to obtain a result; determining depletion of specific cell population in a subject as a function of treatment response, disease remission, disease relapse, etc.; determining re-population of a specific cell population as a function of treatment response, disease remission, disease relapse, etc.; stratifying a disease, e.g., rheumatoid arthritis, into distinct subsets of diseases or into categories of subsets based on disease severity; stratifying patients based on one or two functional polymorphisms that are relevant to the mechanism of the action of a drug, and in one instance these polymorphisms are FcGR-3A V/F158 and FcGR-2A H/R131 polymorphisms, and the mechanism of action Is antibody-mediated cellular
• the decision to treat a disease with a specialty drug is a function of the mechanism of action of the drug.
• the specialty drug is rituximab antibody therapy and the mechanism of action is antibody- dependent cellular cytotoxicity (ADCC), and the neoplastic disease is B-cell non-Hodg kin's lymphoma (B-NHL), e.g., follicular lymphoma.
• B-NHL B-cell non-Hodg kin's lymphoma
• the cobas ® KRAS Mutation Test is used as an aid in the identification of colorectal patients for whom treatment with Erbitux ® (cetuximab) may be indicated if mutations are not detected.
• the decision to treat a disease with a specialty drug is a function of the pathophysiology of the disease as stratified based on immunologically defined subtypes of disease and disease severity.
• the disease is rheumatoid arthritis (RA), and subtypes of RA include: IgG RF + or IgA RF + (rheumatoid factor of IgG or IgA subtypes); IgG ACPA or IgA ACPA + (anti-citrullinated peptide antibodies of IgG or IgA subtypes); fibrinogen-induced arthritis (FIA) or collagen- induced arthritis (CIA) in defined subsets of populations, e.g., as characterized by the FcGR3A (V/F 58 ) and FcGR2A (H/R 13 ) polymorphisms.
• RA rheumatoid arthritis
• subtypes of RA include: IgG RF + or IgA RF + (rheumatoid
• theragnostics is used to select a specialty drug for treatment a priori.
• theragnostic guidance is provided to the patient during the treatment in regards to differential dosing, differential dosing schedule, differential dosing frequency, disease remission, disease relapse, etc.
• theragnostics provides a treatment decision to discontinue the current therapy and select an alternate therapy. Such reasons for discontinuations include: in one instance, the subject may develop serious side effects to the current therapy; and in other instances, the drug is no longer efficacious in the subject; and in yet other instances, the subject may have developed resistant mutation(s) that makes the drug ineffective.
• a specialty drug is specifically chosen from a panel of therapies available in a drug formulary or prescription drug plan, including from a panel of specialty drugs, for treatment.
• a patient or subset(s) of patients is specifically chosen for a specialty drug treatment; and in other embodiments of theragnostics, based on the understanding that the patients will respond poorly to the therapy, a patient or subset(s) of patients is specifically not chosen for a specialty drug treatment.
• the specialty drug chosen for treatment is an induction therapy.
• the specialty drug is a maintenance therapy.
• the specialty drug can be used as a monotherapy in both induction and maintenance therapy settings.
• the specialty drug can be used as one of the therapies of a combination therapy in both induction and maintenance therapy settings.
• the specialty drug can be an antibody therapy, and one such therapy is rituximab for the treatment of B-NHL.
• an antibody therapy and chemotherapy can form the combination therapy.
• methods are provided for therapeutic guidance based on theragnostics. This includes selection of a specialty drug from a panel of marketed specialty drugs for a subject or a patient subset; selection of a treatment regimen (single course versus maintenance therapy; monotherapy versus combination therapy; or simply a 'watch and wait' regimen in the case of B-NHL).
• the methods comprise mechanism-driven theragnostic methods: (a) based on the mechanism of action by which the drug exerts therapeutic response in an individual or in individuals having the desired genetic or immunological makeup, and by determining whether the said patient will then respond to that therapy or not; (b) based on the disease severity mechanisms patient population can be stratified and the appropriate specialty drugs are then administered to achieve better clinical responses, preferably clinical remission.
• the methods comprise continued, systematic monitoring of disease remission and relapse patterns during the course of administration— to ascertain how well the drug is working (or not working) in a given subject or vice versa; and/or when to administer the next course of therapy (e.g., as-needed versus fixed time intervals).
• a medical record is provided of an individual patient comprising: diagnostic evaluation determining development or existence of a chronic disease or disorder; and theragnostic evaluation of the patient based upon therapeutic appropriateness, therapeutic guidance, and/or therapeutic effectiveness, and often also including selection of an alternative therapeutic strategy, the evaluation leading to selection of a treatment strategy.
• the record will further provide patient identification information, patient medical history data, patient therapy adherence data, therapeutic assurance data, patient health insurance data, therapy payment data, and/or details on execution and progression of the selected treatment strategy.
• Additional aspects of the inventions include a database comprising a plurality of such medical records, e.g., wherein: a large majority of the medical records in the database include treatment response data; in some medical records the treatment strategy is complete and the patient has achieved remission or excellent response; the database comprises at least 2000 medical records with treatment response data; the database is in a form of electronic, optical, paper, or some combination; the database further comprises one or more of patient identification data, patient medical history data, patient health insurance data, patient therapy adherence data, therapeutic assurance data, or therapy payment data; the database comprises response data from alternative treatments of different patients; the database further incorporates a mechanism to identify when the therapeutic strategy for a patient differs from the accepted therapeutic guidelines; and/or the database further incorporates a mechanism to identify when the response of a patent to an alternative therapeutic strategy differs from the expected response to accepted therapeutic guidelines.
• the invention provides an entity selected from: a pharmacy; a pharmacy benefits management entity; an employer or insurance entity, including a health insurer, commercial health insurer, or public/government health insurer; a healthcare provider entity, including a clinic, hospital, outpatient facility, specialty clinic, or physician's office; a pharmaceutical company; or a diagnostic company; which uses or possesses a medical record, as described, or a database, as described.
• FIG. 1 indicates essential stakeholders of the Klaritos platform.
• a marketed, specialty drug can be efficiently delivered directly to the patient or her physician through Klaritos' formulary and specialty pharmacy.
• Klaritos platform is here depicted as a telehealth medium consisting of: drug formulary, specialty pharmacy, disease and therapy
• a disease population e.g., rheumatoid arthritis
• KlariPay provides therapeutic efficacy assurance to payers and employers.
• Theragnostics-mediated therapeutic guidance is provided by theragnostic laboratories.
• the platform further provides product differentiation and presumably market enrichment for a specialty drug.
• FIG. 2 provides the workflow involved in a Klaritos platform. Steps 1-5 represent the current treatment model that is generally followed by specialty physicians and payers. Steps 6-17 involve the components of Klaritos platform. See Example-1.
• FIG. 3 provides a pathway of money flow when therapeutic efficacy assurance is achieved.
• KlariPay is the financial transaction platform between a payer(s) and an assurance company or theragnostic platform company including e.g., prescription drug plan.
• a pharmaceutical company and (or) a financial risk assurance (re-insurance) company may involve as stakeholders in this transaction.
• FIG. 4 provides a pathway of money flow when therapeutic efficacy assurance threshold is not achieved.
• a pharmaceutical company and (or) a financial risk assurance (re-insurance) company is not part of such assurance, such assurance is provided by KlariPay to payers.
• the present disclosure provides methods, processes, reagents and kits for novel healthcare delivery, treatment and payment, particularly for achieving improved economic and treatment outcomes in patients treated with specialty drugs.
• Methods, processes, and kits provide several uses, including, for providing therapeutic guidance, for providing therapeutic efficacy assurance, for providing product differentiation and presumably market enrichment for a specialty drug, for delivering the drug directly from a pharmaceutical company to a patient or to her specialty physician through a novel healthcare delivery platform.
• specialty drugs are fairly expensive drugs prescribed by specialist doctors to treat complex, chronic, rare, or difficult-to-manage diseases and disorders such as cancers, autoimmune diseases, inflammatory disorders, chronic viral infections, etc.
• specialty drugs include therapeutic antibodies, protein and peptide therapies, small molecules, therapeutic vaccines, stem cell therapies, and blood derivatives including IVIG therapies.
• a specialty drug typically meets five or more of the following criteria: specialist- initiated (e.g., oncologist, rheumatologist); biotech product (covers both IP protected drugs, generics and biogenerics); injectable formulation; costs more than $6,000 per year; requires special handling; limited distribution; necessitates risk evaluation and mitigation strategies (REMS) program (Duffant, et al. (2014) Succeeding in the Rapidly Changing U.S. Specialty Market IMS Health).
• specialist- initiated e.g., oncologist, rheumatologist
• biotech product covers both IP protected drugs, generics and biogenerics
• injectable formulation costs more than $
• specialty drugs are typically via self-administered injections or intravenous infusions in the physician's office, specialized administration facility, or in a hospital setting.
• specialty drugs are orally administered. Not all biologic drugs come under specialty drugs (e.g., insulins).
• specialty drugs e.g., insulins.
• small molecule drugs can be categorized as specialty drugs (e.g., sofosbuvir, tofacitinib).
• CMS Centers for Medicare and Medicaid Service
• a specialty drug as one with a minimum monthly cost of $600.
• Some insurance plans also set cost thresholds, which can be up to double this amount.
• Private payers classify specialty drugs based on the cost, with $1 ,154 determined as the average minimum monthly cost.
• specialty drugs Several factors drive the specialty drug spend, including: (a) the rising interest in personalized medicine and targeted therapies, e.g., stratified medicine, and therapies to treat rare and orphan disorders: approximately 700 specialty drugs are in clinical development; (b) price inflation has been a leading driver with prices of some drugs growing at double-digit rates; (c) many specialty drugs including biologies are considered
• the targeted cancer therapies costs are very high. Many of them are priced between $6000 to 12,000 per month, or approximately $70,000 to $1 15,000, annually.
• Brentuximab Adcetris, Seattle Genetics/Millennium-Takeda Oncology
• Patients typically need 3 vials per dose, and usually 7 to 9 doses per course of treatment resulting in a total of $135,000 or more.
• Ipilimumab (Yervoy, Bristol-Meyers Squibb) is used to treat melanoma, costs $30,000 per injection, which translates to $120,000 for a course of therapy, based on the approved dosing regimen of 3 mg/kg every 3 weeks for 4 doses.
• novel or reformulated chemotherapy drugs are also priced very high. These include pralatrexate (Folotyn, Alios Therapeutics), at $120,000 per course; omacetaxine (Synribo, Teva Pharmaceuticals), at $28,000 for induction and $14,000 for monthly treatments; and pegylated asparaginase (Oncaspar, Sigma-Tau Pharma.), at $22,000 (Kantarjian, et al. (2013) J. Clin. Oncol. 31 :3600-3604).
• Expensive drugs are also being developed and approved for other, non-oncology, medical conditions.
• One such agent is ivacaftor (Kalydeco, Vertex Pharmaceuticals), which is the first drug that targets the underlying molecular defect in cystic fibrosis. It is designed to treat the disease in a small subpopulation of patients who carry a specific genetic mutation, G551D, and costs $31 1 ,000 a year— making it one of the most expensive drugs currently on the market. Of the ⁇ 30,000 U.S. patients with cystic fibrosis only ⁇ 1200 patients carry this mutation.
• sofosbuvir Sovaldi, Gilead
• Sovaldi, Gilead Another high-priced drug
• the drug has been shown to be highly effective for treating hepatitis C virus, which afflicts more than 3 million people in the United States. Because sofosbuvir needs to be taken in combination with other drugs, full treatment can cost upward of $100,000, because some patients require re-treatment.
• Gilead has developed Harvoni to treat hepatitis C virus. It is a ledipasvir/sofosbuvir (Harvoni) combination drug that is the first treatment that does not require administration with either interferon or ribavirin. The current price of the drug is $63,000 for 8 weeks of treatment, $94,500 for 12 weeks, and $189,000 for 24 weeks. But these costs might be lower than for sofosbuvir, because it is taken without companion medications (ribavirin, interferon) with serious side effects, and because many patients will only require 8 weeks of therapy.
• Harvoni ledipasvir/sofosbuvir
• Specialty drugs to treat relapsing-remitting multiple sclerosis include Peginterferon ⁇ - 1 a ⁇ Plegridy, Biogen), listed at $62,036 for a year's treatment; dimethyl fumarate (Tecfidera, Biogen), priced at $60,121 a year.
• Specialty drugs to treat various autoimmune diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis cost approximately $20,000 or more per year.
• Some of these drugs are infliximab, etanercept, adalimumab, rituximab, certolizumab pegol, golimumab, tocilizumab, abatacept, etc.
• Another specialty drug pill to treat rheumatoid arthritis tofacitinib (Xeljanz, Pfizer) is priced at $24,600 a year.
• Some of the approved specialty drugs (injectables, oral/topical) to treat various cancers include: Abraxane, Adcetris, Afinitor, Arranon, Arzerra, Avastin, Beleodaq, Blincyto, Bosulif, Caprels, Cometriq, Crinone, Cyramza, Dacogen, Eligard, Elspar, Erbitux, E rived ge, Farydak, Firmagon, Folotyn, Gazyva, Gilotrif, Gleevec, Halaven, Herceptin, Hycamtin capsules, Hycamtin (topotecan injection), Ibrance, lclusig, Imburvica, Inlyta, Intron A, Istodax, Ixempra, Jakafi, Jevtana, Kadcyla, Kepivance, Keytruda, Kyprolis, Levoleucovorin Calcium, Lupron Depot, Marqibo, Matu
• Some of the approved specialty drugs to treat multiple sclerosis include: Ampyra, Aubagio, Avonex, Betaseron, Copaxone, Extavia, Gilenya, Lemtrada, Mitoxantrone, Plegridy, Rebif, Tecfidera, Tysabri.
• Some of the approved specialty drugs to treat inflammatory indications such as rheumatoid arthritis are: Actemra, Arcalyst, Benlysta, Cimzia, Enbrel, Entyvio, Humira, Maris, Kineret, Krystexxa, Orencia, Ortexup, Rasuvo, Remicade, Rituxan, Simponi, Simponi Aria, Stelara, Xeljanz.
• Some of the approved specialty drugs to treat inflammatory bowel diseases such as Crohn's and ulcerative colitis are: Cimzia, Entyvio, Humira, Remicade, Simponi, Tysabri.
• Some of the approved specialty drugs to treat psoriasis are Cosentyx, Enbrel, Humira, Otezla, Otrexup, Rasuvo, Remicade, Stelara.
• Some of the approved specialty drugs to treat osteoarthritis include: Euflexxa, Gel- One, Hyalgan, Monovisc, Orthovisc, Supartz, Synvisc.
• Some of the approved specialty drugs to treat osteoporosis include: Boniva, Forteo, Prolia, Reclast.
• Some of the approved specialty drugs to treat ophthalmic conditions include:
• Some of the approved specialty drugs to treat blood cell deficiency include: Aranesp, Epogen, Granix, Leukine, Mozobil, Neulasta, Neumega, Neupogen, Nplate, Proctir, Promacta.
• Some of the approved specialty drugs to treat alpha-1 deficiency include: Aralast NP, Glassia, Zemaira, Prolastin C.
• Some of the approved specialty drugs to treat anticoagulant include: Arixtra, Fragmin, Privask, Lovenox.
• Some of the approved specialty drugs to treat enzyme deficiency and lysosomal storage disorders include: Adagen, Aldurazyme, Carbaglu, Cerdelga, Cerezyme, Cystagon, Elaprase, Elelyso, Fabrazyme, Lumizyme, Myozyme, Naglazyme, Orfadin, Sucraid, VPRIV, Vimizim, Vpriv, Zavesca.
• Some of the approved specialty drugs to treat asthma and allergy include: Xolair, Oralair.
• Some of the approved specialty drugs to treat growth deficiency include: Genotropin, Humatrope, Increlex, Norditropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Tev-Tropin, Zorbtive.
• HCV hepatitis C virus
• HIV human immunodeficiency virus
• Aptivus Atripla
• Combivir lamivudine/zidovudine
• Complera Crixivan
• Edurant Egrifta
• Emtriva Epivir
• Epzicom Egrifta
• Emtriva Emtriva
• Epivir Epzicom
• Fuzeon Intelence
• Invirase Isentress
• Kaletra Lexiva
• Norvir Prezista
• Rescriptor Retrovir
• Retrovir Reyataz
• Selzentry Stribild
• Sustiva Tivicay
• Triumeq Trizivir
• Viramune Viramune XR
• Viread Viread
• Zerit Ziagen.
• Some of the approved specialty drugs to treat pulmonary hypertension include:
• Adcirca Adcirca, Adempas, Flolan, Flolan Diluent, Letairis, Opsumit, Orenitram, Remodulin, Revatio, Tracleer, Tyvaso, Veletri, Ventavis.
• An approved specialty drug (antibody) to treat respiratory synctial virus is: Synagis.
• Some of the approved specialty drugs to treat cystic fibrosis include: Bethkis, Cayston, Kalydeco, Pulmozyme, Tobi (tobramycin), Tobi Podhaler.
• Some of the approved specialty drugs in the contraceptive space include: Mirena, Nexplanon, Paragard, Skyla.
• Some of the approved specialty drugs to treat infertility include: B ravel le, Cetrotide, Chorionic Gonadatropin (brands include Novarel, Pregnyl), Crinone, Endometrin, Follistim AQ, Ganirelix, Gonal-F, leuprolide, Menopur, Ovidrel, progesterone, injection, Repronex.
• PCSK9 inhibitors Some of the approved specialty drugs to treat lipid disorders (PCSK9 inhibitors) include: Praluent, Repatha.
• Some of the approved specialty drugs to treat miscellaneous specialty conditions include: Acthar H.P. Gel, Apokyn (movement disorder), Arestin, Botox (botulinum toxin), Botox Cosmetic, Ceprotin (coagulation disorder), Chenodal, Cystadane, Dysport (botulinum toxin), Gattex (gastrointestinal disorders), Hetlioz, Juxtapid, Kynamro, Kuvan
• Some of the approved specialty drugs to treat hemophilia include: Advate, Alphanate, Alphanine SD, Alprolix, Bebulin, Benefix, Corifact, DDAVP, Eloctate, FeibaNF, Helixate FS, Hemofil M, Humate-P, Koate-DVI, Kogenate FS, Monoclate-P, Mononine, Novoseven RT, Profilnine SD, Recombinate, RiaSTAP, Rixubis, Stimate, Tretten, Wilate, Xyntha.
• Some of the approved specialty drugs to treat endocrine disorders include: Aveed, Korlym, Kuvan, Lupaneta Pack, Lupron Depot-Ped, Ruconest, Sandostatin, Sandostatin LAR, Signifor, Somatuline Depot, Somavert, Supprelin LA.
• Rare disease refers to a disease or disorder affecting fewer than 1 in 2000 in Europe.
• a disease or disorder is defined as rare in the USA when it affects fewer than 200,000 Americans at any given time.
• One rare disease may affect only a handful of patients in the EU (European Union), and another may affect as many as 245,000.
• In the EU as many as 30 million people alone may be affected by one of over 6,000 rare diseases existing ( www. rarediseases. org) .
• These disorders are characterized by a broad diversity of disorders and symptoms that vary not only from disease to disease but also from patient to patient suffering from the same disease. Though these phrases are used interchangeably, an orphan disease need not be a rare disease.
• orphan diseases also include neglected diseases which inflict severe health burdens on the world's poorest people.
• Examples include lymphatic filariasis, malaria, leishmaniasis, etc.
• Ultra-rare disease refers to a disease affecting fewer than 20 patients per million of population (or, one patient per 50,000 people). Most ultra-rare diseases affect far fewer than this, as few as one per million or less.
• Aldurazyme (Laronidase; enzyme replacement therapy; Genzyme) for mucopolysaccharidosis-l can range from $200,000 in children to $500,000 in adults.
• Vimizin elosulfase alpha; BioMarin
• Alexion Pharmaceuticals' Soliris (eculizumab) is a $440,000-a-year treatment for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), while Cinryze (C1 esterase inhibitor [human]; Viropharma) treats hereditary angioedema for $417,000 a year.
• Some of the FDA-approved BLA-designated drugs to treat rare diseases include: elosulfase alfa (Vimizim; mucopolysaccharidosis type IVA, Morquio A syndrome); Metreleptin (Myalept; leptin deficiency with congenital or acquired generalized
• ramucirumab Cyramza; advanced gastric cancer or gastro-esophageal adenocarcinoma
• siltuximab Sylvant; multicentric Castleman's disease
• pembrolizumab Ke truda; unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor
• blinatumomab Blincyto; Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute
• nivolumab Opdivo; unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
• trametinib (Mekinist; unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by FDA-approved test); dabrafenib (Tafinlar; unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by FDA-approved test); PCI-32765 (Ibrutinib; mantle cell lymphoma who have received at least one prior therapy; chronic lymphocytic leukemia who have received at least one prior therapy);
• escallantide Kerbitor; acute attacks of hereditary angioedema in patients 12 years of age or older); ethiodized oil (Lipiodol; hysterosalpingography in adults, lymphography in adult and pediatric patients, selective hepatic intra-arterial use for imaging tumors in adults with known hepatocellular carcinoma); ofatumumab (Arzerra; in combination with chloranmbucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate; CLL refractory patients to fludarabine and alemtuzumab);
• relapsed B-cell non-Hodgkin's follicular lymphoma FL
• SLL small lymphocytic lymphoma
• PCI-32765 Ibrutinib
• MCL mantle cell lymphoma
• CLL chronic lymphocytic leukemia
• alglucosidase alpha2 Lizyme; Pompe disease, acid a-glucosidase GAA deficiency
• bortezomib (Velcade; Treatment of patients with multiple myeloma and patients with mantle cell lymphoma who have received at least 1 prior therapy); eltrombopag (Promacta; Thrombocytopenia in patients with chronic immune (idi
• Thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.
• immunomodulators such as azathioprine, 6-mercaptopurine or methotrexate); adalimumab (Humira; expanded indication: Reducing signs and symptoms of moderately to severely active polyarticular Juvenile Idiopathic Arthritis (J I A) in patients 2 years of age and older); bortezomib (Velcade; multiple myeloma or mantel cell lymphoma); ramucirumab (Cyramza; advanced gastric or gastro-esophageal junction adenocarcinoma, as a single agent or in combination with paclitaxel); bevacizumab (Avastin; cervical cancer, in persistent, recurrent, or metastatic disease; platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer); cinacalcet HCI (Sensipar; hypercalcemia in adult patients with parathyroid carcinoma); ruxoutinib phosphate (Jakafi; intermediate
• lanreotide Somatuline Depot; unresectable, well/moderately differentiated, locally advanced or metastatic
• FDA-approved drugs to treat ultra-rare diseases include: Procysbi. (nephropathic cystinosis); Soliris (atypical hemolytic uremic syndrome); Soliris (paroxysmal nocturnal hemoglobinuria).
• Pembrolizumab (Keytruda; Merck) is approved for treating NSCLC cancer.
• PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay for use in the detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissues.
• FFPE paraffin-embedded
• NSCLC non-small cell lung cancer
• the therascreen® EGFR RGQ PCR Kit is a real-time PCR test for the qualitative detection of exon 19 deletions and exon 21 (L858R) substitution mutations of the epidermal growth factor receptor (EGFR) gene in DNA derived from formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tumor tissue.
• the test is intended to be used to select patients with NSCLC for whom GILOTRIF® (afatinib) or IRESSA® (gefitinib), EGFR tyrosine kinase inhibitors (TKIs), is indicated.
• the cobas® KRAS Mutation Test for use with the cobas® 4800 System, is a realtime PCR test for the detection of seven somatic mutations in codons 12 and 13 of the KRAS gene in DNA derived from formalin-fixed paraffin-embedded human colorectal cancer (CRC) tumor tissue.
• the test is intended to be used as an aid in the identification of CRC patients for whom treatment with Erbitux® (cetuximab; IgGi) or with Vectibix®
• panitumumab may be indicated if mutations are not detected.
• a second companion diagnostic product, therascreen KRAS RGQ PCR Kit (Qiagen Manchester, Ltd.) is also available to aid in the identification of CRC patients for treatment with Erbitux (cetuximab) and Vectibix (panitumumab) based on a KRAS if no mutation were detected.
• Another CDx product DAKO EGFR PharmDx kit (Dako North America, Inc.) is approved, indicated as an aid in identifying CRC patients eligible for treatment with Erbitux (cetuximab) or Vectibix (panitumumab).
• the EGFR pharmDxTM assay is a qualitative immunohistochemical (IHC) kit system to identify epidermal growth factor receptor (EGFR) expression in normal and neoplastic tissues routinely-fixed for histological evaluation.
• BRACAnalysis CDxTM developed by Myriad Genetic Laboratories, is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Results of the test are used as an aid in identifying ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants eligible for treatment with LynparzaTM (olaparib).
• the FerriScan R2-MRI Analysis System (Resonance Health Analysis Services Pty Ltd) is intended to measure liver iron concentration to aid in the identification and monitoring of non-transfusion dependent thalassemia patients receiving therapy with deferasirox (Exjade; Novartis).
• the c-Kit pharmDX assay (Dako North America, Inc.) is an IHC kit system for the differential diagnosis of gastrointestinal stromal tumors (GIST). After diagnosis of gastrointestinal stromal tumor (GIST), results from c-Kit pharmDx may be used as an aid in identifying those patients eligible for treatment with imatinib mesylate (Gleevec/Glivec;
• the Inform Her-2/Neu gene detection system (Ventana Medical Systems, Inc.) is a fluorescence in situ hybridization (FISH) DNA probe assay that determines the qualitative presence of Her-2/Neu gene amplification on formalin-fixed, paraffin embedded human breast tissue as an aid to stratify breast cancer patients according to risk for recurrence or disease-related death.
• FISH fluorescence in situ hybridization
• PathVysion HER-2 DNA Probe Kit P980024 S001-S012; PathVysion Kit; Abbott Molecular, Inc.
• PATHWAY ANTI-HER-2/NEU P990081 S001-S028; Ventana Medical System, Inc.
• INSITE HER-2/NEU KIT P040030; Biogenex Laboratories, Inc.
• HercepTest (P980018 S001-S018; Dako Denmark A/S) is a semi-quantitative immunocytochemical assay to determine HER2 protein overexpression in breast cancer tissues routinely processed for histological evaluation and formalin-fixed, paraffin-embedded cancer tissue from patients with metastatic gastric or gastroesophageal junction
• HercepTest is indicated as an aid in the assessment of breast and gastric cancer patients for whom Herceptin (trastuzumab) treatment is being considered; and for breast cancer patients for whom PERJETA (pertuzumab; Genentech/Roche) treatment or KADCYLA (ado-trastuzumab emtansine; Genentech/Roche) treatment is being considered.
• the THxID BRAF kit (P120014; bioMerieux Inc.) is an in vitro diagnostic device intended for the qualitative detection of the BRAF V600E and V600K mutations in DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) human melanoma tissue. It is an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with dabrafenib [Tafinlar; Novartis] and as an aid in selecting melanoma patients whose tumors carry the BRAF V600E or V600K mutation for treatment with trametinib
• the cobas® EGFR Mutation Test (P120019 S001-S004; Roche Molecular) is a realtime PCR test for the qualitative detection of exon 19 deletions and exon 21 (L858R) substitution mutations of the epidermal growth factor receptor (EGFR) gene in DNA derived from formalin-fixed paraffin-embedded (FFPET) human non-small cell lung cancer (NSCLC) tumor tissue.
• FPET formalin-fixed paraffin-embedded
• NSCLC human non-small cell lung cancer
• VENTANA ALK D5F3 CDx Assay (P140025; Ventana Medical Systems, Inc.) is intended for the qualitative detection of the anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tissue stained with a BenchMark XT automated staining instrument. It is indicated as an aid in identifying patients eligible for treatment with crizotinib (XALKORI ® ; Pfizer).
• ALK anaplastic lymphoma kinase
• FFPE paraffin-embedded non-small cell lung carcinoma
• the Vysis ALK Break Apart FISH Probe Kit (P110012 S001-S003; Abbott Molecular Inc.) is a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens to aid in identifying patients eligible for treatment with crizotinib (Xalkori ® ; Pfizer). This is for prescription use only.
• FISH fluorescence in situ hybridization
• FFPE paraffin-embedded
• NSCLC non-small cell lung cancer
• the Cobas 4800 BRAF V600 Mutation Test (P1 10020 S001 -S010; Roche Molecular Systems) is an in vitro diagnostic device intended for the qualitative detection of the BRAF V600E mutation in DNA extracted from formalin-fixed, paraffin-embedded human melanoma tissue.
• the Cobas 4800 BRAF V600 Mutation Test is a real-time PCR test on the Cobas 4800 system, and is intended to be used as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with vemurafenib (Zelboraf ® ;
• Cancer drug costs can vary depending on who is administering the drug. If a chemotherapy is administered in a hospital outpatient setting instead of a physician's office, costs can be as much as 53% higher.
• Paymenter in healthcare generally refers to entities that finance or reimburse the cost of drugs, devices, and related healthcare services. In most cases, this term refers to insurance carriers, other third-party payers, or health plan sponsors (e.g., employers, unions, pension funds). If a patient pays for any of the products and services, albeit a portion of this payment, e.g., 5%, 15%, or more, for payment purposes he is considered as a payer, and this amount is referred to as coinsurance amount.
• PBMs refers to a third-party administrator of prescription drug programs for plan sponsors (e.g., employers and health plans). PBMs are generally responsible for developing and maintaining the drug formulary, e.g., a listing of approved and available drugs in the prescription drug plan and formulary; managing utilization and cost; contracting with pharmacies; negotiating discounts and rebates with drug
• PBMs also offer value-added services such as patient therapeutic adherence and compliance and therapy management programs that help high risk patients stay on their medications and avoid drug-related complications.
• PBMs manage pharmacy benefits.
• PBMs may be an extension of a payer and may provide specialty pharmacy services.
• features such as therapeutic efficacy assurance including the associated financial assurance, theragnostic guidance in a patient or subset(s) of patients, disease and therapy management care, and product differentiation of specialty drugs are not provided by the current PBMs, either individually or collectively. See generally Danzon vifty .do! .aov/ebsa/pdf AC Danaon061914. ⁇ ⁇ .
• Specialty pharmacies refers to a pharmacy that delivers specialty drugs, typically to patients, physicians, or hospitals. Specialty pharmacies combine medication dispensing with clinical disease management. Their services have been used to improve patient outcomes and contain costs of specialty pharmaceuticals. These pharmacies may be part of independent pharmacy businesses, retail pharmacy chains, wholesalers, pharmacy benefit managers (PBMs), or health insurance companies. Presumably, benefits from more restricted specialty networks include more cost-effective pricing and less variability in patient care and experience. Specialty pharmacies manage the complex reimbursement process, with the goal of making it easier for patients, providers, and payers. PBMs can reject filling or covering a specialty pharmaceutical product if it is not dispensed through its preferred specialty pharmacy providers (SPP).
• SPP preferred specialty pharmacy providers
• specialty pharmacies either individually or collectively.
• Specialty pharmacies are reimbursed for the drugs.
• Current delivery models adopt either white or brown bagging delivery. Specialty distributors and physicians are not part of the drug acquisition in these models.
• a PBM may deliver or send a specialty drug directly to the patient. In this scenario, the PBM will be reimbursed for the specialty drug.
• insurance companies With "white bag" delivery model, insurance companies (payers) contact patients through their PBMs or in-network pharmacies and provide an option as to where they would like to have their drug sent for administration— directly to them or to a physician's office or hospital.
• this model ensures better product integrity (e.g., proper storage, handling, package integrity, and associated labeling) than the brown bag model.
• Specialty drugs can be sent directly from a licensed pharmacy, e.g., a specialty pharmacy, to a licensed clinician (physician or hospital pharmacist), shipped at the correct temperature and tracked during shipping. If required, such documentation may be sent with the drug. Administration can be directly documented by a health care professional, ensuring correct dose and timing, with recordation of delivery details.
• Prior authorization refers to a process used by some health insurance companies in the United States to determine if they will cover payment for a prescribed procedure, service, or medication. The process is intended to act as safety and cost savings measures. All, or at least most, of the specialty drugs require prior authorization. Specialty pharmacies assist patients to obtain prior authorization. Current prior authorization procedures aim at (a) drug utilization management to control cost, and (b) hopefully achieving better patient outcomes compared to all-comers strategy. However, these procedures do not aim for achieving excellent treatment responses, e.g., remission or cure in a patient or subset(s) of patients, nor do they provide efficacy or financial assurance.
• Assurance-based prior authorization refers to the prior authorization process that is based on assurance, e.g., efficacy and financial. Such assurance is dependent on theragnostic evaluation. Efficacy assurance aims for achieving excellent treatment responses, e.g., remission or cure in a patient or subset(s) of patients.
• More advanced systems may combine these two concepts and further enhance the interaction with other 'Tele' functions to provide more extensive temporal coverage beyond a single time zone 8-hour business day, e.g., a 24/7 continuous engagement, with patients in support of their drug therapy and disease management.
• This may be accomplished, e.g., via a cloud based platform that supports secure, e.g., Health Insurance Portability and Accountability Act (HIPAA) compliant, databases and secure rich media communications.
• HIPAA Health Insurance Portability and Accountability Act
• Advanced platforms may support tele-consults in real time between the Klaritos team including specialist doctors and nurses, patient, patient's physician, rheumatologist or other (medical or other) specialist, and payers, as necessary, for consideration of options and selection of a drug therapy as well as for prior authorization.
• Such platforms might enable patient education and promote patient therapeutic adherence and compliance via video presentations, video support group participation, and video chat options, and real-time recording support for patients to self-administer medicine effectively with certain levels of certification of timing and location.
• Such platform also supports secure messaging (individuals and groups) to allow patients to have 24/7 access to the disease and therapy management and/or monitoring teams for both advice and addressing questions.
• the platform may provide support for a drug formulary and specialty pharmacy that acquires and delivers appropriate drug(s) for treatment based on therapeutic guidance
• Such a platform can handle acquisition, and delivery of the medicines as well as handling of payment via efficient electronic financial processing systems.
• the platform may also be designed to support an electronic payment system for efficient and timely management of money transfers between payers, employers, patients, and pharmaceutical companies.
• the system may be made available via a Mobile device App and enables patients to pay their copays (co-insurance).
• Such payment model may facilitate automatic monitoring and determination of patient therapeutic adherence and
• the invention may utilize a platform (hosted, e.g., by a cloud based system) that supports drug therapy and disease management for patients.
• the platform may provide a combination of Telemedicine/Telepharmacy services like remote video consults, patient assessment as well as an online place for patients to monitor and help with their drug therapy.
• Telemedicine/Telepharmacy services like remote video consults, patient assessment as well as an online place for patients to monitor and help with their drug therapy.
• all communication streams (audio, video and data) are encrypted, and all data and APPs are secured (encrypted and permission-accessible) to comply with HIPAA.
• the platform has several novel features:
• the APP reminds patients when to next administer medication; and verifies the patient medication tag on the medication container or dispenser, and automatically captures in real time video and audio of patient while self-administering medication. It may automatically update and store all this information for verification of patient therapeutic adherence and updates patient scores in therapeutic efficacy assurance model.
• Patients can engage in electronic payment of coinsurance, e.g., KlariPay, as well as receiving any refunds.
• coinsurance e.g., KlariPay
• Drug therapy (patient therapeutic) adherence is very important in achieving remission or excellence in treatment particularly for enabling therapeutic efficacy assurance.
• the methods herein provide (a) materials and tools to encourage patient therapeutic adherence, and (b) protocols to follow and achieve high compliance.
• the system may include, e.g., a specialty pharmacy that receives drugs from distributors or pharmaceutical companies and incorporates custom tags that link patients' medication uniquely with patient ID, dosage sequence number, treatment ID, and Drug ID, using a Computer generated QR code, e.g., a Patient Med Tag (PMT).
• the protocol may require the patient to scan the tag (a) when they receive the drug and (b) when they self-administer the medication, e.g., by using the App to visually scan the tag.
• Additional features incorporated into the protocols may include integrity checks of storage conditions, conditions of containers, download of data from package monitoring sensors (e.g., temperature extremes), and others.
• the App may then upload all the information from the PMT along with time and location to contemporaneously record a patient taking medication, and enables patient to visually or textually acknowledge that they have taken the medication (e.g., time and location-dependent authentications).
• the patient can also extend the visual connection to a conversation with the monitoring team if the patient has further questions.
• This system can be designed to provide and integrate the delivery, administration of medication, collection of data, and patient therapeutic adherence assessment into a single loop such that all the steps are done in a timely and efficient manner.
• the system may include feedback from the patient to monitor or evaluate response to dosing, e.g., track minor issues, note indications of possible adverse reactions, etc.
• Telesystems may provide an e-payment or accounting system to enable fast, electronic tracking and/or payment for patients ⁇ via the APP), payers, pharmaceutical company and an efficacy assurance company.
• the assurance company may facilitate collection of copay (coinsurance) data from patients, and payment for acquisition of drugs.
• the company may manage therapeutic efficacy assurance as its own fund. In which case, it monitors closely the individual patient's suggested therapy, lab results to provide therapeutic guidance, lab results indicating efficacy, and patient therapeutic adherence for each patient. Based on these data, the company runs proprietary algorithms to determine as to how well patients have responded to the prescribed therapies and which patients are eligible for therapeutic efficacy assurance including financial assurance. No other third parties need be involved in these decision-making processes.
• Telemedicine refers to the practice of improving a patient's health by permitting two- way, real-time (or near) interactive communication between a patient and a healthcare provider who are geographically separated (CMS definition). This communication is conducted via interactive telecommunications equipment that includes, at a minimum, audio and, typically, video equipment, to meet standards for telehealth set, e.g., by the U.S.
• Telepharmacy refers to the "Practice of Telepharmacy” as "the provision of Pharmacist Care by registered Pharmacies and Pharmacists located within U.S. jurisdictions through the use of telecommunications or other technologies to patients or their agents at distances that are located within U.S. jurisdictions” (Model Act; The Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy).
• the American Society of Health-System Pharmacists (ASHP) defines telepharmacy as a method used in pharmacy practice in which a pharmacist utilizes telecommunication technology to oversee pharmacy operations or provide patient care services.
• Telepharmacy operations and services may include, but are not limited to: drug review and monitoring, dispensing, oral and sterile compounding verification, medication therapy management (MTM), patient assessment, and patient counseling.
• Analogous systems may incorporate communications outside the U.S., or similar systems in other countries may provide similar operations, including specific functions or expertise provided from disperse locations.
• MTM Medical Therapy Management
• MTM refers to services for individuals with multiple chronic diseases who are taking multiple medications. According to CMS guidance documents for 2013, reimbursable MTM services provided by Medicare Part D sponsors must meet the following conditions for beneficiaries: (i) a minimum of two or three chronic disease states, (ii) taking a minimum of two to eight medications, and (iii) likely to incur approx. $3,144 in annual costs for Part D drugs.
• Analogous management may be provided, e.g., in other countries or jurisdictions, which might approach but not technically comply with all of the above criteria.
• DTM Disease and Therapy Management
• DTM Care refers to providing either or both disease management care and therapy management care.
• DTM care provides continued theragnostic guidance as part of the integrated delivery and treatment model, and the offerings will often include: personalized drug dosing, dosing schedule, monitoring of disease remission and relapse patterns, patient therapeutic adherence and compliance, etc.
• DTM care is typically managed by, or at least advised by, in-house specialist physicians and specialist nurses specialized in specific disease indications such as rheumatology, neurology, and oncology.
• Patients are the ultimate end users of the drugs, diagnostic services, theragnostic products, and services. In some countries including the United States, patients also pay for some or all of the drugs and services. This form of payment is referred to as co-pay or coinsurance. From the payment context, patients are treated as one of the payers. In appropriate circumstances, guardians or agents of the patient are included, e.g., when the guardian or agent is a medical decision maker for the patient, who often may be a dependent. This is particularly true in the context of financial obligations, where the financially responsible party (e.g., guardian, agent) may be different from the patient herself.
• the financially responsible party e.g., guardian, agent
• CMS The Centers for Medicare and Medicaid Services
• CMS is the single largest payer for healthcare in the United States, covering nearly 90 million Americans through Medicare, Medicaid, and the State Children's Health Insurance Program. Medicare itself covers approximately 50 million beneficiaries.
• the federal government cannot negotiate for Medicare drug prices or obtain any sort of volume discounts.
• the 2003 Medicare Modernization Act explicitly prohibits the federal government from negotiating drug prices or establishing a list of preferred drugs.
• Part D drug prices are determined through a negotiation between the private drug plan that administers the benefit and the drug manufacturer.
• ACA Affordable Care Act
• ACA Affordable Care Act
• Some policies offer lower deductibles and cost-sharing, but the tradeoff is higher monthly premiums.
• an individual who is enrolled in a standard (e.g., silver) plan would be responsible for no more than 6.8% of the total cost of a drug. For a drug costing $150,000 per year, that would be $10,200, but the health plan would be paying for more than 93% of the remaining cost. Still, that can be a significant amount for many patients.
• PBMs Pharmacy Benefit Managers
• PDP Medicare Part D Prescription Drug Plans
• PBM services include prior authorization, pharmacy claims processing, dispensing prescriptions via mail order, reimbursing retail and specialty pharmacies in their network and drug formulary design and management.
• Employers may contract with PBMs directly or allow the health plans they use to provide medical benefits to select the PBM.
• PBMs charge employers for the cost of reimbursed drugs, claims adjudication and other administrative fees.
• Employers receive a share of pharmaceutical company rebates that the PBMs negotiate with pharmaceutical companies on branded pharmaceutical products.
• the PBMs develop drug formularies, with input and ultimate approval from the employer, to manage utilization and control costs. They use various tools such as formulary tiers with restricted access, prior authorization on expensive medications, step therapy where a generic must be used prior to a branded drug, and escalating patient co-pays or coinsurance depending on the cost of the medication and the formulary tier.
• patient co-pays may range from $0/Rx for certain generics to over $100/Rx for branded drugs dispensed at retail pharmacies.
• Payments for specialty drugs often require coinsurance of 20% or more of the drug cost leading to out-of-pocket expense for patients exceeding $3,000 per year. Co-pays and coinsurance drug costs paid by patients lower PBM drug reimbursement amounts, and these savings are reflected in lower overall drug costs for employers.
• diseases populations are rheumatoid arthritis, multiple sclerosis, as well as specific oncology indications such as B-NHL, CLL, etc.
• Yet another example is to provide excellent clinical outcome for 10-20%, or 30-60%, or 80% of a particular disease population, e.g., rheumatoid arthritis.
• Clinical outcome is a function of therapeutic efficiency and treatment efficiency.
• Therapeutic efficiency determines whether a drug is clinically and therapeutically effective in a given patient or subset(s) of patients. The way a patient is treated with a drug refers to treatment (or therapy) efficiency. Examples include monotherapy versus combination therapy. Monotherapy could be, e.g., a small molecule therapy or antibody therapy. An antibody therapy along with chemotherapy is an example of combination therapy.
• Therapeutic guidance based on theragnostics This involves selection of a specialty drug from a panel of marketed specialty drugs for a subject or a patient subset(s); selection of a treatment regimen (single course versus maintenance therapy; monotherapy versus combination therapy; or simply a 'watch and wait' regimen in the case of B-NHL).
• Such theragnostic methods are mechanism-driven: (a) based on the mechanism of action by which the drug exerts therapeutic response in an individual or in individuals having the appropriate or desired genetic or immunological makeup, and by determining whether the patient will then respond to that therapy or not; (b) based on the disease severity mechanisms, patient populations can be stratified and appropriate specialty drugs are then administered selected to achieve better clinical responses, preferably clinical remission.
• Efficacy assurance consists of therapeutic efficacy assurance (TEA) and financial assurance (FA).
• TEA refers to an assurance of achieving significantly better therapeutic efficacy in a given patient, within a reasonable time-frame, e.g., 1 month, 2-3 months; this assurance is provided to patients, or payers, and employers.
• TEA is not therapeutic risk assurance; that is, this does not cover risks and side effects associated with the drugs.
• Financial assurance refers to a form of money-back guarantee, e.g., co-insurance amount, if the therapy has not achieved desired therapeutic outcome within a reasonable time-frame, e.g., 2-3 months; this assurance is provided to patients, and in some instances, it may also be provided to payers and employers. Such assurance is theragnostics-guided in specific disease indications, provided the patient establishes and maintains excellent patient therapeutic adherence rate.
• Both TEA and FA are inter-related: it is essentially a warranty that some or all of the cost of drug, with or without treatment costs, will be returned if the patient does not achieve a designated treatment response provided the therapy plan is carefully adhered to by the patient.
• excellent therapeutic efficacy would be: disease remission, relapse-free survival, significantly extended progression-free survival, etc.
• subject achieving ACR 70 criteria is considered excellent therapeutic efficacy.
• the payment is made to the specialty pharmacy by the payers (herein payers mean government or private payers, employers, pension funds, and patients) immediately upon dispensing the drug.
• the payment is made by the payers during the treatment period, e.g., 2-3 months after the initiation of treatment, provided the expected, pre-approved excellent (or good) clinical outcome is achieved as determined by theragnostic guidance.
• This electronic financial transaction occurs through KlariPay, preferably instantly, e.g., in the order of hours or days.
• the payment is made to the payers as per the pre-agreed terms; in this context, the term payers may include employers and patients.
• the payer(s) agrees to pay a higher price for the specialty drug (FIG-3). For example, if the annual drug price is $50,000, then the payer agrees to pay, e.g., additional $15,000 (30%) through KlariPay. Specialty drug provider and the theragnostic guidance provider may split this additional 30% payment, e.g., in equal halves.
• the payer will pay, e.g., additional $50,000 through KlariPay. Specialty drug provider and the theragnostic guidance providers will split this $50,000 payment, e.g., in two equal halves.
• the current standard of care for treating a B-NHL patient may involve rituximab+CHOP combination therapy.
• rituximab+CHOP combination therapy e.g., rituximab+CHOP combination therapy.
• payer has to pay additional payment, e.g., $25,000 per year, through KlariPay.
• the theragnostic payer may or may not have the reason to share this incentive with the specialty drug company.
• the current standard of care to treat a rheumatoid arthritis patient is to first treat with methotrexate, and upon failed treatment, treated with infliximab, and then with etanercept, and then with adalimumab, and then with tocilizumab.
• the patient has spent nearly 5-15 years before he could find the right treatment that works, and during this period, the disease progression is extremely severe involving several surgeries.
• the patient has lost the effective window-of-opportunity- to-treat, just because even the therapy, e.g., tocilizumab, that might work for that patient might not be efficacious anymore, given the severity of the disease.
• the specialty drug company agrees to pay royalty to Klaritos platform, and such royalty is tiered, for e.g., anywhere from 2% to 70% of the net sales of the drug in that market.
• Klaritos platform will receive payments from the specialty drug company based on the pre-negotiated contingent value rights (CVR).
• Managed care organizations and pharmacy benefit managers serve either through commercial or government payers to control or slow the rate of cost increases while ensuring a reasonable level of patient care.
• PBMs pharmacy benefit managers
• Utilization management is implemented through a drug benefit design developed by PBMs as part of the prescription drug plan (PDP). It consists of a formulary with multiple tier designation for drugs (generic, innovator brand, non-preferred brand and specialty tiers). Drugs listed on innovator brand and non-preferred brand tiers have significantly higher patient co-payments than the generic drug tier, and the specialty drug tier requires a patient to pay co-insurance or a percentage of the cost of the drug. The goal of higher (co-pays) coinsurance is to steer patients to lower cost alternatives.
• Innovator brand companies help off-set the cost of drug co-payments and coinsurance for patients covered through commercial insurers by offering co-pay cards and covering the cost of co-insurance for patients who are income-eligible. Medicare patients can obtain coverage through charitable organizations many of which are funded by pharmaceutical companies.
• Step Therapy where a patient is required to try a lower cost alternative or generic pharmaceutical, if available, before they can receive a higher cost brand drug
• Prior Authorization where a physician must document the medical reasons (medical necessity) for a patient to achieve such a particular therapy. This approach is widely used for most specialty drugs
• Quantity Limits wherein the patient may receive a prescription for a smaller quantity, such as one-week or one-month supply of an expensive medication at any given time.
• PBMs maintain a formulary committee consisting of credentialed pharmacists and physicians qualified in various subspecialties (i.e., neurology, oncology), experts in health economics and relevant business people.
• the committee will assign one or more individuals within the group to review all published data on the product including any comments from FDA (advisory committee) about the product label, and consider the product in the context of other therapies currently available.
• the manufacturer will provide a dossier on the product to supplement the review which will include certain unpublished data and the wholesale acquisition price.
• a PBM will develop a policy describing guidelines for coverage of the product. These guidelines are added to existing drug formulary information and electronically communicated to specialty pharmacies within the PBM network. Usually physicians become aware of the guidelines through biopharmaceutical sales representatives and reimbursement specialists who work for the company.
• PBMs have the delicate task of maintaining satisfaction among their key stakeholders each of whom have diverse needs and expectations: employers who ultimately pay the cost for prescription drugs and want to control cost; employees (patients) who use the prescription drug plan and want the most effective drug at the lowest co-insurance cost to them; and physicians who determine the appropriate medication within the guidelines of the formulary of the PDP who want to have broad discretion on what they can prescribe. In general, PBMs do not try to dictate the usage of particular medicines but steer the utilization towards the least costly but most effective option(s).
• Physician evaluates patient and decides on a specialty drug.
• Office staff/physician checks guidelines for use of therapy based on patient's PDP and formulary, or works with reimbursement specialists at the biopharmaceutical company or a third-party organization retained by the biopharmaceutical company to obtain financial support. This may also include the need to obtain information through companion diagnostic testing prior to prescribing the drug.
• Office staff submits prescription to PBM which is approved or denied based on PBM prior approval process/medical policy guidelines. If prescription is denied, physician must complete a special medical necessity form to obtain approval.
• physician's office contacts an approved specialty pharmacy (SP) in the PBM network where the patient has drug coverage and transmits prescription electronically or by fax.
• SP specialty pharmacy
• the specialty pharmacy confirms electronically that the prescription has been approved by the PBM. 7.
• Patient calls SP and pays all or partial co-insurance cost or reimbursement support specialists contact SP and make payment on behalf of biopharmaceutical company.
• a SP gets authorization from a charitable organization.
• SP dispenses or delivers drug to the patient.
• SP submits a claim for drug reimbursement to the PBM after deducting the amount of patient's co-insurance.
• PBM reimburses SP, and submits a separate charge to the employer of the patient or Medicare depending on the coverage for payment of the drug cost.
• Physician's office collects co-insurance from patient or from biopharmaceutical company or charitable organization depending on the types of coverage and income eligibility.
• Physician submits a claim for drug reimbursement to the patient's PBM after deducting the amount of the patient's co-insurance for commercially insured patients.
• PBM reimburses physician's office and submits a separate charge to the employer of the patient for payment of the drug cost.
• CMS Centers for Medicare and Medicaid Services
• Subject generally refers to humans.
• subject includes one who is to be tested, or has been tested for prediction, assessment, diagnosis, theragnostics of a disease or disorder to be treated, wholly or partially, with a specialty drug.
• Small molecule drug refers to a pharmacologically active compound, e.g., as metabolized, having a molecular weight of less than about 1000 daltons, and typically between 300 and 700 daltons. Most drugs are small molecules, administered orally.
• small molecule drugs are tofacitinib and sofosbuvir.
• “Significant” in the context of a measure e.g., therapeutic or economic measure, e.g., in a difference in efficiency or response, will generally mean a number which can be objectively determined with some accuracy, and in the context is measurable and easily detectable. In most circumstances, e.g., it may be at least about 3%, 6%, 9% or more, and more preferably at least in the 10-15% or more range, as much as about 20% to 30% or more.
• the measure may refer to either an individual measure, averaged over a group, or measured over appropriate comparison groups. In many situations, the effects may be more easily or only identified in certain subsets or segments of the patient pools compared to others.
• High or “highly” will typically be at least significant, and will be a measure greater than threshold for statistically significant. Preferably it will be about 1.5 to 2X, whether on an individual or patient group basis, but which may be readily detectable in only certain subsets.
• an eligible patient or subset will be a patient or subset who initially is considered within the class of patients for whom the drug or treatment is considered appropriate.
• an eligible patient, payer, or employer in the context of assurance is one who qualifies according to the terms of the assurance, who has complied with the terms to an acceptable degree, e.g., patient therapeutic adherence, or timely payments by the payer or employer.
• Product differentiation herein refers to differentiation, e.g., theragnostics-guided, of a drug from another, commercially available drug(s) for treatment of a particular disease or cancer.
• One of the objectives being achieving better therapeutic and economic outcomes.
• Such differentiation can lead to selection of that particular drug instead of other intellectual property-protected drugs, or its biosimilars or generics.
• Product differentiation can enhance efficacy in patient subsets or segment(s), therapeutic value, economic value, financial value, or better pricing.
• This feature may be exploited by (a) a prescription drug plan, (b) a drug formulary, (c) a specialty pharmacy, (c) a payer, (d) an employer, (e) a pharmaceutical company, (f) a diagnostic company, (g) a drug distributor, or (h) a healthcare provider.
• Market enrichment herein refers to identification, e.g., theragnostics-guided, of a treatable patient, treatable subset(s) of patients, a treatable segment of patient market in a particular disease indication for the purposes of distribution, delivery of a drug, and treatment with a drug, with an objective of achieving better therapeutic and economic outcomes. This method selectively avoids patients who are considered not eligible for a particular therapy.
• This market enrichment feature may be exploited by (a) a prescription drug plan, (b) a drug formulary, (c) a specialty pharmacy, (c) a payer, (d) an employer, (e) a pharmaceutical company, (f) a diagnostic company, (g) a drug distributor, or (h) a healthcare provider.
• Prescription Drug Plan refers to a drug plan managed and administered by a PBM.
• PBM a disease-specific PDP consisting of specialty drugs and non- specialty drugs that are selected by a theragnostics-guided strategy.
• An exemplary disease- specific PDP targets rheumatoid arthritis.
• Antibody refers to an immunoglobulin or fragment thereof, and encompasses any such polypeptide comprising an antigen-binding fragment of an antibody.
• the term includes but is not limited to polyclonal, monoclonal, monospecific, multispecific (e.g., bispecific antibodies), humanized, human, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, grafted, antibody fragments (e.g., a portion of a full-length antibody, generally the antigen binding or variable region thereof, e.g., Fab, Fab', F(ab')2, and Fv fragments and in vitro generated antibodies so long as they exhibit the desired biological activity).
• Antibody therapy refers to a medical treatment involving an antibody.
• An “antibody therapy” in reference to an ADCC-treatable disease refers to an antibody that has a therapeutic mechanism based wholly or in part on ADCC.
• Biosimilar herein refers to a biological drug, e.g., an antibody such as adalimumab, that is structurally (i.e., gene and amino acid sequences; glycosylation and post translational modifications all combined) and functionally (i.e., therapeutically, immunologically, pharmacologically, etc.) similar or identical, but not necessarily identical to the original biological drug that is referred to as reference product.
• Intentional or unintentional changes e.g., amino acid changes or glycosylation heterogeneity, may or may not be present in biosimilars.
• Biosuperiors and biobetters are biosimilars. A biosimilar may not be
• Bioequivalent herein refers to a biological drug that is structurally an exact copy of the reference product, and thus therapeutically and functionally expected to be equivalent, e.g., not significantly better or worse than the original molecule, i.e., reference product. Minor glycosylation heterogeneity with little or no impact on therapeutic efficacy can be observed in bioequivalents.
• a bioequivalent can be a biosimilar but not all biosimilars are bioequivalents.
• Biosimilar substitution herein refers to the process by which an FDA-approved, interchangeable biosimilar product may be substituted for the prescribed biological product, e.g., a reference product developed by the innovator. Patients or physicians or payers or all of the above may have to be notified of the substitution. Under applicable provisions, payers, PBMs, or specialty pharmacies can authorize and (or) initiate substitution, e.g., preauthorized or authorized substitution. If the drug is interchangeable, it may be substituted (interchanged) for the reference product without the intervention of the healthcare provider who prescribed the reference product.
• Biosimilar extrapolation refers to approval, prescription, and administration of a biosimilar in other disease indications, though typically a clinical trial in that particular disease indication is not conducted.
• a reference product may have been approved in multiple disease indications. This extrapolation is based on the premise that if a biosimilar, preferably a bioequivalent, is shown to be comparable (e.g., indistinguishable) to the reference product in one disease indication in regards to safety and clinical efficacy, then it is expected to work similarly in other approved indications as that of the reference product.
• substitution herein refers to the prior authorization, dispensing and delivery, and treatment of a disease indication in the patient with another drug, e.g., specialty drug, non- specialty drug, that is other than the originally prescribed drug by the patient's disease specialist. Substitution will typically be approved by the prescribing physician, but in certain jurisdictions and appropriate situations, may be substituted without such when permitted.
• another drug e.g., specialty drug, non- specialty drug
• isolated cells refers to a preparation of cells that have been separated from other components in a mixture containing the cells.
• the cells are in the form of a "substantially purified" cell preparation, e.g., containing substantially lesser amounts of extraneous cells or materials.
• Genotype refers to the alleles present in DNA from a subject or patient, where an allele can be defined by the particular nucleotide(s) present in a nucleic acid sequence at a particular site(s). Often a genotype is the nucleotide(s) present at a single polymorphic site known or found to vary in the population. In some embodiments, a “genotype” is reflected in an expressed protein, which may be detected by known procedures, such as by using antibodies or protein sequencing. [00185] "Polymorphism” refers to the coexistence of more than one form of a gene or portion thereof. While a polymorphism is present at the nucleotide level, it may also manifest in an expressed gene product, e.g., a protein.
• Alleles refers to alternative forms of a gene or portions thereof. Alleles occupy the same locus or position on homologous chromosomes. When a subject has two identical alleles of a gene, the patient is said to be homozygous for the gene or allele. When a subject has two different alleles of a gene, the patient is said to be heterozygous for the gene. Alleles of a specific gene, including FcyRIIA, can differ from each other in a single nucleotide, or several nucleotides, and can include substitutions, deletions, and insertions of nucleotides. An allele of a gene can also be a form of a gene containing one or more mutations.
• Fey receptor polymorphism refers to more than one form of a gene for a specific Fey receptor.
• FcyRIIA polymorphism it is meant a polymorphism in the FcyRIIA gene which results in an amino acid substitution in the FcyRIIA protein.
• FcyRIIIA FcyRIIIA
• polymorphism it is meant a polymorphism in the FcyRIIIA gene which results in an amino acid substitution in the FcyRIIIA protein.
• amino acid residue and “amino acid position” are used interchangeably herein to refer to the position of the specified amino acid in the polypeptide chain.
• the amino acid residue can be represented as "X N ", where X represents the amino acid and the N represents its position in the polypeptide chain.
• X represents the amino acid
• N represents its position in the polypeptide chain.
• the variations can be represented with a " separating the polymorphisms. For example, two possible variations, e.g., polymorphisms, occur at the same amino acid position, the variations can be represented with a " separating the polymorphisms. For example, two possible
• polymorphisms can be represented as "X/Y N ", where X and Y represent the possible amino acids and N represents the position in the polypeptide chain.
• the two possible variations can also be represented as "XNY", where X, N and Y are as described above, e.g., H131 R.
• Induction therapy refers to the first course of treatment in treating a disease, disorder or medical condition.
• Mainntenance therapy refers to a therapy, therapeutic regimen or course of therapy which is administered subsequent to an induction therapy (an initial course of therapy administered to an individual or subject with a disease or disorder).
• therapy that includes maintenance therapy is included as comprising maintenance therapy.
• Antibody maintenance therapy refers to an antibody therapy, i.e., a therapy comprising one or more antibodies, which is administered as maintenance therapy in the therapeutic regimen or course of therapy.
• Responsiveness in reference to a subject refers to a treatment outcome or a clinical outcome of a treatment or therapy for a disease or disorder.
• the treatment outcome or clinical outcome can be measured according to standards recognized in the art for a specific disease or disorder.
• Predicting refers to determining the probability or likelihood of a particular outcome or event. In reference to responsiveness to treatment, the term refers to the likelihood of a particular treatment outcome or clinical outcome.
• Predicting responsiveness or “providing a prognosis” or “prognosing”, it is meant predicting whether or not the antibody maintenance therapy will have an impact on disease progression.
• OS “Overall survival” or “OS” refers to the time (in years) measured from diagnosis, study entry, or early randomization (depending on the study design) to death from any cause. Overall survival is a term that denotes the chances of staying alive for a group of individuals suffering from a disease or disorder.
• PFS progression free survival
• Progression free survival is a metric that denotes the chances of a disease stabilizing or being reversed in a group of individuals suffering from the disease. For instance, it denotes the percentage of individuals in the group who are likely to be as healthy if not healthier after a particular period of time following the start of maintenance therapy.
• RFS Relapse-free survival
• RFS refers to the time (typically in years) measured from diagnosis to first recurrence of the disease, e.g., first recurrence of a malignancy in a neoplastic disease.
• RFS is defined only for patients achieving complete remission, and is measured from the date of achievement of a remission until the date of relapse or death from any cause.
• EFS Event-free survival
• Time to Progression refers to a measure of time after a disease is diagnosed (or treated) until the disease begins to worsen.
• “Chemotherapy” or “chemotherapeutic regimen” refers to the administration of at least one chemotherapy agent that is used to treat a disease or disorder. Chemotherapy agents may be administered to a subject in a single bolus dose, or may be administered in smaller doses over time. A single chemotherapeutic agent may be used (single-agent therapy) or more than one agent may be used in combination as combination therapy.
• a chemotherapeutic agent as used herein comprises a non-biologic therapeutic, including small molecule drugs, peptide drugs, anti-sense nucleic acids, etc.
• administering an antibody therapy or “administering an antibody maintenance therapy” refers to administering an antibody to a subject for purposes of therapy (e.g., induction therapy) or maintenance therapy, respectively.
• administering regularly refers to administration of a therapeutic (e.g., drug or biologic) or treatment at periodic intervals.
• administering refers to administration of a therapeutic (e.g., drug or biologic) or treatment when the subject suffers a relapse or a diagnostic measure indicates the need for retreatment (e.g., target cell repopulation), and is generally determined by a medical doctor of skill in the art. This may involve continued monitoring of the patient, e.g., daily, weekly, monthly, etc., in regards to her disease state.
• a therapeutic e.g., drug or biologic
• a diagnostic measure indicates the need for retreatment (e.g., target cell repopulation)
• This may involve continued monitoring of the patient, e.g., daily, weekly, monthly, etc., in regards to her disease state.
• “Course of treatment” or “course of therapy” refers to administration of a drug or therapeutic for a period of time as part of a defined treatment plan.
• the course of treatment or therapy can be a first course, second course, third course, etc.
• the courses may or may not use the same therapeutic.
• the drug or therapeutic can be administered as a single dose or in multiple doses in a single course. Multiple doses in a course of therapy can be administered over a period of time, such as days, weeks or months, depending on the therapeutic and the disease or disorder to be treated. Subsequent treatment strategies may be adjusted according to previous treatment response or disease progression, remission, or relapse patterns.
• “Differential dosing” refers to the selection and/or administration of a treatment regimen in which the dose of an active pharmaceutical ingredient (e.g., drug or biologic) is altered to optimize for efficacy and/or tolerance in the treatment of a subject.
• the active pharmaceutical ingredient for which the dose is altered can be in the form of a monotherapy or as a component in a combination therapy.
• differential dosing schedule refers to the selection and/or administration of a treatment regimen in which the length of time the patient is treated is altered to optimize for efficacy and/or tolerance in the treatment of a subject.
• differential dosing schedule includes a form of maintenance therapy.
• “Differential dosing frequency” refers to the selection and/or administration of a treatment regimen in which the frequency of administration or dosing cycle is altered to optimize for efficacy and/or tolerance in the treatment of a subject.
• Step therapy or "fail first” or “fail-this-one-first therapy” refers to a process an insurance company requires the patient to go through first and fail a medication or service preferred by the insurance provider, typically considered more cost effective, often on the short term, or safer, before the insurance company will cover a different drug or service. Unless absolutely necessary, majority of specialty drugs are not currently favored by PBMs as the first therapy particularly when less-expensive therapies or treatment modalities are available.
• Personalized medicine refers to methods of identifying the right patient(s) for the right therapy.
• the patient may have a characteristic genotypic and (or) phenotypic feature(s) and such features are mechanistically relevant for achieving better, e.g., excellent response or remission, therapeutic efficacy when an appropriate therapy is administered.
• Such mechanistic features may involve better binding of the drug, better mechanism of action of the drug, better cell killing of specific cell types, etc.
• ADCC is one such mechanism of action that is linked to genetic polymorphisms in patients.
• individualized medicine or precision medicine contemplates the longitudinal and temporal disease states of the individual; the matching of the therapy to the individual will typically include evaluating the changes in that individual with time in regards to: disease progression, remission, relapse patterns, and other physiological factors which affect the disease state.
• individualized medicine is a more temporally-based matching of treatment to the current state of the individual with the main objective of achieving better treatment and economic outcomes.
• Theragnostic methods guide such individualized or precision medicine.
• Matching an appropriate drug to an appropriate individual patient is selecting a combination that both are correct, i.e., both the drug to the patient, and the patient to the drug. Sometimes there will be multiple matches, in which case, certain pairings will be preferred for various reasons, whether medical, convenience, practical, economic, or other reasons. Theragnostics methods help guide such matching.
• Stratifying or “stratification” refers to classifying subjects into distinct groups based common characteristic(s) or trait(s). Stratification can be based on a single trait or two or more traits, e.g., of disease presentation. When the occurrences of two or more
• Reference stratification refers to an established stratification scheme that has stratified a treatment response/clinical outcome-genotype association, with statistically significant differences between the different groups in the stratification.
• a subject afflicted with an ADCC treatable disease whose genotype for the Fey receptor polymorphism e.g., FcyRIIA and/or FcyRIIIA
• an ADCC treatable disease whose genotype for the Fey receptor polymorphism (e.g., FcyRIIA and/or FcyRIIIA)
• FcyRIIA and/or FcyRIIIA genotype for the Fey receptor polymorphism
• Correlating refers to the establishment of a relationship, e.g., mutual or reciprocal, between, e.g., genotype status and therapeutic efficacy of certain treatments as described herein. That is, correlating may refer to relating the genotype status to responsiveness to treatment or therapy.
• Excluding a treatment or therapy refers to removing a possible treatment from consideration, e.g., for use on a particular patient, based on the presence or absence of a particular variance(s) in one or more genes of that patient. This typically means the treatment or therapy is counter-indicated or inappropriate for the particular patient.
• Excluding a subject refers to removing the subject from consideration of a treatment or therapy, including in reference to treatment or therapy in clinical trials, based on the presence or absence of a particular variance(s) in one or more genes of that patient. This typically means the patient is therapeutically ineligible for such treatment or therapy.
• “Selecting a treatment or therapy” refers to including a possible treatment for consideration, e.g., for treating a particular patient based on the presence or absence of a particular variance(s) in one or more genes of that patient. Such a treatment or therapy is considered an option for the patient, though some options may be of higher or lower appropriateness, depending upon the specific criteria being applied based on theragnostic methods.
• Selecting a subject refers to including the subject for consideration of a treatment or therapy, including in reference to treatment or therapy in clinical trials, based on the presence or absence of a particular variance(s) in one or more genes of that patient.
• “Companion diagnostics” refers to devices or tests that provide information that is essential (required) for the safe and effective use of a corresponding therapeutic product, typically linked to a specific drug within its approved labeling. Others refers this to determining suitability of patients for tailored or targeted forms of therapy. Currently, these tests do not provide efficacy or financial assurances. [00220] “Complementary diagnostics” refers to tests intended but not required to indicate whether a patient should be treated with certain therapies rather than one particular drug. Currently, these tests do not provide efficacy or financial assurances.
• biomarkers are commonly used for diagnostic (disease identification) and prognostic (predicted outcome or progression) purposes.
• a theranostic biomarker could identify the most appropriate treatment for an individual, indicate the correct dose, or predict response to treatment. This approach attempts to maximize drug efficacy, minimize toxicity and provides a more informed treatment choice (for physicians and patients). Perhaps for a theranostic biomarker to be truly clinically useful, it should retain predictive value for response irrespective of the methods used to assess improvement in disease activity.
• Neoplastic disease or disorder refers to a disease state in a subject in which there are cells and/or tissues which proliferate abnormally. Neoplastic disorders can include, but are not limited to, cancers, sarcomas, tumors, leukemias, lymphomas, and the like.
• Hyperproliferative disorders are conditions in which there is at least some element of unregulated cell growth.
• cancer nuclear cells
• nonenoplasm cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
• Cancerous cells can be benign or malignant.
• Viral infections e.g., HCV infection in B-cells
• hyper(lympho)proliferative disorders can lead to hyper(lympho)proliferative disorders.
• Autoimmune disease or disorder refers to a disease state or condition caused by immune-responsiveness against self-tissues and/ or substances normally present in the body. It is generally associated with production of inflammatory factors, which further promote tissue destruction and disease progression. Inflammatory macrophages, inflammatory NKT cells, etc., can cause chronic inflammatory diseases such as
• Autoimmune diseases can be systemic or organ-specific.
• systemic autoimmune diseases include: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma and Sjogren's syndrome.
• organ-specific autoimmune diseases include: Addison's disease, Autoimmune hemolytic anemia, Goodpasture's syndrome, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, insulin- dependent diabetes mellitus, myasthenia gravis, pernicious anemia, poststreptococcal glomerulonephritis and psoriasis.
• Inflammatory disease or disorder refers to a disease or disorder caused by or resulting from or resulting in inflammation.
• the term "inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and cell death.
• an inflammatory disease or disorder can be an aspect of other diseases, such as autoimmune diseases.
• Microbial infections refers to a disease or disorder caused by or resulting from a microbial infection. Microbial infections refer to diseases caused by bacteria, fungi, viruses. Examples include infections by hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
• HCV hepatitis C virus
• HAV human immunodeficiency virus
• Allograft rejection refers to a reaction within a transplanted organ or tissue involving both immunologic and non-immunologic responses that ultimately lead to damage or necrosis of some or all of the transplanted organ or tissue.
• An "organ” refers to a part of the body of a subject exercising a specific function (such as a heart, kidney, liver, or lung).
• a "tissue” refers to a collection of similar cell types (such as epithelium, connective, muscle and nerve tissue).
• a "transplanted tissue or organ” is meant to refer to a tissue or organ taken from one subject and implanted into a subject other than the subject from which the organ or tissue was taken.
• kits for selecting from a disease or condition means that a subject is either presently subject to the signs and symptoms, or is more likely to develop such signs and symptoms than a normal subject in the population.
• methods of the present invention which relate to treatments of patients (e.g., methods for selecting a treatment, selecting a patient for a treatment, and methods of treating a disease or condition in a patient) can include primary treatments directed to a presently active disease or condition, secondary treatments which are intended to cause a biological effect relevant to a primary treatment, and prophylactic treatments intended to delay, reduce, or prevent the development of a disease or condition, as well as treatments intended to cause the development of a condition different from that which would have been likely to develop in the absence of the treatment.
• Treatment refers to a process that is intended to produce a beneficial change in the condition of a mammal, e.g., a human, often referred to as a patient.
• a beneficial change can, e.g., include one or more of restoration of function, reduction of symptoms, limitation or retardation of progression of a disease, disorder, or condition or prevention, limitation or retardation of deterioration of a patient's condition, disease or disorder.
• targeted therapies e.g., ADCC-based therapy
• “treatment” or “treatable” is meant the ADCC- based therapy achieves a desired pharmacologic and/or physiologic effect on the disease or disorder.
• the effect may be prophylactic in terms of completely or partially preventing the disease/disorder or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the disease/disorder and/or adverse effect attributable to the disease/disorder.
• the terms include: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing remission or regression of the disease.
• the therapeutic agent may be administered before, during or after the onset of the disease or disorder.
• the treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues.
• Target cell depletion assay refers to a depletion assay, e.g., an ADCC assay measuring the reduction, depletion, or killing of cells targeted by an antibody.
• Target cell depletion assay can be done in vitro, e.g., human B cells used ex vivo with an anti-CD20 antibody and effector cells.
• the target cell depletion assay can be in vivo, e.g., by measuring number of B cells in a subject after the administration of an anti- CD20 antibody by withdrawing blood samples, and measuring time-dependent depletion assays over a period of several weeks. Typically, MRD-FC is used to measure these populations. See Dass, et al.
• Target cell repopulation assay refers to a repopulation assay, e.g., an ADCC assay measuring the recovery (slow or fast) or recover rate of a target cell population following administration of an antibody, e.g., repopulation of B cells following administration of an anti- CD20 antibody.
• Assays can be in vivo, e.g., by measuring number of specific subsets of B cells repopulating in a subject after the administration of an anti-CD20 antibody by withdrawing blood samples, and measuring time-dependent depletion assays over a period of several weeks.
• MRD-FC is used to measure these populations in vitro.
• Faster repopulation is a measure of imminent disease relapse.
• Cell population targeted by an antibody refers to a cell or group of cells that are specifically recognized by the antibody of interest, and in the context of ADCC, killed or lysed through an ADCC mechanism.
• Clinical trial refers to an investigation of safety and efficacy of a treatment for a disease or disorder. Typically, clinical trials are carried out to obtain approval from a governmental regulatory agency for marketing a drug.
• Health service payer refers to an entity that finances or pays for the medical treatment or therapy.
• a health service payer can include among others, an insurance company, a government entity, a private company, a PBM, an employer, a pension fund, or a patient.
• the term theragnostic herein refers to products, tests, methods and procedures that can inherently guide treatment in (i) a single patient or (ii) a collection of patients, e.g., subset(s) of patients, entire disease-specific population covered by a payer or employer, suffering from a particular disease with a core objective of achieving excellent or near-excellent treatment outcomes in a reasonable timeframe. Such outcomes include disease remission, cure, excellent response, etc.
• Theragnostic procedures are inherently linked to therapies, treatments, and treatment guidance that collectively dictate efficacy and financial assurances, prior authorization, and the designing of a drug-specific formulary. Such assurances are products offered to payers and employers. Patients typically pay 20- 30% of the specialty drug cost and hence, from the payment standpoint, patients are also payers.
• Such theragnostic results are necessary for (a) prior authorization of a specialty drug mandating efficacy and financial assurances; (b) designing and developing a formulary, e.g., disease-specific drug formulary, such that the decision to include or not include a drug in the formulary is governed by the theragnostic results.
• Theragnostic products will guide in the selection of drugs, e.g., mechanism of action based treatment options in specific subsets of patients, with an objective of achieving remission or excellent response in defined subsets of patients. Some approved drugs with moderate or substandard efficacy profiles may be excluded entirely from the formulary.
• a drug that is selected to the formulary based on such theragnostic products will have product differentiation and market enrichment advantages.
• theragnostic methods are mechanistic: (a) based on the mechanism of action of the drug itself and understanding why a patient or subset(s) of patients respond well given their particular genetic makeup (e.g., the primary therapeutic mechanism of rituximab monotherapy in B-NHL is ADCC); and (b) based on the pathophysiology of the disease itself as stratified, e.g., according to immunologically defined subtypes of disease (e.g., fibrinogen induced arthritis), disease severity, pharmacology, disease states, and physiology.
• the resolution of theragnostic procedures can be enhanced by combining more than one mechanistic determinants.
• the core objectives of the use of theragnostics are: (i) to select an appropriate therapy for a given patient, given her disease characteristics, when multiple therapies are available to choose from; (ii) alternatively, to decide when not to select a particular therapy for a given patient, given her disease characteristics; (iii) to achieve clinical remission or excellent response when the patient is administered with a carefully chosen therapy, e.g., using a particular drug of choice at the first instance. Any or all of the above objectives can be accomplished by the use of theragnostic procedures.
• Theragnostic functions entail: (a) therapeutic appropriateness, which is the selection of a therapeutic (drug), typically based on use of a particular drug, preferably a priori, when multiple therapeutics are available in a formulary to choose from, for a particular subset(s) of patients or an individual patient; (b) therapeutic guidance, which provides details of therapy, including aspects of specific drug dosing and schedule details during a treatment cycle; (c) therapeutic effectiveness, which is a measure of how well the therapy, including the drug, worked in that patient or how well the patient responded to that treatment during and at the end of the treatment cycle; and (d) selection of an alternate therapeutic (drug) that is considered as the next best choice based on, e.g., a mechanistic rationale, if the first choice failed to achieve reasonable therapeutic effectiveness. Any or all of the above objectives can be accomplished by the use of theragnostic procedures.
• theragnostic procedures provide reliable, actionable treatment (and therapeutic) guidance for a single patient (what is generally referred to as precision or individualized medicine), subset(s) and subtype(s) of patients (stratified medicine), as well as for the entire disease population.
• Theragnostic methods provide significant advantages to patients (considered one of the payers in the specialty drug context), payers and employers in not only managing diseases and therapies, but also controlling costs both on a per patient basis and for the entire disease population being managed by a payer or employer.
• the theragnostic procedures can provide actionable treatment guidance by summary guidelines to achieve preferred outcomes.
• the guidance might be summarized by directing specific drug selection (from among alternatives; i.e., therapeutic appropriateness) for defined ranges of theragnostic readouts, directing specific therapy selection (from among alternatives of how drug is administered; i.e., therapeutic guidance) for defined ranges of theragnostic readouts, and directing overall therapy strategy (from among alternatives; i.e., therapeutic effectiveness) for defined ranges of theragnostic readouts, and specific exclusion criteria (from among alternatives; i.e., selection of alternative therapeutic) for particular other theragnostic readouts where treatment strategy is contraindicated (e.g., by toxicity or side effect) or first strategy fails.
• a single or a combination of DNA, RNA, protein, or immunological features may constitute a theragnostic product or evaluation.
• it may include metabolic evaluation, which may be useful for individualized pharmacology of half-life, absorption, distribution, metabolism, excretion, turnover, etc.
• Such examples include biomarkers, polymorphisms, gene expression profiles, protein expression profiles, presence or absence of specific protein markers or immunological, metabolic, physiological profiles, and many aspects which affect the therapy response.
• a single or a combination of companion diagnostic tests or in vitro diagnostic tests may constitute a theragnostic procedure.
• NSCLC non-small-cell lung cancer
• Such ambiguities are also observed in other therapies, e.g., cetuximab (K-RAS mutations in metastatic colorectal cancer versus NSCLC), trastuzumab (Her-2 expression with a 3 + score in breast cancer).
• cetuximab K-RAS mutations in metastatic colorectal cancer versus NSCLC
• trastuzumab Her-2 expression with a 3 + score in breast cancer.
• PDL1 IHC is approved as a companion diagnostic only for pembrolizumab in NSCLC.
• FDA has approved it as a 'complementary diagnostic' in melanoma and for nivolumab in NSCLC, to assist but not dictate treatment decision-making.
• the value of the biomarker may be limited by technical pitfalls such as irregular expression levels throughout the tumor and lack of a single, standardized IHC test. But a more fundamental limitation is that tumor expression of PDL1 does not provide the whole picture (Nature Rev. Cancer 16, 275-287; 2016).
• specialty drugs e.g., small molecule pharmaceuticals, protein biologies, therapeutic antibodies, etc.
• populations generally show wide variations in response to the drug treatment, due in part, to genetic variations in populations, where the genetic variations affect therapeutic properties of the drug.
• genetic variations can affect, among others, the direct biological target of the drug, metabolism of the drug, and/or the biological mechanisms by which the drug mediates its therapeutic effect.
• a drug may only be effective in individuals or subset(s) of individuals, or subjects who have a particular genetic or protein variation and ineffective in those individuals who do have the particular genetic or protein variation, and may experience adverse side effects (e.g., increased toxicity).
• a number of therapeutic antibodies have been developed for treating a variety of diseases including cancers, autoimmune diseases, and inflammatory disorders.
• these antibodies e.g., rituximab in follicular lymphoma
• Genetic variations can be determined at the DNA or RNA level whilst protein variations can be observed at the amino acid level.
• stratification of patients can be based on the therapeutic mechanism of action, e.g., ADCC. See US patent publication 20100291549 and WO 201309047820, both of which are incorporated herein by reference.
• stratification of patients can be based on disease severity mechanisms: (a) enhanced proinflammatory potential, and (b) impaired immune complex clearance.
• multiple stratification mechanisms e.g., ADCC and EPP mechanisms, or ADCC and ICC mechanisms, can be combined to develop a theragnostic strategy. See U.S. Provisional Patent Applications 62,332,315 and 62,322,325 both dated May 05, 2016, both of which are incorporated herein by reference.
• ADCC antibody dependent cell-mediated cytotoxicity
• effector cells of the immune system such as natural killer (NK) cells, macrophages, neutrophils, and eosinophils, kill target cells that have been bound by specific antibodies. Destruction or killing of the target cell can occur through phagocytosis; ADDC-mediated lysis; ADCC-mediated apoptosis; and trogocytosis (antibody- dependent cytotoxicity mediated by polymorphonuclear granulocytes).
• the posited mechanism of ADCC is the binding of the effector cells to the Fc (constant) portion of the bound antibody through Fc receptors, particularly the Fey receptors, present on the effector cells.
• Fc receptors particularly the Fey receptors
• variations or polymorphisms in the Fc receptor can affect the effectiveness of antibodies that work via the ADCC mechanism.
• the association between Fc receptor polymorphisms and ADCC has led to use of Fc genotypes for selecting patients for antibody- based therapies, e.g., US patent publication 20100291549 and WO 201309047820, both of which are incorporated herein by reference. While antibodies may have multiple
• ADCC mechanisms of action, e.g., ADCC, blocking cell signaling or neutralization
• ADCC may be a major or contributory mechanism to the therapeutic effects. The contribution by other mechanisms does not preclude or obviate the ADCC mechanism.
• EPP enhanced proinflammatory potential
• a disease or disorder characterized by enhanced proinflammatory potential refers to a process in which immune cells involved in inflammation, e.g., neutrophils, monocytes and macrophages, migrate, accumulate, and become activated at the sites of disease activity.
• the disease or disorder characterized by enhanced proinflammatory potential is described as “AAI” or “attraction, accumulation, and activation of immune cells”.
• AAA attraction, accumulation, and activation of immune cells.
• this mechanism leads to the localized accumulation of cytokines (e.g., TNF-oc, IL-1 , ⁇ _-1 ⁇ , IL-6, GM-CSF, etc.), reactive oxidants, proteolytic enzymes which then collectively contribute to EPP.
• cytokines e.g., TNF-oc, IL-1 , ⁇ _-1 ⁇ , IL-6, GM-CSF, etc.
• Immuno complex clearance refers to clearance of immune complexes from a subject's body.
• the ICC mechanism is mediated by the interactions of IgG to Fey receptors.
• the clearance can be systemic or organ specific clearance.
• Immunopaired ICC disease or “impaired ICC disorder” refers to a disease or disorder characterized by abnormal or pathogenic levels of immune complexes, including immune complexes comprised of autoantibodies or microbial pathogens. See U.S. Provisional Patent Application 62,332,315 dated May 05, 2016, which is incorporated herein by reference.
• responsiveness to antibody maintenance therapy can also allow selection of various treatment options, including alternatives to antibody therapy if the subject responds poorly to antibody maintenance therapy.
• This a priori identification and selection of patients who will respond (and not respond) to a therapy has significant commercial and therapeutic advantages, and will be useful to drug developers, theragnostic providers, physicians, health care payers, pharmacy benefit managers, disease and therapy management care specialists, and/or specialty pharmacists.
• the reference stratification also referred to as a reference index can be prepared for an ADCC treatable disease for a particular specialty drug.
• the reference stratification can be prepared by determining the genotype of each subject in plurality of subjects having a disease or disorder treated with a specialty drug, and determining the treatment outcome or clinical outcome. The statistical significance of the linkage between the genotype and the responsiveness can be determined by standard statistical methods.
• the treatment outcome or clinical outcome assessments can use diagnostic measures known in the art and typically specific to each disease or disorder. See, e.g., World Health Organization International Classification of Diseases (ICD), e.g., ICD 10 and Merck Manual of Diagnosis and Therapy, Merck Publishing (201 1 ).
• the reference stratification data can be in printed form or stored in a computer memory.
• the comparing of the determined genotype of the subject to the reference stratification can be implemented by a computer using methods standard in the art.
• the terms "reference” and "control” as used herein refers to a standardized genotype to be used to interpret the genotype of a given patient and assign a prognostic class thereto.
• the reference or control may be a genotype that is obtained from a cell/tissue known to have the desired phenotype, e.g., responsive phenotype, and therefore may be a positive reference or control genotype.
• the reference/control genotype may be from a cell/tissue known to not have the desired phenotype, and therefore be a negative reference/control genotype.
• a subject or patient sample e.g., cells or collections thereof, e.g., a blood sample or tissue or biopsy sample
• an antibody therapy e.g., antibody maintenance therapy.
• a patient with an ADCC-treatable disease who is responsive to antibody maintenance therapy will experience at least a slowing in disease progression; in some instances, at least a cessation of disease progression; in some instances, an improvement in health, i.e., a reversal of disease progression, a loss of disease symptoms, etc.
• a patient with an ADCC- treatable disease who is not responsive to antibody maintenance therapy will not experience at least a slowing in disease progression, or at least a cessation in disease progression, or an improvement in health.
• responsiveness to an antibody maintenance therapy is responsiveness to maintenance therapy with the same antibody used in the induction therapy.
• responsiveness to an antibody maintenance therapy is responsiveness to maintenance therapy with an antibody other than that used in the induction therapy.
• PFS progression free survival
• OS overall survival
• RFS relapse-free survival
• EFS event-free survival
• the above-obtained information about the cell/tissue being assayed is employed to diagnose a host, subject or patient with respect to responsiveness to antibody maintenance therapy, as described above. In some embodiments, the above- obtained information is employed to give a refined probability prediction as to whether a subject will or will not respond to a particular specialty drug therapy and a financial payment decision based thereon.
• excellent responders may exhibit, e.g., at least about 85%, 90%, or higher mean or median response rates (or better than about 85 percentile measure of outcome among the unstratified population); very good responders may exhibit lesser measures of responsiveness, e.g., at least about 70%, 75%, or 80% response rates (or from about top 75th percentile to 85th of outcomes); good responders may have better than average response rates, e.g., at least about 55%, 60%, or 65% response rates (or from about top 55th percentile to 75th of outcomes); moderate responders will typically have near average response rates, e.g., in the range of about 45%, 50%, or 55% response rates (or from about 45th to 55th percentile of outcomes); below average responders may have lower response rates, e.g., below about 45%, 35%, or 30% (or from about 25th percentile to about 45th percentile of outcomes); very poor responders may have even lower response rates, e.g., below about 25%
• the average overall response rates to treatment for overall unstratified population will be in the 40% to 60% range.
• the above and below average responder subsets will preferably have at least about 7-15% better and lower relative mean or median responsiveness measures, respectively, and the good and poor responders will preferably have at least another 7-15% better and lower mean or median responsiveness measures, respectively.
• the very good and very poor responders will have correspondingly better and worse mean or median responsiveness measures, and the excellent and non- responders even more extreme. How many different stratification categories are used will depend largely upon the dispersion of the responsiveness measures across categories of treatment response, and the variation of individual responsiveness measures within each category of treatment response.
• the range of responsiveness across the categories will range from less than about 10% to at least about 90%.
• the patients may be stratified by strata of percentile responsiveness ranges.
• the highest may be the top 15 percentile stratum of response, the next the second top 15 percentile stratum, etc., down to the lowest category of the bottom 15 percentile stratum, providing six strata of responsiveness. Improvement of responsiveness may be moving from one stratum to a higher stratum, preferably two or more.
• a reference stratification or reference index relating genotype group to categories of antibody maintenance treatment response can be used in both directions. It can be used to predict the responsiveness to maintenance treatment based on genotype at the relevant positions. This will be very useful for the patient and treating doctor, to provide means to arrive at likely response to alternative treatments. Conversely, for a given responsiveness to maintenance treatment, one can identify genotypes of patients which should achieve such response. Thus, a theragnostic provider or treatment payer may identify which patients are likely to response as indicated by the reference. Alternatively, for those who respond poorly, additional or alternative treatment strategies may be applied. In other embodiments, those who would respond poorly are not treated with an available treatment with low efficacy for those patients.
• the subject preferably a human subject, has had or will have a specialty drug as an induction therapy.
• the induction therapy can comprise chemotherapy.
• the induction therapy can comprise antibody therapy.
• the subject has previously received or is receiving antibody maintenance for the disease or disorder.
• the genotype and the predicted responsiveness can be applied to many antibodies, particularly where the Fc region is human Igd, that have ADCC as a therapeutic mechanism across many different diseases and disorders, and therefore applicable to the various methods described in the present disclosure.
• genotype evaluation results may be reported separately from therapy recommendations, the interpretation of genotype results will often be provided in a report describing preferred or standard treatment options.
• the genotype information, the stratification, the selection/exclusion of subjects for therapy, the predicted treatment outcome, and the treatment options, as further discussed in the present disclosure can be reported in electronic, web-based, or paper form to the human subject, a health care payer, third party payer, a health care provider, a specialty pharmacist, a DTM care provider, a physician, a pharmacy benefits manager, or a government office. Insurance coverage or financial obligations may then be based thereon.
• the methods for predicting responsive can be applied to the selection of subjects who are likely to respond positively to specialty drugs. Conversely identification of subjects who respond poorly provides an opportunity to choose alternative treatments that could produce better treatment outcomes than the said specialty drug. In addition to the benefit for the patient, the ability to select subjects who are likely to have a more favorable treatment outcome provides many advantages to payers, providers, theragnostic providers, DTM care providers, specialty pharmacists, and insurers.
• the method of treating can further comprise measuring the level of functional capacity of immune cells, e.g., immune effector cells, specifically, ADCC capacity or function in the subject, thus providing another independent criterion or metric for selecting subjects who will likely have a positive treatment outcome for the antibody maintenance therapy.
• immune cells e.g., immune effector cells, specifically, ADCC capacity or function in the subject. Examples include selective or non-selective depletion of specific subsets of B-cells, inflammatory macrophages, tumor infiltrating macrophages, inflammatory NKT-cells, etc. Selective repopulation of specific subsets of B-cells is yet another example of measurement of ADCC function.
• the present disclosure further provides methods of treating subjects with a specialty drug, e.g., an ADCC treatable disease or disorder based on selection of a subject who is likely to have positive treatment outcomes.
• a specialty drug e.g., an ADCC treatable disease or disorder based on selection of a subject who is likely to have positive treatment outcomes.
• a method of treating a human subject having an antibody dependent cell- mediated cytotoxicity (ADCC)-treatable disease or disorder with an antibody maintenance therapy comprises:
• Fey receptor functional polymorphism affecting ADCC activity, wherein the Fey receptor functional polymorphism is selected from a FcyRlla polymorphism and a FcyRIIIA polymorphism;
• a method of treating a subject having an antibody dependent cell-mediated cytotoxicity (ADCC)-treatable disease or disorder with an antibody having an antibody dependent cell-mediated cytotoxicity (ADCC)-treatable disease or disorder with an antibody
• the human subject for antibody maintenance therapy by stratifying the human subject into a responsiveness group based on a determined genotype of the human subject for one or more Fey receptor functional polymorphisms affecting ADCC activity, wherein the Fey receptor polymorphism is selected from a FcyRlla functional polymorphism and a FcyRIIIA functional polymorphism; and
• stratification of the subject into a responsiveness group is carried out by comparing the determined genotype of the human subject to a reference stratification that relates responsiveness to antibody maintenance therapy for the ADCC treatable disease to genotypes of the Fey receptor polymorphism.
• the method of treating can further comprise measuring the level of ADCC capacity or function in the subject, providing another independent criterion or metric for treating subjects who will likely have a positive treatment outcome for the antibody maintenance therapy.
• Examples include selective or non-selective depletion of specific subsets of B-cells, inflammatory macrophages, tumor infiltrating macrophages, inflammatory NKT-cells, etc.
• Selective repopulation of specific subsets of B-cells is yet another example of measurement of ADCC function as well as disease remission and relapse patterns. Responsiveness predictions may be a component of an insurance coverage decision.
• the treatable disease or disorder is selected from a neoplastic disease, an autoimmune disease, an inflammatory disorder, a microbial infection, or allograft rejection.
• the disease treated with a specialty drug comprises a neoplastic disease, i.e., hyperproliferative disorders, or malignancies, which are
• Neoplastic diseases include, among others, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); bladder cancer; bone cancer; bowel cancer; brain tumors; breast cancer; cancer of unknown primary; carcinoid; cervical cancer; choriocarcinoma; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); colon cancer; colorectal cancer; endometrial cancer; eye cancer; gallbladder cancer; gastric cancer; gestational trophoblastic tumors (GTT); hairy cell leukemia; head and neck cancer; Hodgkin's lymphoma; kidney cancer; laryngeal cancer; leukemia; liver cancer; lung cancer; non-small cell lung cancer; lymphoma; melanoma skin cancer; molar pregnancy; mouth and oropharyngeal cancer; myeloma; nasal and sinus cancers; nasopharyngeal cancer; B-cell non-Hodgkin'
• one class of neoplastic diseases for which a number of ADCC-based therapies have been developed is the hematological malignancies, e.g., B-cell malignancies, including non-Hodgkin's Lymphomas (B-NHL).
• B-cell malignancies are those disorders that derive from cells in the B cell lineage, typically including hematopoietic progenitor cells expressing B lineage markers, pro-B cells, pre-B cells, B-cells and memory B cells; and that express markers typically found on such B lineage cells.
• the B-NHL are a variety of B-cell neoplasms, and include precursor B-lymphoblastic leukemia/lymphoma; peripheral B-cell neoplasms, e.g., B-cell chronic lymphocytic leukemia; prolymphocyte leukemia; small lymphocytic lymphoma; mantle cell lymphoma; follicular lymphoma; marginal zone B-cell lymphoma; splenic marginal zone lymphoma; hairy cell leukemia; diffuse large B- cell lymphoma; T-cell rich B-cell lymphoma, Burkitt's lymphoma; high-grade B-cell lymphoma, (Burkitt-like); etc.
• B-cell chronic lymphocytic leukemia e.g., B-cell chronic lymphocytic leukemia
• prolymphocyte leukemia e.g., prolymphocyte leukemia
• small lymphocytic lymphoma
• Markers that are specifically found on B cells that may be used as target antigens for ADCC-based therapies include CD45R, which is an exon-specific epitope found on essentially all B cells, and is maintained throughout B cell development (Coffman, et al. (1982) Immunol. Rev. 69:5-23); CD19, CD20, CD22, and CD23, which are selectively expressed on B cells and have been associated with B cell malignancies (Kalil and Cheson (2000) Drugs Aging 16:9-27; U.S. Patent No. 6,183,744, herein incorporated by reference); surface immunoglobulin, including epitopes present on the constant regions or idiotypic determinants, which have been utilized in immunotherapy (Caspar, et al.
• CD20 antigen a human B cell marker that is expressed during early pre-B cell development and remains until plasma cell differentiation.
• C2B8 chimeric antibody
• ADCC-based therapies have also been developed for solid tumors, e.g., colorectal cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, breast cancer, head and neck cancer, renal cell carcinoma, and the like.
• the exemplary antigens include— CD52, VEGF, CD30, EGFR, CD22, CD33, CD20, CTLA4, CD2, CD25, EphA2, G25, ErbB2, phosphatidyl serine, and HER2.
• the disease or disorder treated with a specialty drug is an autoimmune disease.
• Autoimmune diseases are diseases characterized by an overactive immune response of the body against substances and tissues normally present in the body.
• autoimmune diseases include, among others, agammaglobulinemia, amyotrophic lateral sclerosis, ankylosing Spondylitis, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune uveitis, Behcet's disease, Berger's disease, celiac disease, Chagas disease, chronic obstructive pulmonary disease, Churg-Strauss syndrome, Crohn's disease, colitis, diabetes mellitus type 1 , discoid lupus erythematosus, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), idiopathic pulmonary fibrosis, idi
• the disease treatable with specialty drug is an inflammatory disease.
• inflammatory diseases or disorders occur in the context of autoimmune diseases.
• Exemplary inflammatory diseases include, among others, Crohn's disease, ulcerative colitis, inflammatory bowel disease, ileitis and enteritis; vaginitis;
• psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; spondyloarthropathies; scleroderma;
• respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, diabetes mellitus, glomerulonephritis, and the like.
• the disease or disorder treated with a specialty drug is a microbial infection by a pathogen, including viruses, bacteria, fungi, protozoa, and multicellular parasites.
• Microbial infections of interest include hepatitis C virus, HIV, malaria, and tuberculosis.
• the disease or disorder treated with a specialty drug is an allograft, i.e. transplant, rejection.
• Organs that are typically transplanted include heart, kidneys, liver, lungs, pancreas, intestine, and thymus.
• Antibodies used to treat organ rejection can be targeted to markers expressed on cells that mediate allograft rejection, e.g., CD25 (anti-CD25) and CD3 (anti-CD3).
• An antibody for any of the methods in the present disclosure e.g., predicting responsiveness, selection, treatment, theragnostic applications, payment decisions, etc., is used in the broadest sense, as defined herein, so long as they exhibit the desired biological activity (e.g., binding to target and mediating ADCC).
• Antibodies for the purposes herein include, among others, chimeric, humanized or fully human antibodies. In some aspects, a combination of one or more antibodies with different specificities, either for epitopes of a single antigen, or for multiple antigens, may be used.
• the appropriate antibody can be chosen by the skilled artisan in view of the treatable disease or condition and the target of the antibody.
• the antibodies can comprise an anti-CD19 antibody, anti-CD20 antibody, anti-CD22, anti-CD25 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD52 antibody, anti-EGFR, anti-EphA2 antibody, anti- GD2 antibody, anti-G250 antibody, anti-ErB2 antibody, anti-folate receptor a antibody, anti- folate receptor ⁇ antibody, or anti-phosphatidylserine antibody, or combinations thereof, depending on the specific neoplastic disease.
• the antibody can comprise anti-CD20 antibody.
• anti-CD20 antibodies can be selected from, among others, rituximab, ofatumumab, ibritumomab, tositumomab, veltuzumab, and obinutuzumab.
• a biosimilar or biosuperior anti-CD20 antibody can also be selected instead.
• the antibody for maintenance therapy can comprise, among others, an anti-CD29 or anti-CD20 antibody.
• anti-CD20 antibodies that can be used to treat autoimmune diseases include those described for neoplastic diseases above.
• an anti-CD20 antibody such as rituximab or veltuzumab can be selected.
• Exemplary antibodies or antibody fusion therapies that can be used to treat autoimmune diseases include infliximab, etanercept, adalimumab, rituximab, certolizumab pegol, golimumab, tocilizumab, abatacept, etc.
• various methods can be used to assess whether a specialty drug exerts a specific therapeutic mechanism in a specific indication, e.g., an antibody has a therapeutic mechanism involving ADCC.
• in vitro or ex vivo ADCC assays can be employed, with effector cells from healthy subjects or from subjects suffering from an ADCC treatable disease, e.g., B-NHL.
• the ADCC activity can be compared between high responders, e.g., genotype group I, H/H 131 FcyRIIA and V/V 158 FcyRIIIA, and low responders, e.g., genotype group IX, R/R 31 for FcyRIIA and F/F 158 for FcyRIIIA, where a significant difference in ADDC activity would implicate an ADCC-based therapeutic mechanism.
• the association or linkage of Fey polymorphisms that affect ADCC e.g., FcyRIIA and FcyRIIIA polymorphisms
• responsiveness to antibody therapy can also be a basis for ascertaining ADCC activity.
• a subject or patient sample e.g., cells or collections thereof, e.g., a blood sample or tissue sample
• a specialty drug therapy e.g., an antibody maintenance therapy.
• a patient with an ADCC-treatable disease who is responsive to antibody maintenance therapy will experience at least a slowing in disease progression; in some instances, at least a cessation of disease progression; in some instances, an improvement in health, i.e., a reversal of disease progression, a loss of disease symptoms, etc.
• a patient with an ADCC-treatable disease that is not responsive to antibody maintenance therapy will not experience at least a slowing in disease progression, or at least a cessation in disease progression, or an improvement in health.
• the induction therapy comprises antibody therapy
• responsiveness to an antibody maintenance therapy is responsiveness to maintenance therapy with the same antibody used in the induction therapy.
• responsiveness to an antibody maintenance therapy is responsiveness to maintenance therapy with an antibody other than that used in the induction therapy.
• the genotype is evaluated to determine whether the subject/host/patient is responsive to the anti-neoplastic therapy of interest.
• the obtained genotype may be compared with a reference or control to make a diagnosis regarding the therapy responsive phenotype of the cell or tissue, and therefore host, from which the sample was obtained/derived.
• the terms "reference” and "control” as used herein mean a standardized genotype to be used to interpret the genotype of a given patient and assign a prognostic class thereto.
• the reference or control may be a genotype that is obtained from a cell/tissue known to have the desired phenotype, e.g., responsive phenotype, and therefore may be a positive reference or control genotype.
• the reference/control genotype may be from a cell/tissue known to not have the desired phenotype, and therefore be a negative reference/control genotype.
• any convenient metric may be used to measure and convey predictions of responsiveness to maintenance therapy.
• responsiveness and associated predictions may be made in terms of remission, progression free survival (PFS), overall survival (OS), relapse-free survival (RFS), time to progression (TTP), and/or event-free survival (EFS) as defined herein and as practiced in the art.
• Evaluation of target lesions include Complete Response (CR), which is
• Partial Response which is at least a 30% decrease in the sum of the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD
• Stable Disease which is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
• Progressive Disease which is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
• evaluation of target lesions include Complete Response (CR), which is disappearance of all target lesions; Partial Response (PR), which is at least a 30% decrease in the sum of the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD; Stable Disease (SD), which is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started; or Progressive Disease (PD), which is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
• CR Complete Response
• PR Partial Response
• SD Stable Disease
• PD Progressive Disease
• CR Complete response
• PR Partial response
• NR non-responders
• ACR scores represent the percentage of reduction (20%, 50%, 70%) in tender and swollen joint counts, in addition to a corresponding improvement in three of the following five parameters: acute phase reactant (such as erythrocyte sedimentation rate), Patients Global Assessment of Disease Activity, Physicians Global Assessment of Disease Activity, Pain scale, and Health Assessment Questionnaire (HAQ).
• DAS28 is a measure of disease activity in RA.
• the score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (a marker of systemic inflammation), and the patient's 'global assessment of global health' (indicated by marking a 10 cm line between 'very good' and 'very bad').
• a DAS28 score greater than 5.1 indicates severe active disease, less than 3.2 suggests low disease activity, and less than 2.6 is considered DAS remission.
• SLE Disease Activity Index SLE Disease Activity Index
• BILAG British Isles Lupus Activity Group
• SLEDAI is a list of 24 items, 16 of which are clinical items such as seizure, psychosis, organic brain syndrome, arthritis, blood vessel inflammation, etc.
• the other criteria are laboratory results such as urinalysis testing, blood complement levels, increased anti-DNA antibody levels, low platelets, and low white blood cell count. These items are scored based on whether these manifestations are present or absent in the previous 10 days. Organ involvement is weighted.
• BILAG is an organ-specific 86-question assessment based on the principle of the doctor's intent to treat, which requires an assessment of improved (1 ), the same (2), worse (3), or new (4) over the last month.
• ACR guidelines are adopted (ACR Ad Hoc Committee on SLE Guidelines (1999) Arth. Rheum 42:1785-96; Hahn, et al. (2012) Arth. Care & Res. 64:797-808).
• patient medication adherence (or compliance) into three features: patient initiation adherence, which is the initiation of the pharmacotherapy by patient; patient persistence, which is defined as the length of time a patient fills his/her prescriptions; and patient execution adherence, which is the comparison between the prescribed drug-dosing regimen and the real patient's drug-taking behavior.
• patient initiation adherence which is the initiation of the pharmacotherapy by patient
• patient persistence which is defined as the length of time a patient fills his/her prescriptions
• patient execution adherence which is the comparison between the prescribed drug-dosing regimen and the real patient's drug-taking behavior.
• Non-adherence to these medications causes a substantial economic burden to the healthcare system by way of wasted drug costs and the costs associated with poor patient outcomes in often difficult-to-treat chronic diseases and cancers.
• Rheumatoid arthritis is an illustrative example of the problem.
• Biologic disease modifying anti-rheumatic drugs (DMARDs) on average cost over $3,000 per month, and these agents are effective in reducing disease activity and radiological progression and can improve long-term functional outcomes in patients.
• Non-adherence can lead to disease flares and increased disability, yet patient therapeutic adherence rates in people with RA are low.
• Literature reviews and reports from large pharmacy benefit managers indicate biologic DMARD medication non-adherence is in the 40-45% range (Duffant, et al. (2014)
• a method or system to identify the most appropriate biologic DMARD at therapy initiation and during treatment would, on average, markedly improve both the patient therapeutic adherence rate for these medications and treatment outcomes, and thus significantly lower direct medical costs, and reduce the costs associated with inappropriate drug usage by hundreds of millions of dollars.
• novel methods to improve therapeutic outcomes could therefore significantly improve patient therapeutic adherence of specialty drugs.
• theragnostic evaluation procedures are used a priori to identify and administer the right specialty drug in a given patient such that remission or excellent response can be achieved, which leads to better patient therapeutic adherence in that patient, preferably 60-80%. In some instances, 80-90% patient therapeutic adherence is achieved; and in yet other instances, 90-100% patient therapeutic adherence is achieved. Improved therapeutic response results in decreased current and future treatment costs.
• novel methods of providing therapeutic efficacy and (or) financial assurances can improve patient therapeutic adherence of specialty drugs. In one instance, such assurances are guided by theragnostic-evaluation procedures.
• providing therapeutic efficacy assurance or financial assurance leads to better patient therapeutic adherence in a patient, preferably 60-80%.
• a patient fails to take 4 injections in a timely manner, then the patient therapeutic adherence rate is 60%.
• 80-90% patient therapeutic adherence is achieved; and in yet other instances, 90-100% patient therapeutic adherence is achieved.
• providing financial assurance leads to better patient therapeutic adherence in a patient, preferably 60-80%.
• 80-90% patient therapeutic adherence is achieved; and in yet other instances, 90- 100% patient therapeutic adherence is achieved.
• the target polymorphism will be detected at the protein level, e.g., by assaying for a polymorphic protein.
• the target polymorphism can be detected at the nucleic acid level, e.g., by assaying for the presence of nucleic acid polymorphism, e.g., a single nucleotide polymorphism (SNP) that causes expression of the polymorphic protein.
• SNP single nucleotide polymorphism
• Fey receptor polymorphism can be determined by various methods known in the art. Generally, a sample is obtained from an individual with an ADCC- treatable disease, the sample is assayed to determine the genotype of the individual from which the sample was obtained with respect to at least one, i.e., one or more,
• polymorphisms in the FcyRIIA gene and/or at least one, i.e., one or more polymorphisms in the FcyRIIIA gene. Nucleic acid sequencing or analytical methods will often be used.
• polynucleotide samples derived from (e.g., obtained from) an individual may be employed.
• a biological sample that comprises a polynucleotide from the individual is suitable for use in the methods of the invention.
• the biological sample may be processed to isolate the polynucleotide.
• whole cells or other biological samples may be used without isolation of the polynucleotides contained therein.
• Detection of a target polymorphism in a polynucleotide sample derived from an individual can be accomplished by means well known in the art, including, but not limited to, amplification of a sequence with specific primers; determination of the nucleotide sequence of the
• Detection of a target polymorphism can also be accomplished by detecting an alteration in the level of a mRNA transcript of the gene; aberrant modification of the corresponding gene; the presence of a non-wild-type splicing pattern of the corresponding mRNA; an alteration in the expression level of the corresponding polypeptide; and/or an alteration in corresponding polypeptide activity.
• Detailed description of these techniques can be found in a variety of publications, including, e.g., Taylor (ed.
• genomic DNA or mRNA can be used directly.
• the region of interest can be cloned into a suitable vector and grown in sufficient quantity for analysis.
• the nucleic acid may be amplified by conventional techniques, such as a polymerase chain reaction (PCR), to provide sufficient amounts for analysis. See, e.g., Bartlett and Stirling (eds. 2000) PCR Protocols in Methods in Molecular Biology, Humana Press; and Innis, et al. (eds. 1999) PCR Applications: Protocols for Functional Genomics Academic Press.
• PCR polymerase chain reaction
• the target polymorphism can be detected in the PCR product by nucleotide sequencing, by SSCP analysis, or any other methods known in the art. PCR may also be used to determine whether a target polymorphism has been amplified.
• polymorphism is present by using a primer that is specific for the polymorphism. Parameters such as hybridization conditions, polymorphic primer length, and position of the
• polymorphism within the polymorphic primer may be chosen such that hybridization will not occur unless a polymorphism present in the primer(s) is also present in the sample nucleic acid.
• Those of ordinary skill in the art are aware of how to select and vary such parameters. See, e.g., Saiki, et al. (1986) Nature 324:163-66; and Saiki, et al. (1989) Proc. Natl. Acad. Sci. USA 86:6230-34.
• polymorphisms are described in Delgado, et al. (2010) Cancer Res. 70:9554-61. Direct sequencing methods may also be used.
• oligonucleotide ligation can be used to detect polymorphisms. See, e.g., Riley, et al. (1990) Nucleic Acids Res. 18:2887-2890; and Delahunty, et al. (1996) Am. J. Hum. Genet. 58:1239-1246.
• hybridization with the variant sequence may also be used to determine the presence of a target polymorphism.
• Hybridization analysis can be carried out in a number of different ways, including, but not limited to Southern blots, Northern blots, dot blots, microarrays, etc.
• the hybridization pattern of a control and variant sequence to an array of oligonucleotide probes immobilized on a solid support, as described in U.S. 5,445,934, or in WO 95/35505, may also be used as a means of detecting the presence of variant sequences.
• Identification of a polymorphism in a nucleic acid sample can be performed by hybridizing a sample and control nucleic acids to high density arrays containing hundreds or thousands of oligonucleotide probes. See, e.g., Cronin, et al.
• the genotype is determined by assaying the polymorphic protein. Detection may utilize staining of cells or histological sections with labeled antibodies, performed in accordance with conventional methods. Cells are permeabilized to stain cytoplasmic molecules. The antibodies of interest are added to the cell sample, and incubated for a period of time sufficient to allow binding to the epitope. The antibody may be labeled with radioisotopes, enzymes, fluorescers, chemiluminescers, or other labels for direct detection.
• a second stage antibody or reagent is used to amplify the signal.
• the primary antibody may be conjugated to biotin, with horseradish peroxidase-conjugated avidin added as a second stage reagent.
• the secondary antibody conjugated to a fluorescent compound, e.g., fluorescein, rhodamine, Texas red, etc.
• Final detection uses a substrate that undergoes a color change in the presence of the peroxidase. The absence or presence of antibody binding may be determined by various methods, including flow cytometry of dissociated cells, microscopy, radiography, scintillation counting, etc.
• FACS fluorescence-activated cell sorting
• a method for selecting a treatment option for a disease treated by an ADCC-mediated drug can comprise:
• the stratifying of the various treatment options is done by comparing the determined genotype to a reference stratification that relates responsiveness to antibody and/or antibody maintenance therapy to genotypes of the FcyR polymorphism affecting ADCC activity. As noted herein, the stratification allows predicting the stratification
• the FcyR polymorphism affecting ADCC activity can be based on one or more FcyRIIA polymorphisms and/or one or more FcyRIIIA polymorphisms described above, particularly amino acid position 131 of FcyRIIA and amino acid position 158 of FcyRIIIA.
• the treatments options can be selected based on the genotype groups. See US patent 8592149, US patent publication 20100291549 and WO 201309047820, all of which are incorporated herein by reference; additionally, U.S. Provisional Patent Applications 62,332,315 and 62,322,325 dated May 05, 2016, both of which are incorporated herein by reference.
• the treatment option can comprise antibody maintenance therapy for a subject in genotype group (a), (b) or (c) in Table 2 of US Pat 8,592,149, given the likelihood of excellent to good responsiveness.
• a subject in genotype group (a), (b) or (c) can be given induction therapy with an antibody therapeutic, followed by the antibody maintenance therapy. Decisions directed to financial coverage of treatment are also possible.
• the treatment option for a subject in genotype group (d) or (e) can exclude antibody body maintenance therapy as a treatment option.
• a subject in genotype group (d) or (e) can be excluded from both induction therapy and maintenance therapy with an antibody.
• the treatment options for a subject in genotype group (d) or (e) comprise a chemotherapy with a chemotherapeutic agent.
• a treatment option for a subject in genotype group (d) or (e) includes chemotherapy for induction therapy as well as for maintenance therapy.
• the treatment option will depend on the disease or disorder being treated, as described herein, e.g., neoplastic disease, an autoimmune disease, an inflammatory disorder, a microbial infection, or allograft rejection, and that a person of skill in the art can select the appropriate treatment options available to the skilled artisan in view of the guidance and teachings of the present disclosure. See, e.g., Beers, et al. (eds. 201 1 ) Merck Manual of Diagnosis and Therapy, Merck Publishing.
• the selection of a treatment option includes assessment of ADCC function or capacity. See, e.g., US patent publication 20100291549 and WO
• the methods herein allow a healthcare manager to make certain treatment options in order to achieve better therapeutic outcomes and reduce burden on financial resources.
• the present disclosure provides a healthcare management method for determining a healthcare payer coverage of antibody maintenance therapy for treating an ADCC treatable disease, the method comprising:
• genotype information of a human subject having an ADCC treatable disease for a Fey receptor polymorphism affecting ADCC activity obtaining genotype information of a human subject having an ADCC treatable disease for a Fey receptor polymorphism affecting ADCC activity
• determining health payer coverage can comprise (a) comparing the genotype information to a reference stratification relating responsiveness to one or more antibody maintenance therapies to genotypes of the Fey polymorphism, (b) measuring ADCC function or capacity, or (c) using both information, as described throughout the present disclosure.
• the reference stratification can comprise data stored in a computer memory.
• the comparing of the genotype information to the reference stratification can be carried in a computer.
• the method further comprises determining a treatment outcome for the antibody maintenance therapy.
• a treatment outcome that is weak or poor response can be a basis for not covering the maintenance therapy while a treatment outcome that is excellent or good can be a basis for approving coverage of the maintenance therapy.
• the Fey receptor polymorphism affecting ADCC activity can be based on one or more FCYRIIA polymorphisms and/or one or more FcyRIIIA polymorphisms described above, particularly amino acid position 131 of FcyRIIA and amino acid position 158 of FcyRIIIA. Accordingly, in some embodiments, determining coverage can be selected based on the genotypes a subject presents and the corresponding genotype responsiveness established for various specialty drugs.
• the method further comprises determining a treatment option, as described in the present disclosure.
• the determining of coverage, the comparing of the genotype information, treatment outcome, and the treatment options can be reported in electronic, web-based, or paper form to the subject, a health care payer, third party payer, a health care provider, a physician or a government office.
• kits may comprise one or more elements for genotyping a patient to identify a polymorphism or genotypic variation, or gene deletions or duplications, and one or more elements for genotyping a patient to identify a FcyRIIIA polymorphism.
• kits may comprise one or more elements for detecting and measuring cells in a human sample, i.e. cells that are targeted for depletion and/or repopulation by an antibody induction therapy, for e.g., used to treat an ADCC-treatable disease.
• Such elements may include, e.g., antibodies, e.g., an antibody that is specific for a marker on the targeted cell, an antibody that is specific for a larger population of cells that comprise the targeted population, etc., a vital dye for determining cell viability, etc.
• the kit may further comprise a reference that correlates a genotype in the patient and/or the extent of target cell depletion and/or repopulation in a patient with patient groups having known responsiveness to the antibody maintenance therapy.
• the subject kits will often further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit.
• One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc.
• Yet another means would be a computer readable medium, e.g., diskette, CD, etc., on which the information has been recorded.
• Yet another means that may be present is a website address which may be used via the internet to access the information at a remote site. Any convenient means may be present in the kits.
• a patient with significantly severe joint pain and early morning stiffness is referred to a rheumatologist for further evaluation (FIG-2; step-1 ).
• the specialist requests for diagnostic procedures including X-ray exams of hands, wrists, and knees, as well as blood tests that include rheumatoid factor (RF) and anti-CCP levels (step-2).
• RF rheumatoid factor
• step-3 the rheumatologist diagnoses that the patient has moderate to severe RA, and informs the patient (step-4) and the payer for determining appropriate treatment decisions (step-5).
• the payer uses Klaritos platform and its disease-specific PDP for the selection of specialty drugs and treatment procedures, and in fact, all RA patients covered by the payer in the United States are asked to go through Klaritos platform for the next steps in treatment.
• the platform comprises, e.g., all, or at least some, of (i) theragnostic labs, (ii) formulary; (iii) telepharmacy; (iv) teleconsult room; (v) disease and therapy management care (FIG-2).
• the payer refers the patient to the theragnostic labs of Klaritos platform (step 6), and the patient provides a blood sample for further analyses (step 7).
• the patient is then evaluated to determine which tests are performed to evaluate the status and progression of disease individually. Certain tests may be performed to eliminate various possibilities, others to confirm others, and still others to determine disease progression and baseline status.
• the in-house rheumatologist provides an opinion to the patient's rheumatologist regarding: (a) whether to proceed with antibody maintenance therapy using rituximab, and if so, under what regimen, and (b) whether to withhold methotrexate administration or administer on as- needed basis.
• rituximab a group of antibodies that are associated with antibodies that are administered to rituximab.
• reference indices relating genotype groups to (a) disease severity, and (b) category of treatment response to antibody maintenance therapy and it is predicted that the patient will have an extremely severe disease course, however, an excellent candidate for rituximab maintenance therapy.
• rituximab induction therapy The patient's rheumatologist and the in-house rheumatologist agree on the selection of therapy and treatment guidance protocols: rituximab induction therapy.
• the patient is prescribed a 4-week course of rituximab induction therapy (375mg/m 2 once per week).
• Electronic prescription is sent to telepharmacy (step-9), which initiates prior authorization request with payer, and the payer duly authorizes through electronic means (step- 10).
• step-1 1 The specialty pharmacist requests the drugs from the drug formulary (step-1 1 ), and the drugs are shipped to patient's physician's office (step-12; "white bagging” process).
• patient is prescribed a 4-week course of rituximab induction therapy (375mg/m 2 once per week).
• the drugs are administered by the patient's rheumatologist with the location and time recorded, providing location-specific and time-specific authentication of dosing.
• Rheumatology specialist from Disease and Therapy Management care is in touch with the patient and provides guidance and follow-up (step-13). Two months after induction therapy, the patient provides blood sample to Theragnostic Labs (step-14) for the analyses of: IgG-RF, ACPA, IgA-RF, ACPA levels, B-cell subsets by MRD flow cytometry. The RF and ACPA levels have significantly reduced 60% less compared to the pre-treatment levels.
• the flow cytometry results indicate ⁇ 5 CD19 + naive and memory B-cells per microliter, ⁇ 10 CD19 + CD27 ++ , CD38 ++ plasma B-cells, i.e., substantial depletion with the anti-CD20 antibody therapy, correlating to excellent therapeutic response (Step-14). All these results are discussed with the patient and her rheumatologist (step-15) through teleconsult process. The rheumatologists agree that the patient responds excellently to rituximab induction therapy based on the B-cell depletion profiles, disease severity indices.
• rituximab maintenance therapy a 2-week course of therapy (375mg/m 2 once per week), to be administered at 3-month intervals for the first 4 cycles after the induction therapy (375mg/m 2 once per week), and then an as-needed rituximab regimen as determined by B-cell depletion profile.
• Methotrexate known to have serious side effects in the patient, is determined not to be necessary and hence not administered.
• Electronic prescription for rituximab maintenance therapy is sent to telepharmacy (step- 16), which initiates prior authorization request with payer, and the payer duly authorizes through electronic means (step-17).
• step-1 1 The specialty pharmacist requests the drugs from the drug formulary (step-1 1 ), and the drugs are shipped to patient's physician's office (step-12; "white bagging” process). The drugs are administered by the patient's rheumatologist.
• the patient is in full clinical remission in Year-1 and Year-2.
• Telemedicine which includes at least near-real-time teleconference between medical professionals, will typically include a plurality of locationally-disperse specialists, who may have disparate or overlapping expertises, to discuss a patient's case. Communications will typically be in real-time, and each participant has access to some or all of relevant features of diagnostic evaluations, medical record and history, past treatment, perhaps insurance coverage details and options, and other relevant details, both medical and treatment-related. Included may be specialist doctors, e.g., rheumatologist, neurologist, immunologist, and likely the patient's primary treating physician.
• the telemedicine group may be, or include, substantial overlap with, the Disease and Treatment Management team, which may include specialty nurses and other healthcare professionals.
• the communication systems will require substantial security to handle confidential patient information and data, as well as have means to ensure only appropriate persons have access to the system and data.
• Telepharmacy will typically include connection, often real-time, which allows communication between the prescribing physician(s), which may include disease specialist on the Disease and Treatment Management team, and the pharmacist, who fulfills the prescription. Because of the high cost of the specialty drug, typically the payer is also connected whose approval or pre-approval is generally needed before the drug is dispensed or delivered to the patient.
• the drug may be delivered directly to the patient or to someone who is responsible for ensuring proper administration of the drug, one who typically ensures and documents both timing and dosing for patient therapeutic adherence. In some cases, the drug is provided to the guardian of the patient, e.g., where the patient is pediatric or geriatric, or may need assistance in healthcare needs.
• the payer may be the insurer, or there may be one of various intermediaries including, e.g., a pharmacy benefits management (PBM) entity, a specialty pharmacy, or others who may be included to coordinate the prescribing, ordering, stocking, delivery, drug administration, and patient therapeutic adherence verification with use of a drug, e.g., specialty drug.
• PBM pharmacy benefits management
• the intermediaries may be fewer and may include or overlap with other social services entities which may include aspects of healthcare provision or monitoring by trained healthcare professionals or which may include forms of nursing care and the like.
• the invention conceives of further remote communication networks directed to ensure that the patient/guardian is provided access to treatment decision-making process.
• the goal is to minimize or eliminate hurdles that prevent patient therapeutic adherence.
• the invention further conceives of telehealth electronic payment system for efficient and timely management of money transfers between payers, employers, patients, and pharmaceutical companies.
• the system may be made available via a Mobile App and enables patients to pay their copays (co-insurance).
• co-insurance copays
• Such a payment model inherently guided by theragnostic methods, may facilitate automatic monitoring and determination of patient therapeutic adherence and implementation of therapeutic efficacy assurance without involving any other third party. This allows timely determination of patients' remission and excellence as well as transfers of refunds where appropriate.
• the assurance company may facilitate collection of copay (coinsurance) from patients, and payment for acquisition of drugs.
• the company may manage therapeutic efficacy assurance as its own fund.
• Theragnostics entail various evaluations of the patient to determine disease status; help match an appropriate drug to the patient; and provide therapeutic guidance in how best to treat that individual patient with the matched drug.
• theragnostics consider the dynamic nature of temporal and longitudinal follow-up of disease progression, mechanism of action of drug, pharmacological features, e.g., absorption, distribution, metabolism, excretion (ADME) for the drug.
• ADME absorption, distribution, metabolism, excretion
• Theragnostic evaluation may consider the immunological function of the individual upon dosing, with feedback used to evaluate whether the treatment is effective, or if treatment is approaching effectiveness.
• the individualized nature of the evaluation will allow dosing to be matched temporally with the individual's tolerance to the drug.
• the mechanism may be dynamic, changes can be tracked to determine whether the desired endpoint may be reached before toxicity or other limitations are reached to prevent the desired endpoints. With such dynamic tracking, the ability to project outcomes will improve.
• Theragnostic criteria are used to evaluate the current status of the individual patient, to predict shorter or longer-term progression of disease; to determine what is an appropriate drug for that individual patient, to determine who is identified as a therapeutically ineligible patient for a particular drug, and to determine whether a particular drug is achieving its appropriate mechanism to treat disease, and how quickly it may lead to better treatment results, e.g., complete remission, or alternatively if failing, how quickly it is failing. In this latter case, a quicker switch to an alternative may be effected, perhaps within a limited window-of-effective-opportunity, which may have significantly desirable effects on treatment and economic outcomes. In other circumstances, it may be possible to combine drugs having two different mechanisms of action together to achieve desired therapeutic effect. In other situations, where the mechanism of action is not working, perhaps supplementing or treating that deficiency may reconstitute the normal mechanism sufficiently to achieve desirable treatment outcomes.
• theragnostics allow individualized treatment to achieve significantly better treatment response, e.g., clinical remission or excellent response, and doesn't rely upon a presumption that all patients are uniform in response.
• the individualized diagnosis and therapy are different from the old style "personalized medicine" which accounts overly inclusive patient pool for treatment.
• TGA Therapy Guideline Adherence
• TGA also varied among rheumatologists, and several rheumatologist and patient-related determinants (e.g., patient sex, number of DMARD options already exhausted, presence of erosions, RF or anti-CCP positivity,) were found to be related to rheumatologists' guideline adherence. TGA varied from 21-72% in one study, and 24- 90% in other studies. See Harrold, et al. (2016) Arthritis Res, and Ther. 18:94; Lesuis, et al. (2016) Rheumatism and Musculoskeletal Diseases Open 2:e000195; and Harrold, et al. (2012) Arthritis and Rheumatology 64:630-638.
• patient's economic or insurance status, employment status, cost of the specialty drugs, guidelines set forth by payers are expected to greatly influence TGA as it will have direct bearing whether a rheumatologist would want to prescribe a specialty drug or switch to another specialty drug. Streamlining these inefficiencies can greatly enhance TGA, or at least ensure that any divergence from TGA is reasoned, intentional, and not inadvertent.
• TGA can be improved through adoption of (a) theragnostic evaluation, (b) efficacy and financial assurances, and (c) patient therapeutic adherence.
• novel theragnostic evaluations for the effective selection and treatment strategies with specialty drugs can significantly improve TGA.
• TGA is theragnostics-based, e.g., theragnostic evaluation procedures are used a priori to identify and administer the right specialty drug in a given patient, e.g., instead of fail-this-one-first treatment strategy in RA, such that remission or excellent response can be achieved in very early RA and early RA patients, which leads to better TGA, preferably 60-80%. In some instances, 80-90% TGA is achieved; and in yet other instances, 90-100% TGA is achieved.
• TGA is favorably influenced by assurances, e.g., providing efficacy and financial assurances to patients and payers will enable physicians to adopt higher TGA rates, e.g., 70% or preferably 80-90% or higher.
• assurances e.g., providing efficacy and financial assurances to patients and payers will enable physicians to adopt higher TGA rates, e.g., 70% or preferably 80-90% or higher.
• better patient therapeutic adherence and compliance, and hence much better therapeutic outcomes can positively impact better TGA rates.
• improved TGA leads to improved patient response to treatment, which will lead to advantages in assurance, e.g., efficacy assurance or financial assurance. These will have positive financial effects for the individual patients and for the patient pools, e.g., payers or health insurers.
• the Klaritos platform will also provide medical records which track both the diagnostic and theragnostic evaluations of individual patients, which are combined into a database with a plurality of records.
• the records and databases can be sorted into disease- specific subsets, or the disease-specific databases can be combined across different diseases for a larger database, which can be deconvoluted back into smaller disease- specific database subsets.
• the databases will typically include: patient identification information, patient history information, theragnostic evaluation information, therapeutic and therapy guidance information, treatment information such as patient therapeutic adherence, response evaluation (both interim and longer term; with focus on remission and excellent response rates, or low or extremely low response rate subsets), therapeutic assurance information, financial assurance information, health insurance and drug delivery or prior authorization information, and related information which allows tracking of medical aspects of the patient case, which may be linked to financial and other insurance or assurance related aspects of patient activities.
• the databases may be separated into regional, geographical, national (e.g., US, Canada, European, UK, Scandinavian, etc.), or by other parameters as desired.
• the database may start small, e.g., 100 patients, and grow to 500, 10000, 200000, and so on, and as the size grows the statistical power of contained data also grows.
• Some databases will be composed primarily of disease-specific databases, others may combine one or more disease-specific databases, and others may be combined with other databases comprising other databases.
• the combined databases may be deconvoluted to separate back out various components, e.g., the theragnostic-guided treatment cases, and allowing tracking of response results of various treatment strategies.
• the databases will allow dynamic tracking of patient therapeutic adherence, e.g., timing and accuracy of drug dosing, tracking of when theragnostic evaluations are performed to track Therapy Guidelines Adherence (TGA), and to dynamically compare new treatment strategies with prior standard of care (SOC) responses.
• TGA Therapy Guidelines Adherence
• SOC prior standard of care
• these databases are continuously iterative (evolving, and improving as additional patients are added), and inherently archivable.
• the database in a disease-specific group may include a large fraction, e.g., 20%, 40%, 60%, or more, of the entire disease pool within the system, which may include a regional or other mostly inclusive category.
• the database also provides insights into how a new drug will perform where it uses a related mechanism of action to another drug, e.g., anti-TNF-alpha therapies for RA, within the Klaritos formulary, and will allow selection of patients for fast internal clinical or comparison trials, e.g., with new or similar drugs or with modifications to therapeutic use of existing drugs.
• another drug e.g., anti-TNF-alpha therapies for RA
• the Klaritos integrated treatment model when implemented, can address the dual problem of patient therapeutic adherence (PTA) and TGA by rheumatologists
• the Klaritos disease-specific databases track PTA to a therapy as a condition for efficacy (financial) assurance.
• a patient-specific tailored treatment recommendation is available to rheumatologists that influences favorably TGA.
• specialty drugs e.g., biologic DMARDs, which leads to expanded patient therapeutic adherence resulting in improved outcomes and demonstrably lower healthcare costs.
• Efficacy assurance consists of therapeutic efficacy assurance (TEA) and financial assurance (FA).
• TEA refers to an assurance of achieving significantly better therapeutic efficacy in a given patient or subset(s) of patients, within a reasonable time-frame, e.g., 1 month, 2-3 months; this assurance is provided to patients, or payers, and employers.
• TEA is not therapeutic risk assurance; that is, this does not cover risks and side effects associated with the drugs.
• Financial assurance refers to a form of money-back guarantee, e.g., co-insurance amount, if the therapy has not achieved desired therapeutic outcome within a reasonable time-frame, e.g., 2-3 months; this assurance is provided to patients, and in some instances, it may also be provided to payers and employers.
• Such assurance is theragnostics-guided in specific disease indications, provided the patient establishes and maintains excellent PTA therapeutic adherence rate.
• Both TEA and FA are inter-related: it is essentially a warranty that some or all of the cost of drug, with or without treatment costs, will be returned if the patient does not achieve a designated treatment response.
• the designated target response is likely to be at least, e.g., excellent response or more preferably remission.
• the treatment may be to treatment with a monoclonal antibody therapy such as rituximab induction therapy, as described above.
• a monoclonal antibody therapy such as rituximab induction therapy, as described above.
• some or all of the out-of-pocket cost of drug will be returned to the patient, e.g., all of the patient drug co-insurance costs.
• the therapeutic efficacy assurance is satisfied and thus she will not get any co-insurance amount back. This can serve as an incentive to patient therapeutic adherence as a condition of the financial assurance, e.g., money-back guarantee.
• the treatment may be a predesignated treatment protocol, where all aspects of the therapy are specified before the treatment is begun and no adjustments are introduced thereafter; alternatively, patient therapeutic adherence criteria might be adjusted during the course of treatment, e.g., adjusted by disease specialist, e.g., according to theragnostic criteria and theragnostic evaluation of the individual patient while the treatment schedule is underway.
• Table AA is a 2-dimensional matrix that shows the financial assurance in terms of percentage cost savings potentially achieved by employers and payers when patients achieve remission and excellent response through Klaritos model.
• Each cell in the matrix provides an estimate of the percentage of overall combined (specialty) drug cost and direct medical cost savings, and thus, that is the financial assurance provided to employers and payers for its RA disease-specific population (e.g., 20,000 or 250,000 patients).
• Percentage cost savings are provided in this matrix for remission and excellent response rates achieving 10, 20, 30, and 40%, and can be compared in various
• the per patient cost basis can then be used to project the total specialty drug costs and direct medical costs for any population size, e.g., RA patient population of an employer or payer, being treated with specialty drugs. By applying variable remission and excellent response rates as noted above the total cost savings can be calculated. [00363] For example, in populations of 7,500 and 25,000 RA patients treated with specialty drugs the following scenarios are average baseline costs for the major elements of care prior to initiating Klaritos system:
• Several approved drugs may be commercially available for treatment of a particular disease indication, e.g., rheumatoid arthritis, relapsing-remitting multiple sclerosis.
• a particular disease indication e.g., rheumatoid arthritis, relapsing-remitting multiple sclerosis.
• not all drugs are therapeutically effective in a patient or subset(s) of patients, and this is information may not be known a priori.
• features such as therapeutic efficacy assurance including the associated financial assurance, theragnostic guidance in a patient or subset(s) of patients, disease and therapy management care, and product differentiation of specialty drugs are not provided by prescription drug plans (PDPs), PBMs or specialty pharmacies.
• step-therapy e.g., fail-this-one-first
• payers and providers differentiating a particular drug from others have significant advantages to all stakeholders: patients, payers and employers, healthcare providers, and pharmaceutical companies.
• the annual net sales of the drug can be considerably higher, e.g., 2-fold or 5-fold higher, if the product is subject to product differentiation.
• Employers and payers may be willing to approve and administer the drug even if it is priced higher, e.g., 25% more, or 100% more than the alternative drugs.
• Market enrichment refers to theragnostics-guided identification of a treatable patient, treatable subset(s) of patients, a treatable segment of patient market in a particular disease indication for the purposes of distribution, delivery of a drug, and treatment with a drug, with an objective of achieving better therapeutic and economic outcomes.
• This method selectively avoids patients who are considered not eligible for a particular therapy.
• Treatable herein means treatment-eligible patients.
• This market enrichment feature may be exploited by (a) a prescription drug plan, (b) a drug formulary, (c) a specialty pharmacy, (c) a payer, (d) an employer, (e) a pharmaceutical company, (f) a diagnostic company, (g) a drug distributor, or (h) a healthcare provider.
• One way to accomplish this is to achieve enrichment of a hidden but treatable patients, segments of patients, or subsets of patients (e.g., collectively called addressable market) who otherwise are not eligible for treatment or prior authorization.
• Such an enriched market becomes a significant and addressable market size for the drug, e.g., specialty drug.
• Another way to accomplish is to identify subset(s) of patients who will respond better to a therapy, e.g., a specialty drug, based on the mechanism of action of the drug. This may initially be construed as an aspect leading to market fragmentation, e.g., market
• Example 1 Workflow Involved in Klaritos Platform
• a patient with significantly severe joint pain and early morning stiffness is referred to a rheumatologist for further evaluation (FIG-2; step-1 ).
• the specialist requests for diagnostic procedures including X-ray exams of hands, wrists, and knees, as well as a blood test that includes rheumatoid factor (RF) and anti-CCP levels (step-2).
• RF rheumatoid factor
• step-3 the rheumatologist diagnoses that the patient has moderate to severe RA, and informs the patient (step-4) and the payer for determining appropriate treatment decisions (step-5).
• the payer uses Klaritos platform for the selection of specialty drugs and treatment procedures, and in fact, all RA patients covered by the payer in the United States are asked to go through Klaritos platform for the next steps in treatment.
• the platform consists of (i) theragnostic labs (theragnostic facility), (ii) formulary; (iii) telepharmacy; (iv) teleconsult room; (v) disease and therapy management care (FIG-2).
• the payer refers the patient to the theragnostic labs of Klaritos platform (step 6), and the patient provides blood sample for further analyses (step 7).
• the patient is seropositive with the following characteristics: IgG-RF " ; lgG-ACPA + ; fibrinogen immune complex " ; very high levels of TNF-a as determined by the EPP/AAI assays.
• a blood sample taken from the patient is used to prepare genomic DNA, which is amplified by PCR using pairs of primers specific for the FcyRIIA, FcyRIIIA, and FcyRIIIB loci (see, e.g., Lehrnbecher, et al. (1999) Blood 94:4220- 32).
• Baseline characteristics of B-cell subsets are also determined by minimal residual disease flow cytometry (MRD-FC; See Dass, et al. (2008) Arth. Rheum. 58:2993-2999; Vital, et al (201 1 ) Arth. Rheum. 63:603-608). By way of teleconsultation, all of these results are further discussed with the patient and her rheumatologist (step-8).
• the in-house rheumatologist provides an opinion to the patient's rheumatologist regarding: (a) whether to proceed with antibody maintenance therapy using rituximab, and if so, under what regimen, and (b) whether to withhold methotrexate administration or administer on as-needed basis.
• rituximab rituximab
• reference indices relating genotype group to (a) disease severity, and (b) category of treatment response to antibody maintenance therapy and predicts that the patient will have an extremely severe disease course, however, an excellent candidate for rituximab maintenance therapy.
• rituximab induction therapy The patient undergoes induction therapy with rituximab, a therapy comprising rituximab and methotrexate.
• the patient is prescribed a 4-week course of rituximab induction therapy (375mg/m 2 once per week).
• Electronic prescription is sent to telepharmacy (step-9), which initiates prior authorization request with payer, and the payer duly authorizes through electronic means (step- 10).
• step-1 1 The specialty pharmacist requests the drugs from the drug formulary (step-1 1 ), and the drugs are shipped to patient's physician's office (step-12; "white bagging” process).
• patient is prescribed a 4-week course of rituximab induction therapy (375mg/m 2 once per week).
• the drugs are administered by the patient's rheumatologist.
• Rheumatology specialty from Disease and Therapy Management care is in touch with the patient and provides guidance and follow-up (step-13). Two months after induction therapy, the patient provides blood sample to Theragnostic Labs (step- 14) for the analyses of: IgG-RF, ACPA, IgA-RF, ACPA levels, B-cell subsets by MRD flow cytometry. The RF and ACPA levels have significantly reduced 60% less compared to the pre-treatment levels.
• the flow cytometry results indicate ⁇ 5 CD19 + naive and memory B-cells per microliter, ⁇ 10 CD19 + CD27 ++ , CD38 ++ plasma B-cells, i.e., substantial depletion with the anti-CD20 antibody therapy, correlating to excellent therapeutic response (Step-14). All these results are discussed with the patient and her rheumatologist (step-15) through teleconsult process.
• the rheumatologists agree that the rituximab induction therapy puts the patient's disease in excellent treatment response category based on B-cell depletion profile, disease severity indices.
• the patient's rheumatologist then prescribes a 2-week course of therapy
• Methotrexate is not administered as part of the maintenance treatment strategy.
• Electronic prescription for rituximab maintenance therapy is sent to telepharmacy (step-16), which initiates prior authorization request with payer, and the payer duly authorizes through electronic means (step-17).
• the specialty pharmacist requests the drugs from the drug formulary (step-11 ), and the drugs are shipped to patient's physician's office (step-12; "white bagging” process). The drugs are administered by the patient's rheumatologist.
• the patient is in full clinical remission in Year-1 and Year-2.

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