EP-4739304-A1 - METHODS FOR TREATING ATRIAL FIBRILLATIONS WITH BUDIODARONE

Abstract

Patients with either paroxysmal or persistent AFib and whose untreated AFib is greater than a threshold level of AFib are qualified as eligible for treatment with a drug, (e.g., budiodarone) capable of controlling heart rhythm in the patient. Qualified patients are treated with the drug while their heart rates are monitored with a wearable, and if a given dose of the drug is deemed ineffective, the dose is adjusted until an effective dose is determined for the patient of the patient is deemed non-responsive to the drug and removed from therapy.

Inventors

• DRUZGALA, PASCAL
• MILNER, PETER GERARD

Assignees

• Xyra, LLC

Dates

Publication Date

20260513

Application Date

20230712

Claims (1)

1. Attorney Docket: 009643.00011\WO WHAT IS CLAIMED IS: 1. A method of treating a patient diagnosed with either paroxysmal or persistent atrial fibrillation (AFib) and qualified for budiodarone therapy, said method comprising: a) administering a first dose of budiodarone or a pharmaceutically acceptable salt thereof to said qualified patient while employing a wearable to monitor heart rhythm data of said qualified patient, wherein said first dose is an approved therapeutic dose that is less than a maximum approved dose of budiodarone or a pharmaceutically acceptable salt thereof; b) monitoring said qualified patient for efficacy of the administered first dose of budiodarone or a pharmaceutically acceptable salt thereof to assess whether said first dose is efficacious for said patient during a comparison period of 1 or more days, provided that assessing the efficacy of budiodarone is delayed for at least 7 or 14 days after start of budiodarone therapy at said first dose; c) if the first dose is assessed as not efficacious for said patient by an end of the comparison period, dose adjusting the amount of budiodarone or a pharmaceutically acceptable salt thereof one or more times as necessary to achieve an efficacious result using at least the same delay and comparison period as in b), provided that the adjusted dose does not exceed the maximum approved dose; or, if an efficacious result is not achieved when evaluated at the maximum approved dose, removing said patient from budiodarone therapy; and d) if an administered dose of the first dose or an adjusted dose is efficacious for the patient, continuing to monitor the patient’s heart rhythm data to ensure that the administered dose of budiodarone or a pharmaceutically acceptable salt thereof remains efficacious, provided that, if said administered dose is no longer efficacious, step c) is repeated with said administered dose as the first dose. 2. The method of claim 1, wherein said patient has been qualified for budiodarone therapy based on at least one AFib episode of at least about 5 hours or at least about 5.5 hours over at least 7 or 14 days during which said patient is not administered budiodarone therapy. 3. The method of claim 1, wherein said patient has been qualified for budiodarone therapy based on having a baseline level of AFib burden of at least 5 hours over at least 7 or 14 days during which said patient is not administered budiodarone therapy. Attorney Docket: 009643.00011\WO 4. The method of any one of claims 1-3, wherein monitoring in step b) is conducted in a continuous manner. 5. The method of any one of claims 1-4, wherein the efficacy of said budiodarone therapy at an administered dose is evaluated by comparing baseline levels of AFib against corresponding levels of AFib in the comparison period. 6. The method of any one of claims 1-5, wherein the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months. 7. The method of claim 6, wherein a first comparison period is followed by a second comparison period of a similar length of time. 8. The method of any one of claims 1-7, wherein episodes of AFib over about 5 hours are monitored. 9. The method of any one of claims 1-7, wherein episodes of AFib over about 5.5 hours are monitored. 10. The method of any one of claims 1-9, wherein one or more symptoms associated with AFib are evaluated using a patient report of one or more of a number or a severity of the one or more symptoms. 11. The method of any one of claims 1-10, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate. Attorney Docket: 009643.00011\WO 12. The method of any one of claims 1-11, further comprising, if the patient is removed from budiodarone therapy in step c), referring the patient for electrophysiological intervention. 13. A method of treating a patient diagnosed with either paroxysmal or persistent atrial fibrillation (AFib) and qualified for budiodarone therapy, said method comprising: for said patient who has been qualified for budiodarone therapy, wherein said qualification requires that said patient experiences at least one episode of long duration AFib of at least 1 hour over a qualification period or has an AFib burden of at least 2.5% during the entire qualification period, wherein said qualification period is at least 2 weeks during which the patient is not treated with budiodarone: a) administering a first dose of budiodarone or a pharmaceutically acceptable salt thereof to said qualified patient while employing a wearable to monitor heart rhythm data of said qualified patient, wherein said first dose is an approved therapeutic dose that is less than a maximum approved dose for budiodarone; b) monitoring said patient for efficacy of the administered first dose of budiodarone or a pharmaceutically acceptable salt thereof to assess whether said first dose is efficacious for said patient during a comparison period of 1 or more days, provided that assessing the efficacy of budiodarone is delayed for at least 7 or 14 days after start of budiodarone therapy at said first dose; c) if the administered first dose is assessed as not efficacious for said patient by an end of the comparison period, dose adjusting the amount of budiodarone or a pharmaceutically acceptable salt thereof one or more times as necessary to achieve an efficacious result using at least the same delay and comparison period as in b), provided that the adjusted dose does not exceed the maximum approved dose; or, if an efficacious result is not achieved when evaluated at the maximum approved dose, removing said patient from budiodarone therapy; and d) if an administered dose of the first dose or an adjusted dose is efficacious for the patient, continuing to monitor the patient’s heart rhythm data to ensure that the administered dose of budiodarone or a pharmaceutically acceptable salt thereof remains efficacious, provided that, if said administered dose is no longer efficacious, step c) is repeated with said administered dose as the first dose. Attorney Docket: 009643.00011\WO 14. The method of claim 13, wherein monitoring in step b) is conducted in a continuous manner. 15. The method of any one of claims 13 or 14, wherein the efficacy of said budiodarone therapy at an administered dose is evaluated by comparing baseline levels of AFib against corresponding levels of AFib in the comparison period. 16. The method of any one of claims 13-15, wherein the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months. 17. The method of claim 16, wherein a first comparison period is followed by a second comparison period of similar length of time. 18. The method of any one of claims 13-17, wherein episodes of AFib over about 5 hours are monitored. 19. The method of any one of claims 13-18, wherein episodes of AFib over about 5.5 hours are monitored. 20. The method of any one of claims 13-19, wherein one or more symptoms associated with AFib are evaluated by the patient using a patient report of one or more of a number or a severity of the one or more symptoms. 21. The method of any one of claims 13-20, wherein the budiodarone or a pharmaceutically acceptable salt thereof is budiodarone tartrate. Attorney Docket: 009643.00011\WO 22. The method of any one of claims 13-21, further comprising, if the patient is removed from budiodarone therapy in step c), referring the patient for electrophysiological intervention. 23. A method of treating a patient diagnosed with either paroxysmal or persistent atrial fibrillation (AFib) and qualified for pharmacotherapy with a pharmaceutical, said method comprising: a) administering a first dose of said pharmaceutical to said qualified patient while employing a wearable to monitor heart rhythm data of said qualified patient, wherein said first dose is an approved therapeutic dose that is less than a maximum approved dose for said pharmaceutical; b) monitoring said patient for efficacy of the administered first dose of said pharmaceutical to assess whether said dose is efficacious for said patient during a comparison period of 1 or more days, provided that assessing the efficacy of said pharmaceutical is delayed for at least 7 or 14 days after start of pharmacotherapy with said pharmaceutical at said first dose; c) if the first dose is assessed as not efficacious for said patient by an end of the comparison period, dose adjusting the amount of said pharmaceutical one or more times as necessary to achieve an efficacious result using at least the same delay and comparison period as in c), provided that dose adjustment does not exceed the maximum approved dose; or, if an efficacious result is not achieved when evaluated at the maximum approved dose, removing said patient from said pharmacotherapy; and d) if an administered dose of the first dose or an adjusted dose is efficacious for the patient, continuing to monitor the patient’s heart rhythm data to ensure that the administered dose of said pharmaceutical remains efficacious, provided that, if said administered dose is no longer efficacious, step c) is repeated with said administered dose as the first dose. 24. The method of claim 23, wherein said patient has been qualified for pharmacotherapy with said pharmaceutical based on at least one AFib episode of at least about 5 hours or at least about 5.5 hours over at least 7 or 14 days during which said patient is not administered said pharmaceutical. Attorney Docket: 009643.00011\WO 25. The method of claim 23, wherein said patient has been qualified for pharmacotherapy with said pharmaceutical based on having a baseline level of AFib burden of at least 5 hours over at least 7 or 14 days during which said patient is not administered said pharmaceutical. 26. The method of any one of claims 23- 25, wherein monitoring in part c) is conducted in a continuous manner. 27. The method of any one of claims 23-26, wherein the efficacy of said pharmacotherapy with the pharmaceutical at an administered dose is evaluated by comparing baseline levels of AFib against corresponding levels of AFib in the comparison period. 28. The method of any one of claims 23-27, wherein the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months. 29. The method of claim 28, wherein a first comparison period is followed by a second comparison period of similar length of time. 30. The method of any one of claims 23-29, wherein episodes of AFib over about 5 hours are monitored. 31. The method of any one of claims 23-29, wherein episodes of AFib over about 5.5 hours are monitored. 32. The method of any one of claims 23-31, wherein one or more symptoms associated with AFib are evaluated using a patient report of one or more of a number or a severity of the one or more symptoms. Attorney Docket: 009643.00011\WO 33. The method of any one of claims 23-32, further comprising, if the patient is removed from the pharmacotherapy in step c), referring the patient for electrophysiological intervention. 34. A method of treating a patient diagnosed with either paroxysmal or persistent atrial fibrillation (AFib) and qualified for pharmacotherapy with a pharmaceutical, said method comprising: for said patient who has been qualified for pharmacotherapy with said pharmaceutical, wherein said qualification requires that said patient experiences at least one episode of long duration AFib of at least 1 hour during a qualification period or has an AFib burden of at least 2.5% during the entire qualification period, wherein said qualification period is at least 2 weeks during which the patient is not treated with said pharmaceutical; a) administering a first dose of said pharmaceutical to the qualified patient while employing a wearable to monitor heart rhythm data of said qualified patient, wherein said first dose is an approved therapeutic dose which is less than a maximum approved dose for said pharmaceutical; b) monitoring said patient for efficacy of the administered first dose of said pharmaceutical to assess whether said first dose is efficacious for said patient during a comparison period of 1 or more days provided that assessing the efficacy of said pharmaceutical is delayed for at least 7 or 14 days after start of said pharmacotherapy at said first dose; c) if the administered first dose is assessed as not efficacious for said patient by an end of the comparison period, dose adjusting the amount of said pharmaceutical one or more times as necessary to achieve an efficacious result using at least the same delay and comparison period as in b), provided that the adjusted dose does not exceed the maximum approved dose; or if an efficacious result is not achieved when evaluated at the maximum approved dose, removing said patient from said pharmacotherapy; and d) if an administered dose of the first dose or an adjusted dose is efficacious for the patient, continuing to monitor the patient’s heart rhythm data to ensure that the administered dose of said pharmaceutical remains efficacious, provided that, if said administered dose is no longer efficacious, step c) is repeated with said administered dose as the first dose. Attorney Docket: 009643.00011\WO 35. The method of claim 34, wherein monitoring in step b) is conducted in a continuous manner. 36. The method of any one of claims 34 or 35, wherein the efficacy of said pharmacotherapy with the pharmaceutical at an administered dose is evaluated by comparing baseline levels of AFib against corresponding levels of AFib in the comparison period. 37. The method of any one of claims 34-36, wherein the comparison period is one or more of about a day, about a week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or up to about 6 months. 38. The method of claim 37, wherein a first comparison period is followed by a second comparison period of a similar length of time. 39. The method of any one of claims 34-38, wherein episodes of AFib over about 5 hours are monitored. 40. The method of any one of claims 34-38, wherein episodes of AFib over about 5.5 hours are monitored. 41. The method of any one of claims 34-40, wherein one or more symptoms associated with AFib are evaluated using a patient report of one or more of a number or a severity of the one or more symptoms. 42. The method of any one of claims 34-41, further comprising, if the patient is removed from pharmacotherapy in step c), referring the patient for electrophysiological intervention.

Description

Attorney Docket: 009643.00011\WO METHODS FOR TREATING ATRIAL FIBRILLATIONS Field [0001] Disclosed are methods for treating atrial fibrillation (AFib) in patients diagnosed with paroxysmal or persistent atrial fibrillation (AFib) who are determined to potentially benefit from pharmacotherapy. Reference to Related Applications [0002] This application claims benefit of U.S. Provisional Application 63/525,093, filed on July 5, 2023, the entire contents of which are herein incorporated by reference in their entirety. State of the Art [0003] AFib is a serious medical condition characterized by an abnormal heart rhythm often at accelerated heart rates. There are three basic types of AFib, paroxysmal, persistent, and permanent. Paroxysmal AFib and persistent AFib are characterized by spontaneous periods of AFib that occur between periods of sinus rhythm, whereas permanent AFib is characterized by a constant state of atrial fibrillation that can only be treated indirectly with medications such as blood thinners. [0004] Untreated paroxysmal and persistent AFib lead to an increased risk of strokes, congestive heart failure, and death. These increased risks vary with the extent of AFib in a given patient. Variability in the increased risk is due to the extent of AFib in a given patient. Untreated patients suffering from either paroxysmal or persistent AFib will see a progression of their disease over time from paroxysmal to persistent or from persistent to permanent AFib respectively. [0005] Some patients with paroxysmal or persistent AFib have short fleeting episodes of AFib each of which are less than 1 hour in duration and/or have a cumulative AFib burden over any 24-hour period of less than 5 hours. Such patients have what will be referred to herein as de minimis AFib. These patients have a sufficiently lower risk of strokes, congestive heart failure, and death than similar patients having longer or more frequent episodes of AFib. Patients with permanent AFib bear the highest risk of stroke, congestive heart failure, and death and typically do not respond to medical intervention. [0006] Current pharmacotherapy for patients with AFib does not aim to control their AFib but, rather, minimizes the associated risk of stroke due to clot formation associated with AFib by, for example, prescribing blood thinners. The use of such blood thinners is not a panacea Attorney Docket: 009643.00011\WO but comes with a price. The underlying rationale for prescribing the use of blood thinners is that they carry less risk of harm to patients with AFib than does untreated AFib itself even though the risk of harm using blood thinners is significant. According to the report cited by Market Insider, QuarterWatch’s 2016 Annual Report Issue (Institute for Safe Medication Practices. (2016). Quarterwatch: Monitoring FDA MedWatch reports. Annual Report Issue), anticoagulant drug use accounted for the most adverse events of all prescription or over-the- counter drugs in 2016, specifically 21,996 severe injuries in the U.S., including 3,018 reported deaths. In clinical trials, anticoagulants have repeatedly demonstrated high injury rates, causing bleeding in 8% to 19% of patients treated for a year. The Quarterwatch 2016 report estimates that 6.3% of patients exposed to an anticoagulant for one year will require an emergency department visit due to the drug’s adverse effects, with 3.1% requiring hospitalization. [0007] About two-thirds of all AFib patients are symptomatic with symptoms ranging from mild to debilitating. Physical symptoms include but are not limited to, general fatigue, fatigue when exercising or during exertion, faintness, light-headedness, confusion, a rapid and/or irregular heartbeat, fluttering or thumping in the chest, shortness of breath, dizziness, weakness, confusion, sweating, chest pain and/or pressure. However, regardless of the extent of any physical symptoms, the corresponding mental anxiety concerning potential cardiac issues can be severe and can be manifested by psychological symptoms such as anxiety, stress, and/or depression in the patient. In turn, these psychological symptoms aggravate the AFib in the patient and, in their own right, are serious health issues. As such, the ability to reduce the symptoms of AFib is an important aspect of treating symptomatic patients with AFib. [0008] Regardless of whether the patient’s AFib is symptomatic or asymptomatic, studies have shown that the risk of stroke and/or heart failure is independent of whether the patient suffers symptoms associated with AFib. See, e.g., Flaker, et al., “Asymptomatic Atrial Fibrillation: Demographic Features and Prognostic Information from the Atrial Fibrillation Follow-Up Investigation of Rhythmic Management (AFFIRM) Study,” American Heart Journal, April 2005, pages 657-663, which is incorporated herein by reference in its entirety. A patient’s recognition or lack thereof of periodic AFib episodes does not correlate to a differential risk o