Subcutaneous foslevodopa / foscarbidopa treatment for advanced Parkinson's disease

Abstract

The present disclosure relates to a safe and effective subcutaneously administered treatment for advanced Parkinson's disease.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 272,574, filed October 27, 2021; U.S. Provisional Application No. 63 / 291,207, filed December 17, 2021; U.S. Provisional Application No. 63 / 297,513, filed January 7, 2022; U.S. Provisional Application No. 63 / 318,567, filed March 10, 2022; U.S. Provisional Application No. 63 / 327,441, filed April 5, 2022; and Canadian Application No. 3,156,401, filed April 25, 2022. The entire contents of each of these applications are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to a safe, tolerable and effective subcutaneously administered treatment for advanced Parkinson's disease. [Background technology]

[0003] Parkinson's disease is a chronic and progressive neurodegenerative condition characterized by a decrease in the brain levels of the neurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine). Administration of levodopa (i.e., L-3,4-dihydroxyphenylalanine) is currently the most effective therapy for treating patients with Parkinson's disease. Coadministration of carbidopa with levodopa inhibits the peripheral metabolism of levodopa to dopamine, significantly reducing the dose of levodopa required for a therapeutically effective clinical response and reducing associated side effects. Summary of the Invention [Problem to be solved by the invention]

[0004] To date, there remains a need for safe, tolerable and effective subcutaneously administered therapies for the treatment of advanced Parkinson's disease. [Means for solving the problem]

[0005] Summary of the Invention The present disclosure relates to a safe, tolerable and effective subcutaneously administered therapy for the treatment of advanced Parkinson's disease.

[0006] Stable liquid formulations comprising a combination of the levodopa acid prodrug "foslevodopa" and the carbidopa acid prodrug "foscarbidopa" suitable for use in the present disclosure are described in WO 2020 / 102628, the entirety of which is expressly incorporated by reference herein.

[0007] As disclosed herein, the present disclosure relates to the following embodiments:

[0008] Embodiment 1. A method of treating advanced Parkinson's disease in a subject by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves increased "on" time without troublesome dyskinesias.

[0009] Embodiment 2. A method of treating advanced Parkinson's disease by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves a reduction in "off" time without disabling dyskinesias.

[0010] Embodiment 3. A method of treating advanced Parkinson's disease by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves a reduction in sleep symptoms as assessed by the Parkinson's Disease Sleep Scale-2 (PDSS-2) total score.

[0011] Embodiment 4. A method of treating advanced Parkinson's disease by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves an increase in PD-related quality of life as assessed by the Parkinson's Disease Questionnaire-39 Items (PDQ-39) Summary Index.

[0012] Embodiment 5. A method of treating advanced Parkinson's disease by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves an increase from baseline to final visit in health-related quality of life as assessed by the EQ-5D-5L summary index.

[0013] Embodiment 6. A method of treating advanced Parkinson's disease by subcutaneous administration of a composition comprising foslevodopa and foscarbidopa, wherein the composition achieves a reduction from baseline to final visit in PD symptoms as assessed by a wearable motion sensor device.

[0014] Embodiment 7. The method of any one of embodiments 1-6, wherein the composition is administered in an amount effective to reduce Parkinson-like symptoms by at least 46% from baseline.

[0015] Embodiment 8. The method of any one of embodiments 1-6, wherein the composition is administered in an amount effective to reduce the baseline MDS-UPDRS total score by at least 9 units.

[0016] Embodiment 9. The method of any one of embodiments 1-6, wherein the composition is administered in an amount effective to reduce the baseline PDQ-39 score by at least 6.9 units.

[0017] Embodiment 10. The method of any one of embodiments 1-6, wherein the composition is administered in an amount effective to reduce the baseline PDSS-2 total score by at least 2 units.

[0018] Embodiment 11. The method of any one of embodiments 1 to 6, wherein the treatment period is at least 10 days without the development of skin nodules.

[0019] Embodiment 12. A method for reducing the incidence of Parkinsonian "off" time in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0020] Embodiment 13. The method of embodiment 12, wherein the incidence of parkinsonian "off" time in a subject is reduced while increasing "on" time without disabling dyskinesias.

[0021] Embodiment 14. A method of improving the average normalized daily "off" time as assessed by a PD diary in a subject compared to a subject receiving an oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0022] Embodiment 15. A method of improving Motor Aspects of Experiences of Daily Living as assessed by MDS-UPDRS Part II score in a subject compared to a subject receiving an oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0023] Embodiment 16. A method of reducing morning immobility in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0024] Embodiment 17. A method of improving health-related quality of life as assessed by the EQ-5D-5L summary index in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0025] Embodiment 18. A method of improving the median bradykinesia score (BK50) as assessed by a wearable motion sensor device in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0026] Embodiment 19. A method of improving the interquartile range (BK75-BK25) of bradykinesia scores as assessed by a wearable motion sensor device in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1-6.

[0027] Embodiment 20. A method of improving the median dyskinesia score (DK50) as assessed by a PKG wearable device in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0028] Embodiment 21. A method of improving tremor and daytime somnolence as assessed by a wearable motion sensor device in a subject compared to a subject receiving an oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0029] Embodiment 22. A method of improving MDS-UPDRS Part I score, Part III score, Part IV score, and Part I-III total score in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1-6.

[0030] Embodiment 23. A method of improving "on" time with non-interfering dyskinesias and "on" time with interfering dyskinesias as assessed by a PD diary in a subject compared to a subject receiving an oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1-6 to a patient in need of treatment for Parkinson's disease.

[0031] Embodiment 24. A method of improving average daily normalized "OFF" times, "ON" times without interfering dyskinesias, "ON" times without dyskinesias, "ON" times with non-interfering dyskinesias, and "ON" times with interfering dyskinesias in a subject as assessed by a PD diary, compared to a subject receiving an oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1-6 to a patient in need of treatment for Parkinson's disease.

[0032] Embodiment 25. A method of improving mean daily absolute "OFF" time, "ON" time without interfering dyskinesias, "ON" time without dyskinesias, "ON" time with non-interfering dyskinesias, "ON" time with interfering dyskinesias, and "Deep Sleep" time as assessed by a non-normalized PD diary in a subject compared to a subject receiving an oral dose of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0033] Embodiment 26. A method of improving PDSS-2 domain scores in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0034] Embodiment 27. A method of improving PDQ-39 domain scores in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0035] Embodiment 28. A method of improving the EQ-5D-5L visual analog scale (VAS) score in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6.

[0036] Embodiment 29. The method of any one of embodiments 1-28, wherein the weight ratio of foslevodopa to foscarbidopa is about 20:1.

[0037] Embodiment 30. The method of any one of embodiments 1-29, wherein the composition comprises about 240 mg / mL foslevodopa and about 12 mg / mL foscarbidopa.

[0038] Embodiment 31. The method of any one of embodiments 1 to 30, wherein the composition has a pH of between about 6.6 and about 8.1.

[0039] Embodiment 32. The method of any one of embodiments 1 to 6, wherein the composition has an osmolality of up to about 2700 mOsmol / kg.

[0040] Embodiment 33. The method of any one of embodiments 1 to 6, wherein the composition has an osmolality of between about 2200 and about 2500 mOsmol / kg.

[0041] Embodiment 34. A method of improving "on" time without disabling dyskinesias as assessed by a PD diary in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1-6 to a patient in need of treatment for Parkinson's disease, wherein the mean time to reach "on" time is between 10 and 60 minutes.

[0042] Embodiment 35. The method of embodiment 34, wherein the average time to reach the "on" time is from about 15 minutes to about 50 minutes.

[0043] Embodiment 35A. The method of embodiment 35, wherein the average time to reach the "on" time is about 20 minutes to about 40 minutes, or about 30 minutes.

[0044] Embodiment 35B. The method of embodiment 35A, wherein the time to reach the "on" time is 28.9 minutes.

[0045] Embodiment 36. A method of improving "on" times with non-interfering dyskinesias as assessed by a PD diary in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6 to a patient in need of treatment for Parkinson's disease, wherein the frequency of "on" times is about twice as high as in a subject receiving oral administration of a tablet containing levodopa and carbidopa.

[0046] Embodiment 37. A method of improving "off" times with dyskinesias that do not interfere with daily living as assessed by a PD diary in a subject receiving oral administration of a tablet containing levodopa and carbidopa as described in any one of embodiments 1 to 6 to a patient in need of treatment for Parkinson's disease, wherein the frequency of "off" times within 30 minutes of waking up is about ¼ less frequent in a subject receiving oral administration of a tablet containing levodopa and carbidopa.

[0047] Embodiment 38. The method of any one of embodiments 1 to 6, wherein the frequency of "off" periods is sustained for at least 24 hours.

[0048] Further advantages of the present disclosure will be apparent to those skilled in the art from reading this patent application. The disclosed embodiments described in the following paragraphs are intended to illustrate the present invention and should not be considered as narrowing the scope of the present invention. [Brief description of the drawings]

[0049] [Figure 1] Figure 1 is a schematic overview of the study design. [Diagram 2] FIG. 2 is a graphical representation showing the distribution of the Modal Daily Dose for the oral CD / LD groups. [Diagram 3] FIG. 3 is a graphical representation showing the distribution of the modal daily dose for the foslevodopa and foscarbidopa groups. [Figure 4]FIG. 4 is a graphical representation showing the LS mean change (±SE) from baseline in mean daily normalized "on" time without disabling dyskinesias by treatment group (full analysis set) over the DB treatment period. [Diagram 5] FIG. 5 is a graphical representation showing the S mean change (±SE) from baseline in average normalized daily "off" time by treatment group (full analysis set) over the DB treatment period. [Figure 6] FIG. 6 is a graphical representation showing the LS mean change (±SE) from baseline in MDS-UPDRS part II score by treatment group (full analysis set) over the DB treatment period. [Figure 7] FIG. 7 is a graphical representation showing the distribution of mean normalized daily "OFF" and "ON" times over time (Full Analysis Set). [Figure 8] FIG. 8 is a graphical representation showing the distribution of early morning non-sleep symptoms over time (full analysis population). [Figure 9] FIG. 9 shows the results of the Study Blinded Assessment: Safety Analysis Set. [Figure 10] FIG. 10 is a graphical representation of normalized "off" and "on" time: as number of hours and percent of wakefulness. [Figure 11] FIG. 11 is an exemplary Parkinson's disease diary. [Figure 12] FIG. 12 is a graphical representation of the percentage of subjects receiving the highest grade on the Infusion Site Evaluation Numeric Scale during any 10 day period for pharmaceutical compositions (levodopa 4′-monophosphate and carbidopa 4′-monophosphate in a ratio of 20:1) and placebo. [Figure 13] FIG. 13 is a graphical representation of the percentage of subjects receiving the highest grade on the Infusion Site Assessment Letter Grade Scale during any 10 day period for pharmaceutical compositions of levodopa 4′-monophosphate and carbidopa 4′-monophosphate in a 20:1 ratio and placebo. [Figure 14A] FIG. 14A is a graphical representation of the study design for Clinical Trial A to evaluate the safety, efficacy, and tolerability of 12-week continuous subcutaneous infusion of a pharmaceutical composition of levodopa 4′-monophosphate and carbidopa 4′-monophosphate in a 20:1 ratio in patients. [Figure 14B] FIG. 14B is a graph showing the results for Clinical Trial A of grading injection sites using a numerical scale in patients. [Figure 14C] FIG. 14C is a graph showing the results for Clinical Trial A of grading injection sites using a letter scale in patients. [Figure 14D] FIG. 14D is a graph showing the mean (SD) change from baseline in MDS-UPDRS total score for Clinical Trial A in patients. [Figure 14E] FIG. 14E is a graph showing the mean (SD) change from baseline in "off" time during regularly scheduled visits for Clinical Trial A in patients. [Figure 15] FIG. 15 is a plasma time-concentration profile of levodopa plasma concentrations (± standard deviation) in healthy human volunteers after subcutaneous administration of a bolus dose of a pharmaceutical composition of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1, followed by continuous subcutaneous administration of the pharmaceutical composition for 24 hours (Clinical Study B). [Figure 16] FIG. 16 shows the percentage of patients experiencing "off" time during the day receiving the pharmaceutical composition compared to patients orally administering Sinemet® (Clinical Trial B). [Figure 17A] FIG. 17A shows the mean levodopa exposure (±SD) after 24-hour foslevodopa and foscarbidopa infusions and after a 16-hour Duopa infusion, followed by oral LD / CD administration at 18 and 21 hours. [Figure 17B] FIG. 17B shows the mean levodopa exposure (±SD) following 24-hour foslevodopa and foscarbidopa infusions and 24-hour Duopa infusions. [Figure 18] Figure 18 is a schematic diagram of the study design. D = day; V = visit; W = week. [Figure 19] FIG. 19 shows an illustration of the narrowing of the therapeutic window for levodopa as Parkinson's disease (PD) progresses. [Figure 20] FIG. 20 shows a schematic diagram of the study design. [Figure 21] FIG. 21 shows the average observations over time for average daily normalized "OFF" time, "ON" time with disabling dyskinesias, and "ON" time without disabling dyskinesias. [Figure 22] FIG. 22 shows the average normalized daily time obtained from the PD diary, as mean time and percentage of waking. [Figure 23] FIG. 23 shows the modal total daily dose (mg LD by molecular weight). [Figure 24] Figure 24 shows the change in efficacy outcomes from baseline to 6 months. *P<0.05; **P<0.01. MDS-UPDRS II, Movement Disorder Society Unified Parkinson's Disease Rating Scale part II; PD, Parkinson's disease; PDQ-39, 39-item Parkinson's Disease Questionnaire. [Diagram 25] FIG. 25 shows the adjusted percentages of responders (≧1 hour) and robust responders (≧3 hours) for "OFF" time and "ON" time without disabling dyskinesias (ONwoTD) between foslevodopa and foscarbidopa versus levodopa and carbidopa immediate-release oral tablets (LCIR) at Week 12. [Figure 26] FIG. 26 shows adjusted percentages of responders (≧1 hour) and robust responders (≧3 hours) for "off" time and "on" time without disabling dyskinesias (ONwoTD) for foslevodopa and foscarbidopa at weeks 13 and 52. [Figure 27] FIG. 27 shows the change in "on" time without disabling dyskinesias ("good on") from baseline to week 12 for foslevodopa and foscarbidopa versus levodopa and carbidopa immediate release oral tablets (LCIR). [Figure 28] FIG. 28 shows the change in "off" time from baseline to week 12 for foslevodopa and foscarbidopa versus levodopa and carbidopa immediate release oral tablets (LCIR). [Figure 29] FIG. 29 shows Sankey diagrams of motor status transition categories for baseline and week 12 visits for (a) levodopa and carbidopa immediate release oral tablet (LCIR) and (b) foslevodopa and foscarbidopa patients. [Diagram 30] FIG. 30 shows the patients and the number or percentage of Parkinson's disease medications administered in Example 14. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] This disclosure describes the unexpected discovery that subcutaneous administration of the pharmaceutical composition foscarbidopa / foslevodopa at 12 mg / 240 mg per ml of subcutaneous infusion solution is safe, tolerable, and effective for the treatment of diurnal motor variation in patients with advanced Parkinson's disease not adequately controlled with current medical therapies.

[0051] As used herein, the terms "levodopa acid prodrug," "levodopa-4'-monophosphate," and "phoslevodopa" are used interchangeably to refer to the compound:

[0052] [ka] It has been assigned CAS Registry Number 97321-87-4. As used herein, the terms "carbidopa acid prodrug," "carbidopa-4'-monophosphate," and "foscarbidopa" are used interchangeably to refer to the compound:

[0053] [ka] .

[0054] It has been assigned CAS Registry Number 28860-95-9. As used herein, the terms "foscarbidopa / foslevodopa for subcutaneous injection," "foscarbidopa / foslevodopa," and "products of the disclosure" may be used interchangeably.

[0055] When numerical ranges are recited herein, each intervening number within the range is specifically contemplated with the same degree of precision. For example, in the range of 6 to 9, 7 and 8 are specifically contemplated in addition to 6 and 9, and in the range of 6.0 to 7.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are specifically contemplated.

[0056] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0057] As used herein, the term "and / or" when used in the form of phrases such as "A and / or B" is intended to mean "A and B", "A or B", "A" and "B".

[0058] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" can include numbers that are rounded to the nearest significant figure. In certain embodiments, the term "about" can be used to indicate values ​​within ±20% of the recited value, for example, within ±15%, within ±10%, within ±7.5%, within ±5%, within ±4%, within ±3%, within ±2%, or within ±1% of the recited value.

[0059] The term "baseline" refers to the first measurement of the target variable immediately prior to administration of the therapy being tested.

[0060] The term "container" means any suitable container, coated or uncoated, made of any suitable material, including, but not limited to, vials, cartridges, syringes, bottles, and materials such as glass, plastic, and / or combinations thereof.

[0061] Unless otherwise required by context, the terms "comprise", "comprises" and "comprising" are used with the basic and clear understanding that they are to be interpreted inclusively, rather than exclusively, to indicate the inclusion of the recited features without the exclusion of one or more other such features.

[0062] The terms "patient," "subject," "individual," and the like refer to a human.

[0063] The term "carrier" used in connection with pharmaceutical excipients refers to any and all solvents, dispersion media, preservatives, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.

[0064] As used herein, the term "off" time refers to the period of the day when a medication does not work sufficiently to cause the re-emergence or worsening of Parkinsonian symptoms (including, for example, tremor, rigidity, bradykinesia, as well as non-motor symptoms such as depression, pain, anxiety, etc.).

[0065] As used herein, the term "on time" refers to the period of adequate control of symptoms.

[0066] As used herein, the term "dyskinesia" refers to a neurological syndrome, both spontaneous and drug-induced, consisting of spontaneous and largely uncontrollable movements or lack of movement. When a subject evaluates their dyskinesia, they determine whether it is "disabling" (e.g., involuntary movements) or "not disabling."

[0067] As described herein, the pharmaceutical composition may have a final pH of about 5 to 11, including pH values ​​between 5 and 11 in increments of 0.1. In particular embodiments, the pH may be between 6.5 and pH 9.2, including pH values ​​between 6.5 and 9.2 in increments of 0.1. In one embodiment, the pharmaceutical composition has a final pH (e.g., after reconstitution with water) of between about 6.8 and about 7.8. Thus, the pharmaceutical composition may have a final pH selected from about 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, or 7.8. In one embodiment, the pharmaceutical composition has a final pH of between about 7.0 and about 7.5. Thus, the pharmaceutical composition may have a final pH selected from about 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5.

[0068] The present disclosure also relates to a method of treatment in which the pharmaceutical composition is used. In one aspect, the present disclosure provides a method of treating advanced Parkinson's disease in a subject, comprising subcutaneously administering a pharmaceutical composition disclosed herein to a patient in need thereof. In some aspects and embodiments, the present disclosure provides a method in which a particular measure of advanced Parkinson's disease is improved. Thus, the present disclosure provides a method of improving the "off" time of parkinsonian symptoms in a subject, comprising subcutaneously administering a pharmaceutical composition disclosed herein to a patient in need of treatment for advanced Parkinson's disease in an amount effective to reduce parkinsonian symptoms by at least 46% from baseline.

[0069] The disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline MDS-UPDRS total score by about 5 units to about 15 units. The disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline MDS-UPDRS total score by at least 9 units. The disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Disease Questionnaire-39 Items (PDQ-39) summary index score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline PDQ-39 score by about 2 units to about 10 units. The disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Disease Questionnaire-39 Items (PDQ-39) summary index score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline PDQ-39 score by at least 6.9 units.

[0070] The present disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Sleep Scale-2 (PDSS-2) total score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline PDSS-2 total score by about 1 unit to about 10 units. The present disclosure also provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Sleep Scale-2 (PDSS-2) total score a pharmaceutical composition disclosed herein in an amount effective to reduce the baseline PDSS-2 total score by at least 2 units. In a detailed embodiment, the treatment disclosed herein can be continued for at least 10 days without the subject developing skin nodules. The present disclosure also provides a method of reducing the incidence of parkinsonian "off" time in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa, the method comprising subcutaneously administering to a patient in need of treatment for advanced Parkinson's disease a pharmaceutical composition disclosed herein. EXAMPLES

[0071] Example 1: A randomized, double-blind, double-dummy, active-controlled study comparing the efficacy, safety, and tolerability of foscarbidopa / foslevodopa for subcutaneous infusion with oral CD / LD in patients with advanced Parkinson's disease (aPD) (Phase 3 study)

[0072] Clinical Trial A Study design and objectives Clinical hypothesis: 24-hour / day CSCI of foscarbidopa / foslevodopa for subcutaneous infusion will increase "on" time without interfering dyskinesias ("on" time without dyskinesias + "on" time with interfering dyskinesias), decrease "off" time, and improve motor symptoms experienced in daily life compared to CD / LD immediate-release (IR) tablets in patients with aPD whose diurnal variation in motor symptoms is not adequately controlled by current Parkinson's disease PD medications.

[0073] This was a phase 3, randomized, double-blind, double-dummy, 12-week, parallel-group, active-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of foscarbidopa / foslevodopa 24-h / day continuous subcutaneous infusion (CSCI) for the treatment of patients with aPD whose diurnal motor fluctuations are not adequately controlled by current medications.

[0074] Primary objective: To demonstrate the superiority of continuous subcutaneous infusion of foscarbidopa / foslevodopa (CSCI) compared with carbidopa / levodopa (CD / LD) immediate-release (IR) oral tablets for the treatment of diurnal fluctuations in motor symptoms in subjects with advanced Parkinson's disease (aPD) after 12 weeks of treatment.

[0075] Secondary objective: To evaluate the local and systemic safety and tolerability of foscarbidopa / foslevodopa for subcutaneous infusion delivered as a CSCI 24 hours per day for 12 weeks.

[0076] Test Plan: A schematic overview of the study is shown in FIG. 1, where CD / LD=carbidopa / levodopa; CSCI=continuous subcutaneous infusion; D=day; IR=immediate release; PD=Parkinson's disease; V=visit.

[0077] a. V3 can be performed at least 6 days after V1 to ensure that the results of V1 are sufficiently available for review and for training and familiarization with the appropriate infusion delivery system.

[0078] b. Screening period activities last at least 6 days; PD diary is collected for at least 3 consecutive days during the screening period prior to V3; PD diary collection may be repeated only once for an additional 3 consecutive days during the period prior to the start of the oral CD / LD stabilization period prior to V3.

[0079] c. The oral CD / LD stabilization period is expected to take 14-21 days to accommodate schedules, unscheduled additional visits, and repeat evaluations if permitted. PD diaries are collected for at least 3 consecutive days prior to Day 1.

[0080] d. If a subject prematurely discontinues participation in the study or completes the study and does not participate in the open label extension study M20-098, then, if the subject is willing, a follow-up visit or phone call will be completed 30 days after the last date of use of the product of the present disclosure (foscarbidopa / foslevodopa for subcutaneous infusion) to ensure that all treatment-emergent AEs / SAEs have resolved.

[0081] The primary objective was to demonstrate the superiority of CSCI of foscarbidopa / foslevodopa for subcutaneous injection compared with CD / LD IR oral tablets for the treatment of diurnal fluctuations of motor symptoms in subjects with aPD after 12 weeks of treatment.

[0082] The secondary objective was to evaluate the local and systemic safety and tolerability of the disclosed product (foscarbidopa / foslevodopa for subcutaneous infusion) delivered as a CSCI 24 hours per day for 12 weeks.

[0083] Screening Period This 6-60 day period consisted of two screening visits (V1 and V2).

[0084] Oral CD / LD stabilization period This 14-21 day period consists of three visits (V3, V4, V5). V4 is an optional visit. V5 is the baseline visit for most evaluation assessments.

[0085] Double-blind treatment period The 12-week period begins with the initiation of blinded subcutaneous infusions of foscarbidopa / foslevodopa and blinded oral capsules and consists of two parts: a 4-week CSCI optimization phase and an 8-week maintenance phase.

[0086] Post-treatment activities There will be no post-treatment activity, except for subjects who discontinue study participation early.

[0087] Treatment Allocation and Blinding After completion of the oral CD / LD stabilization period, eligible subjects were randomized in a 1:1 ratio to one of two treatment arms for a 12-week double-blind treatment period. - oral placebo capsules for 24h / day CSCI+CD / LD IR of the product of the present disclosure (foscarbidopa / foslevodopa for subcutaneous infusion) (also referred to as the investigational group or the foscarbidopa / foslevodopa for subcutaneous infusion group) or - 24h / day CSCI of placebo solution for the product of the present disclosure + oral encapsulated CD / LD IR tablets (also referred to as the active control group or oral CD / LD group)

[0088] Randomization was stratified by study center with a block size of 2.

[0089] The first day of administration of blinded foscarbidopa / foslevodopa for subcutaneous infusion is defined as day 1.

[0090] To aid in assessing maintenance of the blind, exit interviews were conducted if subjects discontinued the study early or if they completed the study. Data collected during the exit interviews were summarized.

[0091] Determining sample size A sample size of 52 subjects per arm will have 90% power to detect a statistically significant difference between the two treatment arms at a two-sided significance level of 0.05 (using nQuery version 8.4.0.0), assuming that the difference in change from baseline to week 12 in mean daily normalized "on" time without disabling dyskinesias is 1.86 hours between the investigational and active control groups, with a common standard deviation of 2.9 hours. Approximately 130 subjects will be randomized, assuming that approximately 20% of subjects will prematurely discontinue blinded foscarbidopa / foslevodopa for subcutaneous infusion during the double-blind treatment period. This sample size will also have approximately 90% power for the key secondary endpoints of change from baseline in mean daily normalized "off" time, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II score, and the presence of morning akinesia at week 12 (the first morning symptom of "off" after awakening).

[0092] An adequate number of subjects will be enrolled in the oral CD / LD stabilization period to meet the randomization objectives of the study.

[0093] Endpoints: Primary Endpoint The primary efficacy endpoint was the change from baseline to week 12 of the double-blind treatment period in mean daily normalized "on" time (hours) without disabling dyskinesias as assessed by a PD diary.

[0094] Secondary Endpoints The primary secondary endpoint following the double-blind treatment period and other secondary endpoints will be included in the multiplicity adjustment for type I error to control the familywise error rate (FWER) at a two-sided significance level of 0.05 for the entire study. These variables will be tested in the following routine order as a gatekeeping approach:

[0095] Primary secondary endpoints: Change from baseline to week 12 in mean normalized daily "OFF" time as assessed by PD diary. Change from baseline to week 12 in motor symptoms experienced in daily living as assessed by MDS-UPDRS part II score. Presence of morning immobility at week 12 (defined as reporting an "off" state as the first morning symptom after awakening) as assessed by PD diary. Other secondary endpoints included in the control of the familywise error rate (FWER): - Change from baseline to week 12 in mean daily normalized "on" time without dyskinesias as assessed by PD diary. Change from baseline to final visit in sleep symptoms as assessed by the Parkinson's Disease Sleep Scale-2 (PDSS-2) total score Change from baseline to final visit in PD-related quality of life as assessed by the Parkinson's Disease Questionnaire-39 (PDQ-39) summary index Change from baseline to final visit in health-related quality of life as assessed by the EQ-5D-5L summary index. Change from baseline to week 12 in median bradykinesia score (BK50) as assessed by Parkinson's KinetiGraph™ / Personal KinetiGraph™ (PKG) wearable device Change from baseline to week 12 in the interquartile range of bradykinesia scores (BK75-BK25) as assessed by the PKG wearable device Change from baseline to week 12 in median dyskinesia score (DK50) as assessed by the PKG wearable device Change from baseline to week 12 in the interquartile range of dyskinesia scores (DK75-DK25) as assessed by the PKG wearable device

[0096] Other Efficacy Endpoints The primary and secondary efficacy endpoints included in the FWER multiplicity adjustment are shown above. Additional efficacy endpoints during the double-blind treatment period were: Percent change from baseline to week 12 in tremor and daytime somnolence duration as assessed by the PKG wearable device. Change from baseline to week 12 in MDS-UPDRS Part I score, Part III score, Part IV score, and total score for Parts I-III Change from baseline to week 12 in mean daily normalized "on" time with non-interfering dyskinesias and mean "on" time with interfering dyskinesias as assessed by PD diary Percent change from baseline to week 12 in mean daily normalized "off" time, "on" time without interfering dyskinesias, "on" time without dyskinesias, "on" time with non-interfering dyskinesias, and "on" time with interfering dyskinesias, as assessed by PD diary Change from baseline to week 12 in mean daily absolute "OFF" time, "ON" time without interfering dyskinesias, "ON" time without dyskinesias, "ON" time with non-interfering dyskinesias, "ON" time with interfering dyskinesias, and "Deep sleep" time, as assessed by non-normalized PD diaries. Change in PDSS-2 domain scores from baseline to final visit Change in PDQ-39 domain scores from baseline to final visit Change in EQ-5D-5L visual analog scale (VAS) score from baseline to final visit

[0097] Safety Endpoints Safety endpoints were as follows: Adverse events (AEs), serious AEs (SAEs) and adverse events of special interest (AESIs) Local tolerance as measured by the injection site assessment scale Laboratory test values Vital signs Electrocardiogram (ECG) Columbia-Suicide Severity Rating Scale (C-SSRS) Questionnaire on Impulsivity-Obsessive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS) Endpoints during the oral CD / LD stabilization period, the following variables for the oral CD / LD stabilization period are summarized: Change from screening to study baseline (pre-randomization) in mean daily normalized "off" time, "on" time without interfering dyskinesias, "on" time without dyskinesias, "on" time with non-interfering dyskinesias, and "on" time with interfering dyskinesias, as assessed by PD diary Change from screening scores to study baseline (pre-randomization) in PD symptoms (including tremor, bradykinesia, dyskinesia, and daytime somnolence) assessed by the PKG wearable device

[0098] Analysis population The following analysis set is used for the analysis:

[0099] The oral CD / LD analysis set includes all subjects who received at least one dose of open-label CD / LD IR tablets during the oral CD / LD stabilization period. The oral CD / LD analysis set will be used to summarize premature discontinuations and adverse events during the oral CD / LD stabilization period.

[0100] The Full Analysis Set (FAS) includes all randomized subjects who receive any dose of the disclosed product during the double-blind treatment period and have a baseline and at least one post-baseline observation for at least one efficacy assessment. Unless otherwise stated, the FAS is used for all efficacy analyses. Subjects are included in the analysis by randomized treatment group.

[0101] The safety analysis population consisted of all subjects who received any dose of foscarbidopa / foslevodopa for subcutaneous infusion during the double-blind treatment period. The safety analysis population was used for all demographic, baseline, and safety analyses unless otherwise stated. Subjects were included in analyses by foslevodopa and foscarbidopa actually administered, regardless of randomization. If a subject received both active treatments (foscarbidopa / foslevodopa for subcutaneous infusion and oral CD / LD), the subject was included in the treatment group that received them for the majority (cumulative >50%) of their foscarbidopa / foslevodopa for subcutaneous infusion exposure time during the double-blind treatment period. Subjects were included in the randomized treatment group if they received both active treatments for equal amounts of time or if they received both forms of placebo treatment (placebo solution CSCI and oral placebo capsules) for any amount of time.

[0102] Baseline demographic characteristics and subject breakdown The majority of the demographic baseline characteristics and safety data from this study are presented by dose category (LD low dose < 1800 mg / day or LD high dose > 1800 mg / day) within the randomized groups of foscarbidopa / foslevodopa for subcutaneous infusion and oral CD / LD. The LD dose for each subject was based on their individual need. Categorization of each subject into a low or high dose group was based on the actual modal (most frequent) total daily dose of LD received during the double-blind treatment period as recorded in the subject's medication diary. Doses of foscarbidopa / foslevodopa for subcutaneous infusion are presented as LD equivalents by converting foslevodopa to LD based on molecular weight (100 mg foslevodopa is equivalent to 71 mg LD).

[0103] Breakdown of targets The total number of subjects who were screened, entered the oral CD / LD stabilization period, and randomized to receive blinded foscarbidopa / foslevodopa for subcutaneous infusion are summarized. Reasons for exclusion, including failure to screen, are summarized.

[0104] A summary of subject accountabilities was provided, showing the number of subjects in each of the following categories, summarized by dose subgroup (low or high dose) within each treatment group: Subjects enrolled in the oral CD / LD stabilization period Subjects who discontinued early during the oral CD / LD stabilization period (all reasons and major reasons) Randomized subjects Subjects receiving either dose of blinded foscarbidopa / foslevodopa administered by subcutaneous infusion - Subjects who completed the double-blind treatment period Subjects who prematurely discontinued blinded foscarbidopa / foslevodopa for subcutaneous infusion during the double-blind treatment period (all reasons and major reasons) Subjects who discontinued study participation early during the double-blind treatment period (all reasons and major reasons) Targets in each analysis set Each subject was categorized into dose subgroups based on the modal total daily dose over the treatment period. Calculation of the modal total daily dose is defined in the section entitled "Analysis of Daily Levodopa Dose."

[0105] A list by subject number and site ID of all subjects affected by COVID-19 related study interruptions, and a description of how the subject's participation was modified due to COVID-19: - Subjects who prematurely discontinued foscarbidopa / foslevodopa for subcutaneous injection Subjects who discontinued the study early

[0106] Discontinuation of foscarbidopa / foslevodopa for subcutaneous infusion Subjects who missed a visit Those who underwent a virtual visit

[0107] The study was conducted at 63 sites in the United States and Australia. A total of 270 subjects were screened, 174 subjects enrolled in the oral CD / LD stabilization period, 145 subjects randomized to double-blind treatment, 141 subjects received blinded foscarbidopa / foslevodopa by subcutaneous infusion, and were included in the safety analysis population, with 110 subjects completing the study.

[0108] Duration and Compliance For the safety analysis population, duration of treatment was summarized within each treatment group and by dose subgroup (low or high dose) for both treatment groups combined. Duration of double-blind treatment (in days) was defined for each subject as the date of last dose minus the date of first dose plus one. Duration of treatment was summarized using the number of subjects treated, mean, standard deviation, median, minimum, and maximum. Additionally, the number and percentage of subjects in each treatment period interval (1-7 days, 8-14 days, 15-28 days, 29-56 days, and >56 days) were summarized.

[0109] Percent treatment compliance for foscarbidopa / foslevodopa and foslevodopa and foscarbidopa capsules for subcutaneous infusion will be calculated for each subject and defined as follows: Foslevodopa and foscarbidopa solution (foslevodopa and foscarbidopa CSCI or placebo solution CSCI): Calculated as the number of hours the pump is infused relative to a 24 hour / day target and averaged over the number of days in the appropriate medication diary.

[0110] Evodopa and carbidopa capsules (placebo capsules or encapsulated CD / LD 25 / 100 mg IR tablets): Calculated as actual levodopa and carbidopa capsules taken relative to the number prescribed, averaged over the number of days in the appropriate medication diary. A valid dosing diary day was defined as a day on which the pump infused (foslevodopa, foscarbidopa or placebo solution) for ≧80% (ie, ≧19.2 hours) of the total 24-hour period.

[0111] Percentage treatment compliance was summarized by treatment group for the entire double-blind treatment period and for both groups combined for the safety analysis population, using the number of subjects with non-missing observations, mean, standard deviation, median, minimum, and maximum.

[0112] Rescue medication was defined as the use of open-label CD / LD IR tablets and blinded foscarbidopa / foslevodopa for subcutaneous infusion during the double-blind treatment period. Mean daily levodopa from blinded foscarbidopa / foslevodopa for subcutaneous infusion, mean daily levodopa from rescue medication, and the sum of blinded foscarbidopa / foslevodopa for subcutaneous infusion and rescue medication were calculated for each visit where a medication diary was collected. Mean daily levodopa equivalents (LED) from all PD medications (blinded foscarbidopa / foslevodopa for subcutaneous infusion, loading dose, rescue medication, and concomitant PD medications) were also calculated for each visit where a medication diary was collected using the conversion factor for each PD medication (Tomlinson et al. 2010). Mean daily levodopa dose and mean daily LED were presented using the number of subjects with complete diaries, mean, standard deviation, median, minimum, and maximum by treatment group and for both groups combined in the safety analysis population.

[0113] Demographic and baseline clinical characteristics, medical history, prior / concomitant medications and dosages Demographic and baseline clinical characteristics, medical history, and prior and concomitant medications were summarized by dose subgroup (low or high dose) within each treatment group and by the overall safety analysis population. Subjects were categorized into dose subgroups based on the modal total daily dose over the treatment period. Calculation of the modal total daily dose is defined in the section entitled "Analysis of Daily Levodopa Dose."

[0114] Categorical variables were summarized and presented as number of subjects and percentages; percentages were calculated based on the number of nonmissing observations. Continuous variables were summarized and presented with descriptive statistics (number of nonmissing observations, mean and standard deviation, median, minimum, and maximum).

[0115] The majority of subjects were male (70.2%) and the majority of subjects were white (92.9%). The overall mean age was 66.4 years, with a median age of 68 years. Demographic and clinical characteristics were generally balanced between treatment groups.

[0116] Demographic and baseline clinical characteristics Demographic and clinical continuous variables were age, weight, height, body mass index (BMI), Mini-Mental State Examination (MMSE) score, baseline levodopa dose, and baseline LED. Categorical demographic and clinical variables were sex, ethnicity, race, age category (<50, 50-<65, 65-<75, or ≥75 years), BMI (<18.5, 18.5-<25.0, 25.0-<30.0, ≥30.0), country, tobacco use (current, former, never, unknown), alcohol use (current, former, never, unknown), and all brief neurological examination variables.

[0117] Medical history Medical history data will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA). The actual version of MedDRA used was specified in statistical tables and clinical trial reports. Numbers and percentages of subjects in each medical history category (by MedDRA system organ class [SOC] and preferred term [PT]) were presented overall and by treatment group. SOCs were presented in alphabetical order, and PTs were presented in alphabetical order within each SOC. Subjects reporting more than one condition / diagnosis were counted in each column (SOC or PT) only once.

[0118] History of Parkinson's disease was summarized by the following variables: Continuous variables: age at onset of PD (years), duration of PD from onset of symptoms (years), age at PD diagnosis (years), duration of PD from diagnosis (years), age at onset of diurnal variation of motor symptoms (years), duration from onset of diurnal variation of motor symptoms (years).

[0119] · Categorical variables: duration of PD from diagnosis (<10 years, ≥10 years), history of levodopa-induced dyskinesia (yes, no), levodopa response for ≥5 years (yes, no), and Horn and Yahr stage.

[0120] Prior and concomitant medications Prior and concomitant PD and non-PD medications are summarized separately. Prior medications are defined as any medication administered before the start of the oral CD / LD stabilization period. Concomitant medications during the double-blind treatment period are defined as any medication initiated before the date of the first blinded foscarbidopa / foslevodopa subcutaneous infusion and continued after the first dose of foscarbidopa / foslevodopa subcutaneous infusion, or any medication initiated at or after the date of the first dose of foscarbidopa / foslevodopa subcutaneous infusion but not after the date of the last dose of foscarbidopa / foslevodopa subcutaneous infusion. Numbers and percentages of subjects taking medications are summarized by ATC level 3, ATC level 4, and generic name from the World Health Organization (WHO) Drug Dictionary for both prior and concomitant PD medications. Numbers and percentages of subjects taking medications are summarized by ATC level 3 and generic name from the WHO Drug Dictionary for non-PD medications.

[0121] PD medications used at screening (the day before the start of open-label foscarbidopa / foslevodopa subcutaneous infusions during the oral CD / LD stabilization period) and at baseline (day 2 of treatment) are summarized by the number of classes of PD medications administered for all subjects and by treatment group.

[0122] Medication Analysis Based on molecular weight, 100 mg of foslevodopa is equivalent to 71 mg of levodopa. Unless otherwise stated, all foslevodopa and foscarbidopa doses are listed as LD equivalents.

[0123] All analyses of medication diary data were performed on the relevant diary day unless otherwise stated.

[0124] Analysis of daily prescription amount Summary statistics (mean, SD, median, minimum and maximum) provided dosage information, including loading dose and continuous infusion rate for the study group, and oral levodopa dose (from encapsulated CD / LD IR) for the active control group.

[0125] When available, summary statistics will be provided for the first prescription, the first maintenance prescription after the optimization phase, the last prescription during the 8-week maintenance phase, and the last prescription in the study. First to first maintenance, first to last maintenance, first to last, and first to last changes in maintenance will also be summarized.

[0126] Analysis of the first optimization The period of initial optimization of the pump infusion rate is defined as the number of days from Day 1 to the first day that there is no change in the pump infusion rate setting for at least 7 days.

[0127] Duration of initial optimization is summarized by the following intervals (days): 1, 2, 3, 4, 5, 6, 7, 8-14, 15-21, 22-28, and >28. Summary statistics include mean, SD, median, minimum, and maximum, where applicable.

[0128] Analysis of daily dose of levodopa Daily levodopa doses were summarized for blinded foscarbidopa / foslevodopa subcutaneous infusions and open-label CD / LD IR oral tablets at each protocol-defined visit. Summary statistics included mean, SD, median, minimum, and maximum.

[0129] The modal total daily levodopa dose during the study was determined for each subject by first assigning the subject's total daily levodopa dose to narrow dose ranges in 100 mg increments (e.g., 1000 to <1100 mg, 1100 to <1200 mg) and then selecting the narrow dose range that was most frequent for the subject. If two or more dose ranges had the same most frequent dose, the highest dose range was selected.

[0130] The most frequent continuous pump infusion rate for the foscarbidopa / foslevodopa subcutaneous infusion treatment group was similarly defined for each subject.

[0131] The modal total daily dose is presented together for the safety analysis population. The modal pump infusion rates are presented together for the foscarbidopa / foslevodopa subcutaneous infusion treatment groups in the safety analysis population.

[0132] Other Medication Analyses The frequency with which subjects received rescue medication is summarized by categories of 0, 1, 2, and ≥3 times, and by the following study day intervals: 1–7, 8–14, 15–21, 22–28, 29–42, and ≥43. Additionally, the number of subjects with at least one occurrence and the total number of occurrences are summarized by mean, SD, median, minimum, and maximum.

[0133] Most frequent (modal) dose Figures 2 and 3 show the distribution of the modal total daily dose of levodopa for the two treatment groups. The median total daily dose was 1000-1100 mg for the oral CD / LD group and 1500-1600 mg for the foscarbidopa / foslevodopa subcutaneous injection group (Table 1).

[0134] [Table 1]

[0135] Other Medication Analyses The frequency with which subjects received rescue medication was summarized by categories of 0, 1, 2, and ≥3 times and by the following study day intervals: 1–7, 8–14, 15–21, 22–28, 29–42, and ≥43. Additionally, the number of subjects with at least 1 occurrence and the total number of occurrences were summarized by mean, SD, median, minimum, and maximum.

[0136] Effectiveness General Considerations All efficacy analyses were performed in the FAS. All tests were two-sided with an alpha level of 0.05.

[0137] The primary analysis was performed after all subjects had completed the double-blind treatment period and the database was locked.

[0138] Unless otherwise specified, continuous variables were analyzed using the Mixed-Effect Model Repeat Measurement (MMRM) method.

[0139] Baseline for PD diary variables was the average of 3 valid diaries completed before day 1. Baseline for all efficacy assessments other than the PD diary was defined as the last nonmissing observation that was on or before the start date of double-blind foscarbidopa / foslevodopa subcutaneous infusion.

[0140] Post-baseline efficacy and safety assessments, other than AEs and infusion site assessments, that were collected more than 1 day after the last dose of double-blind foscarbidopa / foslevodopa subcutaneous infusion were not used for efficacy and safety analyses because data after discontinuation of foscarbidopa / foslevodopa subcutaneous infusion may be confounded by the various PD treatments subjects may have received after discontinuing study treatment.

[0141] Variables derived from the PD diary The primary variable, two of the most important secondary variables, and several other secondary efficacy variables were obtained from the PD diary. On the day of recording the PD diary, subjects were instructed to fill out the diary after awakening from deep sleep and every 30 minutes during their usual waking hours for the entire 24-hour period from 12:00am to 11:30pm each day (48 entries, each entry representing 0.5 hours). Each entry could be in one of five categories: deep sleep, "off", "on" with no dyskinesias, "on" with dyskinesias that do not interfere with daily life, and "on" with dyskinesias that interfere with daily life. The absolute time spent in each category was summed for each diary day. Daily awake time was the sum of the absolute time spent in the four non-deep sleep categories. Daily "off" and "on" times were normalized to a typical waking day (16 hours) to account for different sleep patterns in all subjects, e.g., normalized "on" time without interfering dyskinesias = (absolute "on" time without interfering dyskinesias / wake time) x 16).

[0142] The daily normalized "off" and "on" times are averaged over the number of days of a valid PD diary for each visit to obtain the average daily normalized "off" and "on" times. The number of days of a valid PD diary is defined in the section entitled "Handling Missing Items in Efficacy Instruments."

[0143] The first state in the morning after awakening is determined by examining the PD entries between 0:00 am and 12:00 pm on the last valid PD diary day. The first state in the morning after awakening is defined as the first non-sleep, non-missing entry in the PD diary after at least four consecutive entries of "deep sleep" (i.e., at least 2 hours of continuous sleep).

[0144] Missing data handling: PD diary A valid PD diary day was defined as one that occurred within 7 days prior to the clinical visit, but not on or after the day of the visit, with no more than 2 hours of missing data (no more than 4 missing 30-minute entries) for the entire 24-hour diary.

[0145] For baseline, subjects are required to not receive any PD medications for at least 12 hours prior to the randomization visit (V6), so the number of days of a valid PD diary cannot be the day prior to V6 either.

[0146] The number of days in the valid PD diary will not be used in calculating the average daily normalized time or absolute "OFF" or "ON" time for the visit associated with that PD diary.

[0147] If 3 or more valid PD diaries were available for a baseline or post-baseline visit, the 3 days closest to the clinical visit were used. If only 2 days of valid PD diaries were available prior to the visit, data from the 2 days were used to calculate the mean daily normalized "OFF" or "ON" time. If only 1 day of valid PD diary was available, the value from the valid PD diary for that day was the visit value. If no valid PD diary was available for a visit, the mean daily normalized "OFF" or "ON" time was missing for that visit.

[0148] MDS-UPDRS MDS-UPDRS total and individual part scores were calculated as long as 15% or more of the responses were missing for that assessment. Missing items were imputed as the average of nonmissing items from the same MDS-UPDRS assessment. Imputation of Part I, Part II, Part III, or Part IV scores used missing items within a particular part, whereas imputation of the total score for Parts I-III used nonmissing items from all 59 items across the three parts.

[0149] PDSS-2 There was no imputation of missing responses for the PDSS-2. If any item score was missing, the total score and corresponding domain score were not calculated.

[0150] PDQ-39 A PDQ-39 summary index was calculated whenever 15% (i.e., 5) or more of the responses were missing for that assessment. This was imputed as the average of the nonmissing items from the same PDQ-39 assessment. Domain scores were calculated only if all questions were answered.

[0151] EQ-5D-5L The EQ-5D-5L summary index was calculated only if all five individual questions were answered. The EQ-5D-5L VAS collects a single value and there is no imputation for missing VAS values.

[0152] Handling of intercurrent events and missing visits for efficacy endpoints Intercurrent events and missing data will be handled using the following methods for efficacy analyses: The primary approach to handle missing data for all efficacy endpoints was a mixed-effects repeated measures model (MMRM). All observations from day 1 through 1 day after the last dose of double-blind foscarbidopa / foslevodopa subcutaneous infusion were included (regardless of rescue medication use during this period). Rescue medication is defined in the section entitled "Duration and Compliance with Foslevodopa and Foscarbidopa". Repeated measures analyses were performed using mixed models, including observed measures at all visits. The mixed models included fixed effects for treatment, country, and visit classification, treatment-by-visit and treatment-by-baseline interactions, and continuous fixed covariates for baseline measures. An unstructured variance-covariance matrix was used. MMRM was the primary approach for the analysis of continuous variables during the double-blind treatment period.

[0153] Primary Efficacy Endpoint Analysis The primary analysis will include data on the change from baseline to each post-baseline visit during the double-blind treatment period in mean normalized daily "on" time without disabling dyskinesias obtained from PD diaries using MMRM. The mixed model includes fixed effects for treatment, country, and visit classification, treatment-by-visit and treatment-by-baseline interactions, and continuous fixed covariates of baseline measurements. Although randomization is stratified by study center, the MMRM model does not include a "center" effect due to the large number of planned centers compared to the number of subjects randomized in the study. If the final number of centers randomized with at least one subject is 30 or less, a "center" effect may be added to the model. The primary approach to handling intercurrent events and missing data is based on the MMRM methodology specified in the section entitled "Handling Intercurrent Events and Missing Visits in Efficacy Endpoints".

[0154] An unstructured variance-covariance matrix is ​​used. Due to the short half-life of foscarbidopa / foslevodopa subcutaneous infusion (approximately 1.5 hours), if the model does not converge with an unstructured matrix, a compound symmetric variance-covariance matrix is ​​used. Parameter estimation is based on REML. The primary comparison is the change from baseline between the investigational drug and active control groups at week 12.

[0155] The changes from baseline in mean normalized daily "on" time without disabling dyskinesias performed in the MMRM are shown in the figures for the investigational and active control groups.

[0156] The proportion of subjects who met the responder criteria for mean daily normalized "on" time without disabling dyskinesias at week 12 is shown for thresholds from 0% to 100% in 10% increments, summarized by treatment group and active control group. P values ​​for tests of distribution differences between the two groups are generated by performing a Monte Carlo exact Kolmogorov-Smirnov test. The percentage of subjects who achieved at least exactly a 1% reduction in mean daily normalized "on" time without disabling dyskinesias at endpoint is shown in the figures for treatment group and active control group. The same analysis is performed for mean daily normalized "off" time.

[0157] Additional analyses of the primary efficacy endpoint Two sensitivity analyses will be performed on the primary efficacy endpoint to account for missing data.

[0158] Sensitivity Analysis #1: A "jump-to-reference" analytical approach to account for missing data due to subjects prematurely discontinuing blinded foscarbidopa / foslevodopa subcutaneous infusion during the double-blind treatment period will be performed as described in the section entitled "Handling of Intercurrent Events and Missing Visits in Efficacy Endpoints."

[0159] Sensitivity analysis #2: Changes in mean daily normalized "on" time without disabling dyskinesias from baseline to last available value will be analyzed using an ANCOVA model with fixed effects for treatment and country classification, and baseline score as a covariate. A "center" effect may be added to the model if the final number of centers randomized with at least one subject is 30 or less. Missing data at week 12 will be handled using the last available value approach as specified in the section titled "Handling of intercurrent events and missing visits in efficacy endpoints".

[0160] A summary of the primary and secondary sensitivity analyses of the primary efficacy endpoint is shown in Table 2.

[0161] [Table 2]

[0162] Secondary efficacy analyses Primary and other secondary efficacy analyses The primary secondary efficacy endpoint and other secondary endpoints included in the FWER control are described in the section entitled "Secondary Endpoints."

[0163] Changes from baseline to week 12 in mean daily normalized "off" time, MDS-UPDRS part II score, mean daily normalized "on" time without dyskinesia, and PKG variables will be analyzed using the same MMRM model as the primary efficacy analysis.

[0164] Changes from baseline to final visit in PDSS-2 total score, PDQ-39 summary index, and EQ-5D-5L summary index will be analyzed using ANCOVA models with fixed effects for treatment and country classification, and baseline score as a covariate. If the final number of centers randomized with at least one subject is 30 or less, a "center" effect may be added to the model.

[0165] The percentage of subjects in each category of state first thing in the morning after awakening ('OFF', 'ON' with no dyskinesias, 'ON' with non-interfering dyskinesias, and 'ON' with interfering dyskinesias) is shown by visit and treatment group.

[0166] The first morning state after awakening ('OFF' or not 'OFF') on the last day of the valid PD diary at each post-baseline visit is analysed using a generalised linear mixed model (GLMM) with a logit link function to compare the probability of having morning immobility between treatment groups. The model includes fixed categorical effects of treatment, country, visit, treatment by visit interaction and baseline first morning state after awakening. An unstructured variance-covariance matrix is ​​used. If the model does not converge with an unstructured matrix, a compound symmetric variance-covariance matrix is ​​used. Odds ratios and their associated 95% CIs for treatment comparisons at week 12 are estimated from the GLMM.

[0167] Other Efficacy Analyses Other secondary efficacy variables are described in the section entitled "Other Efficacy Endpoints". Variables derived from the PD diary, MDS-UPDRS and PKG wearable device will be analyzed using the same MMRM model as the primary efficacy analysis. Variables derived from the PDSS-2, PDQ-39 and EQ-5D-5L will be analyzed using the same ANCOVA model as described in the section entitled "Primary and Other Secondary Efficacy Analyses".

[0168] The distribution of time spent on different motor symptoms based on PD diary data is shown in pie charts for the baseline and week 12 visits.

[0169] Efficacy analysis during oral CD / LD stabilization period Additional efficacy variables for the oral CD / LD stabilization period are described in the section entitled Safety Endpoints. These variables are presented by investigational arm, active control arm, and summarized for all subjects in the FAS. No statistical tests will be performed.

[0170] Efficacy subgroup analysis Subgroup analyses of the change from baseline to the final visit in the double-blind treatment period in mean normalized daily "on" and "off" times will be performed for the following subgroups: Age category (<65 years or ≥65 years) Gender (male or female) Race (White or Other) Country (US or Australia) Duration of PD (time from diagnosis to randomization) (<10 years or ≥10 years) Concomitant use of dopamine agonists (yes or no) Dose category (low or high dose levodopa). Each subject will be categorized into dose subgroups based on the modal total daily dose over the treatment period. Calculation of the modal total daily dose will be defined in the "Analysis of Daily Levodopa Dose" section.

[0171] Subgroup analyses were performed on dose subgroups for the primary secondary endpoints described in the section entitled "Secondary Endpoints" and other secondary endpoints, except for variables obtained from the PD diary, which were analyzed for all subgroups described in the paragraph above.

[0172] Subgroup analyses did not need to be performed if one stratum of a subgroup variable accounted for <20% of the FAS analysis set.

[0173] Subgroup analyses were performed on the FAS using an ANCOVA model with treatment, subgroup variables, treatment-by-subgroup variable interactions, and baseline as covariates. Statistical comparisons of the investigational drug and active control groups within each subgroup stratum were performed when the treatment-by-subgroup interaction terms reached the 0.100 level of statistical significance.

[0174] result A multiple testing procedure was used to powerfully control the type I error rate with α=0.05 (2-sided) across analyses comparing the foscarbidopa / foslevodopa subcutaneous infusion group with the oral CD / LD group for the primary efficacy endpoint and ranked secondary endpoints. In particular, tests were utilized in the following order: hypothesis testing for the primary endpoint, followed by hypothesis testing for the ranked secondary endpoints. Treatment with foscarbidopa / foslevodopa subcutaneous infusion resulted in statistically significant and clinically meaningful improvements compared to oral CD / LD in the primary efficacy endpoint and the first top-ranked secondary endpoint.

[0175] [Table 3] TIFF2024541978000006.tif205166

[0176] Figures 4-5 show the longitudinal treatment profile of the primary endpoint and the first top-line secondary endpoint. Improvements (nominal p-value ≦0.05) were observed as early as week 1 (day 8), the first time point at which post-baseline PD diaries were collected, and were sustained until the end of the double-blind treatment period at week 12, except for week 3 (day 22), which was an optional visit and had a small sample size.

[0177] FIG. 6 shows the longitudinal treatment profile of MDS-UPDRS part II scores.

[0178] Figure 7 showed that subcutaneous foscarbidopa / foslevodopa infusion was superior to oral CD / LD in: · Decrease: ○ "Off" Time "On" times with dyskinesias that interfere with daily life ○ A relatively better state of "on" time with dyskinesias that do not interfere with daily life Complementary increase in optimal "on" time without dyskinesia FIG. 8 demonstrates that in the foscarbidopa / foslevodopa (study drug) subcutaneous infusion group, the percentage of subjects reporting morning akinesia (awakening in the "off" state) dramatically decreased from 80% at baseline to 30% at the end of the 12-week treatment period, with 70% of subjects reporting awakening in the "on" state without dyskinesia at the end of the study.

[0179] The increase in "on" time at week 12 was 2.72 hours for subcutaneous foscarbidopa / foslevodopa infusions vs. 0.97 hours for oral levodopa / carbidopa (LD / CD) (p=0.0083). Improvements in "on" time vs. baseline were observed as early as the first week and sustained throughout the 12 weeks of the study.

[0180] Improvements from baseline in mean daily normalized "off" time were also observed vs. placebo following a similar pattern with decreases observed after week 1 and sustained through week 12. The decrease in "off" time after week 12 was 2.75 hours for foscarbidopa / foslevodopa subcutaneous infusions vs. 0.96 hours for oral LD / CD (p=0.0054).

[0181] safety Subcutaneous foscarbidopa / foslevodopa infusions were generally safe and well tolerated. The systemic safety profile of subcutaneous foscarbidopa / foslevodopa infusion was generally consistent with the well-established safety profile of CD / LD drugs. The majority (>90%) of reported AEs were non-serious and mild / moderate in severity. The incidence of SAEs was similar between foscarbidopa / foslevodopa subcutaneous injections and oral CD / LD agents. The incidence of infusion site events was higher in the subcutaneous foscarbidopa / foslevodopa group than in the oral CD / LD group. Rates of early discontinuation and TEAEs leading to discontinuation were higher in the foscarbidopa / foslevodopa subcutaneous injection group than in the oral CD / LD group. Most infusion site events observed with foscarbidopa / foslevodopa subcutaneous injection were non-serious, mild or moderate in severity, and resolved with or without treatment. The incidence of hallucinations / psychosis was higher in the foscarbidopa / foslevodopa subcutaneous injection group than in the oral CD / LD group. The incidence of falls and related injuries was higher in the oral CD / LD group than in the subcutaneous foscarbidopa / foslevodopa group. The incidence of other AESIs (weight loss, somnolence and polyneuropathy) was low and similar between the two treatment groups.

[0182] [Table 4]

[0183] Test items, vital signs, ECG and C-SSRS findings No clinically meaningful changes or trends from baseline were observed in either treatment group based on review of clinical laboratory results, vital signs, and ECGs, and no safety issues were identified. There was no evidence of increased suicidality in either treatment group based on review of the C-SSRS data.

[0184] Primary and most significant secondary endpoints: Full analysis set

[0185] [Table 5]

[0186] [Table 6]

[0187] Other secondary endpoints included in the full multiplicity control analysis set

[0188] [Table 7]

[0189] PKG wearable device endpoints included in the full multiplicity control analysis set

[0190] [Table 8] TIFF2024541978000012.tif181166

[0191] Sensitivity analysis for the primary endpoint and the first most significant secondary endpoint full analysis set Missing data in the active comparator oral CD / LD group will be assumed to be missing at random (MAR). Missing data in the foscarbidopa / foslevodopa subcutaneous infusion group are assumed to jump to the distribution of the reference group (J2R) after cessation of foscarbidopa / foslevodopa subcutaneous infusion. Use an analytical approach to estimate standard errors. · Results from the J2R sensitivity analysis confirm those from the main MMRM analysis.

[0192] [Table 9]

[0193] Laboratory parameters, vital signs, ECG and C-SSRS findings: Safety analysis population No clinically meaningful changes or trends from baseline were observed in any treatment group based on a review of clinical laboratory results, vital signs, and ECGs, and no safety issues were identified. There was no evidence of increased suicidality for either treatment group based on a review of the C-SSRS data.

[0194] Blinded evaluation

[0195] [Table 10]

[0196] conclusion Efficacy: Treatment with subcutaneous foscarbidopa / foslevodopa resulted in statistically significant and clinically meaningful improvements compared to oral CD / LD in:

[0197] Primary efficacy endpoint: "on" time without disabling dyskinesias First primary secondary endpoint: "off" time

[0198] Example 2: Safety, tolerability and pharmacokinetics in healthy subjects In this example, we demonstrate that foslevodopa and foscarbidopa in a 20:1 ratio is safe and also evaluate its pharmacokinetics.

[0199] methodology A total of eight healthy elderly human subjects (ages 45-75 years) participated in a single-blind, placebo-controlled, three-period crossover design clinical trial to evaluate the safety, tolerability, and pharmacokinetics of foslevodopa and foscarbidopa delivered as a single continuous subcutaneous infusion (CSCI) over 16 hours. Each dose of foslevodopa and foscarbidopa or placebo was administered in a single-blind fashion as a single CSCI delivered at a constant rate into the abdomen over 16 hours via an infusion set connected to a portable pump. Regimen A, B, C, and D consisted of levodopa 4'-monophosphate / carbidopa 4'-monophosphate 640 / 160 mg, levodopa 4'-monophosphate / carbidopa 4'-monophosphate CSCI 640 / 64 mg, levodopa 4'-monophosphate / carbidopa 4'-monophosphate CSCI 640 / 32 mg, or placebo CSCI delivered at a constant rate into the abdomen for 16 hours.Blood samples were collected for pharmacokinetic analysis from each of eight healthy elderly human subjects (age 45-75 years) before priming the catheter, before infusion (0 hours), and 0.5, 1, 2, 4, 8, 12, 16, 20, 24, 26, and 28 hours after initiation of infusion.

[0200] population Eligible subjects were healthy male and female volunteers, ages between 45 and 75 years. If female, subjects must have been menopausal or surgically infertile for at least one year. Exclusion criteria included a history of significant skin conditions or disorders (e.g., psoriasis, atopic dermatitis, etc.) or recent sunburn, acne, scar tissue, tattoos, open wounds, branding, or staining.

[0201] Safety Results No patterns were evident regarding the nature or frequency of treatment-emergent adverse events following CSCI infusion or bolus injection of levodopa 4'-monophosphate and carbidopa 4'-monophosphate compositions compared to subjects receiving placebo. All regimens tested were well tolerated by these subjects. No worrisome patterns of adverse events or clinical laboratory findings were reported. There were no notable observations from either individual measurements of blood pressure or pulse rate or from quantitative measurements obtained from ECG.

[0202] Example 3: 24-hour continuous subcutaneous infusion of levodopa and carbidopa prodrugs in healthy volunteers: Safety and tolerability over 10 days simulating a one-year exposure This study was designed to evaluate the safety and local tolerability of 24-hour continuous subcutaneous infusion of an aqueous pharmaceutical composition containing foslevodopa and foscarbidopa, simulating a one-year exposure by administering the pharmaceutical composition to a limited site in the abdomen of healthy volunteers for 10 consecutive days.

[0203] methodology The study was a Phase 1 randomized, placebo-controlled study of healthy volunteers receiving sufficient pharmaceutical composition to provide 600 mg of levodopa and an equal volume of saline by continuous 24-hour subcutaneous infusion simultaneously on opposite sides of the abdomen for 10 days. The study consisted of three periods, as shown in Table 11.

[0204] [Table 11]

[0205] As shown in Table 11, the screening period lasted 28 days and was also conducted to ensure that patients met the eligibility and criteria and to collect medical history and baseline clinical evaluations. The next period was the confinement period, during which patients were confined to the study facility for 13 days (days 1-12). During the confinement period, infusions began on day 1 and each patient was administered the pharmaceutical composition and an equal volume of placebo (saline) simultaneously. The infusions were administered into two 5 cm diameter areas on opposite sides of the abdomen. Subjects and infusion site assessors were blinded as to which treatment was administered on each side of the abdomen. Infusion sets were changed daily and the catheter of each infusion set was placed within a 5 cm diameter area at the site used the previous day. Infusions continued 24 hours / day for 10 days and subjects were administered approximately 600 to approximately 700 mg / day of levodopa equivalent. A 28-day follow-up was then conducted to allow for ad-hoc reporting of any adverse events. The infusion set was changed daily and reapplied to the same skin surface each day.

[0206] Rotating injection sites To reduce the risk of infection or irritation, fatty tissue buildup (hypertrophy), and scar formation (fibrosis), good clinical practice and anecdotal data recommended that injection sites be rotated regularly and spaced at least 2.5 cm apart. The infusion set selected for this study (Smith Cleo 90) recommended changing the set every 3 days to keep the set sterile. In clinical practice, it is expected that patients will adopt a rotation scheme, such as a clock, that allows for rotation, and that the same injection site will be used after 11 alternate sites have been used. For each individual, a rotation schedule for injection sites around the umbilicus (center) will be adopted. If rotation begins at the 12 o'clock position and proceeds clockwise, assuming each injection site is used for 3 days, the patient will return to the 12 o'clock injection site after approximately 36 days - (12*3=) 36 days, using the same site of injection an average of 10 times / year. This study provided an accelerated simulation of long-term use for evaluation of local tolerance in healthy human volunteers for the number of repeat injection sites that a patient would use over a one-year period.

[0207] population The primary inclusion criteria for this study were: Healthy male or female adult human volunteers aged 45–75 years; Body mass index (BMI) 18.0kg / m2~32.0kg / m2 included; · General good health based on medical history, physical examination, and clinically insignificant laboratory findings, electrocardiogram (ECG) or vital parameters. No history of significant skin conditions or disorders that, in the opinion of the investigator, may interfere with the evaluation of the study.

[0208] Evaluation and Analysis Systemic and local safety and tolerability were assessed daily. Notable skin reactions were predefined as events not usually associated with predictable reactions from the use of the infusion set (grades ≧D or ≧6 on the infusion site assessment scale). Both subjects and assessors were blinded to both sides of the abdomen into which the aqueous pharmaceutical composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate and the placebo were infused. In detail, the local skin tolerability of 10 days of 24-hour continuous subcutaneous infusion of the pharmaceutical composition into the abdomen was evaluated in 33 healthy human volunteers who completed the 10-day dosing period. Local skin tolerability was assessed by blinded assessors using the infusion site assessment 2-part scale (Table 12). This assessment included a numeric rating (0-7) and a letter rating (A-G) scale. Notable skin reactions were predefined as events not usually associated with predictable reactions from the use of the infusion set (grades ≧D or ≧6). The primary endpoint was the number of healthy human volunteers with notable skin reactions at the pharmaceutical composition injection site on >2 days out of 10 days of infusion. The 95% upper confidence limit for the proportion of the population with notable skin reactions on >2 days out of 10 days of infusion was obtained by the Clopper-Pearson method. For each injection site assessment scale, a one-sided signed test was performed to test the hypothesis that there was no difference between the pharmaceutical composition and placebo at the final assessment against the alternative hypothesis that the pharmaceutical composition was more likely to be of higher grade.

[0209] [Table 12]

[0210] In addition to infusion site evaluations, safety assessments included: percentage of subjects with treatment-emergent AEs and serious adverse events (SAEs); changes from baseline to the end of the study in clinical laboratory values, vital sign measurements, electrocardiogram (ECG), and physical examination findings.

[0211] result The safety dataset included 34 subjects, as shown in Table 13.

[0212] [Table 13]

[0213] Tolerability The highest grade reported for each healthy human volunteer subject (pharmaceutical composition site vs. placebo site) from days 1 to 10 of the study is summarized graphically in Figures 12 and 13 for each injection site assessment scale. The percentage of subjects who completed 10 days of dosing who reported notable skin reactions was 0% (0 / 33) at the pharmaceutical composition injection site and 3.0% (1 / 33) at the placebo injection site. The difference between the pharmaceutical composition and placebo for the dermatological assessment on day 10 of injection was not statistically significant on the numeric rating (P=0.828) or letter rating (P=0.363) scale. The 95% upper confidence limit for the proportion of the population that should have notable skin reactions on 2 or more days of the 10-day injection of the pharmaceutical composition administered in this study is 0.087 (8.7% of the population). The 95% upper confidence limit for the proportion of the population that should have a notable skin reaction on 2 or more of the 10-day placebo infusions administered in this study is also 0.087 (8.7% of the population).

[0214] safety There were no clinically significant laboratory values, vital signs, or ECG findings. Overall, 97% of subjects reported at least one adverse event (AE). One serious AE was reported 4 days after study completion and was not considered likely related to foslevodopa or foscarbidopa. There were no discontinuations due to AEs (Table 14). The most frequently reported adverse events were infusion site erythema (91%), infusion site reactions (44%), and infusion site pain (32%) (Table 15). All infusion site AEs were mild or moderate in severity and resolved rapidly.

[0215] [Table 14]

[0216] [Table 15]

[0217] The pharmaceutical compositions described herein, including foslevodopa and foscarbidopa, provide the broad range of levodopa exposure required to adequately control motor symptoms and to be an alternative treatment option for Parkinson's disease patients. In this study, it was demonstrated that the pharmaceutical compositions were generally well tolerated and did not cause any notable skin reactions when administered continuously subcutaneously at limited sites in the abdominal region for 10 consecutive days at low, but clinically relevant, doses.

[0218] Example 4: Design for a Phase 1b study evaluating the safety and tolerability of 4-week continuous subcutaneous infusions of levodopa and carbidopa prodrugs in patients with Parkinson's disease.

[0219] This study was designed to evaluate the safety and tolerability of a 4-week continuous subcutaneous infusion of an aqueous pharmaceutical formulation of foslevodopa and foscarbidopa in a 20:1 ratio (w / w). Additionally, steady-state plasma levodopa levels achieved by continuous subcutaneous infusion of the pharmaceutical composition were evaluated, and exploratory efficacy was assessed by change from baseline in the endpoints shown in Table 21A.

[0220] method A single-arm, open-label, Phase 1b study was designed in which patients with Parkinson's disease were treated with individualized therapeutic doses of the pharmaceutical composition by continuous 24-hour subcutaneous infusion for 28 days. Patients were recruited from centers in the United States. The study consisted of four periods, which are graphically depicted in FIG. 14A. The screening period included two visits to establish eligibility and to ensure that patients' current Parkinson's disease therapy was stable for 30 days, including a monitoring period. The screening period also included a 7-day monitoring period immediately following the second visit. Patients recorded their Parkinson's disease medications using a subject's medication diary and monitored motor symptoms using a wearable motion sensor device configured to detect abnormal movements.

[0221] The titration period was part of the enrollment period followed by a screening period. On day 1 of the titration period, patients received a bolus of the pharmaceutical composition, followed by a continuous infusion at a constant rate, with the dose then adjusted at the investigator's discretion based on the patient's clinical response. The therapeutic dose is defined as the dose capable of eliciting adequate control of motor symptoms by minimizing the number of "off" episodes and maximizing functional "on" time, while minimizing disabling dyskinesias. Patients continued to receive the therapeutic dose of the pharmaceutical composition established during the titration period - treatment period until day 28. The most important inclusion criteria for this study are summarized in Table 16.

[0222] [Table 16]

[0223] Global safety and tolerability were assessed by safety scales, including adverse event monitoring, clinical laboratory values, vital signs, electrocardiograms, and the Columbia Suicide Rating Scale. The results of the study were assessed using an infusion site grade scale (Table 17A) and exploratory efficacy assessments (Table 17B).

[0224] Subjects recorded parkinsonian symptoms based on a questionnaire in a Parkinson's disease diary. Each subject recorded whether they were "on", "off", or "deep sleep" and the severity of their dyskinesias (interfering with daily living or not interfering with daily living). Statistical significance for changes from baseline was shown at each visit for normalized "off" time, normalized "on" time without dyskinesias, and normalized "on" time without interfering with daily living. No statistical significance was shown at any visit for normalized "on" time with non-interfering dyskinesias and normalized "on" time with interfering dyskinesias.

[0225] The subject's MDS-UPDRS assessment consisted of the following sections: Part 1: Non-motor aspects of everyday life experiences (nM-EDL) Part 2: Motor aspects experienced in daily life (M-EDL) Part 3: Musculoskeletal examination (including Hoehn-Yarr stage) Part 4: Motor complications

[0226] MDS-UPDRS total scores ranged from 0 to 176, with 176 representing worst (total) disability and 0 representing no disability. Mean total baseline scores ranged from approximately 45 to 47 for all visits, and mean visit total scores ranged from approximately 34 to 45 for all visits. Statistically significant changes from baseline were noted at Day 7, Day 28, and the final visit for total, Part 1, and Part 2 scores, and at Day 28 and the final visit for Part 4 scores. There were no statistically significant changes at any visit for Part 3 "on" scores.

[0227] The PDQ-39 measured aspects of health relevant to subjects with Parkinson's disease. Each item was scored on a 5-point scale: 0=never, 1=occasionally, 2=occasionally, 3=frequently, 4=always (not at all, if applicable). The higher the score, the more severe the symptoms of the disease, such as tremors and stiffness, are always present. The majority of subjects answered "never" or "occasionally", while seven subjects answered "always" or "not at all". These results are presented as a summary index. The PDQ-39 summary index ranges from 0 to 100, with lower scores indicating better health status. The domains and indicators used for evaluation are as follows: Summary Index Mobility Domain Score Activities of Daily Living Domain Mental well-being domain score Stigma domain score Social Support Domain Score Cognitive domain scores Communication Domain Score Physical discomfort domain score

[0228] Statistically significant changes from baseline were demonstrated at all visits for summary index scores.

[0229] The PDSS-2 scale characterizes various aspects of nighttime sleep disturbance in patients with Parkinson's disease. The PDSS-2 consists of 15 questions that assess motor and non-motor symptoms at night and during awakening, and grouped sleep disturbance into three domains: nocturnal motor symptoms, nocturnal PD symptoms, and sleep disturbance. Scores were calculated for each domain and a total score was also calculated. The frequency of sleep problems was assessed on a 5-point Likert scale ranging from 0 (never) to 4 (very often). The majority of subjects answered "never" or "occasionally", and seven subjects answered "always" or "never".

[0230] The KPPS assessed pain among patients with Parkinson's disease. The scale measured frequency and severity of pain in seven domains: musculoskeletal, chronic, fluctuating related, nocturnal, orofacial, localized limb pain / edema / swelling, and radicular pain. A total score was also assessed. Statistically significant changes from baseline are shown for the total score at day 28 and the final visit, and for the fluctuating related pain score at day 28.

[0231] The PAS measured the severity of anxiety in patients with Parkinson's disease. Scores for persistent anxiety, episodic anxiety, and avoidance behavior, as well as a total score, were assessed. Statistically significant changes from baseline were demonstrated for the total score and avoidance behavior at day 28 and the final visit.

[0232] All subjects were fitted with the Kinesia 360 device, which continuously recorded data for assessment of tremor, dyskinesia, and mobility. There were no statistically significant changes from baseline in tremor, dyskinesia, and slowness at any visit.

[0233] An injection site assessment grade scale and exploratory efficacy assessments were performed and are shown below in Tables 17A and 17B.

[0234] [Table 17]

[0235] [Table 18]

[0236] Exploratory analyses were performed to evaluate the efficacy of pharmaceutical compositions on Parkinson's disease symptoms in reducing "off" time and motor and non-motor symptoms.

[0237] result Twenty-one patients were enrolled. The study population was primarily male (61.9%) and Caucasian (100%); one (4.8%) was Hispanic or Latino. Mean (SD) age was 61.6 (10.3) years. Mean (SD) Parkinson's disease duration from diagnosis was 9.0 (4.0) years, and mean (SD) duration of diurnal motor fluctuations was 6.0 (4.1) years. Mean "off" time / day at baseline was 6.54 hours, ranging from 3.77 to 9.46 hours. Seven subjects (33%) discontinued prematurely. Two subjects discontinued due to adverse events.

[0238] The baseline demographics and disease characteristics of the subjects are shown in Table 18.

[0239] [Table 19]

[0240] The results of the injection site evaluation criteria are shown in Figures 14B and 14C and Table 19 below.

[0241] [Table 20]

[0242] In Parkinson's disease, "off"-times refer to periods of days when medications do not work adequately, causing the reappearance or worsening of Parkinson-like symptoms (tremor, rigidity, bradykinesia, and non-motor symptoms such as depression, pain, anxiety, etc.). In contrast, the term "on"-times refers to periods of adequate control of symptoms. "Off"-times may be predictable and occur gradually ("wearing off"), or may appear suddenly and unexpectedly ("sudden off", "yo-yo episodes"). The frequency and timing of wearing-off periods, as well as the number of hours in "off" time, correlate significantly with worsening quality of life in Parkinson's disease patients.

[0243] Quality of life in Parkinson's disease can be assessed using tools and questionnaires, such as the Parkinson's Disease Questionnaire-39 items (PDQ-39), a self-report questionnaire that assesses the impact of Parkinson's disease on specific dimensions of function and well-being, and the revised Parkinson's Disease Sleep Scale-2, designed to characterize and quantify different aspects of nocturnal sleep disturbance in Parkinson's disease. Disease severity is alternatively assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) or the Movement Disorder Society Revised (MDS-UPDRS), a tool consisting of rater-based interviews and clinical assessments designed to provide a quantifiable score for longitudinal evaluation and follow-up of the disease.

[0244] Patient changes from baseline normalized "off" time were measured as shown in Table 20 and in Figure 14E. A summary of pre-specified efficacy endpoints is provided in Table 21A, and efficacy assessments are shown in Table 21B.

[0245] [Table 21]

[0246] [Table 22]

[0247] [Table 23]

[0248] Analysis of efficacy data showed that 17 of 20 patients had an improvement in "off" time. The mean (SD) reduction in "off" time from baseline to end of study was 3.24 (3.65) hours across subjects (46.2% improvement). Four subjects reported a >90% reduction in daily "off" time at end of study. There was a mean reduction in normalized "off" time, "on" time with non-interfering dyskinesias, and "on" time with interfering dyskinesias, resulting in a mean (SD) improvement in normalized "on" time without dyskinesias of 3.99 (5.37) hours. As shown in Figure 14D, the mean (SD) reduction from baseline was 9.0 (11.87) for the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score, 6.9 (8.39) for the Parkinson's Disease Questionnaire-39 item (PDQ-39) summary index, and 2.0 (11.48) for the Parkinson's Disease Sleep Scale-2 (PDSS-2) total score. After continuous subcutaneous infusion of the pharmaceutical composition, statistically significant changes from baseline were observed for Parkinson's "on" and "off" time for dyskinesia, MDS-UPDRS total score, non-motor symptoms experienced in daily living, motor symptoms experienced in daily living, and motor complications, and PDQ-39 summary index, as well as the domains of activities of daily living, emotional well-being, cognition, communication, mobility, stigma, and bodily discomfort.

[0249] Figure 16 and Table 21C show the percentage of patients receiving the pharmaceutical composition and experiencing "off" time compared to patients receiving oral Sinemet®. As shown in Figure 16, patients receiving oral Sinemet® show undesirable spikes in "off" time in the morning and around mealtime compared to patients receiving CSCI pharmaceutical composition. Table 21C shows that about 86.7% of the first morning symptom time after waking was "off" at baseline for patients receiving oral Sinemet®. Meanwhile, about 84.2% of the first morning symptom time was "on" without dyskinesia at the end of the 28-day study for patients receiving CSCI pharmaceutical composition.

[0250] [Table 24]

[0251] [Example 5] Determining the starting dose To facilitate physicians in determining the most appropriate starting dose for the study described in Example 4, an algorithm was created to convert oral levodopa to carbidopa 4'-monophosphate and levodopa 4'-monophosphate pharmaceutical compositions that takes into account the low variability and fluctuation of levodopa exposure when delivered continuously subcutaneously, the 24 hour exposure, the pharmacokinetic profile of levodopa obtained from previous studies with the composition, and other clinical considerations.

[0252] Data obtained from patients who completed dosing were used to assess the dose. All patients who completed the study (N=14) achieved the desired dose range within 3 weeks after starting the pharmaceutical composition; 3 patients achieved the desired dose range on the same day after conversion from oral to pharmaceutical composition, 7 subjects required 1 week, 1 subject required 2 weeks, and the remaining 3 patients required 3 weeks. The adjustments at each time ranged from -0.04 mL / h to +0.08 mL / h (equivalent to -136 mg / day of levodopa to 273 mg / day of levodopa), and the difference in infusion rate from day 1 to day 28 (taking all adjustments into account) ranged from -0.06 mL / h to +0.08 mL / h (equivalent to -204 mg / day of levodopa to +273 mg / day of levodopa). Considering that at enrollment, all subjects were asked to report diurnal variations in motor symptoms that could not be adequately controlled by the best oral medication, these data suggest that the conversion algorithm is effective in guiding the starting dose of the pharmaceutical composition, as the magnitude of change in continuous infusion rate was small (within 20% in all but one subject) and the desired dose range was considered to be achieved within 3 weeks.

[0253] The levodopa dose levels per subject at the beginning and end of the study are shown in Table 22. The doses of pharmaceutical composition delivered during the 24-hour treatment period ranged from approximately 28.8 / 576 mg to approximately 240 / 4800 mg of carbidopa 4'-monophosphate / levodopa 4'-monophosphate per day (equivalent to approximately 400 mg to 3400 mg of levodopa, respectively, based on molecular weight). The mean dose at the end of the study was approximately 117.5 / 2350 mg, and the median dose was approximately 96 / 1920 mg (equivalent to 1670 mg and 1360 mg of levodopa, respectively, based on molecular weight).

[0254] [Table 25]

[0255] As described, if a patient has a levodopa equivalent of 2000 mg prior to study enrollment, the recommended starting dose of the 20:1 w / w ratio foslevodopa and foscarbidopa (levodopa 4'-monophosphate and carbidopa 4'-monophosphate) pharmaceutical composition is 4032 mg levodopa 4'-monophosphate delivered over 24 hours. Because the levodopa dose for each patient is determined by individualized patient dose titration, it is expected that patients in these studies will be initiated on doses of the levodopa 4'-monophosphate prodrug and carbidopa 4'-monophosphate pharmaceutical composition that will provide exposures close to their previous regimen, with the option to further adjust the dose to achieve optimal clinical response. In this manner, individualized dose-titrable dosing can be achieved across a range of doses to address therapeutic needs.

[0256] Example 6: Full Prescribing Information 1. Pharmaceuticals Foscarbidopa / Foslevodopa Foslevodopa and Foscarbidopa 240mg / ml+12mg / ml solution for subcutaneous injection (products described herein).

[0257] 2. Qualitative and quantitative composition Each ml contains 240 mg of foslevodopa and 12 mg of foscarbidopa.

[0258] 10 ml contains 2400 mg of foslevodopa and 120 mg of foscarbidopa. Foslevodopa and foscarbidopa are prodrugs equivalent to approximately 170 mg of levodopa and 9 mg of carbidopa per ml.

[0259] The pH is approximately 7.4.

[0260] Osmolality is approximately 2200-2500 mOsmol / kg, but can range up to 2700 mOsmol / kg.

[0261] Excipients with known effects Foscarbidopa / foslevodopa subcutaneous injection contains approximately 1.84 mmol (42.4 mg) of sodium per ml.

[0262] 3. Pharmaceutical Form Solution for injection (injection).

[0263] Foscarbidopa / foslevodopa subcutaneous injection is a sterile, preservative-free, clear to slightly opalescent solution in a glass vial. The solution should be free of particulates. Foscarbidopa / foslevodopa subcutaneous injection may vary from colorless to yellow to brown, and may have a purple or red tinge. Color variations are expected and do not affect the quality of the product. The solution may darken in color after the vial stopper is punctured or while in the syringe.

[0264] 4. Clinical matters 4.1 Indications Treatment of progressive levodopa-responsive Parkinson's disease with severe diurnal motor fluctuations and hyperactivity or dyskinesia when available combinations of Parkinson's disease medications do not produce satisfactory results.

[0265] Indications and Usage The product described herein (foscarbidopa / foslevodopa for subcutaneous infusion) is a combination of foscarbidopa (an aromatic amino acid decarboxylation inhibitor) and foslevodopa (an aromatic amino acid) indicated for the treatment of diurnal motor fluctuations in adults with advanced Parkinson's disease.

[0266] 4.2 Dosage and Method of Administration Usage and dosage Subcutaneous infusions of foscarbidopa / foslevodopa are administered as a 24 hour continuous subcutaneous infusion per day.

[0267] The recommended starting daily dose of foscarbidopa / foslevodopa subcutaneous infusion is determined by converting the daily levodopa intake into levodopa equivalents (LE) and then titrating to account for 24-hour dosing. Dose can be adjusted to achieve a clinical response that maximizes functional "on" time and minimizes the number and duration of "off" episodes and "on" episodes with disabling dyskinesias.

[0268] DOSAGE and Administration For subcutaneous administration only. Do not administer intravenously or intramuscularly.

[0269] Parenteral preparations should be visually inspected for particulate matter and discoloration prior to administration where solutions and containers permit. Color variations are expected. The solution may vary from colorless to yellow to brown and may have a purple or red tinge.

[0270] The maximum recommended daily dose of the product foscarbidopa / foslevodopa described herein is about 4000 mg of foslevodopa (2850 mg of levodopa equivalent) administered over 24 hours. The recommended starting daily dose of foscarbidopa / foslevodopa subcutaneous infusion is determined by converting the daily levodopa intake to levodopa equivalent (LE) and then adjusting for 24-hour administration. The daily dose is titrated based on the patient's clinical response. The foscarbidopa / foslevodopa subcutaneous infusion is administered subcutaneously, preferably in the abdominal region, using an infusion set and a subcutaneous infusion pump.

[0271] Subcutaneous foscarbidopa / foslevodopa injections are substituted with levodopa-containing medications and catechol-O-methyltransferase (COMT) inhibitors. Other Parkinson's disease medications can be administered simultaneously if necessary.

[0272] contraindication Foscarbidopa / foslevodopa subcutaneous infusion is contraindicated in patients receiving nonselective monoamine oxidase (MAO) inhibitors.

[0273] Initiation of treatment Patients selected for treatment with subcutaneous foscarbidopa / foslevodopa infusion should be able to understand and use the delivery system themselves, or with assistance from a caregiver.

[0274] Patients should be trained in the proper use of foscarbidopa / foslevodopa subcutaneous infusion and delivery systems (see Methods of Administration) prior to initiating treatment with foscarbidopa / foslevodopa subcutaneous infusion and thereafter, if necessary.

[0275] Three steps are required to initiate treatment with subcutaneous foscarbidopa / foslevodopa infusion. Step 1: Calculate LE based on levodopa-containing medications and COMT inhibitors used during the patient's waking hours. · Step 2: Determine the hourly infusion rate of foscarbidopa / foslevodopa subcutaneous infusion. · Step 3: Determine the volume of the loading dose.

[0276] Step 1: Calculate LE based on levodopa-containing medications used during the patient's awake time.

[0277] The amount of levodopa obtained from all levodopa-containing formulations used during the waking hours of the day should be converted to LE using the appropriate dose multiplier from Table 23 and then summed. For this calculation, only levodopa and COMT inhibitors are considered. No nighttime dosing of any medication is included, and this calculation does not include rescue levodopa or any other anti-Parkinson's medication or therapy. If any COMT inhibitor is administered within a 24-hour period, regardless of the dose of the COMT inhibitor, a correction factor should be applied to the sum of LE as shown in Table 23.

[0278] [Table 26]

[0279] Step 2: Determine the hourly infusion rate of foscarbidopa / foslevodopa subcutaneous infusion.

[0280] See Table 24 for suggested recommended foscarbidopa / foslevodopa subcutaneous infusion starting infusion rates based on the LE calculated in Step 1.

[0281] The hourly infusion rates for foscarbidopa / foslevodopa subcutaneous infusion in Table 24 are based on the patient's LE intake during a typical 16 hour awake period (LE16).

[0282] If the LE determined in step 1 was based on wakefulness time greater than or less than 16 hours, the LE should be adjusted to 16 hours. To adjust to 16 hours, take the LE calculated in step 1, divide by the number of hours the patient is usually awake, and then multiply by 16. Then refer to Table 24 for suggested starting infusion rates for foscarbidopa / foslevodopa subcutaneous infusion.

[0283] The hourly infusion rate determined in this step should be entered as the basal infusion rate when programming the pump (see pump manual for details).

[0284] [Table 27]

[0285] Step 3: Determine the volume of the loading dose.

[0286] If foscarbidopa / foslevodopa subcutaneous infusion therapy is initiated in the "off" state (or if the pump has been off for more than 3 hours), a loading dose can be administered immediately prior to commencing the hourly infusion to rapidly achieve symptom control.

[0287] Table 25 provides the recommended loading dose volume (ml) for foscarbidopa / foslevodopa subcutaneous infusion to be programmed into the pump (see pump instructions for details) and the corresponding amount (milligrams) of immediate release levodopa, regardless of the co-administered peripheral inhibitor of DOPA decarboxylase (e.g., carbidopa, benserazide).

[0288] [Table 28]

[0289] Foscarbidopa / foslevodopa subcutaneous infusion therapy can be initiated while the patient is in either the "off" or "on" state. Patients initiating foscarbidopa / foslevodopa subcutaneous infusion therapy in the "on" state can begin the infusion without the need for a loading dose of foscarbidopa / foslevodopa subcutaneous infusion. The loading dose can be administered via a pump or with an oral levodopa tablet.

[0290] Optimization and Maintenance The healthcare professional can adjust the starting hourly infusion rate to achieve the optimal clinical response for the patient. The hourly infusion rate should be delivered continuously over the 24-hour infusion period per day. If desired, the healthcare professional can program and enable two alternative infusion rates (low / high). All infusion rates can be adjusted in increments of 0.01 ml / hr (equivalent to approximately 1.7 mg / hr of levodopa) and should not exceed 1.04 ml / hr (or approximately 4260 mg / day of levodopa [approximately 6000 mg / day of phoslevodopa]). The infusion pump has built-in safe access to the dosing configuration to prevent the patient from altering the preprogrammed flow rate or the top-up dose function.

[0291] Foscarbidopa / foslevodopa subcutaneous infusion may be administered alone or, if necessary, with other concomitant Parkinson's disease medications based on the medical professional's judgment. Reductions in the dosage of other concomitant Parkinson's disease medications, followed by adjustments in the dosage of foscarbidopa / foslevodopa subcutaneous infusion, may be considered during foscarbidopa / foslevodopa subcutaneous infusion. The combination of foscarbidopa / foslevodopa subcutaneous infusion with other levodopa-containing medications or with medications that significantly modulate synaptic dopamine levels (e.g., COMT inhibitors) has not been tested.

[0292] Alternative Flow Rate The infusion pump can also be programmed with two alternative infusion rate options for patient use. The alternative infusion rates must be enabled and pre-programmed by a healthcare professional and can be selected by the patient to accommodate changing functional needs, e.g., lowering the dose at night or increasing the dose for sustained strength.

[0293] additional dose If permitted by a medical professional, patients may self-administer additional doses to manage acute "off" symptoms experienced during continuous infusion.

[0294] Method of administration Foscarbidopa / foslevodopa subcutaneous injections are administered subcutaneously, preferably in the abdomen, avoiding a 5 cm radius area from the umbilicus. The infusion set (cannula) can be left in place for up to 3 days if the medication is to be infused continuously. Infusion sites were rotated and a new infusion set was used at least every 3 days. It was recommended that a new infusion site be at least 2.5 cm from a site used within the previous 12 days.

[0295] In a pharmacokinetic crossover study, foscarbidopa / foslevodopa administered via subcutaneous injection via the arm and thigh resulted in similar abdominal exposure (see Section 5.2 Absorption). The long-term safety and efficacy of administration to the arm and thigh were not evaluated.

[0296] This medicinal product should be stored and handled as described in the section entitled "Handling and Storage". The medicinal product vial is for a single dose. After the contents of the vial have been transferred to the syringe, the contents of the syringe should be administered within 24 hours. Used medicinal product vials and syringes should be disposed of in accordance with national regulations. Syringes must be disposed of as directed by a healthcare professional, even if residual products remain.

[0297] Special Populations Gender or race After administration of foscarbidopa / foslevodopa subcutaneous infusion, the exposure of carbidopa and levodopa in Japanese and Han Chinese subjects was comparable to that in Caucasian subjects.

[0298] 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapy group: antiparkinsonian drugs, foslevodopa, and decarboxylase inhibitors

[0299] Mechanism of action The product described herein (foslevodopa / foscarbidopa) 240mg / 12mg per ml infusion solution is a combination of levodopa monophosphate and carbidopa monophosphate prodrugs (ratio 20:1) in solution for 24 hour / day continuous subcutaneous infusion in advanced Parkinson's disease patients not adequately controlled by current medical therapy. Foslevodopa and foscarbidopa are converted in vivo to levodopa and carbidopa. Levodopa relieves Parkinson's disease symptoms after decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the extracerebral decarboxylation of levodopa to dopamine, meaning that more levodopa is available for transport to the brain and conversion to dopamine.

[0300] Pharmacodynamic effects Foscarbidopa / foslevodopa subcutaneous injection and Duodopa intestinal administration are the C maxThe results show that the mean mean , AUC, and degree of variability are comparable, supporting a comparable efficacy profile. By achieving the same concentration of levodopa as Duodopa, subcutaneous foscarbidopa / foslevodopa infusion reduces the diurnal motor variation and increases the "on" time in levodopa-responsive patients with advanced Parkinson's disease. As the plasma concentration of levodopa is maintained at a stable level within the individual therapeutic range, the diurnal motor variation and hyperactivity or dyskinesia are reduced. The therapeutic effect on motor symptoms (the "on" state) is achieved on the first treatment day.

[0301] Clinical Efficacy and Safety Studies with Duodopa intestinal gel formulations The efficacy of Duodopa intestinal gel was confirmed in two identically designed phase 3, 12-week, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter studies to evaluate the efficacy, safety, and tolerability of the Duodopa intestinal gel system versus levodopa / carbidopa 100 / 25 mg tablets. The studies were conducted in patients with advanced Parkinson's disease who were levodopa-responsive and had persistent diurnal motor fluctuations despite optimal treatment with oral levodopa / carbidopa and other available antiparkinsonian medications, and enrolled a total of 71 patients. The results of the two studies were combined in a single analysis.

[0302] The primary efficacy endpoint, change in normalized "OFF" time (from baseline to endpoint) based on Parkinson's Disease Diary (PD Diary) data using rollup of the last observation date, demonstrated a statistically significant least squares mean (LS) difference in favor of the Duodopa-treated group (Table 26).

[0303] The primary endpoint results were supported by mixed-model repeated measures (MMRM) analyses examining change from baseline to each post-baseline visit. Analysis of "off" time demonstrated a statistically significant improvement in the Duodopa group compared with the active control group at week 4, with improvements shown to be statistically significant at weeks 8, 10, and 12.

[0304] This change in "off" time was associated with a statistically significant LS mean difference from baseline in average daily normalized "on" time without disabling dyskinesias between the Duodopa intestinal gel-treated and active control groups, based on PD diary data. Baseline values ​​were collected 3 days prior to randomization and 28 days after oral therapy standardization.

[0305] [Table 29]

[0306] Analysis of other secondary endpoints, in the order of the hierarchical testing procedure, demonstrated statistically significant results for Duodopa enteral gel compared with oral levodopa / carbidopa for the Parkinson's Disease Questionnaire (PDQ-39) summary index (a measure of Parkinson's-related quality of life), Clinical Global Impression-Improvement (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) part II score (activities of daily living). The PDQ-39 summary index showed a reduction of 10.9 points from baseline at week 12 in the Duodopa enteral gel group. The other secondary endpoints, UPDRS part III score, EuroQol 5-Dimension Questionnaire (EQ-5D) summary index, and Zarit Burden Interview (ZBI) total score, did not meet statistical significance based on the hierarchical testing procedure.

[0307] A phase 3, open-label, single-arm, multicenter study was conducted to evaluate the long-term safety and tolerability of Duodopa over 12 months in 354 patients. The target population was levodopa-responsive patients with advanced Parkinson's disease and diurnal fluctuations in motor symptoms despite optimal treatment with available Parkinson's medications. Mean daily normalized "off" time changed by 4.44 hours from baseline to endpoint (6.77 hours at baseline and 2.32 hours at endpoint), with a corresponding increase of 4.8 hours in "on" time without disabling dyskinesias.

[0308] A phase 3, open-label, randomized, multicenter study was conducted to evaluate the effect of Duodopa intestinal gel on dyskinesias compared with optimized medical therapy (OMT) over 12 weeks in 61 patients. The target population was levodopa-responsive patients with advanced PD and diurnal motor fluctuations not adequately controlled on OMT, and with a baseline Unified Dyskinesia Rating Scale (UDysRS) total score of ≥30. The change from baseline to week 12 in the UDysRS total score (primary efficacy endpoint) demonstrated a statistically significant LS mean difference (-15.05; P<0.0001) in favor of the Duodopa-treated group compared with the OMT group. Analyses of secondary efficacy endpoints with routine sequence testing procedures demonstrated statistically significant results in favor of Duodopa compared with OMT for "on" time without disabling dyskinesias measured by PD diary, for the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index, Clinical Global Impression-of-Change (CGI-C) score, UPDRS part II score, and for "off" time measured by PD diary. UPDRS part III score did not meet statistical significance.

[0309] Study using subcutaneous foscarbidopa / foslevodopa injection Foslevodopa and foscarbidopa are combinations of levodopa monophosphate and carbidopa monophosphate prodrugs (20:1 ratio) in a solution intended for continuous subcutaneous infusion 24 hours / day. Subcutaneous foscarbidopa / foslevodopa infusion administration and Duodopa enteral administration are max The AUC and AUC parameters were shown to be comparable, supporting comparable efficacy profiles. In this study, variability values ​​for foscarbidopa / foslevodopa subcutaneous infusion and Duodopa were 0.262 and 0.404, respectively, indicating stable levodopa exposure (see Section 5.2 Pharmacokinetic Properties).

[0310] A phase 3, open-label, single-arm study was conducted to evaluate the safety and tolerability of 24-h daily exposure to continuous subcutaneous infusion of foscarbidopa / foslevodopa over 52 weeks in 223 patients. The target population was levodopa-responsive patients with Parkinson's disease whose motor symptoms were not adequately controlled with current treatment and who experienced at least 2.5 h of "off" time per day as assessed by a Parkinson's disease (PD) diary. Dose conversion from oral medication to foscarbidopa / foslevodopa subcutaneous infusion was accomplished in a single outpatient visit.

[0311] Mean normalized daily "off" time (PD diary) decreased from 5.79 hours at baseline to 2.85 hours at week 26, a mean improvement of 2.94 hours. This change in "off" time was associated with a mean increase from baseline of 3.24 hours in "on" time without dyskinesias interfering with daily life. The mean increase from baseline in "on" time without dyskinesias was 4.00 hours. The percentage of patients with morning akinesia, measured as the first symptom reported after awakening derived from the PD diary, decreased from 77.8% at baseline to 20.8% at week 26. Other secondary endpoints: There were meaningful improvements in motor symptoms experienced in daily life (MDS-UPDRS Part II score), sleep symptoms (Parkinson's Disease Sleep Scale-2 [PDSS-2] total score), and quality of life (PDQ-39 and EQ-5D-5L summary index). (Table 27).

[0312] [Table 30]

[0313] 5.2 Pharmacokinetic properties absorption Foscarbidopa / foslevodopa subcutaneous infusions are administered directly into the subcutaneous space and converted to levodopa and carbidopa. In Phase 1 studies in healthy volunteers, levodopa and carbidopa were detectable in plasma within 30 minutes at the first pharmacokinetic collection point. In most subjects, steady state was reached within 2 hours when foscarbidopa / foslevodopa subcutaneous infusion dosing was delivered as a loading dose followed by a continuous infusion.

[0314] To determine the absorption of foscarbidopa / foslevodopa subcutaneous infusions at different subcutaneous sites, healthy volunteers were administered foscarbidopa / foslevodopa subcutaneous infusions in the abdomen, arms, and thighs using a three-way crossover design. Pharmacokinetic analysis from this study demonstrated that the three sites had nearly identical exposure to levodopa and carbidopa, suggesting that the absorption of foscarbidopa / foslevodopa subcutaneously was similar at the different subcutaneous sites.

[0315] Because subcutaneous foscarbidopa / foslevodopa infusions bypass the intestine, food does not alter the absorption or systemic exposure of levodopa / carbidopa, and therefore food is not expected to have any effect on the bioavailability or systemic exposure of subcutaneous foscarbidopa / foslevodopa infusions.

[0316] After administration of foslevodopa and foscarbidopa in healthy volunteers, a steady state of levodopa is achieved in approximately 2 hours and maintained throughout the infusion period. For a PK equivalence study between the product disclosed herein (foscarbidopa / foslevodopa for subcutaneous infusion) and Duopa (carbidopa / levodopa for enteral suspension) used with a nighttime oral medication, a steady state of levodopa was rapidly achieved and maintained during the infusion period after administration of the product of the present disclosure in healthy volunteers. Results from the study indicate that the PK of levodopa is comparable in both regimens. Figure 17A shows levodopa exposure after 24 hours administration of the product and 16 hours administration of Duopa, followed by nighttime oral administration of levodopa / carbidopa. A follow-up PK equivalence study in patients with advanced PD was completed to evaluate levodopa PK equivalence between Duopa and the product, with both agents infused for 24 hours. Results from this study indicate that levodopa PK was comparable for both regimens based on AUC (Figure 17B).

[0317] distribution The partition ratio for levodopa between red blood cells and plasma is approximately 1. Levodopa is negligibly bound (less than 10%) to plasma proteins. Levodopa is transported to the brain by the transport mechanism for large neutral amino acids.

[0318] Carbidopa is approximately 36% bound to plasma proteins. Carbidopa does not cross the blood-brain barrier.

[0319] Both foslevodopa and foscarbidopa are poorly bound to plasma proteins (24%-26%).

[0320] Metabolism and Excretion / Biodegradation and Excretion Foscarbidopa / foslevodopa subcutaneously injected prodrugs are rapidly converted to carbidopa and levodopa by phosphatases, and therefore the prodrugs are rapidly cleared from the circulation. Levodopa is primarily cleared via metabolism by the enzymes aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT). Other routes of metabolism are transamination and oxidation. In the absence of coadministration of enzyme inhibitors, decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway. O-methylation of levodopa by COMT forms 3-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours. Carbidopa is metabolized to two major metabolites, α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid. These two metabolites are excreted in the urine primarily unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.

[0321] Effects of food Levodopa is transported by the saturable amino acid transporter system active in the small intestine and at the blood-brain barrier. Absorption of foslevodopa and foscarbidopa occurs subcutaneously and not via the gastrointestinal tract. Food is not expected to have any effect on the bioavailability or systemic exposure of foslevodopa and foscarbidopa.

[0322] Example 7: Foslevodopa and foscarbidopa maintain equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum preface The Phase 1 study will characterize the LD PK profile following 16-hour LCIG jejunal infusion with 24-hour foslevodopa / foscarbidopa CSCI and nocturnal oral LD / CD dosing in healthy volunteers. The LCIG and oral LD / CD regimen was chosen as an example of how PD patients experiencing nocturnal symptoms and treated with LCIG may use this product.

[0323] Supply method The products of the present disclosure are supplied in single-dose glass vials filled with approximately 10 mL of solution. Each vial contains colorless to yellow, brown (may have a purple or reddish tint), and clear to slightly opalescent solutions. Each glass vial is fitted with a gray rubber stopper, aluminum crimp cap, and a turquoise plastic flip-off cap. The rubber stopper of the vial does not contain natural rubber latex.

[0324] This product should only be administered using the pump disclosed herein with the sterile, single-patient use infusion components (syringe, infusion set, and vial adapter) provided separately and suitable for use (see pump instructions for use for details).

[0325] Storage and Handling Do not use past the expiration date on the vial / carton label. Store drug vials in outer carton to protect from vial cracking. Store product refrigerated at 36°F-46°F (2°C-8°C). This product may be stored at room temperature up to 86°F (30°C) for a single period of up to 28 days. Do not return product to refrigerator once stored at room temperature. Discard product if not used within 28 days at room temperature. When removing product from refrigerator for the first time, record the date in the designated field on the carton. Do not freeze. Do not use frozen solutions. Do not shake. Do not dilute. Do not mix this product with other products. Use aseptic technique when preparing and administering this product. Drug vials are for single dose use only. The entire vial of product should be transferred to a syringe for administration. Do not remove only partial contents of the vial. Discard vial after transferring product to syringe. After the product in the syringe has been in use for 24 hours, discard the syringe and any unused product in it. Discard all used dosing supplies and any unused product immediately after each injection according to local requirements.

[0326] method: Study Design and Eligibility This was a Phase 1 open-label randomized two-period crossover study conducted in healthy volunteers (ages 45-75). A total of 25 subjects (N=25) who were in generally good health based on medical history, physical examination, vital signs, clinical laboratory profile, and electrocardiogram (ECG) results were enrolled in the study and randomized in equal numbers to one of two sequences, Regimen A or B, as shown in Figure 20. For Regimen A, foslevodopa / foscarbidopa was delivered subcutaneously to the abdomen by a portable infusion pump. Dosing consisted of a loading dose (foslevodopa / foscarbidopa 80 / 4 mg) followed by a 24-hour continuous infusion at a constant rate for the total infusion (foslevodopa / foscarbidopa 700 / 35 mg). For regimen B, LCIG was delivered through a nasojejunal (NJ) tube via a portable infusion pump and consisted of a loading dose (LD / CD50 / 12.5 mg), followed by a 16-h continuous dose at a constant rate for total infusion (LD / CD350 / 87.5 mg), followed by two oral immediate-release LD / CD doses (LD / CD100 / 25 mg), one administered at 18 h and one 21 h after the start of the infusion.

[0327] The study protocol and informed consent forms were approved by the Institutional Review Board of each participating institution prior to the initiation of any screening or study-specific procedures. Written informed consent was obtained from each individual participating in the study. The study was conducted in accordance with the Declaration of Helsinki and the 1975 Good Clinical Practice guidelines defined by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

[0328] Test procedure For each period and regimen, drug administration began on the morning of day 1. The initiation of foslevodopa and foscarbidopa infusions in the two periods was separated by at least 72 hours. Subjects were restrained for 8 days and fasted at least 4 hours before and 1 hour after foslevodopa and foscarbidopa were administered. For regimen B (LCIG plus oral LD / CD), on day 1 of each period, an NJ tube was inserted endoscopically or by interventional radiology into the jejunum just beyond the ligament of Treitz. Proper placement was confirmed radiologically. The NJ tube was removed approximately 30 minutes after completion of the LCIG infusion. Subjects were discontinued from the study if placement of the NJ tube was unsuccessful or if dosing accuracy was deemed compromised (e.g., kinked NJ tube, pump high pressure alarm, infusion set leak, vomiting after oral dosing, etc.). Similarly, for Regimen A (foslevodopa / foscarbidopa regimen), subjects were withdrawn from the study if dosing accuracy was deemed to be compromised (e.g., kinked tubing, pump high pressure alarms, drug leakage at the infusion site, vented cannula, etc.) and were replaced with new subjects and assigned to their respective regimens.

[0329] Safety and tolerability assessments were performed throughout the study and included adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, Columbia-Suicide Severity Rating Scale (C-SSRS), evaluation of local skin reactions, and clinical tests (hematology, chemistry, and urinalysis). Skin tolerability was assessed using an infusion site assessment scale, a two-part numeric rating (0-7) and letter rating (A-G) scale (7 and G indicated the worst outcome). For the two-part (numeric rating and letter rating) scales, frequency tables were provided for the scheduled times of the two assessments (before the start of the foslevodopa and foscarbidopa infusion and at the end of the foslevodopa and foscarbidopa infusion).

[0330] Pharmacokinetic Sampling and Evaluation Serial blood samples for LD, CD, LDP, CDP, and 3-O-methyldopa (3-OMD) were collected from pre-priming through 36 hours after the start of the foslevodopa and foscarbidopa infusions on day 1 of each period. For Regimen A, sampling was collected pre-priming, pre-infusion, and 0.5, 1, 2, 4, 8, 12, 16, 20, 24, 24.5, 25, 26, 28, 30, and 36 hours after the start of the infusion. Regimen B samples were collected pre-priming, pre-infusion, and at 0.5, 1, 2, 4, 8, 12, 16, 16.5, 17, 18, 18.25, 18.5, 18.75, 19, 19.5, 20, 21, 21.25, 21.5, 21.75, 22, 22.5, 23, 24, 26, 28, 30, and 36 hours after the start of the infusion. Oral dosing was performed 18 and 21 hours after the start of the infusion.

[0331] Plasma concentrations of LD, CD, LDP, CDP, and 3-OMD were determined using a validated liquid chromatography method with tandem mass spectrometry detection. Lower limits of quantification (LLOQs) for LD, CD, LDP, CDP, and 3-OMD were established at 9.27 ng / mL, 9.99 ng / mL, 3.00 ng / mL, 8.97 ng / mL, and 400 ng / mL, respectively.

[0332] A linear mixed-effects model was used to analyze the primary variables LD AUC0-16, AUC∞, and Cmax0-16. The model included fixed effects for duration, regimen, and sequence. Subjects were considered as a random sample. Point estimates and 90% confidence intervals for the ratio of the median value of the foslevodopa / foscarbidopa regimen to the median value of the reference LCIG regimen were obtained by exponentiation of the point estimates and 90% confidence limits for the corresponding logarithmic mean difference. Two one-sided test procedures were performed with a significance level of 0.050 using the 90% confidence interval. Equivalent LD exposure between the two regimens was predefined as the point estimates and 90% confidence intervals for the ratio of the Cmax and AUC exposure parameters ([foslevodopa / foscarbidopa]:LCIG) between 0.8 and 1.25.

[0333] For LD Cmax and the two degree of variability (DFL) variables (2-16 hours and 2-24 hours), defined as (Cmax-Cmin) / Cave, analyses were performed again using the linear mixed-effects model described in the primary analysis. A logarithmic transformation was used for Cmax. Transformations were considered separately for each DFL variable, with attention primarily to whether the probability distribution appeared to be significantly asymmetric, e.g., magnitude greater than 1.0.

[0334] result: demographics Sixteen men and nine women were enrolled in the study. The mean age of the 25 subjects was 57.2 years (range 46-70) and the mean weight was 78.2 kg (range 61-94). The subjects had a mean height of 171 cm (range 151-187 cm). Twenty subjects were white (80%), three subjects were black (12%), one subject was Asian (4%), and one subject was of mixed race (4%).

[0335] Pharmacokinetics The difference in LD exposure between the two regimens was less than 8%, well within the defined range of equivalence (Table 28). 0-16 There was little difference in LD AUC∞ and AUC∞. The difference between the median values ​​of the two regimens was not significant, and the percentage difference between the regimens was large for LD AUC∞ and AUC∞. 0-16 (The estimated ratio of the median value for the foslevodopa / foscarbidopa regimen to the median value for the reference regimen was 0.951, a difference of 4.9%). The median LD Cmax0-16 value for the foslevodopa / foscarbidopa regimen was lower than that for the reference regimen. The point estimates of the median values ​​were 605.6 ng / mL for the foslevodopa / foscarbidopa regimen and 656.4 ng / mL for the reference regimen, respectively, a ratio of 0.923. For total LD ​​Cmax, the point estimates were 658 ng / mL for the foslevodopa / foscarbidopa regimen and 1874 ng / mL for the reference regimen.

[0336] Analyses were also performed for LD for DFL2-16 (DFL for the time during which both LCIG and foslevodopa / foscarbidopa infusions were ongoing) and DFL2-24 (DFL 2-24 hours after initiation of foslevodopa and foscarbidopa administration). The foslevodopa / foscarbidopa regimen had smaller DFL2-16 (0.344 ± 0.319) compared to LCIG DFL2-16 (0.453 ± 0.251) for the time during which both infusions were ongoing. 2-24 (0.405 ± 0.283) was the LCIG + oral LD / CD DFL because the oral LD / CD dosing period was included in the DFL calculation. 2-24 The mean LD exposure was significantly lower than that of the LCIG infusion (3.01±0.811). Foslevodopa / foscarbidopa CSCI provided equivalent LD levels to LCIG infusion over a 16-hour interval and maintained those levels throughout the night (FIG. 17). Overall LD exposure over a 24-hour period was also shown to be equivalent between foslevodopa / foscarbidopa CSCI and LCIG plus oral LD / CD.

[0337] safety Twenty subjects completed both periods of the study, and five subjects discontinued. The proportion of subjects reporting at least one treatment-emergent adverse event was higher after foslevodopa / foscarbidopa infusion (19 / 24, 79%) compared with LCIG infusion (20 / 4, 20%), driven primarily by infusion site reactions, and these were reported in 18 of 24 subjects receiving foslevodopa / foscarbidopa. These events were mild in severity, scored 0 or 1 and A on the two-part infusion site assessment scale. One subject discontinued the study due to a serious adverse event of seizures, which was considered by the investigator to not be reasonably likely to be related to foslevodopa and foscarbidopa. All adverse events considered "possibly related" to foslevodopa and foscarbidopa were mild in severity and did not lead to discontinuation of the study.

[0338] Consideration: The current study characterizes the LD PK profile of a 16-hour LCIG jejunal infusion with 24-hour CSCI of foslevodopa / foscarbidopa and nocturnal oral LD / CD dosing. Foslevodopa / foscarbidopa is intended to help manage the nocturnal motor symptoms of PD as well as minimize morning "off" symptoms for a 24-hour continuous infusion. LCIG is usually infused during each patient's waking hours, and nocturnal motor symptoms are often managed with additional oral LD / CD dosing. In this study, two tablets of LD / CD 100 / 25 mg were orally administered at 3-hour intervals at night to provide nocturnal exposure to LD. In clinical practice, PD patients who discontinue LCIG dosing before bedtime may choose to supplement their therapy with oral LD / CD separately based on their individual needs.

[0339] Pharmacokinetics PD patients receiving therapeutic doses of LCIG have been shown to achieve effective steady-state LD concentrations ranging from approximately 1500 to 4000 ng / mL [6], averaging approximately 2910 ng / mL [7]. Recently, LD and CD PK profiles after delivery of four different therapeutic doses of foslevodopa / foscarbidopa at four predefined CSCI rates have been characterized in PD patients, showing effective LD steady-state exposures ranging from approximately 750 to 4700 ng / mL; these data support the ability of foslevodopa / foscarbidopa to deliver a wide range of LD exposures necessary to treat the majority of PD patients. The current study demonstrated that foslevodopa / foscarbidopa SC infusions provided equivalent LD exposures to LCIG infusions, with or without nocturnal oral LD / CD dosing. LD exposure after administration of foslevodopa / foscarbidopa 35 / 700 mg over 24 hours was comparable to LCIG 350 / 87.5 mg LD / CD over 16 hours, followed by two oral doses of LD / CD 100 / 25 mg 18 and 21 hours after the start of the infusion. The doses selected for this study were chosen to be in the range tolerated by healthy volunteers and more therapeutically relevant for patients in the early stages of PD. A previous study in which patients with increasingly severe PD were classified into four categories based on the total LD ​​intake demonstrated that LD exposure increased in direct proportion to the dose of foslevodopa / foscarbidopa administered (dose proportionality), and exposure equivalence was shown to be associated with higher foslevodopa / foscarbidopa doses as well [8].

[0340] In this study, LD variability was consistently low during the first 16 hours for foslevodopa / foscarbidopa and LCIG infusions. This indicates that foslevodopa / foscarbidopa SC infusions are capable of maintaining LD exposure within the narrow therapeutic window required to treat aPD patients. For reference, Yeh et al. [9] previously reported that LD variability in healthy elderly volunteers after oral LD / CD immediate release was 4.3 ± 0.9, and subsequently, Hauser et al.

[10] reported that LD variability in PD patients was 3.2 ± 1.3. Oral LD ​​administration for aPD is often hampered by variable LD plasma concentrations, which results in unpredictable absorption of oral LD ​​tablets. This variability can be mainly attributed to irregular gastric emptying

[11] and the short half-life of LD even in the presence of CD [12, 13]. The advantage of continuous LD infusion compared to oral immediate-release LD / CD has been previously demonstrated in aPD patients using LCIG [3], and this study demonstrates that CSCI with foslevodopa / foscarbidopa achieves therapeutically relevant and stable LD exposure across multiple dosing regimens without the need for surgery or concerns about the effect of food on LD absorption, as subcutaneous delivery does not involve the gastrointestinal system. Furthermore, the foslevodopa / foscarbidopa delivery system is amenable to small infusion rate adjustments, can be individually tailored to the patient's needs, and allows for the delivery of a predictable dose-proportional [8] dose, ultimately providing optimized control of diurnal variation in PD and motor symptoms.

[0341] safety After subcutaneous delivery, foslevodopa and foscarbidopa undergo enzymatic conversion to the active forms LD and CD. The doses of foslevodopa / foscarbidopa in this study were chosen to be at the lower end of the therapeutic range to be tolerated by healthy volunteers, and other studies have demonstrated dose proportionality between foslevodopa dose and LD plasma exposure, and the systemic safety profile of foslevodopa is expected to be consistent with all other LD-containing medications. To this extent, no clinically significant laboratory measurements, vital signs, suicidal behavior / ideations, or other systemic events were observed during the course of this study, consistent with what would be expected due to the low dose of LD administered. At the same time, mild infusion site reactions were reported in subjects receiving foslevodopa / foscarbidopa, consistent with those previously reported with other medications delivered as continuous subcutaneous infusions. Data obtained from diabetic adults and children receiving insulin as a CSCI indicate that adverse events related to insulin pumps are common, but the overall rate of permanent discontinuation due to these events is low. Similarly, clinical experience in countries where CSCI with the dopamine agonist apomorphine is approved for the management of diurnal motor fluctuations in aPD has found that infusion site reactions (including nodules) rarely lead to discontinuation and may be prevented by rotating infusion sites, using correct aseptic technique, and avoiding device reuse. No new safety issues were identified from this study, and the importance of education in aseptic technique and proper application of infusion sets is crucial to ensure an overall positive patient experience and minimize skin reactions.

[0342] [Table 31]

[0343] During the first 16 hours of foslevodopa / foscarbidopa and LCIG infusions, the LD magnitude of variation was consistently low for both regimens (Table 29), indicating that foslevodopa / foscarbidopa SC infusions are able to maintain LD exposure.

[0344] [Table 32]

[0345] The degree of variation was determined as follows: (maximum LD plasma concentration - minimum LD plasma concentration) / mean LD plasma concentration. For comparison, after oral LD / CD immediate release, Yeh et al. 2 4.3±0.9 in healthy elderly volunteers, and Hauser et al. 3 have previously reported a much higher LD variability of 3.2 ± 1.3 in PD patients. All adverse events considered "possibly related" to foslevodopa or foscarbidopa were mild and did not lead to discontinuation of the study.

[0346] [Table 33]

[0347] Example 8: Protocol for a study on Parkinson's disease: Safety and tolerability of 24-hour daily exposure to foscarbidopa / foslevodopa subcutaneous infusions by continuous subcutaneous infusion Clinical Trial B The objective of this study was to evaluate the safety, tolerability, and efficacy of subcutaneous foscarbidopa / foslevodopa infusions as measured by patient-reported and assessor-measured efficacy endpoints, which included: The percentage of subjects with adverse events (AEs) and serious adverse events during the study; The percentage of subjects with AEs of special interest (AESIs) during the study; The percentage of subjects with a numeric rating of 5 or greater and a letter rating of D or greater on the Injection Site Assessment Scale at any time during the study; Changes in laboratory data from baseline to the end of the study; Changes in vital sign measurements from baseline to the end of the study; - Change in electrocardiogram from baseline to end of study; Secondary endpoints were changes from baseline to end of study in: average normalized daily “off” and “on” time as assessed by PD diary, PD symptoms as assessed by the Movement Disorder Society-Uniform Parkinson's Disease Rating Scale (MDS-UPDRS) parts I-IV (or UPDRS IV in countries where a validated translation of the MDS-UPDRS is not available); Sleep symptoms as assessed by the PD Sleep Scale-2 (PDSS-2); Quality of life as assessed by the PD Questionnaire-39 (PDQ-39), and Health-related quality of life assessed by the EuroQol 5-dimension questionnaire (EQ-5D-5L). · Additional endpoints will include PD symptoms assessed by Parkinson's KinetiGraph™ / Personal KinetiGraph™ (PKG) wearable device (as permitted by national regulations) from baseline to the 26-week visit.

[0348] The study was a long-term, phase 3, open-label, single-arm study conducted in an outpatient setting for 52 weeks in patients with Parkinson's disease with 24-hour daily exposure to continuous subcutaneous infusion of foscarbidopa / foslevodopa. Foscarbidopa / foslevodopa subcutaneous infusion was administered via a CSCI 24 hours daily for 52 weeks. The study included approximately 130 adult subjects with Parkinson's disease whose motor symptoms were not adequately controlled by oral medications. A schematic diagram of the study is shown in Figure 18.

[0349] result Treatment with subcutaneous foscarbidopa / foslevodopa infusions resulted in clinically meaningful improvements in "off" and "on" time without disabling dyskinesias. Treatment benefits were observed as early as week 1 and were maintained throughout the 12-month treatment period. At week 52, the observed mean (SD) reduction from baseline in normalized "off" time per PD diary was 3.39 (3.08) hours, and the increase in "on" time without disabling dyskinesias was 3.58 (3.03) hours. As shown in Table 32B, the most frequent adverse events were skin events at the injection site, the majority of which were non-serious and mild / moderate in severity. In this open-label study, individualized 24-h / day subcutaneous infusion of foscarbidopa / foslevodopa was generally safe, improved motor complications and morning akinesia, and offered a potentially effective and minimally invasive treatment alternative for advanced Parkinson's disease.

[0350] Subject distribution, demographics and baseline characteristics A total of 244 subjects were enrolled, of whom 7 had previously received foscarbidopa / foslevodopa in a Phase 1 study. 103 (42.2%) subjects discontinued foscarbidopa / foslevodopa prematurely, 115 (47.1%) subjects completed 52 weeks of study drug treatment, and 26 (10.7%) subjects were continuing on study drug treatment. 145 subjects had at least 180 days of foscarbidopa / foslevodopa exposure, and 112 subjects had at least 360 days of foscarbidopa / foslevodopa exposure.

[0351] Most analyses are presented by foscarbidopa / foslevodopa dose categories. Each subject was individually dose titrated to optimal efficacy, and thus the dose range varied continuously. The low dose category included subjects whose modal total daily dose from foscarbidopa / foslevodopa was less than 1800 mg levodopa (LD) based on the molecular weight conversion of foslevodopa to LD, and the high dose category included subjects whose modal total daily dose was LD 1800 mg or greater.

[0352] [Table 34]

[0353] [Table 35]

[0354] Test period Screening Period The 10-42 day screening period consisted of two screening visits (V1 and V2) and a 6 day monitoring period during which subjects became familiar with the wearable device and PD diary. During the screening period, subjects were required to demonstrate that they had been on a stable oral PD medication regimen for at least 30 days prior to starting foscarbidopa / foslevodopa subcutaneous infusions. Historical data (e.g. medical records) were acceptable documentation of stable medication use.

[0355] Subjects were required to be able to safely discontinue any prohibited medications 5 half-lives or 30 days before the first foscarbidopa / foslevodopa subcutaneous infusion dose, whichever was longer, except for levodopa-containing medications and catechol-O-methyltransferase (COMT) inhibitors, at least 12 hours before the start of the foscarbidopa / foslevodopa subcutaneous infusion and for the duration of treatment. Subjects were required to consent to the study before discontinuing any prohibited medications in order to meet study eligibility.

[0356] Subjects were required to wear the wearable device, in countries where such devices are approved, for 6 consecutive days (i.e., the 6-day monitoring period) prior to Visit 3. PD diaries were completed for at least 2 consecutive days of the 6-day monitoring period prior to Visit 3 (Day 1).

[0357] Duration of treatment The treatment period began with the initiation of foscarbidopa / foslevodopa subcutaneous infusions and consisted of two parts: a 4-week optimization period and a 48-week maintenance period.

[0358] Optimization Period: During the 4-week optimization period, the investigator made any necessary adjustments to the subject's foscarbidopa / foslevodopa subcutaneous infusion dose until the optimal clinical response was achieved for the individual subject. Further adjustments were made to the subject's concomitant PD medications (e.g., dopamine agonists, selective monoamine oxidase B [MAO-B] inhibitors, amantadine, safinamide) in accordance with prescribing information, including tapering or even withholding such medications, to achieve, in the investigator's opinion, a treatment approach that controlled the subject's symptoms in the most satisfactory manner.

[0359] Maintenance Period: The maintenance period consisted of 48 weeks of daily 24-hour CSCI with foscarbidopa / foslevodopa subcutaneous infusions at optimal therapeutic doses. During this 48-week period, subjects maintained a stable regimen of all concomitant medications unless, in the opinion of the investigator, a change was medically necessary. Foscarbidopa / foslevodopa subcutaneous infusions may be adjusted throughout the study. If dose adjustments were made to foscarbidopa / foslevodopa subcutaneous infusions or other concomitant medications (including the addition or withholding of other PD medications), these adjustments were documented on the electronic case report form (eCRF).

[0360] On the morning of Day 1 (V3), subjects were in a clinically defined "off" state (i.e., no PD medications were administered for at least 12 hours prior to starting the foscarbidopa / foslevodopa subcutaneous infusion). After confirmation of eligibility and a brief clinical examination, subjects received an oral loading dose of LD+DDCI and then began the foscarbidopa / foslevodopa subcutaneous infusion at the calculated starting dose.

[0361] For each subject, a starting dose level for the continuous infusion rate of foscarbidopa / foslevodopa subcutaneous infusion was calculated according to the baseline dose of oral levodopa (or levodopa equivalent dose [LED]) based on the suggested conversion rate from Tomlinson et al., guidance from Espay et al., and a conversion algorithm based on Phase 1 data (see Section 4.2).

[0362] Subjects were allowed to resume PD medications that did not contain levodopa or COMT inhibitors (e.g., dopamine agonists, MAO-B inhibitors, amantadine, safinamide, etc.) as these concomitant medications did not need to be held prior to initiating foscarbidopa / foslevodopa subcutaneous infusions. However, at the investigator's discretion and according to prescribing information, subjects were allowed to begin tapering their concomitant PD medications during the 4-week optimization period.

[0363] Subjects were evaluated on the day and the day after starting the foscarbidopa / foslevodopa subcutaneous infusion, and then weekly during the optimization period. During each visit, the investigator assessed the subject's PD symptoms by history taking and neurological examination, and based on the subject's clinical response, the investigator may adjust the subject's treatment regimen by continuing to taper and / or withhold previous concomitant PD medications while simultaneously increasing, decreasing, or maintaining the foscarbidopa / foslevodopa subcutaneous infusion rate. When all concomitant PD medications have been tapered, the dose of the foscarbidopa / foslevodopa subcutaneous infusion may be further adjusted until an optimal clinical response is obtained for the individual subject, as determined by the investigator. The optimal clinical response was defined by maximizing functional "on" time during the day and minimizing the number of "off" episodes. This optimization also minimized "on" time with interfering dyskinesias.

[0364] During the optimization period, study visits were conducted as follows: Day 1 (V3) Day 2 (V4) Week 1 (V5) 2nd week (V6) Week 3 (V7) Week 4 (V8)

[0365] The Investigator may conduct unscheduled visits within the 4-week optimization period to make any necessary adjustments.

[0366] After Week 4 (V8), all subjects should begin the maintenance period, including any PD medications that were being taken after the optimization period, and maintain a stable treatment regimen of foscarbidopa / foslevodopa subcutaneous infusion and other concomitant medications. Adjustments in the dose of medications, including foscarbidopa / foslevodopa subcutaneous infusion, may be made if, in the opinion of the investigator, considered medically necessary. Any changes in the dose of medication or foscarbidopa / foslevodopa subcutaneous infusion were recorded in the eCRF.

[0367] During the maintenance period, study visits were conducted as follows: Week 6 (V9) Week 13 (V10) 26th week (V11) Week 39 (V12) Week 52 (V13) or early discontinuation.

[0368] Apart from the screening visits (V1, V2) and V3 (Day 1), all visits had a ±3 day window.

[0369] If necessary, unscheduled visits may be conducted at the discretion of the investigator.

[0370] [Table 36]

[0371] [Table 37]

[0372] Treatment Arm Subjects received an oral loading dose on day 1 (V3) followed by 24-hour subcutaneous infusion of foscarbidopa / foslevodopa. The loading dose was established by the investigator according to the subject's oral regimen before starting the foscarbidopa / foslevodopa subcutaneous infusion. The continuous infusion starting dose (F1) was calculated taking into account the pharmacokinetic characteristics of the LED and the foscarbidopa / foslevodopa subcutaneous infusion. The investigator could adjust the prescribed infusion rate during the visit to optimize the control of motor symptoms. Subjects could choose the daily continuous infusion dose from three preprogrammed flow rates. The investigator could determine and program the main daily flow rate (F1) within the acceptable range (0.17-1.04 mL / hr) and program two additional flow rates (F2 and F3) within ±20% of the prescribed main flow rate. F2 was the alternative higher continuous dose and F3 was the alternative lower continuous dose. When programmed, the alternative flow rates (F2 and F3) were within acceptable ranges (0.17-1.04 mL / hr). When the alternative flow rates (F2 and F3) were not needed, they were programmed to "off". Subjects received the system user manual.

[0373] 4.2 Study Design Considerations Appropriateness of measurement items Standard statistical, clinical, and laboratory procedures were used in this study. All efficacy measures were suitable for assessing disease activity in patients with PD.

[0374] Target population suitability The study population consisted of patients with PD who reported motor complications not adequately controlled by oral medications and experienced a minimum of 2.5 hours of "off" time per day as assessed by a PD diary completed prior to enrollment / Day 1 (V3). Subjects were on a stable oral PD medication regimen for at least 30 days prior to initiating subcutaneous foscarbidopa / foslevodopa infusions.

[0375] Rationale for choosing a therapeutic dose range CD / LD remains the standard of care for PD. However, it is recognized that treatment for PD is highly individualized; the treatments administered and their doses must be customized based on the patient's signs and symptoms and response to medications. In practice, this results in a wide distribution of patient doses, even within clinical trials.

[0376] In the central LCIG double-blind double-dummy, median levodopa dose was 1013 mg / day and mean was 1117 mg / day for a 16-hour daily infusion. These data represent a small proportion of subjects whose dosing was restricted to maintain blinding of the study. Thus, >90% of subjects used less than 2000 mg over the 16-hour treatment period.

[0377] In an open-label safety study of LCIG that enrolled >300 subjects, dosing more closely reflected clinical practice, and a significant proportion of subjects were able to simplify their therapy by discontinuing concomitant oral medications and maintaining only LCIG during waking hours. Distribution of LD doses in this study (Table) showed that approximately 50% of subjects required daily levodopa doses of 1400 mg / day or more over the 16-h treatment period.

[0378] Foscarbidopa / foslevodopa subcutaneous infusion is a 24 hour / day regimen (i.e., subjects are exposed for 8 more hours - or 50% longer compared to LCIG exposure). Results of a PK study comparing LD plasma concentrations between LCIG plus LD / CD tablets and foscarbidopa / foslevodopa subcutaneous infusion in healthy volunteers demonstrated that the LD from foscarbidopa / foslevodopa subcutaneous infusion is 8% more bioavailable than the LD absorbed enterally. Based on molecular weight (MW), 100 mg of LD is equivalent to 141 mg of LDP.

[0379] Using these data, it was predicted that approximately 50% of subjects should receive a subcutaneous foscarbidopa / foslevodopa infusion dose of LDP >2800 mg (equivalent to approximately 2000 mg levodopa, the current maximum recommended dose of LCIG, over a 16 hour treatment period). This group is defined as "high dose."

[0380] [Table 38]

[0381] Approximately 50% of subjects from this study will require a daily levodopa dose of 1,400 mg / day or more over a 16 hour treatment period; considering the additional 8 hours of treatment and the higher bioavailability of foscarbidopa / foslevodopa subcutaneous infusion compared to LCIG, it is expected that 50% of subjects will require a daily levodopa dose of 2,000 mg / day or more over a 24 hour treatment period. Based on molecular weight, 2000 mg of levodopa is equivalent to approximately 2800 mg of LDP.

[0382] The distribution of dose levels of foscarbidopa / foslevodopa subcutaneous infusion was monitored continuously throughout the study period with the goal of enrolling approximately half of the subjects in the "high dose" group. However, based on the assessment of dose distribution performed when all subjects reached the end of the optimization period, as well as at some other time points during the study, the cutoff for the "high dose" group may be revised lower or higher than LD2000mg (LDP2800mg). This assessment should provide guidance for the analysis of the data and may suggest an appropriate maximum recommended dose of foscarbidopa / foslevodopa subcutaneous infusion over 24 hours.

[0383] 4.3 Loading Dose, Continuous Infusion Rate, Dose Titration, and Booster Doses Oral Loading Dose The purpose of the oral loading dose is to allow the subject to achieve symptom control rapidly after initiating treatment. The loading dose in this study was an oral dose of LD+DDCI that corresponded as closely as possible to the subject's habitual first morning dose of LD+DDCI. For subjects using CD / LD immediate release (IR) for the loading dose, the investigator chose one of three doses: 25 / 100mg (CD / LD IR 25 / 100mg 1 tablet), 37.5 / 150mg (CD / LD IR 1+1 / 2 tablets) or 50 / 200mg (CD / LD IR 2 tablets). Alternatively, LD+DDCI may be used for the loading dose; in that case, the amount of DDCI may vary based on the country of destination; however, the amount of levodopa administered was 100, 150 or 200mg.

[0384] A loading dose was administered only once at the initiation of treatment with foscarbidopa / foslevodopa subcutaneous infusion, unless dosing was discontinued for >8 hours. Temporary disconnections (<1 hour) for daily hygiene or to change an empty syringe did not count as discontinuations and did not require a loading dose after resumption of infusion.

[0385] Continuous Infusion Rate After administration of the oral loading dose, foscarbidopa / foslevodopa subcutaneous infusion was delivered continuously (24 hours per day) via an infusion set connected to a pump. The initial main continuous infusion rate (F1) for each subject was calculated based on an algorithm developed according to the subject's oral LD ​​therapy over the 16-hour treatment period and a combination of PK and clinical considerations derived from Phase 1 studies. The subject's baseline dose of IRLD+DDCI was the starting point for establishing the levodopa equivalent (LED) for dose selection (Note: levodopa contained in Stalevo® [CD / LD / entacapone] counts as IR). If the subject is not receiving an IR formulation of LD+DDCI, the LED is calculated from the main levodopa-containing drug. The conversion factors used to calculate the total LED for dose selection are shown in Table 34 and are based on data from the literature (Tomlinson et al., Mov Dis 2010; Espay et al., Neurol Clinical Practice 2017). The applicable calculations obtained from Table 34 and the subject's baseline CD / LD IR dose should be added together to provide the total starting LED for the foscarbidopa / foslevodopa subcutaneous infusion equivalent.

[0386] [Table 39]

[0387] After the subject's daily LED is determined, the starting infusion rate for foscarbidopa / foslevodopa subcutaneous infusion should be selected from Table 35. The following continuous infusion rates are extrapolated to the midpoint of the LED interval to which they refer and are designed to provide therapeutic levodopa exposure. The infusion rates are delivered continuously via an infusion set connected to a portable pump.

[0388] [Table 40]

[0389] dose titration The main infusion rate (F1) of the foscarbidopa / foslevodopa subcutaneous infusion can be adjusted at any time throughout the study at the investigator's discretion to achieve and maintain the optimal therapeutic response for each individual subject, meaning maximizing functional "on" time during the day by minimizing the number and duration of "off" episodes (bradykinesia) and minimizing "on" time with interfering dyskinesias. The infusion rate can be increased or decreased by 0.022 mL / hr, which equates to approximately 3.75 mg LD / hr (note, pumps display rates rounded to the nearest tenth). Thus, an increase of 0.02 mL / hr in the main infusion rate will result in a total increase of approximately 90 mg LD over 24 hours; an increase of 0.04 mL / hr will result in a total increase of approximately 180 mg LD over 24 hours; a decrease of 0.07 mL / hr will result in a total decrease of approximately 270 mg LD over 24 hours, etc.

[0390] The investigator may decide to increase the infusion rate only after assessing the subject for clinical efficacy (achieving optimal therapeutic response as defined above) and safety by neurological and physical examination. The safety profile of foscarbidopa / foslevodopa subcutaneous infusions at doses higher than 4000 / 200 LDP / CDP resulting in an infusion rate >0.70 mL / hr will be assessed by neurological and physical evaluations (focusing on peripheral neuropathy, weight loss, orthostatic hypotension, and other AESIs such as daytime somnolence and hallucinations / psychosis) throughout the study.

[0391] Alternative continuous infusion rates (F2, F3) Similar to other treatment approaches for PD that require individualized dose titration, and given the widespread knowledge that advanced patients know whether their PD symptoms are adequately controlled by treatment, the study will offer subjects the ability to choose from alternative infusion rates within specified ranges, if permitted by the investigator.

[0392] Two additional infusion rates (F2 and F3) can be pre-programmed into the pump by the investigator.

[0393] F2 should be the alternative higher continuous dose and F3 should be the alternative lower continuous dose. The additional infusion rates should be selected within the limits of ±20% from the predetermined main continuous infusion rate (F1).

[0394] Infusion rates below 0.17 mL / hr or above 1.04 mL / hr are not permitted.

[0395] During the study, if the primary daily infusion rate (F1) is programmed at 0.17mL / hr, the alternate low infusion rate (F3) must be disabled. If at any time during the study, the primary daily infusion rate (F1) is programmed at 1.04mL / hr, the alternate high infusion rate (F2) and the extra dose option (see below) must be disabled.

[0396] The starting infusion rate should not exceed 0.70 mL / hr; adjustments can only be made after clinical evaluation (neurological and physical examination).

[0397] If the alternate infusion rates (F2 and F3) are not required, the Investigator or his / her designee must disable them by programming them to "OFF" and the subject will not be able to select an alternate infusion rate. If the Investigator enables these options, the subject will be able to select an infusion rate from three preprogrammed choices (F1, F2, or F3) and will be required to record in the medication diary the time of day that the alternate infusion rate was selected. The infusion rate values ​​may not be modified by the subject.

[0398] additional dose If permitted by the investigator, subjects may self-administer booster doses of foscarbidopa / foslevodopa subcutaneous infusions during the 24-hour period; the ability to self-administer booster doses, the booster dose volume, and the lockout time (interval between booster doses) are determined and programmed by the investigator or his / her designee and cannot be modified by the subject. The investigator can choose the booster dose volume from the following options: 0.10, 0.15, 0.20, 0.25, or 0.30 mL (equivalent to approximately 17, approximately 26, approximately 34, approximately 43, and approximately 51 mg of levodopa, respectively). The lockout time is programmable in 15-minute increments from 1 hour to 24 hours, with a minimum lockout time of 60 minutes. If the investigator decides not to allow the use of booster doses, the booster dose should be set to "off."

[0399] If the extra dose feature is enabled, subjects will be required to record the time of day they self-administered an extra dose in a medication diary, which will be reviewed by study personnel at every study visit.

[0400] If bolus doses are required frequently (>5 times per day), the investigator should consider increasing the main daily infusion rate and lockout time to limit the number of bolus doses per day. If F1 or F2 is set at 1.04 mL / h at any time in the study, the bolus dose option should be disabled. Doses of LDP greater than 6000 mg / 24 hr (equivalent to an LD of 4260 mg / hr) will not be allowed under any circumstances during the study.

[0401] Investigators should consider this upper limit when programming alternative infusion rates and / or volumes and number of booster doses. Guidance is provided in Table 36.

[0402] [Table 41]

[0403] Conversion Algorithm A conversion algorithm was developed taking into account LDP bioavailability, 24-hour exposure, and pharmacokinetic data obtained from a Phase 1 foscarbidopa / foslevodopa subcutaneous infusion study.

[0404] In a 4-week clinical trial in patients with advanced Parkinson's disease (A 4-week, single-arm, open-label study of subcutaneous foscarbidopa / foslevodopa infusions in subjects with advanced Parkinson's disease), an algorithm was created to convert oral LD ​​to fosulfodopa and foscarbidopa based on a combination of PK and clinical considerations. Evaluation of the pattern of dose adjustments obtained from this study and the results of another study (a three-part, open-label, randomized, two-period crossover study in healthy elderly volunteers) confirmed the appropriateness of such an algorithm in achieving adequate control of motor symptoms in PD patients. Therefore, the current study utilizes a similar approach to the 4-week study to convert oral LD ​​to foslevodopa and foscarbidopa.

[0405] Assumptions used to generate the algorithm Most PD patients are treated with oral PD medications during waking hours; therefore, the calculated LED reflects the dopaminergic drug requirement during an average 16-hour treatment period. Foscarbidopa / foslevodopa subcutaneous infusions are administered over a 24-hour period, so add another 50% of the drug to account for an additional 8 hours of treatment. Data suggest that low variability and fluctuations in plasma LD exposure from continuous delivery translate into an average reduction in effective daily levodopa dose (Othman AA et al., J Parkinson's Dis. 2017;7(2):275-278). Additionally, from a PK study comparing LD plasma concentrations between LCIG and foscarbidopa / foslevodopa subcutaneous infusions, foscarbidopa / foslevodopa subcutaneous infusions appears to be more bioavailable than enterally absorbed levodopa. Finally, the conversion factor from oral levodopa to LDP was determined to be 1.41 based on the difference in molecular weight.

[0406] Each mL of the foscarbidopa / foslevodopa subcutaneous infusion formulation used in this study contains 240 mg LDP and 12 mg CDP. The total daily LDP requirement is calculated and then divided by 240 mg to determine the number of milliliters required per day, which is then divided by 24 hours to determine the flow rate. Each suggested infusion rate is calculated for the midpoint of the LED range shown in Table 35.

[0407] Guidance to enable alternative infusion rates and top-up dose options Investigators should consider whether alternative infusion rates and additional doses are possible and offer these options to patients, based on clinical judgment of the subject's cognitive ability, compliance, and personality characteristics.

[0408] Allowing for an alternative higher infusion rate (F2) can facilitate refinement of the main continuous infusion rate during the optimization period. Subjects who report disabling dyskinesias, freezing of gait, or nocturnal akinesia at baseline are often treated with suboptimal oral daily doses of LD (Cruse, 2018 NPJ Parkinson's Dis; Chang, 2015 PRD). In such cases, programming F1 as suggested in Table 35 may result in suboptimal foscarbidopa / foslevodopa subcutaneous infusion doses. Investigators may program F2 starting with small (e.g., 5-10%) increments, allowing subjects who feel underdosed to switch to the alternative higher infusion rate. Similarly, if a subject is expected to sustain prolonged physical activity (e.g., sports) or requires a higher dose of levodopa at certain times of the day, F2 may be selected temporarily to carry the higher dopaminergic demand. Also, if a subject needs to self-administer 5 or more extra doses during the day, the subject may be instructed, after reviewing the medication diary, to switch to F2 and reduce the number of extra doses, pending the investigator's adjustment of the primary infusion rate at the next visit. It is important for subjects to remember to log on to the medication diary any time they self-administer an extra dose or switch the infusion rate to any of the active options.

[0409] If the Investigator does not wish to offer this option or considers the subject to be unsuitable to choose from among the options offered, the Investigator should disable the alternative higher infusion rate by programming the option to "Off".

[0410] The investigator could consider whether to allow the subject to switch to an alternative lower infusion rate (F3) before bedtime if the subject did not report complaints of nocturnal akinesia or nocturnal symptoms at baseline or if the subject had a known history of impulse control disorders or nocturnal hallucinations (Ricciardi, 2016; Nyholm, 2012; Cruse, 2018). If the subject experienced persistent dyskinesias between visits during the optimization period, the subject could be instructed to select the alternative lower infusion rate and record it in the medication diary until the investigator adjusted the primary parameter at the next visit. The alternative lower infusion rate F2 could be programmed to be up to 20% lower than F1.

[0411] If nocturnal akinesia is present or bothersome nocturnal symptoms are present, the investigator should consider maintaining the main infusion rate (F1) consistently for 24 hours and disabling the option for alternative lower infusion rates (programming the option to "off"). Similarly, if the investigator does not want to offer this option or considers the subject not suitable to choose among the options offered, the investigator should disable the alternative lower infusion rates by programming them to "off".

[0412] 5. Testing Activities 5.1 Eligibility Criteria All subjects were assessed to ensure they met eligibility criteria at Screening Visits 1 and 2 (V1 and V2) and prior to enrollment on Day 1 (V3).

[0413] Demographic and clinical evaluation 1. The subjects must be adult men or women aged 30 or older. 2. Subject is willing and able to comply with the procedures required by this protocol. 3. Target: Low Vitamin B 12 Levels (<200 pg / mL); or low-normal vitamin B 12 levels (<300 pg / mL) with elevated methylmalonic acid (MMA>0.41 mmol / L) at Screening Visit 1 (V1). 4. Subjects will be cognitively normal (Mini-Mental State Examination [MMSE] score ≥ 24). Subjects with mild agnosia (including MMSE scores 19-23) may be enrolled if, in the investigator's opinion, they are able to comply with all study requirements. Subjects with moderate or severe impairment (MMSE score ≤ 18) will not be enrolled. 5. Subject is not considered by the Investigator to be an unsuitable candidate for receiving study drug for any reason. disease activity 6. Subject must be diagnosed with levodopa-responsive idiopathic PD. 7. Subject must meet the following disease activity criteria: Must be on a regimen of oral medications for PD that has not changed for at least 30 days prior to starting study medication; regimen must include levodopa-containing formulations, e.g., CD / LD IR (e.g., Sinemet, Madopar), CD / LD-CR (e.g., Sinemet CR), CD / LD extended release (e.g., Rytary), CD / LD / entacapone (e.g., Stalevo), etc. "OFF" and "ON" states (diurnal variation in motor symptoms) must be recognizable / identifiable, as established by investigator observation and confirmed by a PD diary recorded during a concordance test performed during the screening period. b 8. In the opinion of the investigator, the patient must be not adequately controlled on current treatment and must have experienced a minimum of 2.5 hours of "off" time per day as assessed by PD diary prior to Day 1 (V3). Subjects receiving DBS therapy are eligible for the study if they are deemed stable, levodopa responsive, and meet all other eligibility criteria.

[0414] Foscarbidopa / Foslevodopa Subcutaneous Infusion and Test Device The study drug consists of foscarbidopa / foslevodopa subcutaneous infusion (infusion solution) and a test device, such as an infusion pump with an infusion set, for example, Crono PAR Series 3.

[0415] [Table 42]

[0416] Clinical study personnel will receive a system user manual and a system programming guide. Subjects will receive a foscarbidopa / foslevodopa subcutaneous infusion system user manual and a placemat guide for daily use.

[0417] Subject medications will be recorded in the subject's medication diary for 2 consecutive days prior to any study visit, as specified in the Study Activity Schedule. Subjects will be instructed on how to return all medication containers (even if empty), devices, and accessories. The clinical trial team will document compliance.

[0418] Treatment given Subjects received an oral loading dose of CD / LD on day 1 (V3), followed by 24-h daily CSCI with subcutaneous infusions of foscarbidopa / foslevodopa.

[0419] The oral loading dose will be determined by the investigator for each treatment regimen prior to infusion. The infusion rate of the foscarbidopa / foslevodopa subcutaneous infusion (and therefore the total amount of foscarbidopa / foslevodopa subcutaneous infusion administered) will be calculated based on the subject's Levodopa Equivalent Dose (LED) and the foscarbidopa / foslevodopa subcutaneous infusion conversion algorithm. The initial amount and corresponding flow rate of the foscarbidopa / foslevodopa subcutaneous infusion may be adjusted during the optimization period to arrive at the individualized therapeutic dose that best controls the subject's motor symptoms as assessed by the investigator through subject interview and / or other evaluation of symptom severity. The basal infusion rate of the foscarbidopa / foslevodopa subcutaneous infusion may also be adjusted throughout the study at the investigator's discretion. The investigator can preprogram three flow rates into the pump, the first corresponding to the main prescribed daily flow rate (F1, which can range between 0.17 and 1.04 mL / hr), and the second are supplementary flow rates (F2 and F3) that are programmable within ±20% from the prescribed main flow rate and are always within the acceptable range (0.17 to 1.04 mL / hr); F2 should be the alternative higher continuous dose and F3 should be the alternative lower continuous dose. If the alternative flow rates (F2 and F3) are not required, the investigator or his designee must program them to "off". Thus, the subject can freely choose among the preprogrammed flow rates or self-administer an additional dose of foscarbidopa / foslevodopa subcutaneous infusion during the day at the investigator's discretion. The pump is programmed per site by the instructions in the System Programming Guide.

[0420] During the treatment period, the foscarbidopa / foslevodopa subcutaneous infusion is self-administered by the subject using the study device (i.e., infusion set connected to an infusion pump) designated for subcutaneous delivery. The drug delivery system requires loading of the investigational drug at the same time each day for subjects requiring one vial per day (every 24 hours) or at the same time each day (every 12 hours) for subjects requiring two vials per day. To prepare the drug delivery system, see the instructions in the system user manual: Load the foscarbidopa / foslevodopa subcutaneous infusion into a syringe and then place it in the pump. Prepare the infusion site. Attach the infusion set to the syringe, prime, and then attach to the subject. The daily dose is initiated by starting the pre-programmed pump. When performing a vial exchange, depending on how much use the infusion set has already had, the subject will need to either: a) obtain all new components, or b) obtain all new components except for a new infusion set. In the latter case, they can be temporarily removed from the subject, the other end transferred from the old syringe to a newly primed syringe, primed, and then reattached to the subject.

[0421] The infusion set and infusion site (area of ​​skin where subcutaneous cannula is inserted) may remain unchanged for up to 3 days if the drug is to be infused continuously. This includes maintaining the same infusion set when changing an empty syringe or using a new vial (for individuals requiring 2 vials per day). However, a new vial adapter and a new syringe are required whenever a new vial is used. Infusion sets should be changed and infusion sites rotated every 3 days unless a more frequent rotation schedule is medically indicated. Whenever drug delivery is withheld for 1 hour or more, subjects should resume foscarbidopa / foslevodopa subcutaneous infusion administration after using a new vial, new syringe, new vial adapter, and a new complete infusion set. If the infusion pump is disconnected and foscarbidopa / foslevodopa subcutaneous infusion is not administered for less than 1 hour (e.g., when changing an empty syringe), nothing needs to be done. The investigator will select the length of the infusion set cannula from those provided. If the infusion pump is disconnected and the foscarbidopa / foslevodopa subcutaneous infusion is not administered for 1 hour or longer, the subject should be instructed to do the following before resuming administration of the foscarbidopa / foslevodopa subcutaneous infusion:

[0422] [Table 43]

[0423] Injections should be placed at least 5 centimeters (or 2 inches) away from the application site of the ECG electrodes and at least 5 centimeters (or 2 inches) away from the umbilicus. Injections should not be placed in areas of scarred or hardened tissue or stretch marks, in skin folds or creases where the body naturally bends significantly, or in areas where clothing may irritate (e.g., near the waistline).

[0424] In the event of an infusion pump failure or other event that temporarily prevents delivery of the foscarbidopa / foslevodopa subcutaneous infusion, the period during which the foscarbidopa / foslevodopa subcutaneous infusion was not delivered will be recorded by the site in the electronic data collection system. The subject should contact the clinical trial team so that an attempt can be made to restart the foscarbidopa / foslevodopa subcutaneous infusion. The time the infusion stopped and / or failed will be recorded chronologically if known (if not, record an estimated time). If the infusion is restarted, the time of restart will be recorded chronologically. If the foscarbidopa / foslevodopa subcutaneous infusion cannot be restarted or if the investigator is concerned that the subject may not be able to successfully complete the required amount of foscarbidopa / foslevodopa subcutaneous infusion, the subject may be discontinued from the study; discontinued subjects are not scheduled to be replaced.

[0425] Dose selection and timing for each subject CSCI subcutaneous infusion of foscarbidopa / foslevodopa is delivered via an infusion set connected to a pump over 24 hours daily for up to 52 weeks. The primary continuous infusion rate (F1) for each subject is initially calculated based on the subject's daily LED and an algorithm developed after analysis of pharmacokinetic data from Phase 1 studies. Dose should be adjusted based on the clinical response for each individual subject, which means maximizing functional "on" time during the day by minimizing the number and duration of "off" episodes (bradykinesia) and minimizing "on" time with disabling dyskinesias.

[0426] Accountability for Foscarbidopa / Foslevodopa Subcutaneous Infusion Subjects will be instructed to return used drug vials with the vial adapter still attached in the original vial carton; subjects will be instructed to return unused vials in the original vial carton as well. Used syringes, infusion sets (autoinsertion device and infusion set tubing) will be collected in a waste container. Unused syringes, infusion sets (autoinsertion device and infusion set tubing) and vial adapters will be returned by subjects to the site at the end of the study.

[0427] The Investigator or his / her representative will verify that the foscarbidopa / foslevodopa subcutaneous infusion supplies are received intact and in the correct quantities. This will be documented by signing and dating a receipt or similar document. A current (working) and accurate inventory of foscarbidopa / foslevodopa subcutaneous infusion will be maintained in the IRT system. For subjects who may benefit from having the foscarbidopa / foslevodopa subcutaneous infusion and foscarbidopa / foslevodopa subcutaneous infusion delivery system and its accessories shipped directly to the patient, a third party vendor contracted by the Sponsor may be responsible for these steps above.

[0428] Site personnel will review returned foscarbidopa / foslevodopa SC infusion kits and empty foscarbidopa / foslevodopa SC infusion packages to verify compliance. Each site is responsible for maintaining drug accountability records for all non-investigational medications dispensed by the site (e.g., CD / LD IR rescue therapy), including product description, manufacturer, and lot number.

[0429] 5.9 Protocol Deviations The Investigator is responsible for complying with all protocol requirements, written instructions, and applicable laws and regulations regarding protocol deviations. Protocol deviations are prohibited unless necessary to avoid immediate danger to the study subjects.

[0430] 6.0 Efficacy: At week 52, the observed mean (SD) reduction from baseline in normalized "off" time per PD diary was 3.39 (3.08) hours, and the increase in "on" time without interfering dyskinesias was 3.58 (3.03) hours. "On" time without interfering dyskinesias is the sum of "on" time without dyskinesias and "on" time with non-interfering dyskinesias. These results are shown in Figure 21.

[0431] Example 9: Correlation of sleep and efficacy endpoints after 6 months of subcutaneous foscarbidopa / foslevodopa infusion in Parkinson's disease A post-hoc analysis of 6-month interim results from the Phase 3 study described in Clinical Trial B in Example 8 assessed correlations between sleep, motor complications, motor experience of daily living, and quality of life (QoL).

[0432] Spearman rank correlation coefficients were used to assess sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]), motor complications, motor experiences of daily living (MDS-UPDRS part II), and QoL (PDQ-39).

[0433] Results: Patients improved in outcomes assessed at 6 months (Table 39). Baseline PDSS-2 scores did not correlate with baseline "off" time, were weakly positively correlated with baseline MDS-UPDRS part II scores (P<.001), and were moderately positively correlated with baseline PDQ-39 scores (P<.001). Improvement in PDSS-2 scores from baseline correlated weakly positively with "off" time from baseline (P<.001), MDS-UPDRS part II scores (P<.05), PDQ-39 scores (P<.001), and changes in awake motor status in patients who woke up with dyskinesia-free "on" time at baseline, and weakly negatively correlated with "on" time without interfering with activities of daily living (Table 39). Foscarbidopa / foslevodopa subcutaneous infusions were well tolerated.

[0434] Conclusions: The beneficial effects of subcutaneous foscarbidopa / foslevodopa infusion on sleep in patients with PD correlate with improvements in "off" time, "on" time, motor experience of daily living and QoL.

[0435] [Table 44]

[0436] [Table 45]

[0437] Example 10: Pharmacokinetics of 24-hour continuous subcutaneous infusion of levodopa and carbidopa prodrugs for Parkinson's disease in healthy human volunteers This study was designed to characterize the pharmacokinetics of an aqueous pharmaceutical composition containing a combination of levodopa 4'-monophosphate and carbidopa 4'-monophosphate following continuous subcutaneous infusion into the abdomen.

[0438] method The pharmaceutical composition prodrug was administered subcutaneously for 24 hours to eight healthy volunteers (ages 45-75) in an open-label study. Dosing consisted of a 100 mg loading dose of levodopa, followed by a continuous constant infusion of 850 mg of levodopa over 24 hours. All pharmaceutical composition injections were administered into the subcutaneous space in the abdomen. During and after the pharmaceutical composition injection, serial plasma samples were taken to assay for levodopa and carbidopa. Pharmacokinetic data between the pharmaceutical composition and Duopa were compared using levodopa and carbidopa pharmacokinetic data obtained from a previous Duopa Phase 1 study (Nyholm, D. et al., AAPS Journal 2013;15-2:316-329). Safety and tolerability, including local adverse events (AEs) related to the subcutaneous injection site, were evaluated throughout this study. Following administration of the pharmaceutical composition, the mean pharmacokinetic profile of levodopa over the first 16 hours is similar to that of a previous Phase 1 study of duodopa in Parkinson's disease patients (Nyholm, D. et al., AAPS Journal 2013;15-2:316-329) (Figures 15 and 16).

[0439] result After review, these results were analyzed. Five subjects reported at least one adverse event. Mild injection site reactions and injection site irritation were observed in several subjects. All adverse events were transient, did not lead to discontinuation of the study, and no nodules formed at the injection site.

[0440] The pharmaceutical composition was capable of providing stable levodopa and carbidopa exposure over 24 hours via the subcutaneous route of delivery with very little fluctuation in levodopa concentration levels. The pharmaceutical composition had a good safety profile.

[0441] Example 11: Subcutaneous foscarbidopa / foslevodopa infusion in Parkinson's disease: Subgroup analysis from the 6-month Phase 3 interim data set Introduction: Foslevodopa / foscarbidopa is a soluble combination of levodopa and carbidopa prodrugs delivered by continuous subcutaneous infusion. Six-month interim results of a Phase 3 study (Example 8, Clinical Trial) of foscarbidopa / foslevodopa subcutaneous infusion in Parkinson's Disease (PD) demonstrated significant improvements in "off" time, "on" time, motor experience of daily living, and quality of life (QoL). An analysis of these interim data by age, PD duration, and "off" time at baseline is reported.

[0442] Methods: This is an ongoing, open-label, single-arm study evaluating the safety and tolerability of long-term foslevodopa / foscarbidopa exposure (NCT03781167). Patients with PD whose motor symptoms were not adequately controlled by current treatment are receiving 24-hour / day subcutaneous infusions of optimized doses of foscarbidopa / foslevodopa for 52 weeks.

[0443] Results: Table 40 reports baseline demographics and characteristics of the 223 patients. Patient age and disease duration did not significantly affect the change from baseline to 6 months in "off" time, "on" time, motor experience of daily living (MDS-UPDRS part II), and QoL (PDQ-39 summary index total score) (Figure 24). In contrast, longer "off" time at baseline was associated with significantly greater improvements in absolute reduction of "off" time (P<.01) and greater improvements in PDQ-39 summary index score (P<.05) at 6 months (Figure 24). Safety was generally consistent between groups. Age had the greatest effect on event frequency (Table 41).

[0444] Conclusions: This 6-month interim analysis demonstrated that the beneficial effect of foslevodopa / foscarbidopa in PD was independent of age or disease duration. Patients with more severe diurnal motor fluctuations at baseline showed the greatest absolute improvements in "off" time and QoL.

[0445] [Table 46]

[0446] [Table 47]

[0447] Example 12: Impact of foslevodopa / foscarbidopa treatment on key clinical and humanistic outcomes in patients with advanced Parkinson's disease: Post-hoc responder analysis of two Phase 3 clinical trials Objective: To evaluate the impact of foslevodopa and foscarbidopa on clinical and humane outcomes among patients with advanced Parkinson's disease (aPD), using the minimal clinically important difference (MCID) for levodopa and carbidopa immediate-release oral tablets (LCIR) in RCTs and within-patient change relative to baseline in single-arm studies.

[0448] Context: Results from phase 3 clinical trials establish the greater efficacy of foslevodopa and foscarbidopa and sustained improvements in patient outcomes. Responder analysis may facilitate the interpretation of clinically meaningful treatment effects.

[0449] Methods: Post-hoc analysis of data from a 12-week (wk) randomized controlled trial of foslevodopa and foscarbidopa versus LCIR and a 52wk single-arm trial of foslevodopa and foscarbidopa. Responders were identified relative to baseline for on-time (ONwoTD) and off-time without disabling dyskinesias using thresholds of ≥1 h (≥3 h for robust responders), respectively. Responders were assessed for MDS-UPDRS parts I-IV, quality of life (QoL; PDQ-39 and EQ-5D-5L), and sleep disturbance (PDSS-2) using established MCIDs. Adjusted general linear models compared responder rates between foslevodopa and foscarbidopa (n=46) vs. LCIR (n=60) at wk12 and compared responder rates for foslevodopa and foscarbidopa to baseline at wk13 (n=148) and 52 (n=75).

[0450] Results: After 12 wk of treatment, a significantly higher proportion of foslevodopa and foscarbidopa vs. LCIR patients experienced a decrease in OFF > 1 hr (82.6% vs. 50.0%) and > 3 hr (62.1% vs. 25.7%) and an increase in ONwoTD > 1 hr (82.9% vs. 48.1%) and > 3 hr (63.6% vs. 24.5%), all p<0.001 (Figure 25). For within-patient changes vs. baseline in OFF and ONwoTD, foslevodopa and foscarbidopa demonstrated a significant immediate response at wk13 that was maintained through wk52 (Figure 26). Response rates were significantly higher at wk12 for foslevodopa and foscarbidopa vs LCIR for MDS-UPDRS parts II (47.0% vs 21.4%) and IV (60.7% vs 39.5%), and PDSS-2 (71.5% vs 42.6%) (all p<0.05). Similar findings were observed for foslevodopa and foscarbidopa in documenting immediate and sustained responses (up to week 52) for activities of daily living (ADL), motor complications, QoL, and sleep disorders. (Table 42).

[0451] Conclusions: Greater clinically meaningful improvements in OFF, ONwoTD, ADL, and sleep disturbance were observed with foslevodopa and foscarbidopa versus LCIR. These clinically meaningful improvements were rapid and consistently sustained through week 52.

[0452] [Table 48]

[0453] Example 13: Improved stability of motor states throughout the day and faster onset of good on-time in patients with aPD treated with foslevodopa and foscarbidopa versus LCIR Title: Improved stability of motor states throughout the day and faster onset of good on-time in patients with aPD treated with E-foslevodopa and foscarbidopa versus LCIR Objective: To evaluate the time to ON without disabling dyskinesias ('good ON') and patterns of motor state stability across wakefulness in patients with advanced Parkinson's disease (aPD) treated with foslevodopa and foscarbidopa and in patients with advanced Parkinson's disease (aPD) treated with levodopa and carbidopa immediate-release oral tablets (LCIR).

[0454] Background: 24-hour subcutaneous infusion of foslevodopa and foscarbidopa allows for continuous dopaminergic stimulation and more stable levodopa plasma levels. The temporal pattern of improvement in motor symptoms throughout the day has not been established for foslevodopa and foscarbidopa.

[0455] Methods: Post-hoc analysis of patient PD diary data from a Phase 3 study of foslevodopa and foscarbidopa versus LCIR. Diary data recorded motor states (OFF, good ON, ON with interfering dyskinesias, and deep sleep) at 30-minute (min) intervals over 3 days (normalized to days awake for 16 hours) at baseline and week 12. Adjusted homogeneity of variance-robust linear regression models assessed change from baseline to week 12 and between treatment groups for time to good ON after waking, motor states throughout the day at 30-minute and 4-hour intervals, and mean number of motor state transitions throughout the day.

[0456] Results: Complete diary data were available for 46 foslevodopa and foscarbidopa patients and 60 LCIR patients. After 12 weeks of treatment, foslevodopa and foscarbidopa patients reached good ON faster than LCIR (mean: 28.9 min vs. 82.9 min; p=0.004) and nearly twice as often reached good ON within 30 min of waking (84.7% vs. 47.6%; p<0.001). Nearly four times less foslevodopa and foscarbidopa patients reported OFF within 30 min of waking than LCIR (13.8% vs. 57.8%; p<0.001), a trend that persisted throughout the day. Analysis of 4-hour intervals showed that at week 12, foslevodopa and foscarbidopa patients had significantly more good ON and less OFF compared to baseline, which persisted throughout the day (Figures 27 and 28). Foslevodopa and foscarbidopa patients had fewer daily motor state transitions (mean: 4.7 vs. 7.2, p<0.001), and nearly twice as many foslevodopa and foscarbidopa patients had ≦6 transitions in mean vs. LCIR (64.5% vs. 38.6%, p=0.007) ( FIG. 29 ).

[0457] Conclusion: Foslevodopa and foscarbidopa patients who achieved good ON more quickly after waking had greater stability of OFF and good ON states and less fluctuation in motor states while awake during the day compared to LCIR patients. Consistent control of motor symptoms may improve patients' ability to perform daily activities and their quality of life.

[0458] Example 14: Improved stability of motor states throughout the day and faster onset of good on-time in patients with aPD treated with foslevodopa and foscarbidopa versus LCIR Title: Use of concomitant medications after initiation of foslevodopa / foscarbidopa treatment and required daily levodopa equivalent dose Context: Foscarbidopa / foslevodopa subcutaneous infusion is a soluble formulation of levodopa / carbidopa prodrugs delivered as a 24-hour-per-day continuous subcutaneous infusion (CSCI). Foscarbidopa / foslevodopa subcutaneous infusion provides an individually adjustable dose to control motor complications in patients with advanced PD (aPD).

[0459] Methods: Clinical trial B (Example 8) was a global (USA, Europe, Australia, Japan) 52-week phase 3 open-label, single-arm, multicenter study evaluating the local and systemic safety, tolerability, and efficacy of 24-hour daily subcutaneous infusion of foscarbidopa / foslevodopa for CSCI. The subcutaneous infusion dose of foscarbidopa / foslevodopa was individualized for each patient to achieve optimal clinical response. Intake of prior and tolerated concomitant medication classes (adamantane derivatives, tropine derivatives, catechol-O-methyltransferase [COMT] inhibitors, monoamine oxidase-B [MAO-B] inhibitors, tertiary amines, other antiparkinsonian medications, and non-ergolinic dopamine agonists) was summarized at each study visit. LEDD of LDP / CDP was assessed at each study visit.

[0460] Results: The analysis included 244 patients with aPD. At baseline (BL), the proportions of patients taking 0, 1, 2 and ≥3 classes of PD medications were 0%, 13.5%, 28.3% and 58.2%, respectively. At week 52, the number of patients taking ≥3 PD medications (10.3%) decreased, which was associated with a shift in the number of patients taking 0 (LDP / CDP monotherapy: 23.0%), 1 (43.7%) and 2 (23.0%) classes of PD medications (Figure 30). The LEDD of foscarbidopa / foslevodopa subcutaneous infusions (CSCI and top-up) remained fairly stable over time (range, 1621.9–1847.0 mg / day).

[0461] Conclusions: There was flexibility in the dose of foscarbidopa / foslevodopa subcutaneous infusions and the use of concomitant medications, as demonstrated by the treatment patterns observed. For patients with aPD who initiated foscarbidopa / foslevodopa subcutaneous infusion treatment, 23% achieved LDP / CDP monotherapy by week 52. The daily dose of foscarbidopa / foslevodopa subcutaneous infusions remained stable over time, and the use of concomitant medications decreased, indicating a decreased need for concomitant medications to adequately control the diurnal variation of motor symptoms in patients with aPD.

[0462] (References)

[0463] [Table 49] TIFF2024541978000054.tif79165

[0464] Incorporation by Reference All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0465] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the scope of the following claims.

Claims

1. A composition comprising an effective amount of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, achieves an increase in "on" time without dyskinesias that interfere with daily life.

2. A composition comprising an effective amount of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, said effective amount being an amount that, when administered continuously subcutaneously to a subject, achieves a reduction in "off" time without dyskinesias that interfere with daily life.

3. A composition comprising effective amounts of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, wherein the effective amounts are amounts that, when administered continuously subcutaneously to a subject, achieve a reduction in sleep symptoms as assessed by the Parkinson's Disease Sleepiness Scale-2 (PDSS-2) total score.

4. A composition comprising an effective amount of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, achieves an increase in PD-related quality of life as assessed by the Parkinson's Disease Questionnaire-39 item (PDQ-39) summary index.

5. A composition comprising effective amounts of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, the effective amounts being amounts that, when administered continuously subcutaneously to the subject, achieve an increase in health-related quality of life from baseline to final visit as assessed by the EQ-5D-5L summary index.

6. A composition comprising effective amounts of foslevodopa and foscarbidopa for use in treating advanced Parkinson's disease in a subject, wherein the effective amounts are amounts that, when administered continuously subcutaneously to a subject, achieve a reduction in PD symptoms from baseline to final visit as assessed by a wearable motion sensor device.

7. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, reduces Parkinson's-like symptoms by at least 46% from baseline.

8. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that reduces the baseline MDS-UPDRS total score by at least 9 units when administered continuously subcutaneously to a subject.

9. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, reduces the baseline PDQ-39 score by at least 6.9 units.

10. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that reduces the baseline PDSS-2 total score by at least 2 units when administered continuously subcutaneously to a subject.

11. A composition described in any one of claims 1 to 6, wherein said use does not result in the development of skin nodules after 10 days of said use.

12. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, reduces the incidence of "off" times of Parkinson's-like symptoms in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

13. The composition described in claim 12, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, reduces the incidence of parkinsonian "off" time and increases "on" time without dyskinesias that interfere with daily life.

14. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, improves the average daily normalized "off" time in a subject as assessed by a PD diary compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

15. The composition of claim 1, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves motor symptoms experienced in daily life as assessed by the MDS-UPDRS Part II score in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

16. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, reduces morning immobility in the subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

17. The composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, improves health-related quality of life as assessed by the EQ-5D-5L summary index in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

18. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves the median bradykinesia score (BK50) assessed by a wearable motion sensor device in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

19. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves the interquartile range (BK75 to BK25) of bradykinesia scores in a subject as assessed by a wearable motion sensor device compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

20. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves the median dyskinesia score (DK50) as assessed by a PKG wearable device in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

21. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, improves tremor and daytime somnolence as assessed by a PKG wearable device in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

22. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves MDS-UPDRS Part I score, Part III score, Part IV score, and Part I-III total score in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

23. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves "on" time with non-interfering dyskinesias and "on" time with interfering dyskinesias in a subject as assessed by a PD diary, compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

24. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves the average daily normalized "off" time, "on" time without interfering dyskinesias, "on" time without dyskinesias, "on" time with non-interfering dyskinesias, and "on" time with interfering dyskinesias in a subject as assessed by a PD diary, compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

25. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when continuously administered subcutaneously to a subject, improves the mean daily absolute "off" time, "on" time without interfering dyskinesias, "on" time without dyskinesias, "on" time with non-interfering dyskinesias, "on" time with interfering dyskinesias, and "deep sleep" time in a subject as assessed by a PD diary without normalization, compared to a subject receiving oral tablets containing levodopa and carbidopa.

26. A composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered continuously subcutaneously to a subject, improves the PDSS-2 domain score in a subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa.

27. The composition of any one of claims 1 to 6, wherein the effective amount is an amount that, when administered subcutaneously continuously to a subject, improves the PDQ-39 domain score in the subject compared to a subject receiving oral administration of a tablet containing levodopa and carbidopa.

28. The composition described in any one of claims 1 to 6, wherein the effective amount is an amount that, when administered subcutaneously continuously to a subject, improves the EQ-5D-5L visual analog scale (VAS) score in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

29. The composition of claim 1, wherein the weight ratio of foslevodopa to foscarbidopa in the composition is about 20:

1.

30. 30. The composition of any one of claims 1 to 29, wherein the composition comprises about 240 mg / mL of foslevodopa and about 12 mg / mL of foscarbidopa.

31. The composition of any one of claims 1 to 30, wherein the composition has a pH between about 6.6 and about 8.

1.

32. The composition of any one of claims 1 to 6, wherein the effective amount, when continuously administered subcutaneously to a subject, improves "on" time with non-interfering dyskinesias and "off" time with non-interfering dyskinesias as assessed by a PD diary in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa, wherein the mean "on" time is between 2.5 and 4.5 hours and the mean "off" time is between 2.5 and 4.5 hours.

33. 33. The composition of claim 32, wherein the average "on" time is about 3.6 hours.

34. 33. The composition of claim 32, wherein the average "off" time is about 3.4 hours.

35. The composition of any one of claims 1 to 6, wherein the composition has an osmolality of up to about 2700 mOsmol / kg.

36. 7. The composition of any one of claims 1 to 6, wherein the composition has an osmolality of between about 2200 and about 2500 mOsmol / kg.

37. The composition of any one of claims 1 to 6, wherein the effective amount, when continuously administered subcutaneously to a subject, improves "on" time with dyskinesias that do not interfere with activities of daily living as assessed by a PD diary in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa, and wherein the mean time to reach "on" time is between 10 and 60 minutes for subjects receiving oral administration of tablets containing levodopa and carbidopa.

38. 38. The composition of claim 37, wherein the average time to reach "on" time is from about 15 minutes to about 50 minutes.

39. 38. The composition of claim 37, wherein the time to reach "on" time is about 28.9 minutes.

40. The composition of any one of claims 1 to 6, wherein the effective amount, when continuously administered subcutaneously to a subject, improves "on" times accompanied by dyskinesias that do not interfere with daily living as assessed by a PD diary in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa, and the frequency of "on" times is approximately twice as frequent in a subject receiving oral administration of tablets containing levodopa and carbidopa.

41. The composition of any one of claims 1 to 6, wherein the effective amount, when continuously administered subcutaneously to a subject, improves "off" times accompanied by dyskinesias that do not interfere with activities of daily living as assessed by a PD diary in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa, and the frequency of "off" times within 30 minutes after waking up is about one-quarter less frequent in a subject compared to a subject receiving oral administration of tablets containing levodopa and carbidopa.

42. The composition of any one of claims 1 to 6, wherein the frequency of "off" periods is sustained for at least 24 hours.

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