METHODS OF TREATING AGITATION ASSOCIATED WITH ALZHEIMER'S DISEASE

The present disclosure relates to the treatment of agitation associated with Alzheimer's disease. In some embodiments the present disclosure provides methods of treating agitation associated with Alzheimer's disease using deuterated [d6]-dextromethorphan or a salt thereof and quinidine or a salt thereof. In some embodiments the present disclosure provides methods of treating agitation associated with Alzheimer's disease using deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

BACKGROUND

Alzheimer's disease, the most common form of dementia, is a progressive neurodegenerative disease that eventually leads to death. There are an estimated 5.8 million people in the United States (US) with Alzheimer's dementia and this number is expected to reach 14 million by the year 2050. National estimates of the prevalence of all dementias from population-based studies including the Aging, Demographics, and Memory Study (ADAMS), a nationally representative sample of older adults, show that 14 percent of people age 71 and older in the US have dementia.

Agitation is widely recognized by clinicians as a common and important clinical feature of Alzheimer's disease and other forms of dementia. Agitation, aggression, depression, hallucinations, and delusions are estimated to affect up to approximately 90% of patients with Alzheimer's disease with an increase in prevalence as the disease progresses. In a meta analyses of data from 55 studies, overall prevalence of agitation ranged from 5% to 88% across all studies, with 23 studies reporting the prevalence of at least one neuropsychiatric syndrome with a range of 40% to 100%. Agitation in patients with dementia is associated with increased functional disability, worse quality of life, earlier institutionalization, increased caregiver burden, increased healthcare costs, shorter time to severe dementia, and accelerated mortality. Currently, there is no approved treatment in the US to manage agitation in patients with Alzheimer's disease. Pharmacologic treatments for patients with agitation in Alzheimer's disease include off-label use of atypical antipsychotics, selective serotonin reuptake inhibitors, benzodiazepines, and anticonvulsants. It is widely recognized that a safe and effective treatment for patients with agitation in Alzheimer's disease represents a significant unmet need. Such a treatment could profoundly impact patient care, potentially reduce caregiver burden, and improve overall disease prognosis.

SUMMARY

This disclosure provides, in some embodiments, methods of treating agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

In some embodiments, provided herein is a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, for use in the treatment of agitation associated with Alzheimer's disease in a subject, in administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration.

In some embodiments, provided herein is a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, for use in the treatment of agitation associated with Alzheimer's disease in a subject, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration. Additionally, the present disclosure also provides use of the composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, in the manufacture of a medicament, wherein the composition is to be administered in the treatment of agitation associated with Alzheimer's disease in a subject, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 15, such as 15 to 84, such as 15 to 70, such as 15 to 55, such as 15 to 40, such as 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 10, such as 10 to 42, such as 10 to 35, such as 10 to 30, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 1920, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration.

In some embodiments, provided herein is a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, for use in the treatment of agitation associated with Alzheimer's disease in a subject, in administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration.

In some embodiments, provided herein is a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, for use in the treatment of agitation associated with Alzheimer's disease in a subject, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration. Additionally, the present disclosure also provides use of the composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate, in the manufacture of a medicament, wherein the composition is to be administered in the treatment of agitation associated with Alzheimer's disease in a subject, wherein the subject is a patient that has been diagnosed as having Alzheimer's disease, wherein the method comprises determining the Cohen-Mansfield agitation inventory (CMAI) total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a Cohen-Mansfield agitation inventory (CMAI) total score of greater than or equal to 32, such as 33 to 150, such as 45 to 120, such as 55 to 90.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 15, such as 15 to 84, such as 15 to 70, such as 15 to 55, such as 15 to 40, such as 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 10, such as 10 to 42, such as 10 to 35, such as 10 to 30, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 8, such as 8 to 28, such as 12 to 25, such as 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, or 25.

This disclosure provides, in some embodiments, methods of treating aggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating aggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating aggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating aggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating physically nonaggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating physically nonaggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating physically nonaggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating physically nonaggressive agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating verbal agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating verbal agitation associated with Alzheimer's disease in a subject, comprising administering to the subject therapeutically effective amounts of deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

This disclosure provides, in some embodiments, methods of treating verbal agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan, or a salt thereof, and quinidine, or a salt thereof. In some embodiments, provided herein are methods of treating verbal agitation associated with Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising deuterated [d6]-dextromethorphan hydrobromide (d6-DM) and quinidine sulfate.

In some embodiments, the present disclosure provides a method of treating aggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI aggressive behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating aggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating aggressive agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 15, such as 15 to 84, such as 15 to 70, such as 15 to 55, such as 15 to 40, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 15.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 16.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 17.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 18.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 19.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 20.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 21.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 22.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 23.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 24.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 25.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 26.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 27.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 28.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 29.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 30.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 31.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 32.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 33.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 34.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 35.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 36.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 37.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 38.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 39.

In some more particular embodiments, the patient has been assessed as having a CMAI aggressive behavior score of greater than or equal to 40.

In some embodiments of a method disclosed herein, the method comprises determining the CMAI total score in the patient following the administering step.

In some embodiments of a method disclosed herein, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has
  - a. at least one aggressive behavior occurring at least three times per week;
  - b. at least two aggressive behaviors occurring at least one time per week;
  - c. at least three aggressive behaviors occurring, at a rate of less than once per week; and/or
  - d. at least two aggressive behaviors occurring, less than once per week, and at least one aggressive behavior occurring at least once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least one aggressive behavior occurring at least three times per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least two aggressive behaviors occurring at least one time per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least three aggressive behaviors occurring, at a rate of less than once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate;
  - and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least two aggressive behaviors occurring, less than once per week, and at least one aggressive behavior occurring at least once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate;
- and
- 4) determining the CMAI total score in the patient following the administering step.

In some embodiments, the difference between the CMAI total score in the patient prior to the administering step and the CMAI total score in the patient following the administering step is from 1 to 150, such as from 2 to 130, such as from 3 to 110, such as from 4 to 100, such as from 5 to 90, such as from 6 to 80, such as from 7 to 70, such as from 8 to 60, such as from 9 to 50, such as from 10 to 40.

In some embodiments, the CMAI total score in the patient following the administering step is at least 1% lower, such as 1% to 70% lower, such as 2% to 65% lower, such as 3% to 60% lower, such as 4% to 55% lower, such as 5% to 50% lower, such as 6% to 45% lower, such as 7% to 40% lower, such as 8% to 35% lower, such as 9% to 30% lower, such as 10% to 25% lower, such as 10% to 20% lower, such as 15% lower, than the CMAI total score in the patient prior to the administering step.

In some embodiments of a method disclosed herein, the method comprises determining the CMAI aggressive behavior score in the patient following the administering step.

In some embodiments, the difference between the CMAI aggressive behavior score in the patient prior to the administering step and the CMAI aggressive behavior score in the patient following the administering step is at least 1, such as 1 to 20, such as 2 to 20, such as 3 to 15, such as 4 to 15, such as 5 to 15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

In some embodiments, the CMAI aggressive behavior score in the patient following the administering step is at least 1% lower, such as 1% to 70% lower, such as 2% to 65% lower, such as 3% to 60% lower, such as 4% to 55% lower, such as 5% to 50% lower, such as 6% to 45% lower, such as 7% to 40% lower, such as 8% to 35% lower, such as 9% to 30% lower, such as 10% to 25% lower, such as 10% to 20% lower, such as 15% lower, than the CMAI aggressive behavior score in the patient prior to the administering step.

In some embodiments, the present disclosure provides a method of treating physically nonaggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI physically nonaggressive behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating physically nonaggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating physically nonaggressive agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI physically nonaggressive behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 10, such as 10 to 42, such as 10 to 35, such as 10 to 30, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 10, such as 10 to 42, such as 10 to 35, such as 10 to 30, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 10.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 11.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 12.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 13.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 14.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 15.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 16.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 17.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 18.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 19.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 20.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 21.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 22.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 23.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 24.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 25.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 26.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 27.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 28.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 29.

In some more particular embodiments, the patient has been assessed as having a CMAI physically nonaggressive behavior score of greater than or equal to 30.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has
  - a. at least one physically nonaggressive behavior occurring once or twice a day;
  - b. at least two physically nonaggressive behaviors occurring at least three times per week;
  - c. at least three physically nonaggressive behaviors occurring, at least one time per week; and/or
  - d. at least four physically nonaggressive behaviors occurring less than once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least one physically nonaggressive behavior occurring once or twice a day;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least two physically nonaggressive behaviors occurring at least three times per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least three physically nonaggressive behaviors occurring at least one time per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least four physically nonaggressive behaviors occurring less than once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

In some embodiments of a method disclosed herein, the method comprises determining the CMAI physically nonaggressive behavior score in the patient following the administering step.

In some embodiments, the difference between the CMAI physically nonaggressive behavior score in the patient prior to the administering step and the CMAI physically nonaggressive behavior score in the patient following the administering step is at least 1, such as 1 to 20, such as 2 to 20, such as 3 to 15, such as 4 to 15, such as 5 to 15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

In some embodiments, the CMAI physically nonaggressive behavior score in the patient following the administering step is at least 1% lower, such as 1% to 70% lower, such as 2% to 65% lower, such as 3% to 60% lower, such as 4% to 55% lower, such as 5% to 50% lower, such as 6% to 45% lower, such as 7% to 40% lower, such as 8% to 35% lower, such as 9% to 30% lower, such as 10% to 25% lower, such as 10% to 20% lower, such as 15% lower, than the CMAI physically nonaggressive behavior score in the patient prior to the administering step.

In some embodiments, the present disclosure provides a method of treating verbal agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI verbally agitated behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating verbal agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating verbal agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI total score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the CMAI verbally agitated behavior score in the patient prior to said administration.

some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 8, such as 8 to 28, such as 12 to 25, such as 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, or 25.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 8, such as 8 to 28, such as 12 to 25, such as 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, or 25.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 8.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 9.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 10.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 11.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 12.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 13.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 14.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 15.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 16.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 17.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 18.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 19.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 20.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 21.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 22.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 23.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 24.

In some more particular embodiments, the patient has been assessed as having a CMAI verbally agitated behavior score of greater than or equal to 25.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has
  - a. at least one verbally agitated behavior occurring once or twice a day;
  - b. at least two verbally agitated behaviors occurring at least three times per week;
  - c. at least three verbally agitated behaviors occurring, at least one time per week; and/or
  - d. at least four verbally agitated behaviors occurring less than once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate;
  - and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least one verbally agitated behavior occurring once or twice a day;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least two verbally agitated behaviors occurring at least three times per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least three verbally agitated behaviors occurring at least one time per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

- 1) determining the CMAI total score in the patient prior to the administering step;
- 2) determining that the patient prior to the administering step has at least four verbally agitated behaviors occurring less than once per week;
- 3) administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate; and
- 4) determining the CMAI total score in the patient following the administering step.

In some embodiments of a method disclosed herein, the method comprises determining the CMAI verbally agitated behavior score in the patient following the administering step.

In some embodiments, the difference between the CMAI verbally agitated behavior score in the patient prior to the administering step and the CMAI verbally agitated behavior score in the patient following the administering step is at least 1, such as 1 to 20, such as 2 to 20, such as 3 to 15, such as 4 to 15, such as 5 to 15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

In some embodiments, the CMAI verbally agitated behavior score in the patient following the administering step is at least 1% lower, such as 1% to 70% lower, such as 2% to 65% lower, such as 3% to 60% lower, such as 4% to 55% lower, such as 5% to 50% lower, such as 6% to 45% lower, such as 7% to 40% lower, such as 8% to 35% lower, such as 9% to 30% lower, such as 10% to 25% lower, such as 10% to 20% lower, such as 15% lower, than the CMAI verbally agitated behavior score in the patient prior to the administering step.

In some embodiments, the present disclosure provides a method of treating aggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the NPI-AA score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI-AA score of greater than or equal to 4.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI-AA score of greater than or equal to 3, such as 3 to 12, such as 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments of a method disclosed herein, the method comprises determining the NPI-AA score in the patient prior to the administering step.

In some embodiments the NPI-AA score prior to the administering step is equal to or greater than 4.

In some embodiments, the present disclosure provides a method of treating physically nonaggressive agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the NPI Aberrant Motor Behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the NPI Aberrant Motor Behavior score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI Aberrant Motor Behavior score of greater than or equal to 4.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI Aberrant Motor Behavior domain score greater than or equal to 2, such as 2 to 12, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments of a method disclosed herein, the method comprises determining the NPI Aberrant Motor Behavior domain score in the patient prior to the administering step.

In some embodiments the NPI Aberrant Motor Behavior domain score prior to the administering step is greater than or equal to 2, such as 2 to 12, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, the present disclosure provides a method of treating verbal agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the NPI Irritability/Lability domain score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the method comprises determining the NPI Irritability/Lability domain score in the patient prior to said administration.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI Irritability/Lability domain score of greater than or equal to 4.

In some embodiments, the present disclosure provides a method of treating agitation associated with Alzheimer's disease in a patient having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the patient has been assessed as having a NPI Irritability/Lability domain score greater than or equal to 2, such as 2 to 12, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments of a method disclosed herein, the method comprises determining the NPI Irritability/Lability domain score in the patient prior to the administering step.

In some embodiments the NPI Irritability/Lability domain score prior to the administering step is equal to or greater than 2, such as 2 to 12, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments of a method disclosed herein, the method comprises determining the NPI total score in the patient prior to the administering step.

In some embodiments the NPI total score prior to the administering step is equal to or greater than 1.

In some embodiments of a method disclosed herein, the method comprises determining the NPI-AA score in the patient following the administering step.

In some embodiments, the difference between the NPI-AA score in the patient prior to the administering step and the NPI-AA score in the patient following the administering step is at least 1, such as 1 to 9, such as 1, 2, 3, 4, 5, 6, or 7.

In some embodiments of a method disclosed herein, the method comprises determining the NPI Aberrant Motor Behavior domain score in the patient following the administering step.

In some embodiments, the difference between the NPI Aberrant Motor Behavior domain score in the patient prior to the administering step and the NPI Aberrant Motor Behavior domain score in the patient following the administering step is at least 1, such as 1 to 9, such as 1, 2, 3, 4, 5, 6, or 7.

In some embodiments of a method disclosed herein, the method comprises determining the NPI Irritability/Lability domain score in the patient following the administering step.

In some embodiments, the difference between the NPI Irritability/Lability domain score in the patient prior to the administering step and the NPI Irritability/Lability domain score in the patient following the administering step is at least 1, such as 1 to 9, such as 1, 2, 3, 4, 5, 6, or 7.

In some embodiments of a method disclosed herein, the method comprises determining the NPI total score in the patient following the administering step.

In some embodiments, the difference between the NPI total score in the patient prior to the administering step and the NPI total score in the patient following the administering step is at least 1, such as 1 to 25, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

In some embodiments of a method disclosed herein, the method comprises determining the MMSE score in the patient prior to the administering step.

In some embodiments, the MMSE score prior to the administering step is 4 to 30.

In some embodiments the MMSE score prior to the administering step is from 8 to 24.

In some embodiments the MMSE score prior to the administering step is from 6 to 26.

In some embodiments the MMSE score prior to the administering step is equal to or greater than 17.

In some embodiments of a method disclosed herein, the method comprises determining the CGIS-Agitation score in the patient prior to the administering step.

In some embodiments of a method disclosed herein, the CGIS-Agitation score in the patient prior to the administering step is greater than or equal to 2.

In some embodiments of a method disclosed herein, the CGIS-Agitation score in the patient prior to the administering step is greater than or equal to 3.

In some embodiments of a method disclosed herein, the CGIS-Agitation score in the patient prior to the administering step is greater than or equal to 4.

In some embodiments of a method disclosed herein, the method comprises determining the mADCS-CGIC-Agitation score in the patient following the administering step.

In some more particular embodiments, the mADCS-CGIC-Agitation score is ≤2 following the administering step.

In some more particular embodiments, the mADCS-CGIC-Agitation score is ≤3 following the administering step.

In some more particular embodiments, the mADCS-CGIC-Agitation score is ≤4 following the administering step.

In some embodiments of a method disclosed herein, the method comprises determining the PGIC score in the patient following the administering step.

In some more particular embodiments, the PGIC score is ≤2 following the administering step.

In some more particular embodiments, the PGIC score is ≤3 following the administering step.

In some more particular embodiments, the PGIC score is ≤4 following the administering step.

In some embodiments of a method disclosed herein, the method comprises determining the CGIS-Agitation score in the patient following the administering step.

In some embodiments, the CGIS-Agitation score in the patient following the administering step is at least 15% lower, such as at least 30% lower, than the CGIS-Agitation score in the patient prior to the administering step.

An exemplary embodiment of the present disclosure includes a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the d6-DM is administered in a dose of from 14.4 mg to 22.5 mg twice daily and the quinidine sulfate is administered in a dose of from 3.9 mg to 6.1 mg dose twice daily. An exemplary embodiment of the present disclosure includes a method of treating agitation associated with Alzheimer's disease in a patient, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the d6-DM is administered in dose of from 34.4 mg to 53.8 mg twice daily twice daily and the quinidine sulfate is administered in a from 3.9 mg to 6.1 mg dose twice daily.

An exemplary embodiment of the present disclosure includes a method of treating agitation associated with Alzheimer's disease in a patient that has been diagnosed as having Alzheimer's disease, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the d6-DM is administered in a dose of from 14.4 mg to 22.5 mg twice daily and the quinidine sulfate is administered in a 4.9 mg dose twice daily. An exemplary embodiment of the present disclosure includes a method of treating agitation associated with Alzheimer's disease in a patient, comprising administering to the patient therapeutically effective amounts of d6-DM and quinidine sulfate, wherein the d6-DM is administered in dose of from 34.4 mg to 53.8 mg twice daily twice daily and the quinidine sulfate is administered in a 4.9 mg dose twice daily.

In some embodiments, the d6-DM is administered in an 18 mg dose twice daily and the quinidine sulfate is administered in a 4.9 mg dose twice daily. In some embodiments, the d6-DM is administered in a 42.63 mg dose twice daily and the quinidine sulfate is administered in a 4.9 mg dose twice daily.

In some embodiments of a method disclosed herein, the administration of one component (e.g., d6-DM) is concomitant with the administration of the other component (e.g., quinidine sulfate).

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with memantine prior to the administering step.

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with an acetylcholinesterase inhibitor, such as donepezil, prior to the administering step.

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with an atypical antipsychotic other than clozapine prior to the administering step.

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with an antidepressant other than nefazodone, a tricyclic antidepressant, or a monoamine oxidase inhibitors (MAOI) prior to the administering step.

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with memantine, and the patient has not been treated and is not being treated with antipsychotics, prior to the administering step.

In some embodiments of a method disclosed herein, the patient has been treated or is being treated with an acetylcholinesterase inhibitor, such as donepezil, and the patient has not been treated and is not being treated with antipsychotics, prior to the administering step.

In some embodiments, the d6-DM is administered in a 14.4, mg, 18 mg, or 22.5 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 14.4 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 18 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 22.5 mg dose, e.g., once or twice daily, e.g., twice daily.

In some embodiments, the d6-DM is administered in a 34.4, mg, 42.63 mg, or 53.8 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 34.4 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 42.63 mg dose, e.g., once or twice daily, e.g., twice daily. In some embodiments, the d6-DM is administered in a 53.8 mg dose, e.g., once or twice daily, e.g., twice daily.

In some embodiments, the quinidine sulfate is administered in a 4.9 mg dose, e.g., once or twice daily, e.g., twice daily.

The chemical structure of deuterated [d6]-dextromethorphan is as follows.

embedded image

wherein:

- R¹is CD₃; and
- R²CD₃.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a Sequential Parallel Comparison Design Schematic for Example 3.

FIG. 2 shows a Study Schematic for the Study in Example 4.

DETAILED DESCRIPTION

The following detailed description and examples illustrate certain embodiments of the present disclosure. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure that are encompassed by its scope. Accordingly, the description of certain embodiments should not be deemed to limit the scope of the present disclosure.

In order that the disclosure may be more readily understood, certain terms are defined throughout the detailed description. Unless defined otherwise herein, all scientific and technical terms used in connection with the present disclosure have the same meaning as commonly understood by those of ordinary skill in the art.

All references cited herein, including, but not limited to, published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent a cited reference conflicts with the disclosure herein, the specification shall control.

As used herein, the singular forms of a word also include the plural form, unless the context clearly dictates otherwise; as examples, the terms “a,” “an,” and “the” are understood to be singular or plural. By way of example, “an element” means one or more element. The term “or” shall mean “and/or” unless the specific context indicates otherwise.

As used herein, the term “treating” means improving, ameliorating, or retarding the onset, progress, severity, or frequency of one or more behaviors associated with agitation associated with Alzheimer's disease.

The term “therapeutically effective amounts of deuterated [d6]-dextromethorphan (d6-DM) hydrobromide and quinidine sulfate” refers to the amount of d6-DM and the amount of quinidine sulfate that are sufficient to treat agitation associated with Alzheimer's disease when administered in combination. As an example, the amount of d6-DM and the amount of quinidine sulfate may be sufficient to reduce the CMAI aggressive behavior score in the patient. As an example, the amount of d6-DM and the amount of quinidine sulfate may be sufficient to reduce the CMAI physically nonaggressive behavior score in the patient. As an example, the amount of d6-DM and the amount of quinidine sulfate may be sufficient to reduce the CMAI verbally agitated behavior score in the patient. As used herein, the term “combination” applied to d6-DM and quinidine sulfate means a single pharmaceutical composition (formulation) comprising both d6-DM and quinidine sulfate or two separate pharmaceutical compositions (formulations), each comprising d6-DM or quinidine sulfate, to be administered in combination.

Administered “in combination” or “co-administration,” as used herein, refers to administration of d6-DM and quinidine sulfate concomitantly in one composition, or concomitantly in different compositions, or sequentially in either order. For sequential administration to be considered administration “in combination” or “co-administration,” the d6-DM and the quinidine sulfate are administered separated by a time interval that permits the resultant beneficial effect for treating agitation associated with Alzheimer's disease in a patient.

The term “patient” or “subject” means a human. In some embodiments, the patient is a human that has been diagnosed as having Alzheimer's disease.

Unless otherwise specified, the doses described herein refer to the hydrobromide and sulfate salt forms of deuterated [d6]-dextromethorphan and quinidine, respectively. Based on such information, those skilled in the art can calculate corresponding dosages for the free-base forms of each active ingredient. A person of skill in the art can calculate the molecular weight for the salt of deuterated [d6]-dextromethorphan and the molecular weight for free base of deuterated [d6]-dextromethorphan and use the ratio to calculate appropriate dosages for the free base as well as for a salt.