ALZ-801 for use in treating COVID-19 associated neurological symptoms

Abstract

Provided herein are methods for reducing p-tau, Abeta40, Abeta42, and / or the p-tau / Abeta42 ratio in a subject using ALZ-801. Also provided herein are methods for treating conditions associated with elevated levels of p-tau, elevated levels of Abeta40, elevated levels of Abeta42, and / or an elevated p-tau / Abeta42 ratio.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 307,585, filed February 7, 2022, U.S. Provisional Application No. 63 / 407,816, filed September 19, 2022, and U.S. Provisional Application No. 63 / 412,106, filed September 30, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Infection with the novel coronavirus SARS-CoV-2, which causes severe acute respiratory syndrome, was first identified in late 2019 and designated COVID-19. COVID-19 infection reached pandemic status by early 2020 and has since affected approximately 400 million people worldwide and led to approximately 6 million deaths. In the United States alone, symptomatic COVID-19 infection has affected an estimated 124 million people and led to approximately 7.5 million hospitalizations and 1 million deaths.

[0003] The pathogenesis of CNS dysfunction in COVID-19 is being investigated in brain tissue from autopsy material and from fluid biomarkers obtained from hospitalized COVID-19 patients. Neuropathological studies of patients who died from COVID-19 have shown evidence of focal amyloid deposition, even in young patients (see, e.g., Rhodes et al. β-Amyloid Deposits in Young COVID Patients, Preprint online at Lancet 2022), as well as inflammasome activation and hyperphosphorylated tau (see, e.g., Reiken et al. Alzheimer's Dement. 2022;1-11).

[0004] A large study in hospitalized patients in the United States showed increased plasma levels of p-tau, increased p-tau / Abeta42, increased GFAP and elevated t-tau. See, e.g., Frontera et al. Alzheimer's Dement. 2021;1-12. Similar findings of increased p-tau, p-tau / Abeta42, and t-tau were reported from Spain. See, e.g., Matias-Guiu et al. Front. Psychol. 2021;12:724022. Increased GFAP, a marker of astrocytic vesicle activation, is a stress response to increased amyloid levels, and p-tau is a marker of neuronal damage frequently seen in neurodegenerative diseases such as Alzheimer's disease. These collective data suggest that the stressors of acute systemic inflammation, activated endothelium and complement, hypoxia, and / or hypoxic-ischemic insult induce increased Abeta42 production and tau hyperphosphorylation, leading to increased Abeta42 and p-tau levels in the brain and CSF.

[0005] Therefore, therapeutic treatments that can inhibit the production of Abeta42 or inhibit the formation of toxic Abeta oligomers, reduce p-tau levels, and / or lower the p-tau / Abeta42 ratio should ameliorate neuronal damage, rescue neuronal function, and ameliorate cognitive impairment associated with COVID-19-associated neurological symptoms. Summary of the Invention

[0006] Currently, ALZ-801, a valine prodrug of tramiprosate, is being shown to reduce plasma p-tau in subjects with early Alzheimer's disease (AD) who have at least one ApoE4 allele. 181 and p-tau 181 For example, treatment with 265 mg of ALZ-801 administered twice daily has been found to be effective in reducing plasma p-tau / Abeta42 ratios. 181A 18%, 29%, and 41% reduction in plasma p-tau was observed at 13, 26, and 52 weeks, respectively, see Figure 1. A similar trend was observed for plasma p-tau 181 A 21%, 30%, and 31% reduction in Abeta40 / Abeta42 was observed at 13 weeks, 26 weeks, and 52 weeks, respectively, as shown in Figure 2. Reductions in plasma Abeta40 and Abeta42 were also observed at 52 weeks. See, e.g., Figures 3 and 4.

[0007] Thus, in one embodiment, administering a therapeutically effective amount of ALZ-801 increases the level of p-tau in a subject, in particular, increases the level of p-tau 181 , and more particularly, p-tau 181 Provided herein are methods for reducing plasma levels of.

[0008] In addition, administering a therapeutically effective amount of ALZ-801 can improve the p-tau / Abeta42 ratio in a subject, particularly the p-tau 181 / Abeta42 ratio, and more specifically, p-tau in plasma 181 Methods for reducing the ratio of / Abeta42 are also provided.

[0009] Also provided are methods for reducing Abeta40 levels, particularly plasma levels of Abeta40, in a subject by administering a therapeutically effective amount of ALZ-801.

[0010] Also provided are methods for reducing Abeta42 levels, particularly plasma levels of Abeta42, in a subject by administering a therapeutically effective amount of ALZ-801.

[0011] In addition, administration of therapeutically effective ALZ-801 can be used to treat elevated p-tau levels (e.g., elevated p-tau 181 Levels and / or elevated plasma p-tau 181levels), elevated Abeta40 (e.g., elevated plasma Abeta40 levels), elevated Abeta42 (e.g., elevated plasma Abeta42 levels), and / or p-tau / Abeta42 ratio (e.g., p-tau 181 / Abeta42 ratio and / or plasma p-tau 181 Methods for treating conditions associated with the IL-19 / Abeta42 ratio, including COVID-19 associated neurological conditions, are also provided. [Brief description of the drawings]

[0012] [Figure 1] 1 illustrates the effect of 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD on plasma p-tau181 after 52 weeks of treatment. [Diagram 2] FIG. 1 illustrates the effect of 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD on the p-tau181 / Abeta42 ratio after 52 weeks of treatment. [Diagram 3] FIG. 1 illustrates the effect of 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD on plasma Abeta42 after 52 weeks of treatment. [Figure 4] FIG. 1 illustrates the effect of 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD on plasma Abeta40 after 52 weeks of treatment. [Diagram 5] FIG. 1 illustrates the effect of 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD on memory as measured by the RAVLT after 52 weeks of treatment. [Figure 6] 3 illustrates cognitive improvement after 52 weeks of treatment with 265 mg of ALZ-801 administered orally twice daily to subjects who are APOE4+ and have early stage AD, as determined by a composite Z-score based on the 3RAVLT test and the Digit Symbol Substitution Test (DSST). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] As part of a first embodiment, a method for treating p-tau in a subject, comprising administering to the subject a therapeutically effective amount of ALZ-801, or a pharma- ceutical acceptable salt thereof. 181 Methods for reducing the levels (e.g., plasma levels) of

[0014] As part of a second embodiment, a method for treating p-tau in a subject, comprising administering to the subject a therapeutically effective amount of ALZ-801, or a pharma- ceutical acceptable salt thereof. 181 / Abeta42 ratio (e.g., plasma p-tau 181 Methods for reducing the beta42 / Abeta42 ratio are provided.

[0015] As part of a third embodiment, a method is provided for reducing the level (e.g., plasma level) of Abeta40 in a subject, comprising administering to the subject a therapeutically effective amount of ALZ-801, or a pharma- ceutically acceptable salt thereof.

[0016] As part of the fourth embodiment, a method is provided for reducing the level (e.g., plasma level) of Abeta42 in a subject, comprising administering to the subject a therapeutically effective amount of ALZ-801, or a pharma- ceutically acceptable salt thereof.

[0017] ALZ-801 refers to valyl-3-amino-1-propanesulfonic acid (also known as valyltramiprosate), which is represented by the following structure: [ka]

[0018] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0019] The term "effective amount" or "therapeutically effective amount" refers to an amount that is effective to induce a recited biological or medical response in a subject, e.g., p-tau 181 Reduction of Abeta40, Reduction of Abeta42, p-tau 181 / Abeta42 reduction or treat the recited condition.

[0020] As used herein, the terms "treat," "treating," or "treatment" mean to reverse, alleviate, inhibit, or slow the progression of the recited condition or one or more symptoms associated therewith.

[0021] As part of the fifth embodiment, provided herein is a method of treating a condition associated with elevated p-tau levels (e.g., elevated plasma p-tau levels), elevated Abeta40 levels (e.g., elevated plasma Abeta40 levels), elevated Abeta42 levels (e.g., elevated plasma Abeta42 levels), and / or elevated p-tau / Abeta42 ratio in a subject, comprising administering to the subject a therapeutically effective amount of ALZ-801, or a pharma- ceutical acceptable salt thereof. In one aspect of the fifth embodiment, the method comprises administering to the subject a therapeutically effective amount of ALZ-801, or a pharma-ceutical acceptable salt thereof, 181 In one aspect of the fifth embodiment, the method reduces the p-tau / Abeta42 ratio in plasma. 181 In another aspect of the fifth embodiment, the method comprises decreasing the p-tau / Abeta42 ratio. 181 In another aspect of the fifth embodiment, the method comprises: 181 In another aspect of the fifth embodiment, the method reduces plasma Abeta40 levels. In another aspect of the fifth embodiment, the method reduces plasma Abeta40 levels. In another aspect of the fifth embodiment, the method reduces plasma Abeta42 levels. In another aspect of the fifth embodiment, the method reduces plasma Abeta42 levels.

[0022] Conditions associated with elevated p-tau levels, elevated Abeta40 levels, elevated Abeta42 levels, and / or elevated p-tau / Abeta42 ratios include, but are not limited to, COVID-19 related neurological conditions (e.g., chronic traumatic encephalopathy, thrombotic stroke, short-term memory impairment, cognitive dysfunction such as "brain fog", neuropsychiatric disorders, dizziness, focal symptoms, and other neurological symptoms associated with the long-term effects of COVID-19 infection, commonly referred to as "COVID sequelae"), traumatic brain injury (acute and / or chronic), single or repetitive trauma, mild to severe concussion, hypoxic-ischemic injury after cardiac or cardiothoracic surgery, post-cardiac arrest, and hypertensive vascular dementia. Other conditions include mild cognitive impairment ("MCI"), vascular dementia, Alzheimer's disease (including early AD, mild-to-moderate AD, severe AD, and sporadic (non-hereditary) AD), familial (hereditary) age-related cognitive decline, cerebral amyloid angiopathy ("CAA"), hereditary cerebral hemorrhage, senile dementia, Down's syndrome, inclusion body myositis ("IBM"), and age-related macular degeneration ("ARMD").

[0023] In one aspect, as part of the sixth embodiment, a subject treated herein (e.g., as in any one of the first through fifth embodiments) has AD. Alternatively, as part of the sixth embodiment, a subject treated herein (e.g., as in any one of the first through fifth embodiments) has mild AD. In another alternative, as part of the sixth embodiment, a subject treated herein (e.g., as in any one of the first through fifth embodiments) has mild to moderate AD.

[0024] In one aspect, as part of the seventh embodiment, the subject treated herein (e.g., as in any one of the first through sixth embodiments) is of the APOE4 / 4 or APOE3 / 4 genotype. Alternatively, as part of the seventh embodiment, the subject treated herein (e.g., as in any one of the first through sixth embodiments) is of the APOE3 / 4 genotype.

[0025] In one aspect, as part of the eighth embodiment, a subject treated herein has memory deficits resulting from any of the aforementioned disclosed conditions and exhibits memory improvement following treatment with ALZ-801. In some aspects of the eighth embodiment, the memory improvement occurs within 26 weeks of treatment. In some aspects of the eighth embodiment, the memory improvement occurs between about 13 and about 26 weeks of treatment.

[0026] In one aspect, as part of the ninth embodiment, a subject treated herein (e.g., as in any one of the first through eighth embodiments) is administered 530 mg of ALZ-801 / day. Alternatively, as part of the ninth embodiment, a subject treated herein (e.g., as in any one of the first through eighth embodiments) is administered 265 mg of ALZ-801 twice daily (BID). In some aspects of the ninth embodiment, ALZ-801 is administered orally. In some aspects of the ninth embodiment, ALZ-801 is administered daily at least until improvement of the disease or condition is observed. In some aspects of the ninth embodiment, ALZ-801 continues to be administered daily after improvement of the disease or condition is observed. EXAMPLES

[0027] Evaluation of disease-modifying effects from a phase 2 trial of ALZ-801 (valiltramiprosate) in subjects with early Alzheimer's disease. The study enrolled 84 patients with early AD who carried the APOE4 / 4 or APOE3 / 4 genotype and had MMSE scores ranging from 22 to 30 (CDR-G 0.5 or 1). Each patient received 265 mg of ALZ-801 twice daily. The mean MMSE score of subjects was 26 (mean age 69 years, 52% women). Subjects were either amyloid PET positive or A+ / T+ by CSF assay. CSF criteria were Aβ42 / 40 ratio × 10 ≤ 0.61, and p-tau181 ≥ 61 pg / ml. CSF was evaluated at 52 weeks, and plasma biomarkers were assessed at each visit.

[0028] All fluid biomarker analyses were performed at Dr. Blennow's Neurochemistry Laboratory (Molndal, Sweden) and were blinded to subject demographics or genotype. CSF biomarker assays were analyzed using Lumipulse (Fujirebio) and plasma assays utilized the Simoa assay. Cognitive testing included the Reay Auditory Verbal Learning Test (RAVLT: immediate, delayed, and recognition memory) and Digit Symbol Substitution Test (DSST) and a composite Z-score was calculated (3-item RAVLT+DSST). Analysis of change from baseline (CBL) was performed on the mITT population and included all observed data using paired t-tests and two-sided p-values. The primary biomarker outcome was p-tau 181 It was.

[0029] Of the 84 APOE4 carriers who enrolled and received ALZ-801, 80 and 75 subjects completed 26 and 52 weeks, respectively. In this population, ALZ-801 at 265 mg BID significantly reduced plasma p-tau at 52 weeks. 181 41% reduction in plasma p-tau (p=0.016) at 26 weeks 181 ALZ-801 also demonstrated a 29% reduction in plasma p-tau (p=0.014) at week 10 and an 18% reduction at week 13 (p=0.014). See Figure 1. ALZ-801 also demonstrated a 29% reduction in plasma p-tau (p=0.014) at week 10 and an 18% reduction at week 13 (p=0.014). 181 The study significantly reduced the plasma p-tau / Aβ42 ratio by 37% at 52 weeks (p=0.032), 30% at 26 weeks (p=0.011), and 21% at 13 weeks (p=0.011) (see Figure 2). This is consistent with the plasma p-tau / Aβ42 ratio observed in a recent human clinical trial of the anti-amyloid antibody lecanemab. 181 This is much greater than the approximately 12% annual reduction in pulmonary circulation (van Dyck, CH et al., N Engl J Med 2023;388:9-21, DOI:10.1056 / NEJMoa2212948).

[0030] Target engagement of ALZ-801 was further validated in this population by data showing increased plasma levels of Abeta40 and Abeta42 from 13 to 26 weeks, followed by a significant 5% reduction of each at 52 weeks (p=0.002 and p=0.005, respectively). See Figures 3 and 4. Mechanistically, ALZ-801 is believed to inhibit β-amyloid oligomerization in the brain, resulting in inhibition of both oligomer formation and subsequent aggregation. Aggregation and fibril formation of amyloid-β Abeta40 and Abeta42 peptides are central events in subjects with early Alzheimer's disease. At baseline, untreated subjects possess certain levels of Abeta40 and Abeta42 in both brain and plasma. However, upon treatment with ALZ-801, an initial increase in plasma Abeta40 and Abeta42 was observed, supporting the belief that amyloid aggregation in the brain was being prevented and Abeta40 and Abeta42 were being cleared into the plasma. See, for example, the initial spike in plasma Abeta42 and Abeta40 observed at weeks 1-26 and 1-13 in treated subjects, as illustrated in Figures 3 and 4. Following this, an overall reduction in plasma Abeta40 and Abeta42 was observed, indicating that ALZ-801 promoted efficient clearance of soluble amyloid beta species from the brain.

[0031] In this study population, ALZ-801 also demonstrated sustained improvements in memory tests. Clinical outcomes were obtained from subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI is a longitudinal database registry of clinical, imaging, and biomarkers captured in AD and cognitively normal subjects that is accepted by the FDA for retrospective studies as an external historical control comparison group. Real-word evidence (RWE) is data collected on individuals that are outside the scope of data captured in clinical trials. In this case, we integrated ADNI as an RWE source to serve as an external control treatment group. As shown by Figure 5, treatment with ALZ-801 demonstrated improvements in memory out to approximately 6 months and maintained improvements above baseline using the Rey Auditory Verbal Learning Test ("RAVLT"). These results were consistently superior to the cognitive outcomes of untreated patients matched for AD severity and genotype as obtained from the ADNI database.

[0032] As shown in FIG. 6, subjects in this clinical trial's cognitive composite Z-scores (RAVLT memory score + DSST) showed a significant increase at 26 weeks (p=0.002) and remained numerically above baseline after 52 weeks of treatment with ALZ-801.

[0033] The specific data presented is based on p-tau 181 Although specific to tau protein, applicants are aware of other forms of phosphorylated tau protein, e.g., p-tau 217 and p-tau 231 is also believed to be reduced by treatment with ALZ-801. Thus, the present disclosure also provides for the treatment of diseases and conditions associated with abnormally high levels of any of the isoforms of p-tau by administration of ALZ-801.

[0034] In addition, subjects in this clinical trial showed an approximately 20% annual reduction in hippocampal volume atrophy with ALZ-801 compared to a well-matched ADNI cohort (p=0.05). This preservation of hippocampal volume correlated significantly with cognitive benefit (Spearman's rank correlation coefficient 0.27, p=0.02), suggesting neuroprotection. In contrast, lecanemab did not show any significant annual reduction in hippocampal volume atrophy. See Van Dyck, 2022, supra.

[0035] Unlike anti-amyloid antibodies such as lecanemab, ALZ-801 treatment for 52 weeks also appeared to show approximately a 15% reduction in ventricular volume expansion as measured by MRI (p=0.08).

[0036] Having described several embodiments of the invention, it will be apparent that our basic examples can be modified to provide other embodiments which utilize the compounds and methods of the invention. It will therefore be appreciated that the scope of the invention is intended to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

[0037] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) that may be cited throughout this application are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to one of ordinary skill in the art.

Claims

1. 1. A pharmaceutical composition for treating a COVID-19 associated neurological symptom in a subject in need thereof, comprising a therapeutically effective amount of ALZ-801, or a pharmaceutically acceptable salt thereof.

2. the treatment comprising administering to said subject a therapeutically effective amount of p-tau. １８１ The pharmaceutical composition of claim 1, wherein the composition reduces the level of

3. The treatment comprises administering to the subject a p-tau １８１ The pharmaceutical composition of claim 1, wherein the composition reduces the α-amyloid / Abeta42 ratio.

4. 2. The pharmaceutical composition of claim 1, wherein the treatment reduces Abeta40 levels in the subject.

5. 2. The pharmaceutical composition of claim 1, wherein the treatment reduces Abeta42 levels in the subject.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the COVID-19 associated neurological condition is selected from encephalopathy, thrombotic stroke, short-term memory impairment, cognitive impairment, neuropsychiatric disorders, dizziness, focal symptoms, traumatic brain injury, single or repetitive trauma, mild to severe concussion, hypoxic-ischemic injury after cardiac or cardiothoracic surgery, post-cardiac arrest, and hypertensive vascular dementia.

7. The p-tau １８１ level, the Abeta40 level, the Abeta42 level, and p-tau １８１ The pharmaceutical composition according to any one of claims 1 to 5, wherein the / Abeta42 ratio refers to the level and ratio in plasma.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject is administered 530 mg of ALZ-801 per day.

9. 9. The pharmaceutical composition of claim 8, wherein the subject is administered 265 mg of ALZ-801 twice daily.

10. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject also suffers from mild AD.

11. The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject has the APOE4 / 4 or APOE3 / 4 genotype.

12. The pharmaceutical composition of claim 11, wherein the subject is of the APOE3 / 4 genotype.

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