Peptide for treatment of cognitive diseases

Abstract

The present invention relates to peptides for treatment of cognitive diseases, in particular Alzeheimer's Disease, mild cognitive impairment due to Alzheimer's disease, and mild dementia due to Alzheimer's disease.

Description

[0001] Peptide for treatment of cognitive diseases

[0002] The present invention relates to peptides for treatment of cognitive diseases. In particular, the invention relates to one or more peptides for use in a method of preventing and / or treating Alzheimer’s disease (AD). The invention further relates to a method of preventing and / or treating Alzheimer’s disease (AD) comprising administering one or more peptides to a subject. The invention further relates to one or more peptides for use in a method of preventing and / or treating mild cognitive impairment (MCI) due to AD (MCI-AD). The invention further relates to a method of preventing and / or treating mild cognitive impairment (MCI) due to AD (MCI-AD) comprising administering one or more peptides to a subject. The invention further relates to one or more peptides for use in a method of preventing and / or treating mild dementia (MD) due to AD (MD-AD). The invention further relates to a method of preventing and / or treating mild dementia (MD) due to AD (MD-AD) comprising administering one or more peptides to a subject.

[0003] Background of the invention

[0004] Alzheimer’s disease (AD) results from the buildup of synaptotoxic amyloid beta (Ap) oligomers around neurons, leading to neuronal degeneration and the progressive cognitive and memory deficits associated with the disease. Evidence suggests that the elimination of aggregated Ap will at least attenuate the progression of clinical symptoms in AD patients.

[0005] Various peptides are known to disrupt and disassemble Ap aggregates. For example, PRI- 002 is an all-D-configurated peptide of defined sequence which was developed as a curative and / or disease-modifying therapeutic for the treatment of AD by disassembling toxic Ap oligomers into non-toxic Ap monomers. PRI-002 was developed to bind Ap monomers and stabilizes them in their native, intrinsically disordered conformations. This destabilizes Ap aggregates, disassembling them into monomers regardless of their particular conformation, and reducing the risk of prion strain selection and subsequent development of resistance.

[0006] The beneficial activity of such Ap aggregate-disrupting peptides is dependent, among other things, on establishing and maintaining peptide levels in serum over time which are sufficient to elicit the desired clinical response. With this in mind, initial studies have focused on the pharmacokinetic profiles of such peptides, and achieving adequate peptide uptake and maintaining adequate peptide levels in serum over time have been challenging. A need therefore exists for measures to improve therapeutic peptide uptake, e.g. oral availability of therapeutic peptide, and to improve maintenance of therapeutic peptide levels in serum. The present invention addresses this need. At the same time, a need also exists to extend the spectrum of cognitive diseases treatable with such peptide-based therapies as described above to diseases other than AD, for example to other diseases within the AD spectrum. The present invention addresses this need as well.

[0007] Summary of the invention

[0008] Accordingly, one aspect of the invention relates to a peptide comprising at least one amino acid sequence for use in a method of preventing and / or treating Alzheimer’s disease (AD), wherein the at least one amino acid sequence has the sequence PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof; and wherein the method comprises administering the peptide to a subject at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least 120 min before food intake.

[0009] A further aspect of the invention relates to a method of preventing and / or treating AD, said method comprising administering a peptide comprising at least one amino acid sequence to a subject in need or suspected need thereof, wherein the at least one amino acid sequence has the sequence PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof; and wherein said administering to the subject takes place at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least 120 min before food intake.

[0010] A further aspect of the invention relates to a peptide comprising at least one amino acid sequence for use in a method of preventing and / or treating mild cognitive impairment (MCI) due to AD (MCI-AD) or mild dementia due to AD (MD-AD), wherein the at least one amino acid sequence has the sequence PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof.

[0011] A further aspect of the invention relates to a method of preventing and / or treating MCI-AD or MD-AD, said method comprising administering a peptide comprising at least one amino acid sequence to a subject in need or suspected need thereof, wherein the at least one amino acid sequence has the sequence PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof.

[0012] Description of the figures

[0013] Figure 1 shows a study design and disposition of patients in a phase 1 b trial investigating effects of the peptide PRI-002 (SEQ ID NO: 2) in patients diagnosed with mild cognitive impairment due to AD (MCI-AD) according to the Diagnostic and Statistical Manual of Mental Disorders - for dementia (DSM-V), or in patients diagnosed with mild dementia due to AD (MD-AD) according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10). “IC” means “informed consent”.

[0014] Figure 2A shows the results of an experiment investigating individual and mean plasma concentrations of PRI-002 over time (following administration) on day 1 of a study in which subjects which were diagnosed as having MCI-AD or MD-AD received the peptide PRI-002 by oral administration daily over a period of 28 days. Bold line: mean plasma concentration of PRI-002; Lines with symbols: individual plasma concentrations; B-numbers denote individual patients participating in the study.

[0015] Figure 2B shows the results of an experiment investigating individual and mean plasma concentrations of PRI-002 over time (following administration) on day 28 of a study in which subjects which were diagnosed as having MCI-AD or MD-AD received the peptide PRI-002 by oral administration daily over a period of 28 days. Bold line: mean plasma concentration of PRI-002; Lines with symbols: individual plasma concentrations; Symbol-correlated B-numbers denote individual patients participating in the study.

[0016] Figure 3A shows a bar graph with individual data points depicting the data from a cognitive function experiment in which MCI-AD or MD-AD patients who had received either placebo (grey bar with open square symbols) or PRI-002 (clear square with solid dot symbols) for 1 day or for 28 days. An additional follow-up test 28 days after the last-received administration of PRI-002 on day 28 (i.e. follow up on day 56) was additionally performed to assess longterm effects following cessation of PRI-002 treatment. Cognitive function was assessed by performance based on memory of a word list according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery. A higher “CERAD wordlist score” indicates a higher number of remembered words and therefore better cognitive function. The results show that patients receiving daily doses of PRI-002 from day one through day 28 showed improved cognitive function relative to placebo, and that this improvement persisted following cessation of daily administration on day 28, for an additional 28 days, out to day 56. Figure 3B shows a line graph depicting the data from a cognitive function experiment in which MCI-AD or MD-AD patients who had received either placebo (dotted line with solid squares) or PRI-002 (solid line with solid dots) for one day or for 28 days. An additional follow-up test 28 days after the last-received administration of PRI-002 on day 28 (i.e. follow up on day 56) was additionally performed to assess long-term effects following cessation of PRI-002 treatment. Cognitive function was assessed by performance based on memory of a word list according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery. A higher “CERAD wordlist score” indicates a higher number of remembered words and therefore better cognitive function. The results show that patients receiving daily doses of PRI-002 from day one through day 28 showed improved cognitive function relative to placebo, and that this improvement persisted following cessation of daily administration on day 28, for an additional 28 days, out to day 56. P-values: Two-way RM ANOVA * p<0.05.

[0017] Figure 3C shows a line graph depicting the data from a cognitive function experiment in which MCI-AD or MD-AD patients who had received placebo. Cognitive function was assessed by performance based on memory of a word list according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery, comparing performance at the end of the study (day 56) to performance at the beginning of the study (day 1). A higher “CERAD wordlist score” indicates a higher number of remembered words and therefore better cognitive function. The patients of the placebo group could be divided into 3 categories: those whose “CERAD wordlist score” increased over the course of the study while receiving placebo (solid lines with solid triangle symbols), those whose “CERAD wordlist score” remained the same over the course of the study while receiving placebo (heavy dotted lines with solid square symbols), and those whose “CERAD wordlist score” decreased over the course of the study while receiving placebo (light dotted lines with open circle symbols), p-value placebo: 0.036.

[0018] Figure 3D shows a line graph depicting the data from a cognitive function experiment in which MCI-AD or MD-AD patients who had received PRI-002. Cognitive function was assessed by performance based on memory of a word list according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery, comparing performance at the end of the study (day 56) to performance at the beginning of the study (day 1). A higher “CERAD wordlist score” indicates a higher number of remembered words and therefore better cognitive function. The patients of the PRI-002 uniformly showed improvement (i.e. increase; solid lines with solid triangle symbols) in their “CERAD wordlist score” at the end of the study as compared to their respective values at the beginning of the study. Taken together, the results shown in Figures 3D and 3C indicate that patients receiving daily doses of PRI-002 over the course of the study improved cognitive function relative to placebo. P-value PRI-002: 0.009. Figure 4 shows scatterplots and correlation coefficients including p-values for slope Ap oligomers and PRI-002 level on day 1. A strong and significant inverse relationship was observed between changes in Ap oligomer concentrations (given as slopes from day 1 to day 28) and the PRI-002 plasma levels at day 1. Overall, this figure shows that sufficient plasma levels of PRI-002 are important to achieve efficacy; it demonstrates that the higher the plasma levels of PRI-002 were in the patients, the more beneficial was the development of the Ap concentration for the individual patient in the verum group of the study described herein. Correlations were performed with Spearman (p) analysis at alpha level 0.05 with n = 9.

[0019] Detailed description of the invention

[0020] The following provides definitions of various terms and expressions used in the present application to describe the invention. It is to be understood that definitions of terms and expressions used in more than one aspect or embodiment of the invention apply equally to any aspect or embodiment of the invention described herein in which those terms and expressions appear. This applies equally regardless of where, i.e. which section, within the present application such terms are defined or discussed.

[0021] Definitions

[0022] In this application, the use of the singular (e.g. “a” or “the”) may, but need not necessarily, include the plural unless specifically stated otherwise.

[0023] As used herein the term “comprising” has the standard meaning “including”, “encompassing”, or “containing”. It includes the explicitly recited element(s), and also allows, but does not require, the presence of other or (an)other element(s) not recited. In addition to this broad meaning, as used herein, the term “comprising” also encompasses the limiting meaning “consisting of”, according to which only the explicitly recited element(s), and no other(s) is / are present. In addition, the term “comprising” also includes the meaning of “consisting essentially of”, which means that other element(s) may be present beyond those explicitly recited, provided the additionally present element(s) does not alter the technical effect achieved by the explicitly recited element(s).

[0024] As used herein the term “about” when referring to a particular value, e.g. an endpoint or endpoints of a range, encompasses and discloses, in addition to the specifically recited value itself, a certain variation around the specifically recited value. Such a variation may for example arise from normal measurement variability, e.g. in the weighing or apportioning of various substances by methods known to the skilled person. The term “about” shall be understood as encompassing and disclosing a range of variability above and below an indicated specific value, said percentage values being relative to the specific recited value itself, as follows. The term “about” may encompass and disclose variability of ± 5.0%. The term “about” may encompass and disclose variability of ± 4.9%. The term “about” may encompass and disclose variability of ± 4.8%. The term “about” may encompass and disclose variability of ± 4.7%. The term “about” may encompass and disclose variability of ± 4.6%. The term “about” may encompass and disclose variability of ± 4.5%. The term “about” may encompass and disclose variability of ± 4.4%. The term “about” may encompass and disclose variability of ± 4.3%. The term “about” may encompass and disclose variability of ± 4.2%. The term “about” may encompass and disclose variability of ± 4.1%. The term “about” may encompass and disclose variability of ± 4.0%. The term “about” may encompass and disclose variability of ± 3.9%. The term “about” may encompass and disclose variability of ± 3.8%. The term “about” may encompass and disclose variability of ± 3.7%. The term “about” may encompass and disclose variability of ± 3.6%. The term “about” may encompass and disclose variability of ± 3.5%. The term “about” may encompass and disclose variability of ± 3.4%. The term “about” may encompass and disclose variability of ± 3.3%. The term “about” may encompass and disclose variability of ± 3.2%. The term “about” may encompass and disclose variability of ± 3.1%. The term “about” may encompass and disclose variability of ± 3.0%. The term “about” may encompass and disclose variability of ± 2.9%. The term “about” may encompass and disclose variability of ± 2.8%. The term “about” may encompass and disclose variability of ± 2.7%. The term “about” may encompass and disclose variability of ± 2.6%. The term “about” may encompass and disclose variability of ± 2.5%. The term “about” may encompass and disclose variability of ± 2.4%. The term “about” may encompass and disclose variability of ± 2.3%. The term “about” may encompass and disclose variability of ± 2.2%. The term “about” may encompass and disclose variability of ± 2.1%. The term “about” may encompass and disclose variability of ± 2.0%. The term “about” may encompass and disclose variability of ± 1.9%. The term “about” may encompass and disclose variability of ± 1.8%. The term “about” may encompass and disclose variability of ± 1.7%. The term “about” may encompass and disclose variability of ± 1.6%. The term “about” may encompass and disclose variability of ± 1.5%. The term “about” may encompass and disclose variability of ± 1.4%. The term “about” may encompass and disclose variability of ± 1.3%. The term “about” may encompass and disclose variability of ± 1.2%. The term “about” may encompass and disclose variability of ± 1.1%. The term “about” may encompass and disclose variability of ± 1.0%. The term “about” may encompass and disclose variability of ± 0.9%. The term “about” may encompass and disclose variability of ± 0.8%. The term “about” may encompass and disclose variability of ± 0.7%. The term “about” may encompass and disclose variability of ± 0.6%. The term “about” may encompass and disclose variability of ± 0.5%. The term “about” may encompass and disclose variability of ± 0.4%. The term “about” may encompass and disclose variability of ± 0.3%. The term “about” may encompass and disclose variability of ± 0.2%. The term “about” may encompass and disclose variability of 0.1%. The term “about”, in reference to the particular recited value, may encompass and disclose that exact particular value itself, irrespective of any explicit mention that this exact particular value is included; even in the absence of an explicit indication that the term “about” includes the particular exact recited value, this exact particular value is still included in the range of variation created by the term “about”, and is therefore disclosed. Unless stated otherwise, if the term “about” is recited before the first endpoint of a numerical range, this term refers to both the first endpoint of the range and the second endpoint of the range. For instance, a recited range of “about X to Y” should be read as “about X to about Y”.

[0025] Unless stated otherwise, the designation of a range in the present application using a hyphen separating two bracketing values X and Y is to be understood as meaning and disclosing the specified range in which both endpoint values X and Y are included. The same applies to a range expressed as “from X to Y”. Accordingly, the expressions of ranges as “X - Y”, “of X to Y”, “from X to Y”, “of X - Y” and “from X - Y” are to be understood equivalently as meaning and disclosing a range encompassing the end value X, all values between X and Y, as well as the end value Y.

[0026] The designation of a range in the present application using the word “between” preceding two bracketing values X and Y is to be understood as meaning and disclosing the specified range in which both endpoint values X and Y are excluded, but all values between the specified endpoint values X and Y are included.

[0027] As used herein, the term “subject” refers to a mammal, preferably a human. The subject may be in need of treatment of AD and / or MCI-AD and / or MD-AD. In such cases, this need will typically have been previously determined by obtaining a diagnosis of AD, MCI-AD and / or MD- AD. In such cases, in which a diagnosis or diagnoses of a pathological condition or pathological conditions already exists, the invention as set out herein may be implemented to treat existing pathology (e.g. MCI-AD and / or MD-AD), while simultaneously preventing the development of further pathology (e.g. AD). Similarly, the invention is set out herein may also be implemented to treat an existing pathology (AD or MCI-AD or MD-AD) while simultaneously preventing further progression of the same pathology (AD or MCI-AD or MD-AD, respectively). It is however also contemplated that the subject matter of the invention as set out herein can be applied to subjects which have not yet been positively diagnosed as having AD or MCI-AD or MD-AD, but who are suspected of having one or more of these diseases. Such subjects will typically not have been previously diagnosed for AD or MCI-AD or MD-AD yet such subjects may be at risk for developing this condition. The invention described herein thus also envisions administering the peptide to a subject which has not been previously diagnosed for AD or MCI- AD or MD-AD, with the aim of inhibiting the development of (e.g. further) AD or MCI-AD or MD-AD. Such scenarios are encompassed by the present invention as set out herein.

[0028] Accordingly, as used herein, the term “treat” or grammatically related variants thereof such as “treatment”, “treating” etc. means the amelioration, even temporarily, encompassing but not requiring the complete abolishment of a pathological state. In the broadest sense, treatment as used herein means achieving at least a partial reversion of to a previous of absent or diminished pathology. In particular, treatment in the present sense encompasses restoration or improvement of proper cognitive function as for example measured by one or more standard tests of cognitive function, for example the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test battery or Clinical Dementia Rating scale (CDR). CDR scores are typically given on a scale of 0-3, as follows: 0 - healthy; 0.5 - MCI; 1 - mild AD; 2 - moderate AD; 3 - progressed / full / end stage AD.

[0029] As used herein, the term “prevent”, and grammatically related variants thereof such as “preventing”, “prevention” etc. refer to scenarios in which the medical uses and methods of treatment described herein are applied to avert the possible, suspected or expected occurrence of AD or MCI-AD or MD-AD in a subject. Such suspicion that AD or MCI-AD or MD-AD may for example be present or may develop (even in the absence of a corresponding diagnosis) based on an observed decline in cognitive function, or an observed loss of memory, e.g. short term memory, but in advance of any formal diagnosis of AD or MCI-AD or MD-AD. Also within the definition of “prevention” as used herein is the administration of the peptide to treat and already-diagnosed conditions such as for example MCI-AD or MD-AD, in the absence of any diagnosis of AD, in which case it is contemplated that MCI-AD or MD-AD are treated, while the development of AD is simultaneously prevented, as is the further progression of MCI-AD or MD-AD. Such scenarios are within the meaning of “prevention” as used herein.

[0030] As used herein, the phrases “due to AD”, e.g. as in “mild cognitive impairment due to AD” (MCI-AD) or “mild dementia due to AD” (MD-AD), do not necessarily require that AD be previously or simultaneously present. Without being bound by theory, it is thought that MCI- AD and / or MD-AD represent early forms of AD which are nevertheless diagnosable as diseases distinct from AD per se. Reference is made in this context to the Diagnostic and Statistical Manual of Mental Disorders - for dementia (DSM-V) (for MCI-AD), and to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) (for MD-AD), which demonstrate that each of MCI-AD and MD-AD are distinct, separately identifiable and diagnosable diseases. In this sense, the phrase “due to” denotes a likely similarity in underlying disease mechanism, namely the accumulation of Ap oligomers around neurons, with resulting progressive loss of neuronal function, but with different observable pathologies.

[0031] As used herein, the term “homolog” refers to an amino acid sequence of the same length, i.e. containing the same number of amino acids, as the indicated reference sequence, but of variant sequence. It is contemplated that a “homolog” of the reference peptide is a peptide having the same number of amino acids, but in which one or more amino acids in the reference sequence has / have been replaced by (an)other amino acid(s) of like function, such that the resulting peptide exhibits a qualitatively and / or quantitatively similar function as the reference peptide. As the skilled person will understand, amino acids can be roughly divided into several groups based on the chemical nature of their sidechain, so that replacement of, e.g., an amino acid during a polar sidechain in the reference peptide with an amino acid bearing a different sidechain which is also polar, may have the same or comparable function as the reference peptide even though it has a different overall amino acid sequence due to the substitution. Such variant peptides of sequence diverging from that of the reference peptide indicated would be considered “homologs” of the reference peptide, and are within the scope of the present invention. Such homologs may for example have a sequence about 92 % (e.g. 91.67 %, or 91 % %), about 83 % (83.33 %, or 831 / 3%), about 75 % (e.g. 75.00 %), about 67 % (66.67 %, or 66 % %), about 58 % (58.33 %, or 58 % %) or about 50 % (e.g. 50.00 %) identical to the sequence of the reference peptide. As with the indicated reference peptide, it is preferred that any amino acid substitutions also be D-configurated amino acids, and that any amino acid substitution of the C-terminal arginine residue in the reference peptide also be modified, preferably the amidated to bear an amide group (CONH2) at the C-terminus rather than the free acid group (COOH).

[0032] As used herein, the term “fragment” refers to an amino acid sequence shorter in length, i.e. containing fewer amino acids, than the indicated reference peptide, but which, despite its truncation relative to the reference peptide, still exhibits a qualitatively and / or quantitatively similar function as the reference peptide. It is contemplated that such a fragment also bears a modification at the C-terminal amino acid resulting from truncation, and that this C-terminal modification be an amide group (CONH2) at the C-terminus rather than the free acid group (COOH).

[0033] As used herein, the term “variant” as refers to a subject peptide (e.g. a peptide according to SEQ ID NO: 2) in which one or more of the amino acids in D-configuration is replaced by the corresponding amino acid in L-configuration but which, despite such replacement relative to the reference peptide, still exhibits a qualitatively and / or quantitatively similar function as the reference peptide. Preferably, no more than 5 amino acids in D-configuration should be replaced by the corresponding respective amino acids in L-configuration. In the event that one of the configuration-switched amino acids is replaced at the C-terminus of the peptide, it is preferred that the resulting variant also bears a modification at the C-terminal amino acid resulting from replacement. As set out herein, it is preferable that this C-terminal modification be an amide group (CONH2) at the C-terminus rather than the free acid group (COOH).

[0034] As used herein, the term “food” denotes solid food, e.g. a substance which requires chewing before swallowing.

[0035] Although the present application mentions discrete embodiments, it is to be understood that any embodiment, and the features therein, may be freely combined with any other embodiment and the features therein, even in the absence of an explicit statement to this effect. Such combinations of one embodiment with another, or of one or more features in any one embodiment with one or more features in any other embodiment, thus belong to the disclosure of the present application as filed as understood by the skilled person.

[0036] Treatments for Alzheimer’s disease (AD)

[0037] As stated above, one aspect of the invention relates to a peptide comprising at least one amino acid sequence for use in a method of preventing and / or treating Alzheimer’s disease (AD), wherein the at least one amino acid sequence has the sequence

[0038] PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof; and wherein the method comprises administering the peptide to a subject at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least 120 min before food intake.

[0039] A further aspect of the invention relates to a method of preventing and / or treating AD, said method comprising administering a peptide comprising at least one amino acid sequence to a subject in need or suspected need thereof, wherein the at least one amino acid sequence has the sequence

[0040] PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof; and wherein said administering to the subject takes place at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least 120 min before food intake.

[0041] The amino acid sequence comprised in the peptide is of the following amino acid sequence:

[0042] Pro - Thr - Leu - His - Thr - His - Asn - Arg - Arg - Arg - Arg - Arg

[0043] (PTL HTH NRR RRR)

[0044] In one preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide consists essentially of the amino acid sequence PTL HTH NRR RRR. In a preferred embodiment of the respective aspects or embodiments of the invention set out above, the peptide consists of the amino acid sequence PTL HTH NRR RRR.

[0045] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, it is preferred that the peptide consists essentially of D-amino acids. In such a case, the majority of the amino acids in the peptide, for example all but 1 amino acid in the peptide, all but 2 amino acids in the peptide, all but 3 amino acids in the peptide or all but 4 amino acids in the peptide, are in the D-configuration, the remaining minority of the amino acids in the peptide being in the L-configuration.

[0046] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide consists of D-amino acids. In the case that the peptide consists of the amino acid sequence PTL HTH NRR RRR, this means that each of the 12 amino acids in that sequence, and thereore in the peptide as a whole, is in the D-configuration.

[0047] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide comprises a C-terminal modification, wherein the C- terminal modification is selected from the group consisting of an acid amide group (CONH2- group) and a CONH-alkyl group (with the term “alkyl” denoting a linear or branched C1-C5 alkyl group, that is a linear or branched C1 , C2, C3, C4 or C5 alkyl group). In an especially preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide is C-terminally modified, i.e. at the C-terminal Arg, is a carboxylic acid amide (CONH2-group). In an especially preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide consists of the amino acid sequence PTL HTH NRR RRR (i.e. the the amino acid sequence PTL HTH NRR RRR constitutes the entire peptide), the peptide consists of D-amino acids (every amino acid in PTL HTH NRR RRR has the D- configuration), and the peptide comprises a C-terminal modification in the form of an acid amide group (CONH2-group; is C-terminally amidated on Arg). This corresponds to the 12-D- amino acid peptide PRI-002 (SEQ ID NO: 2). An especially preferred peptide of the invention is thus as represented by SEQ ID NO: 2.

[0048] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, it is preferred that the method comprises administering the peptide by the oral route.

[0049] Orally administered drugs such as therapeutic peptides must be absorbed into the blood system via the gastrointestinal tract in order to have an effect in the body. The effectiveness of this absorption is called oral bioavailability and is usually described as a percentage relative to the same dose administered intravenously. The present inventors have found that one important factor influencing the oral availability of the subject peptide(s) is the temporal proximity of drug intake (administration) relative to food intake. Specifically, the present inventors have found that in preventing and / or treating AD it can be advantageous to separate the administration of the peptide, e.g. PRI-002, chronologically from food intake. Even more specifically, the present inventors have found that in preventing and / or treating AD, waiting a certain length of time after oral administration of the peptide, e.g. PRI-002, before subsequent food intake can increase the oral bioavailability of the peptide, that is can increase the peptide serum levels achieved. As higher serum peptide levels generally correlate to better clinical prognosis in disease prevention and / or treatment, staggering peptide administration and food intake such that food intake follows only a certain time after peptide administration represents one way of increasing clinical prognosis in treatment.

[0050] In aspects and embodiments of the present invention relating to the the prevention and / or treatment of AD, the peptide is administered to a subject at least about 30 min (optionally excluding exactly 30 minutes) before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least about 120 min before food intake. Administration of the peptide to a subject is especially preferred at least about 60 minutes before food intake, or at least about 120 minutes (optionally excluding exactly 120 minutes) before food intake. The preferred route of administration of the peptide is oral. For example, the peptide may be provided in orally administrable form as a tablet, a hard or soft capsule or a powder or granulate (e.g. as a sachet for e.g. dissolving in a liquid to drink).

[0051] A further factor influencing peptide uptake following administration can also be a subject’s fasting status. For this reason, further embodiments of the present aspect of the invention foresee the advantageous possibility that the method comprises administering the peptide to the subject in a fasted state. For example, administering the peptide to the subject can preferably take place following restriction of the subject’s food intake for at least about 12 hours prior to administration. Even more preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 10 hours prior to administration. Even more preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 9 hours prior to administration. Most preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 8 hours prior to administration (optionally excluding restriction of the subject’s food intake for exactly 8 hours prior to administration). The present inventors have found that pre-administering the peptide to the subject as described above (that is, prior to food intake following such administration) can increase oral availability by roughly a factor of 3 when the patient is in a fasted state, as compared to if the patient has recently taken a meal shortly prior to peptide administration.

[0052] Further preferred embodiments in optional combination with any of the above or below aspects or embodiments relate to the amount of peptide to be administered to a subject in accordance with the present aspect of the invention. Accordingly, one embodiment of the invention foresees administering daily from about 10 mg to about 1000 mg of the peptide, or between about 10 mg and about 1000 mg of the peptide. A further embodiment of the invention foresees administering daily from about 40 mg to about 500 mg of the peptide, or between about 40 mg and about 500 mg of the peptide. A further embodiment of the invention foresees administering daily from about 100 mg to about 500 mg of the peptide, or between about 100 mg and about 500 mg of the peptide. A further embodiment of the invention foresees administering daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide. A further preferable embodiment of the invention foresees administering daily from about 150 mg to about 450 mg of the peptide, or between about 150 mg and about 450 mg of the peptide. A further more preferable embodiment of the invention foresees administering daily more preferably from about 200 mg to about 400 mg of the peptide, or between about 200 mg and about 400 mg of the peptide. A further most preferable embodiment of the invention foresees administering daily about 300 mg of the peptide. In further preferred embodiments in optional combination with any of the above or below aspects or embodiments , the total amount of peptide administered be in a single or in multiple doses per day, preferably twice daily (e.g. mornings and afternoons / evenings, especially 150 mg mornings and 150 mg afternoons / evenings) or 3 times daily (e.g. mornings, midday and afternoon / evenings, especially 100 mg mornings, 100 mg midday and 100 mg afternoons / evenings).

[0053] The total duration of treatment may vary depending on disease progression and severity. For example, in one embodiment the method comprises administering the peptide for at least about 28 days. In another embodiment the method more preferably comprises administering the peptide for at least about 35 days. In another embodiment the method more preferably comprises administering the peptide for at least about 45 days. In another embodiment the method more preferably comprises administering the peptide for at least about 56 days. In another embodiment the method more preferably comprises administering the peptide for at least about 112 days. In another embodiment the method more preferably comprises administering the peptide for about 1 month to about 6 months or for between about 1 month and about 6 months. In another embodiment the method more preferably comprises administering the peptide for at least about 3 months. In another embodiment the method more preferably comprises administering the peptide for at least about 4 months. In another embodiment the method more preferably comprises administering the peptide for at least about 5 months. In another embodiment the method more preferably comprises administering the peptide for at least about 6 months. In another embodiment the method more preferably comprises administering the peptide for at least about 7 months. In another embodiment the method more preferably comprises administering the peptide for at least about 8 months. In another embodiment the method more preferably comprises administering the peptide for at least about 12 months. In another embodiment the method more preferably comprises administering the peptide for at least about 16 months. In another embodiment the method most preferably comprises administering the peptide for at least about 24 months.

[0054] In one embodiment, it is also possible that the method additionally comprises further administering the peptide for about the rest of the subject’s life, more preferably for the rest of the subject’s life, wherein the further administering essentially consists of administering the peptide daily from about 10 mg to about 100 mg of the peptide, preferably from about 20 mg to about 60 mg of the peptide, most preferably about 40 mg of the peptide. For example, in one embodiment, the method may comprise initially administering the peptide daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide, for at least about 1 month to at least about 6 months, preferably for at least about 3 months, which is then followed by further administering the peptide for about the rest of the subject’s life, more preferably for the rest of the subject’s life, wherein the further administering essentially consists of administering the peptide daily from about 10 mg to about 100 mg of the peptide, preferably from about 20 mg to about 60 mg of the peptide, most preferably about 40 mg of the peptide.

[0055] In one preferred embodiment, the method may comprise initially administering the peptide daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide, such as 300 mg, for at least about 3 months, which is then followed by further administering the peptide for the rest of the subject’s life, wherein the further administering essentially consists of administering about 40 mg of the peptide daily.

[0056] It is also possible that the peptide may be linked, e.g. covalently linked, to another substance, for example another peptide comprising, consisting essentially of or consisting of D- configurated amino acids.

[0057] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the method comprises administering the peptide in combination with one or more pharmaceutical excipients and / or one or more uptake-enhancers. The “combination” may be as part of the same mixture or composition, or may be in separate physical forms. If separate physical forms, these separate physical forms may be administered contemporaneously or in a time-staggered fashion. Examples of such uptake-enhancers include EDTA, Tween 20, Tween 80, citric acid and / or capric acid and capric acid salts.

[0058] Treatments for further diseases within the AD spectrum

[0059] As already mentioned, there exists a need to extend the spectrum of cognitive diseases treatable with peptide-based therapies as described above to diseases other than AD. The present inventors have surprisingly found that the peptide PRI-002 may also be used to successfully treat other diseases which are associated with A aggregation / deposition, but are nevertheless distinct from AD.

[0060] Accordingly, a further aspect of the present invention relates to a peptide comprising at least one amino acid sequence for use in a method of preventing and / or treating mild cognitive impairment (MCI) due to AD (MCI-AD) or mild dementia due to AD (MD-AD), wherein the at least one amino acid sequence has the sequence

[0061] PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof.

[0062] A still further aspect of the invention relates to a method of preventing and / or treating MCI-AD or MD-AD, said method comprising administering a peptide comprising at least one amino acid sequence to a subject in need or suspected need thereof, wherein the at least one amino acid sequence has the sequence

[0063] PTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof.

[0064] Mild cognitive impairment due to AD (MCI-AD) and mild dementia due to AD (MD-AD) represent clearly defined diseases distinct from AD as such, and are each separately defined and diagnosable by accepted clinical standards, e.g. according to the Diagnostic and Statistical Manual of Mental Disorders - for dementia (DSM-V) (for MCI-AD), and according to the International Statistical Classification of Diseases and Related Health Problems (ICD- 10) (for MD-AD).

[0065] The amino acid sequence comprised in the peptide is of the following amino acid sequence:

[0066] Pro - Thr - Leu - His - Thr - His - Asn - Arg - Arg - Arg - Arg - Arg

[0067] (PTL HTH NRR RRR)

[0068] In one embodiment of the respective aspects of the invention set out above, the peptide consists essentially of the amino acid sequence PTL HTH NRR RRR. In a preferred embodiment of the respective aspects or embodiments of the invention set out above, the peptide consists of the amino acid sequence PTL HTH NRR RRR.

[0069] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, it is preferred that the peptide consists essentially of D-configurated amino acids. In such a case, the majority of the amino acids in the peptide, for example all but 1 amino acid in the peptide, all but 2 amino acids in the peptide, all but 3 amino acids in the peptide or all but 4 amino acids in the peptide, are in the D-configuration, the remaining minority of the amino acids in the peptide being in the L-configuration.

[0070] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide consists of D- configurated amino acids. In the case that the peptide consists of the amino acid sequence PTL HTH NRR RRR, this means that each of the 12 amino acids in that sequence, and thereore in the peptide as a whole, is in the D- configuration. In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide comprises a C-terminal modification, wherein the C- terminal modification is selected from the group consisting of an acid amide group (CONH2- group) and a CONH-alkyl group (with the term “alkyl” denoting a linear or branched C1-C5 alkyl group, that is a linear or branched C1 , C2, C3, C4 or C5 alkyl group). In an especially preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide is C-terminally modified, i.e. at the C-terminal Arg, is a carboxylic acid amide (CONH2-group).

[0071] In an especially preferred embodiment in optional combination with any of the above or below aspects or embodiments, the peptide consists of the amino acid sequence PTL HTH NRR RRR (i.e. the the amino acid sequence PTL HTH NRR RRR constitutes the entire peptide), the peptide consists of D-configurated amino acids (every amino acid in PTL HTH NRR RRR has the D-configuration), and the peptide comprises a C-terminal modification in the form of an acid amide group (CONH2-group; is C-terminally amidated on Arg). This corresponds to the 12-D-amino acid peptide PRI-002 (SEQ ID NO: 2). An especially preferred peptide of the invention is thus as represented by SEQ ID NO: 2.

[0072] In another preferred embodiment in optional combination with any of the above or below aspects or embodiments, it is preferred that the method comprises administering the peptide by the oral route.

[0073] Orally administered drugs such as therapeutic peptides must be absorbed into the blood system via the gastrointestinal tract in order to have an effect in the body. The effectiveness of this absorption is called oral bioavailability and is usually described as a percentage relative to the same dose administered intravenously. The present inventors have found that one important factor influencing the oral availability of the subject peptide(s) is the temporal proximity of drug intake (administration) relative to food intake. Specifically, the present inventors have found that in preventing and / or treating MCI-AD or MD-AD, it can be advantageous to separate the administration of the peptide, e.g. PRI-002, chronologically from food intake. Even more specifically, the present inventors have found that in preventing and / or treating MCI-AD or MD-AD, waiting a certain length of time after oral administration of the peptide, e.g. PRI-002, before subsequent food intake can increase the oral bioavailability of the peptide, that is can increase the peptide serum levels achieved. As higher serum peptide levels generally correlate to better clinical prognosis in disease prevention and / or treatment, staggering peptide administration and food intake such that food intake follows only a certain time after peptide administration represents one way of increasing clinical prognosis in treatment. In aspects and embodiments of the present invention relating to the the prevention and / or treatment of MCI-AD or MD-AD, it can be advantageous and is therefore preferable to administer the peptide, e.g. PRI-002, to a subject at least about 30 min (optionally excluding exactly 30 minutes) before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least about 120 min before food intake. Administration of the peptide to a subject is especially preferred at least about 60 minutes before food intake, or at least about 120 minutes (optionally excluding exactly 120 minutes) before food intake.

[0074] The preferred route of administration of the peptide is oral. For example, the peptide may be provided in orally administrable form as a tablet, a hard or soft capsule or a powder or granulate (e.g. as a sachet for e.g. dissolving in a liquid to drink).

[0075] A further factor influencing peptide uptake following administration can also be a subject’s fasting status. For this reason, further embodiments of the present aspect of the invention foresee the advantageous possibility that the method comprises administering the peptide to the subject in a fasted state. For example, administering the peptide to the subject can preferably take place following restriction of the subject’s food intake for at least about 12 hours prior to administration. Even more preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 10 hours prior to administration. Even more preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 9 hours prior to administration. Most preferably, administering the peptide to the subject can take place following restriction of the subject’s food intake for at least about 8 hours prior to administration (optionally excluding restriction of the subject’s food intake for exactly 8 hours prior to administration). The present inventors have found that pre-administering the peptide to the subject as described above (that is, prior to food intake following such administration) can increase oral availability by roughly a factor of 3 when the patient is in a fasted state, as compared to if the patient has recently taken a meal shortly prior to peptide administration.

[0076] Further preferred embodiments in optional combination with any of the above or below aspects or embodiments relate to the amount of peptide to be administered to a subject in accordance with the present aspect of the invention. Accordingly, one embodiment of the invention foresees administering daily from about 10 mg to about 1000 mg of the peptide, or between about 10 mg and about 1000 mg of the peptide. A further embodiment of the invention foresees administering daily from about 40 mg to about 500 mg of the peptide, or between about 40 mg and about 500 mg of the peptide. A further embodiment of the invention foresees administering daily from about 100 mg to about 500 mg of the peptide, or between about 100 mg and about 500 mg of the peptide. A further embodiment of the invention foresees administering daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide. A further preferable embodiment of the invention foresees administering daily from about 150 mg to about 450 mg of the peptide, or between about 150 mg and about 450 mg of the peptide. A further more preferable embodiment of the invention foresees administering daily more preferably from about 200 mg to about 400 mg of the peptide, or between about 200 mg and about 400 mg of the peptide. A further most preferable embodiment of the invention foresees administering daily about 300 mg of the peptide.

[0077] In further preferred embodiments in optional combination with any of the above or below aspects or embodiments , the total amount of peptide administered be in a single or in multiple doses per day, preferably twice daily (e.g. mornings and afternoons / evenings, especially 150 mg mornings and 150 mg afternoons / evenings) or 3 times daily (e.g. mornings, midday and afternoon / evenings, especially 100 mg mornings, 100 mg midday and 100 mg afternoons / evenings).

[0078] The total duration of treatment may vary depending on disease progression and severity. For example, in one embodiment the method comprises administering the peptide for at least about 28 days. In another embodiment the method more preferably comprises administering the peptide for at least about 35 days. In another embodiment the method more preferably comprises administering the peptide for at least about 45 days. In another embodiment the method more preferably comprises administering the peptide for at least about 56 days. In another embodiment the method more preferably comprises administering the peptide for at least about 112 days. In another embodiment the method more preferably comprises administering the peptide for about 1 month to about 6 months or for between about 1 month and about 6 months. In another embodiment the method more preferably comprises administering the peptide for at least about 3 months. In another embodiment the method more preferably comprises administering the peptide for at least about 4 months. In another embodiment the method more preferably comprises administering the peptide for at least about 5 months. In another embodiment the method more preferably comprises administering the peptide for at least about 6 months. In another embodiment the method more preferably comprises administering the peptide for at least about 7 months. In another embodiment the method more preferably comprises administering the peptide for at least about 8 months. In another embodiment the method more preferably comprises administering the peptide for at least about 12 months. In another embodiment the method more preferably comprises administering the peptide for at least about 16 months. In another embodiment the method most preferably comprises administering the peptide for at least about 24 months.

[0079] In one embodiment, it is also possible that the method additionally comprises further administering the peptide for about the rest of the subject’s life, more preferably for the rest of the subject’s life, wherein the further administering essentially consists of administering the peptide daily from about 10 mg to about 100 mg of the peptide, preferably from about 20 mg to about 60 mg of the peptide, most preferably about 40 mg of the peptide. For example, the method may comprise initially administering the peptide daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide, for at least about 1 month to at least about 6 months, preferably for at least about 3 months, which is then followed by further administering the peptide for about the rest of the subject’s life, more preferably for the rest of the subject’s life, wherein the further administering essentially consists of administering the peptide daily from about 10 mg to about 100 mg of the peptide, preferably from about 20 mg to about 60 mg of the peptide, most preferably about 40 mg of the peptide.

[0080] In one preferred embodiment, the method may comprise initially administering the peptide daily from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide, such as 300 mg, for at least about 3 months, which is then followed by further administering the peptide for the rest of the subject’s life, wherein the further administering essentially consists of administering about 40 mg of the peptide daily.

[0081] It is also possible that the peptide may be linked, e.g. covalently linked, to another substance, for example another peptide comprising, consisting essentially of or consisting of D- configurated amino acids.

[0082] In a further preferred embodiment in optional combination with any of the above or below aspects or embodiments, the method comprises administering the peptide in combination with one or more pharmaceutical excipients and / or one or more uptake-enhancers. The “combination” may be as part of the same mixture or composition, or may be in separate physical forms. If separate physical forms, these separate physical forms may be administered contemporaneously or in a time-staggered fashion. Examples of such uptake-enhancers may for example include EDTA, Tween 20, Tween 80, citric acid and / or capric acid or capric acid salts. The invention will now be described in greater detail by reference to several examples, it being understood that the examples are not limiting for the scope of the invention as claimed.

[0083] EXAMPLE 1

[0084] The present example describes a pharmacokinetic study performed using the peptide PRI- 002, as defined in SEQ ID NO: 2, i.e. the peptide of amino acid sequence PTL HTH NRR RRR in which every amino acid is in the D-configuration and the C-terminal Arg is amidated.

[0085] Example 1.1 : Study design

[0086] The study described here was a single center, randomized, double-blind, placebo-controlled study in parallel-group trial design in patients with mild cognitive impairment due to Alzheimer’s disease or mild dementia due to Alzheimer’s disease. Participants were recruited at the Charite memory clinic (Gedachtnissprechstunde der Charite - Universitatsmedizin Berlin, Klinik und Hochschulambulanz fur Psychiatrie und Psychotherapie, Gerontopsychiatrie / Ambulanz, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin) and had experienced routine assessments prior to screening. The study protocol and consent forms were approved by the local ethical committee, and all participants were fully able to provide written informed consent before study participation. The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice as described in the International Council for Harmonization guidelines.

[0087] Example 1.2: Participants

[0088] Twenty male and female (not of childbearing potential) patients between 50 and 80 years of age, with an MMSE (Mini-Mental State Examination) score of 22 to 30, matching CSF (Cerebrospinal Fluid) parameters (p-tau >62 pg / ml, total CSF A 1-42 / 1-40 ratio <0.055), MRI (magnetic resonance imaging) not older than 3 months, 3 months stable medication prior to screening, and diagnosed with mild cognitive impairment (MCI) due to AD (MCI-AD) according to Diagnostic and Statistical Manual of Mental Disorders - for dementia (DSM-V), or patients diagnosed with mild dementia due to AD (MD-AD) according to International Statistical Classification of Diseases and Related Health Problems (ICD-10) were enrolled and randomised.

[0089] Nineteen patients were treated and analysed, one individual dropped out by withdrawal of the informed consent after the initial screening before treatment start. All patients were exclusively recruited at the Charite memory clinic. They underwent an extensive clinical workup and received an MRI brain scan (if not performed during the preceding three months) as well as a lumbar puncture. A neuropsychological screening examination was performed including the MMSE. Patients who met any of the following criteria were not eligible for enrolment. This included a history of seizures, stroke or transient ischemic attack, unstable medical, neurological, or psychiatric condition, current treatment with one of the following substances such as typical antipsychotic or neuroleptic medication within 6 months of screening, anticoagulation medications within 3 months of screening, chronic use of opiates or opioids (including long-acting opioid medication) within 3 months of screening, stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 1 month of screening and throughout the study, chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening, persons who are legally detained in an official institution or may be dependent on the Sponsor, the Investigator, or the trial site, individuals without caregiver (lack of a spouse or a close relative that can provide information on the patient’s condition), participation in other clinical trials according to AMG (Arzneimittelgesetz', 1 month before the time of this trial), and persons showing EEG abnormalities.

[0090] Example 1.3: Randomisation and masking

[0091] In this trial, a total of 23 patients were assessed for eligibility. Twenty patients, who met all inclusion criteria and gave their written informed consent were enrolled, randomized and allocated to the trial. Randomization to the two individual treatment arms was performed uniformly (block randomization, 1 :1) and emergency letters were produced by the pharmacy of the Charite. However, one patient from the PRI-002 arm was withdrawn after screening before treatment start. Consequently, 9 patients in the PRI-002 arm received the treatment. There was no specific gender distribution as no gender specific differences concerning efficacy and safety of the investigational product were expected. After data cleanup and database lock, the biostatistician was given access to the randomization code.

[0092] Example 1.4: Procedures

[0093] The patients (n=19) received once daily three capsules each containing 100 mg PRI-002 (in total 300 mg PRI-002) (n=9) or placebo medication (n=10), indistinguishable from PRI-002 with respect to color, taste, smell, and shape for 28 days. During treatment, the frequency of study visits at the research center was 14 days (Day 1 , Day 14, Day 28). Follow-up assessment took place on Day 56. At day 7 and day 21 additional phone contacts for safety assessments were performed.

[0094] For Safety assessment during baseline, at Day 14, 28, and 56, laboratory parameters and vital signs were measured, a physical exam performed, and ECGs (electrocardiograms) recorded. A safety MRI took place at screening and within 3 days after Day 28 and 56. During baseline and at Day 28, EEG (electroencephalogram) tests were performed.

[0095] Effect on biomarker and cognition was assessed during baseline and after 28 days of medication. CSF collection and blood sampling were performed to determine PRI-002 concentration, which was conducted by Nuvisan (Neu-Ulm, Germany) and to exploratively estimate the effect of PRI-002 on the modulation of amyloid-p (Ap) 1-40, Ap 1-42, Ap oligomers, total tau (t-tau), and phospho tau (p-tau). Ap 1-40, Ap 1-42, t-tau and p-tau were measured by ELISA-type immunoassays and Ap oligomers concentratrions were determined using sFIDA technology (Pils, M. et al., 2023, “Development and Implementation of an Internal Quality Control Sample to Standardize Oligomer-Based Diagnostics of Alzheimer’s Disease”; Diagnostics 13, 1702; and Kulawik, A. et al., 2018, “Advancements of the sFIDA method for oligomer-based diagnostics of neurodegenerative diseases”, FEBS letters 592, 516-534; and Wang-Dietrich, L. et al., 2013, “The amyloid-beta oligomer count in cerebrospinal fluid is a biomarker for Alzheimer's disease”, Journal of Alzheimer's disease : JAD 34, 985-994) by attyloid GmbH (Dusseldorf, Germany). The effect of PRI-002 on cognitive and functional performance was measured by the change in Consortium to Establish a Registry for Alzheimer’s Disease (CERAD)+ test battery and Clinical Dementia Rating scale (CDR) from baseline to Day 28 and follow-up (Day 56).

[0096] Example 1.5: Outcomes

[0097] Primary objective of the study was the assessment of safety and tolerability of multiple oral doses of PRI-002 in patients with MCI or mild dementia due to AD. Primary endpoints included nature, frequency, and severity; laboratory values (urinalysis, complete blood count (CBC), Quick, partial thromboplastin time (PTT), creatinine, creatine kinase (CK), c-reactive protein (CRP), alanine aminotransaminase (ALT), aspartate aminotransferase (AST)), electrocardiogram (ECG), magnetic resonance imaging (MRI), electroencephalogram (EEG), and vital signs in normal range during trial participation.

[0098] Secondary endpoints included the evaluation of pharmacokinetic characteristics of PRI-002 by determination of maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), half-life (ti / 2) calculated from PRI-002 plasma concentrations; and the determination of cerebrospinal fluid (CSF) concentrations of PRI-002.

[0099] Exploratory objectives included CSF collection in order to assess the effect of PRI-002 on the modulation of Ap 1-40, Ap 1-42, Ap oligomers, t-tau and p-tau. The effect of PRI-002 on cognition and function was tested by the CERAD+ battery and CDR- SB at baseline, Day 28, and Day 56, exploratory endpoints included the change of biomarkers (p-tau, t-tau, Ap 1-40, A 1-42 and Ap oligomers) in CSF, blood plasma; change in CERAD+ test battery and CDR-SB scores.

[0100] Example 1.6: Statistical analysis

[0101] No sample size calculations were done because this trial was exploratory.

[0102] All safety parameters and laboratory values (urinalysis, CBC, Quick, PTT, creatinine, CK, CRP, ALT, AST) as well as ECG, EEG, MRI, and vital signs were analyzed in a descriptive manner according to their scales (frequencies, means). In order to compare a variable between both groups (Placebo vs. PRI-002) at one time point, a parameter free Wilcoxon rank sum test was used. As described in the statistical analysis plan, linear mixed models with random effect were used for the comparison of longitudinal effects between both groups (Placebo vs. PRI-002). ANOVA was also applied to assess longitudinal effects. Since the results are similar to the linear mixed models, results are presented using linear mixed models. A 95 % confidence interval was used to check whether the parameters are within their normal ranges. All statistical data analysis was performed with the certified software Statistical Analysis System (SAS) by MicroDiscovery GmbH (Berlin, Germany).

[0103] Example 1.7: Results

[0104] 23 patients were screened and assessed for eligibility. 20 patients were randomized and allocated to trial. One out of the 20 patients enrolled withdrew consent before treatment start.

[0105] Patients received once daily oral doses of 300 mg PRI-002 or placebo for 28 days. Safety and efficacy assessments were performed at baseline, day 14, day 28 during the treatment period and day 56 at follow up. 10 patients (age 76.9 ± 3.4, MMSE 28 ± 1.6) received placebo and 9 patients PRI-002 (age 72.4 ± 6.9, MMSE 27.2 ± 2.9). There were no significant differences in the patient's baseline characteristics between the placebo and PRI-002 group (see Table 1 below). Table 1: demographic data, cognitive measures and biomarker level at baseline In addition, there were no clinically significant changes detected in laboratory parameters including clinical chemistry, blood count or hematoserology from screening to midterm visit to end of treatment in both groups S2., on vital signs, in general physical examination, in ECG assessment or in any of the tested biomarkers (p-tau, t-tau, Ap 1-42, A 1-40, and Ap oligomers) (See Table 2 below). Also, MRI did not show any safety signals. In contrast to the amyloid-related imaging abnormalities (ARIA) like microhaemorrhages or vasogenic oedema reported after treatment with anti-p-amyloid monoclonal antibodies (Filippi, M. et al. , 2022, “Amyloid-Related Imaging Abnormalities and p-Amyloid-Targeting Antibodies: A Systematic Review”, JAMA Neurology 79, 291-304), no oedematous changes occurred after PRI-002 treatment. A new isolated microbleed right parietal and an approx. 2 mm large bifurcation aneurysm were detected after treatment in two placebo patients. Table 2: Statistics for biomarkers

[0106] Table 3, below, shows the statistics of PRI-002 pharmacokinetic parameters in MCI- and Alzheimer’s patients.

[0107] (Table 3 follows on next page)

[0108] Table 3: Pharmacokinetic parameters

[0109] On the two test days (Day 1 and Day 28), plasma levels were highly variable (see also Figures 2A and 2B herein). Coefficient of variations (CVs) were clearly above 100 % at 0.5 hours after the first treatment and at the pre-treatment time of Day 28 (data not shown). Other samples showed CVs of close to 100 % and a CV of below 60 % was not observed (data not shown). The high variability is due to a non-Gaussian data distribution. Mean maximum plasma levels on Day 1 (Day 28) of 4.46 ± 3.71 ng / ml (12.6 ± 13.2 ng / ml) were reached after about 2 hours (1 hour) and mean AU Co-4 hours were 10 ± 7.5 ng*h / ml (26.8 ± 23.8 ng*h / ml).

[0110] Generally, pharmacokinetic parameters showed high variability characterized by coefficients of variation ranging from 77 % to 134 %. Sampling did not allow for the calculation of ti / 2. Therefore, the percentage of the partial AUC up to 4 hours as calculated for Day 1 of the MAD8study (AUCo-4 hour = 33.7 ng*h / ml corresponding to 44.2 % of total AUC; dose: 320 mg / person) was used to extrapolate the total AUC for the present patient study: 22 ng*h / ml. Using the quotient AUCo-4 hour Day 28 / AUCo-4 hour Day 1 the mean systemic drug increase was 2.5 ± 1.3 fold. No correlations were found between any pharmacokinetic parameter and sex, age, or weight of patients.

[0111] The above shows the results from the randomized, double-blind, placebo-controlled PRI-002 trial that assessed primarily safety, tolerability and pharmacokinetics of the all-D-configurated peptide PRI-002. This study was the first clinical trial collecting safety parameters of PRI-002 in patients with mild cognitive impairment due to AD (MCI-AD) and mild dementia due to AD (MD-AD), including data on neurochemical biomarkers like Ap40, Ap42, tau, ptau, Nfl, and Ap oligomer concentrations in CSF as well as cognitive measures.

[0112] This phase 1 b study met its primary prespecified outcomes and has proven that PRI-002 has an excellent safety profile and tolerability in patients in early stages of the Alzheimer's disease continuum.

[0113] As expected from only 28 days of treatment, no significant changes in any measured biomarker was observed between day 28 versus baseline or verum versus placebo at day 28. The very small individual changes of Ap oligomer concentrations within the verum group, however, correlate strong and significantly with the individual PRI-002 levels in blood at baseline (Figure 4). In previous studies of PRI-002 in AD animal models improvement of memory and cognition was demonstrated as a very robust treatment outcome.

[0114] Therefore, we planned the word list learning within the CERAD battery of neurocognitive testing for day 1 , day 28 and day 56 with different word lists for each time point. The word list score at follow up, that is 4 weeks after treatment had ended, a significant improvement of short-term memory function was observed in the CERAD word list learning in the verum group compared to baseline and compared to the placebo group (see results shown in Table 4 below, and Figures 3A-3D shown herein).

[0115] (Table 4 follows on next page)

[0116] Table 4: Statistics for neuropsychometric testing

[0117] One may speculate whether PRI-002 mediated disassembly of Ap oligomers in monomers was beneficial for the function of synapses and neurons in the verum patients, before the concentration of Ap oligomers in relatively peripheral CSF had a chance to become significantly reduced, too. Regardless of whether this reflects a disease modification, it is quite promising that no immediate deterioration of cognitive function was observed upon PRI-002 treatment, as has for example been observed with other treatment approaches).

[0118] Overall, the above results can be interpreted such that 28 days of treatment with PRI-002 was very well-tolerated in individuals with clinically diagnosed mild cognitive impairment due to AD (MCI-AD) or mild dementia due to AD (MD-AD). The CERAD word list test performance was significantly improved at end of study relative to baseline with other tests of the CERAD+ and CDR batteries remaining unchanged. We propose that PRI-002 with its specific mode of action targeting synaptotoxic oligomers, has the potential to rescue synapses in early disease stages, and by this restores memory function of patients with mild symptoms of AD.

Claims

Claims1. A peptide comprising at least one amino acid sequence, for use in a method of preventing and / or treating Alzheimer’s disease (AD), wherein the at least one amino acid sequence has the sequencePTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof; and wherein the method comprises administering the peptide to a subject at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least about 120 min before food intake.

2. A peptide comprising at least one amino acid sequence, for use in a method of preventing and / or treating mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild dementia due to Alzheimer’s disease (AD), wherein the at least one amino acid sequence has the sequencePTL HTH NRR RRR or a homolog thereof, or a fragment thereof, or a variant thereof, or any combination thereof.

3. The peptide for use according to claim 1 or claim 2, wherein said peptide consists essentially of said amino acid sequence having the sequence PTL HTH NRR RRR, preferably wherein said peptide consists of said amino acid sequence having the sequence PTL HTH NRR RRR.

4. The peptide for use according to any one of claims 1-3, wherein the peptide consists essentially of D-configurated amino acids, preferably wherein the peptide consists of D- configurated amino acids.

5. The peptide for use according to any one of claims 1-4, wherein the peptide comprises a C-terminal modification, wherein the C-terminal modification is selected from the group consisting of an acid amide group (CONH2-group) or a CONH-alkyl group, preferably wherein the C-terminal modification is an acid amide group (CONH2-group).

6. The peptide for use according to any one of claims 1-5, wherein the peptide consists of said amino acid sequence having the sequence PTL HTH NRR RRR, wherein all amino acids in said peptide are D-configurated amino acids, and wherein said peptide comprises a C-terminal modification in the form of an acid amide group (CONH2-group).

7. The peptide for use according to any one of claims 1-6, wherein the method comprises administering the peptide by the oral route.

8. The peptide for use according to any one of claims 2 or 3-7, wherein the method comprises administering the peptide to a subject at least about 30 min before food intake, preferably at least about 45 min before food intake, more preferably at least about 60 min before food intake, more preferably at least about 75 min before food intake, more preferably at least about 90 min before food intake, more preferably at least about 100 min before food intake, more preferably at least about 120 min before food intake.

9. The peptide for use according to any one of claims 1-8, wherein the method comprises administering the peptide to the subject in a fasted state, preferably wherein the subject’s food intake is restricted for at least about 12 hours prior to administration, more preferably for at least about 10 hours prior to administration, more preferably for at least about 9 hours prior to administration, and most preferably for at least about 8 hours prior to administration.

10. The peptide for use according to any one of claims 1-9, wherein the method comprises administering daily from about 10 mg to about 1000 mg of the peptide, or between about 10 mg and about 1000 mg of the peptide; from about 40 mg to about 500 mg of the peptide, or between about 40 mg and about 500 mg of the peptide; from about 100 mg to about 500 mg of the peptide, or between about 100 mg and about 500 mg of the peptide; from about 300 mg to about 600 mg of the peptide, or between about 300 mg and about 600 mg of the peptide;preferably from about 150 mg to about 450 mg of the peptide, or between about 150 mg and about 450 mg of the peptide; more preferably from about 200 mg to about 400 mg of the peptide, or between about 200 mg and about 400 mg of the peptide, or most preferably about 300 mg of the peptide.

11. The peptide for use according to any one of claims 1-10, wherein the method comprises administering the peptide as a single dose once daily or as multiple doses multiple times per day, preferably twice daily or three times daily.

12. The peptide for use according to according to claim 11 , wherein the method comprises administering the peptide for at least about 28 days, more preferably for at least about 35 days, more preferably for at least about 45 days, more preferably for at least about 56 days, more preferably for at least about 3 months, more preferably for at least about 112 days, more preferably for at least about 4 months, more preferably for at least about 5 months, more preferably for at least about 6 months, more preferably for at least about 7 months, more preferably for at least about 8 months, more preferably for at least about 12 months, more preferably for at least about 16 months, and most preferably for at least about 24 months.

13. The peptide for use according to claim 12, wherein the method additionally comprises further administering the peptide for about the rest of the subject’s life, more preferably for the rest of the subject’s life, wherein the further administering essentially consists of administering the peptide daily from about 10 mg to about 100 mg of the peptide, preferably from about 20 mg to about 60 mg of the peptide, most preferably about 40 mg of the peptide.

14. The peptide for use according to any one of claims 1-13, wherein the peptide is linked to another substance.

15. The peptide for use according to any one of claims 1-14, wherein the method comprises administering the peptide in combination with one or more pharmaceutical excipients and / or one or more uptake-enhancers.

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