PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients.

BACKGROUND: The most common dementia worldwide, Alzheimer's disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aß1-42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer's disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer's disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aß42's toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aß-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A's linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aß42's activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer's disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A's altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aß42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer's disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aß42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer's disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aß42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1ß and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aß42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug's mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer's disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aß42's signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aß42 increased slightly - a desirable result because low Aß42 indicates Alzheimer's disease. This increase is consistent with PTI-125's 1,000-fold reduction of Aß42's femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A's conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aß42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer's disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

[Self-healing Hashimoto-Pritzker histiocytosis]. / Histocytose auto-involutive de Hashimoto-Pritzker.

UNLABELLED: Congenital 'self-healing' Langerhans' cell histiocytosis of Hashimoto-Pritzker is a rare disease occurring mainly in the neonatal period. CASE REPORT: We report on the case of a newborn with widespread eruption since birth, consisting of nodules, papulonodules, sometimes with ulcerations and scabs, concerning all the body, with a predilection for the cephalic area and the scalp, without general abnormalities. The clinical examination, histopathological data, immunohistochemistry, and the benign evolution in nine-, 18- and 24-month periods without particular treatment define the diagnosis of congenital self-healing Langerhans' cell histiocytosis of Hashimoto-Pritzker. CONCLUSION: The position of this disease among the Langherans' cell histiocytoses is probably situated at the benign pole. This is a benign self-healing disease restricted to the skin and the prognosis is good (self-involution). It is important to eliminate a malignant form of other Langerhans' cell histiocytosis such as Letterer-Siwe disease by a checkup searching for a visceral disease. The good prognosis should not lead to forget the possibility of error or forms of relapses; it is therefore imperative to have a rigorous, regular and especially long-term follow-up.

[Necrotizing enteritis during the therapeutic induction phase in leukemia. Value of surgical treatment]. / Entérite nécrosante à la phase d'induction thérapeutique d'une leucémie. Intérêt du traitement chirurgical.

A case of typhlitis in a 3,5 year old girl, during induction therapy for acute lymphoblastic leukemia is reported. This typhlitis, or necrotizing enterocolitis involving the coecum and right colon resulted in stercoral peritonitis during the neutropenic phase. After surgery, the patient had a favorable outcome with complete recovery. Knowledge about this uncommon but severe complication of hemopathies leads to follow clinical, microbiologic and radiologic rules of prophylaxis and screening. Typhlitis requires early treatment by supportive care and surgical cure if necessary.

Sindrome de Cushing cinquenta anos depois. (157 refs.). / Cushing syndrome, 50 years latter

Neste quinquagesimo aniversario do trabalho classico de Harvey Cushing - "The Basophil Adenomas of the Pituitary Body and their Clinical Manifestations(pituitary basophilism)", Bull. Johns Hopk. Hosp. 50:137-95, 1932 -, os autores revisam os principais aspectos desta entidade, assim como das sindromes de Cushing adrenal e ectopica. Particular destaque e conferido a etiopatogenia da sindrome de Cushing hipotalamo-hipofisaria (SCHH) com discussao das hipoteses etiologicas disponiveis. A introducao do novo conceito de displasia nodular primaria (DNP) individualiza melhor e torna mais homogeneo o grupo das hiperplasias macro e micronodulares. As repercussoes do hipercortisolismo endogeno sobre o metabolismo dos carboidritos, lipidos e proteinas e sobre as funcoes organicas sao comentadas, assim como o valor relativo das dosagens hormonais, testes e demais exames laboratoriais, para o diagnostico diferencial das sindromes de Cushing. Finalmente, os autores confrontam os muitos tratamentos, quimioterapicos, radioterapicos e cirurgicos disponiveis para a SCHH e analisam a eficacia, indicacoes, vantagens e inconvenientes de cada um

[Enzymatic characteristics of the catalytic subunit of the protein kinase complex of human lymphocytes]. / Caractéristiques enzymatiques de la sous-unité catalytique dans le complexe de la protéine-kinase du lymphocyte humain

In earlier reports we have shown the existence in human lymphocytes homogenate, of a cyclic-AMP dependent protein-kinase activity. We demonstrate by affinity chromatography that two subunits display respectively cyclic-AMP binding and phosphorylating properties. Divalent cations such as Ca++, Mg++ or Mn++ are required for enzymatic activity. ATP which is an obligatory cosubstrate acts as an inhibitor when its concentration is higher than 10(-6)M.

[Identification of cAMP dependant protein kinases in human lymphocytes]. / Identification dans le lymphocyte humain, de protéine-kinases modulées par l'AMP-3',5'-phosphodiester

Chromatographic purification by "DEAE" cellulose resolves the cAMP binding proteins in human lymphocytes into three parts. In presence of Mg++ each one possesses cAMP dependent protein-kinase activity, one of them showing allosteric characteristics.