Archives par mot-clé : thérapeutique

Ophtalmologie

Iontophorèse, Anecortave, Radiothérapie : du nouveau…

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Où l’on reparle de traitements que l’on aurait pu croire à l’abandon…

  1. En l’absence de résultats d’études cliniques depuis 2004, l’avenir de la iontophorèse, dont le principe consiste à faciliter la pénétration intrasclérale de molécules à l’aide d’un courant électrique, était incertain. Or, je l’ai déjà évoqué à plusieurs reprises (voir aussi une revue de la littérature en français sur le sujet dans le JFO de décembre 2007), un des défis pour les années à venir sera certainement d’améliorer les systèmes de délivrance de médicaments dans l’Å“il, afin par exemple de limiter le recours aux injections intra-vitréennes répétées : la iontophorèse pourrait constituer une des pistes.
    EyeGate vient d’annoncer avoir finalisé un nouveau tour de financement, qui devrait donc permettre de débuter deux études de phase II (uvéite et oeil sec) courant 2008… A suivre !

    EyeGate Pharma Secures $15M in Series C Venture Funding
    WALTHAM, MA–(HSMN NewsFeed)–Mar 12, 2008 — EyeGate Pharma, a privately held, specialty pharmaceutical company using iontophoresis technology to safely and non-invasively deliver therapeutics into the front and back of the eye for treating serious ocular diseases, today announced that the company has secured $15 million in a Series C venture financing round. […]
    With this venture financing, EyeGate will enter into two Phase II clinical studies utilizing the EyeGate II Delivery System and a proprietary formulation of a corticosteroid. In the first half of 2008 we will initiate a Phase II trial in severe uveitis, and in the second half of the year we will initiate a Phase II trial in dry eye.[…]

    About EyeGate Pharma

    EyeGate Pharma was founded in 1999 with technology licensed from Bascom Palmer Eye Institute at the University of Miami. EyeGate’s transscleral (across the sclera, or white protective outer membrane of the eye) iontophoresis delivery platform, the EyeGate® II Delivery System, was developed to safely deliver a wide range of therapeutics to both the anterior (front) and posterior (back) chambers of the eye. An 89-patient clinical study, using the company’s first-generation delivery device, demonstrated significant decreases in inflammatory markers and concurrent increases in visual acuity. A typical application takes less than five minutes and has been shown to be extremely well tolerated in patients suffering from severe uveitis and other inflammatory ocular diseases.

    Source : Healthcare Sales & Marketing Network News

  2. Alors que l’Anecortave en traitement curatif de la DMLA exsudative ne trouvera probablement jamais sa place dans notre arsenal thérapeutique, Alcon a présenté au cours du dernier congrès annuel de l’American Glaucoma Society les résultats d’une étude du dépot juxta-scléral d’anecortave en traitement du glaucome chronique à angle ouvert : les deux doses testées (0.25ml ou 0.5ml soit 7.5 ou 15 mg), injectées au maximum tous les mois et demi, ont permis d’observer une réduction significative de la pression intra-oculaire à 3 mois, avec une bonne tolérance…

    Alcon Presents Clinical Trial Data On Anecortave Acetate For Glaucoma
    Article Date: 10 Mar 2008 – 1:00 PDT
    Alcon, Inc. (NYSE: ACL) released the primary efficacy and safety results of the second controlled proof of concept clinical study of anecortave acetate administered as an anterior juxtascleral depot in the sub-Tenon’s space to reduce intraocular pressure in patients with open-angle glaucoma. These initial data were presented at a clinical investigator’s meeting held in association with the annual meeting of the American Glaucoma Society in Washington, DC.

    In this safety and efficacy study, 89 patients were randomly assigned to one of three arms: 7.5mg of anecortave acetate dosed with 0.25 mL of 30 mg/mL suspension, 15mg of anecortave acetate dosed with 0.5 mL of 30mg/mL suspension or 0.5 mL of vehicle. Prior to enrolling in the study, all patients had been diagnosed with open-angle glaucoma, had confirmed visual field changes and had off-therapy intraocular pressures (IOP) between 24 mmHg and 36 mmHg. One injection of drug or vehicle was administered to each patient and intraocular pressures were assessed at two weeks, six weeks and at month three, with month three predefined as the visit for primary efficacy. The study design also allowed for a patient to be retreated if more than 42 days had passed since the last administration of anecortave acetate and the patient’s intraocular pressure exceeded 18 mmHg in two consecutive visits scheduled one week apart. The study will continue with clinical assessments at six-week intervals, potentially through month twenty four. The presented results are based on the intent to treat data set of all 89 patients.

    As explained during the presentation, the primary conclusion was that both the 7.5 mg and 15 mg doses of anecortave acetate demonstrated statistically significant lower mean IOP than vehicle at the month three primary efficacy end-point (ANOVA p < 0.05). Additional data in the presentation supported the activity of anecortave acetate in lowering IOP. [...] In terms of safety, the most frequently reported adverse events were related to the procedure and included eye pain, foreign body sensation, hyperemia and blurred vision, which were reported at an incidence of 5 percent to 15 percent. The most frequently reported events related to test article were conjunctival deposits and eye pain which were reported at an incidence of less than 5 percent

    Source : Medical News Today

  3. La radiothérapie, abandonnée depuis longtemps en traitement de la DMLA, pourrait revenir au gout du jour, en complément d’injections initiales d’anti-VEGF, si l’on en croit un communiqué de presse rapportant une communication lors de la dernière Macula Society. Ces données seront bien sûr à confirmer lors de l’étude randomisée de phase III, dont le recrutement a déjà débuté (CABERNET), ce d’autant que le traitement ne semble pas dénué d’effets indésirables… :

    NeoVista Presents One Year Data on Novel Wet AMD Therapy at Macula Society
    PALM BEACH, Fla., March 28 HSMN NewsFeed — NeoVista, Inc. released today to the eye community updated results from a one-year feasibility study of the companys novel epiretinal brachytherapy for the wet form of age-related macular degeneration AMD at the 31st Annual Macula Society Meeting in Palm Beach, Florida. The promising data from the study, which was initiated by NeoVista to test the efficacy and safety of their novel therapy when used in conjunction with Avastin® bevacizumab, showed a marked improvement in mean visual acuity.

    In the ongoing nonrandomized, multicenter feasibility study, 34 subjects with predominantly classic, minimally classic, or occult with no classic choroidal neovascularization CNV received a single 24 Gy treatment of NeoVistas epiretinal brachytherapy in combination with two injections of Avastin, one dose prior to or at the time of radiation delivery and another one month later, depending on which arm of the trial the patient was enrolled in.

    After 12 months of follow-up on 33 of the trial participants, subjects had experienced a mean improvement in visual acuity of 10 letters using the Early Treatment Diabetic Retinopathy Study ETDRS test; 94 percent of patients lost fewer than 15 letters, 39 percent gained 15 or more letters, and 12 percent gained 30 or more letters. 76 percent of the patients in the study did not require additional injections of Avastin throughout the year.

    Most adverse events were related to the vitrectomy procedure retinal tear, retinal detachment, subretinal hemorrhage, and vitreous hemorrhage. No events related to radiation toxicity have been reported to date.

    Jeffrey S. Heier, MD, a retinal specialist, partner at Ophthalmic Consultants of Boston and a consultant for NeoVista, presented the one-year data obtained from trial participants mean age, 72 years who enrolled from June 2006 to April 2007 at two centers in Brazil and one in Mexico.

    « As more data are collected and analyzed surrounding this one-time surgical procedure, were continuing to see the potential of the concomitant approach to treat wet AMD, » said Dr. Heier. « Unlike previous attempts with radiation therapy, NeoVista has developed a means of delivering targeted beta radiation to choroidal neovascular membranes with minimal penetration, resulting in little effect on the surrounding healthy tissue. »

    In contrast to other forms of radiation therapy for wet AMD, NeoVistas approach delivers the peak dose of energy directly to the lesion without irreparably damaging the normal retinal vasculature. Utilizing strontium 90, the focused energy is delivered to a target area up to 3 mm in depth and up to 5.4 mm in diameter. Importantly for patients, the systemic exposure to radiation is minimal, as the effective dose to the entire body from NeoVistas epiretinal device is less than that from a typical chest x-ray.[…]

    The CABERNET CNV Secondary to AMD Treated with BEta RadiatioN Epiretinal Therapy trial is a multicenter, randomized, controlled study that will enroll 450 subjects at clinical centers worldwide. The study will evaluate the safety and efficacy of NeoVistas epiretinal beta radiation therapy delivered concomitantly with the FDA-approved antiangiogenic therapy Lucentis® ranibizumab versus Lucentis alone.

    Source : Healthcare Sales & Marketing Network

Ophtalmologie

Ophthotech attaque la DMLA sur tous les fronts

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Si les médicaments anti-angiogéniques actuels ont tous le même but (se lier au VEGF afin d’empecher la liaison à ses récepteurs), Ophthotech a dans son pipeline trois molécules qui s’attaquent à d’autres cibles :

  • Suite à un accord de licence avec Biogen Idec et PDL BioPharma, ils développent le volociximab (M200) en ophtalmologie :

    Volociximab is an investigational monoclonal antibody targeting α5β1 integrin, a key protein involved in the formation of blood vessels, a process known as angiogenesis. […] “α5β1 integrin is a critical survival factor for proliferating endothelial cells involved in angiogenesis,” said Samir Patel, MD, president and CEO of Ophthotech. « The preclinical studies to date provide very strong support for developing volociximab for ophthalmic indications. It represents a potential breakthrough for the treatment of AMD.”

    Source : OphthalmologyWeb

  • Un aptamer anti-PDGF (E10030) entre en phase I, afin d’étudier sa tolérance en combinaison avec un anti-VEGF :

    Platelet-derived growth factors (PDGFs) and their receptors are critical targets in anti-angiogenic therapy. PDGF plays a significant role in angiogenesis and has been implicated in ocular neovascularization. The activities of PDGF and VEGF in the initiation of angiogenesis and mediation of blood vessel growth and behavior are independent of each other, suggesting that concurrent inhibition could lead to superior efficacy in treating neovascularization.

    Platelet-derived growth factor B (PDGF-B) is implicated in vascular stability and function through its role in activating the recruitment of mural cells (pericytes) by endothelial cells to envelop the developing vasculature. Pericyte recruitment is part of the maturation process in blood vessel development and pericytes act as support cells for mature blood vessels. Once the mural cell population is well established, the effectiveness of anti-VEGF agents is greatly reduced. It is possible that disruption and stripping of mural cell recruitment by an anti-PDGF agent could potentiate the efficacy of an anti-VEGF attack by causing neovascular regression. Therefore, combination therapy in wet AMD with anti-VEGF and anti-PDGF agents could represent breakthrough therapy.

    E10030, an aptamer-based compound directed against PDGF-B, is being developed for the potential treatment of wet AMD. E10030 is a pegylated aptamer containing 32 monomeric units (32-mer) arranged as a linear sequence of three oligonucleotide segments connected by non-nucleotide hexaethylene glycol spacers. The aptamer terminates in a hexylamino linker to which two 20-kilodalton monomethoxy polyethylene glycol units are covalently attached via the two amino groups on a lysine residue.

    Pharmacology studies indicate that E10030 binds to PDGF-B with high specificity and affinity and inhibits the functions of PDGF-B both in vitro and in vivo. In pre-clinical studies, E10030 demonstrated the potential to regress neovascularization when used in combination with a VEGF-A inhibitor. In experiments involving models of ocular vascularization [1], concurrent inhibition of PDGF-B and VEGF-A signaling was superior to inhibition of the VEGF-A pathway alone. The combined treatment was able to induce the regression of existing vessels, compared to inhibition of VEGF-A alone. Findings from a corneal neovascularization model demonstrated that pericytes were stripped from newly growing vessels, but not from existing limbal vessels. This evidence suggests that combined administration of an anti-PDGF-B agent with an anti-VEGF agent may result in regression of abnormal blood vessels in neovascular AMD while preserving the normal vascular architecture. Therefore, combination therapy with a regimen incorporating an anti-PDGF agent with an anti-VEGF agent holds great promise for enhanced efficacy in wet AMD.

    Source : OSN

  • En parcourant leur site internet, on trouve aussi que la voie du complément n’est pas oubliée, avec un aptamer anti-C5 (ARC1905) :

    Evidence for complement-mediated inflammation in AMD is further reinforced by genetic linkage and association studies which suggest that approximately 50 to 75% of AMD cases have polymorphism in complement regulatory proteins compared to age-matched controls. […]
    Anti-C5 aptamer ARC1905 is a potent and specific inhibitor of complement activation. ARC1905 is a pegylated RNA aptamer. ARC1905 inhibits C5, a central component of the complement cascade, which plays multiple roles in innate immunity and inflammatory diseases. Inhibition of this key step in the complement cascade at the level of C5 prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced their generation. The C5a fragment is an important inflammatory activator inducing vascular permeability, recruitment and activation of phagocytes. C5b-9 is involved in the formation of membrane attack complex (MAC: C5b-9) which initiates cells lysis. By inhibiting these C5-mediated inflammatory and MAC activities, therapeutic benefit may be achieved in both dry as well as wet AMD.

Ophtalmologie

Administration de médicaments en ophtalmologie

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Après les collyres, pommades, injections péri-oculaires (sous-conjonctivale, sous-ténonienne, péri-bulbaire etc) et intravitréennes, voire iontophorèse, un nouveau mode d’administration de médicaments ophtalmologiques pourrait voir le jour : le « dépot sous-palpébral », si l’on en croit Médical News Today rapportant une communication de Y. Chen :

[…] a new gel for under the eyelid could provide an innovative way of delivering drugs to treat age-related retinal diseases such as wet macular degeneration – potentially making some invasive eye injections a thing of the past. […]
Yvonne Chen set out to develop an alternative way of delivering drugs to the retina based on « smart » polymers that behave as liquids at room temperature, but rapidly transform (in less than a minute) to a gel at body temperature. This unique feature offers the advantages of easily adding a drug to a formulation (especially for heat-sensitive biologically-active drugs) and delivering drugs locally.
The liquid is injected under the eyelid and deposits on the white of the eye. Once in contact with the increased temperature of the body, the liquid converts to a gel and provides a depot (or reservoir) for the drug, allowing it to slowly move towards the retina over several hours. This gel system also prolongs the drug release duration so that controlled drug release can be achieved. It is hoped the less invasive gel will lead to better compliance.
Yvonne said: « Experiments have shown that this new gel may well prove to be a breakthrough in treating retinal diseases, with major benefits to patient comfort and healthcare outcomes.

Ophtalmologie

Aspirine et Warfarine : facteurs de risque d’occlusion veineuse rétinienne ?

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Alors que beaucoup préconisent encore de donner en traitement des occlusions de la veine centrale de la rétine des antiagrégants plaquettaires (type aspirine) voire des anticoagulants, une étude présentée à l’ARVO semble démontrer qu’au contraire, certains d’entre eux pourraient en être un facteur de risque indépendant !

FORT LAUDERDALE, Fla. — Antithrombotic medications aspirin and warfarin are independent risk factors for the development of central retinal vein occlusion, according to one researcher speaking here.

« Past hypotheses have centered on the thrombus, » Hideki Koizumi, MD, said at the Association for Research in Vision and Ophthalmology meeting.

Dr. Koizumi presented data from 144 consecutive patients with central retinal vein occlusion CRVO who were compared with 144 gender- and age-matched controls to determine risk factors.

Mean age of CRVO patients was 70 years, and mean age of control patients was 69 years. Male-to-female ratio was 87:57 in both groups.

In addition to known CRVO risk factors such as hypertension, diabetes mellitus, atrial fibrillation and glaucoma, aspirin and warfarin were significantly linked to CRVO by univariate analysis, according to the study results.

Multivariate logistic regression model also found aspirin and warfarin to be independent risk factors for CRVO, he said.

« While these findings imply the vasculopathic and prothrombotic risks in some patients may not be fully addressed by antithrombotic therapy, they also suggest the pathogenesis of CRVO may be more complicated than just the development of a primary thrombus within the vein, » Dr. Koizumi said.

Bien sûr, il faudra lire en détail la publication pour conclure…
Cependant, vu le nombre de patients déjà sous ce type de traitements lorsque survient l’occlusion veineuse rétinienne, il est déjà fort probable qu’ils ne servent à rien…

Via OSN SuperSite.
Abstract complet : Continuer la lecture de Aspirine et Warfarine : facteurs de risque d’occlusion veineuse rétinienne ? →

Ophtalmologie

Le prochain traitement de la DMLA sera-t-il un collyre ?

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Après les traitements par laser, thérapie photodynamique puis injections intra-vitréennes, l’avenir dans la prise en charge de la DMLA pourrait être un collyre. En effet, parallèlement au développement d’OT551 (Othera), au moins deux autres laboratoires travaillent sur cette voie d’administration.

  • Comentis (ex-Athenagen) lance un essai de phase II avec un inhibiteur des récepteurs nicotiniques à l’acétylcholine (ATG3) :

    CoMentis Initiates Phase II Clinical Trial for AMD Eye Drop Therapy
    South San Francisco, CA – April 10, 2007–CoMentis, Inc. (formerly Athenagen), a privately held biopharmaceutical company, announced today the initiation of a Phase II clinical study of ATG3, the company’s topical eye drop therapy for neovascular age-related macular degeneration (NV-AMD). A proprietary ophthalmic formulation of mecamylamine, ATG3 is an antagonist of the nicotinic acetylcholine (nACh) receptor pathway that mediates angiogenesis. The drug was developed to effectively penetrate into the retina and choroid following topical eye drop administration.

    This Phase II study is a double-masked, randomized, placebo-controlled clinical trial designed to evaluate the safety and efficacy of ATG3 in patients with NV-AMD (also known as “wet’ AMD). Approximately 330 patients will be randomized to one of three treatment groups, administered by eye drop twice daily: two different doses of ATG3 or placebo. One eye per patient will receive the study treatment. All patients will be treated for up to 48 weeks, during which time they will be monitored for safety, tolerability and efficacy assessments. Patients will be assessed for change in visual acuity and macular thickness using ocular coherence tomography.
    “In January we completed our Phase I study of ATG3 in healthy volunteers and found excellent ocular safety following eye drop administration,” said Henry Hsu, M.D., Chief Medical Officer of CoMentis. “We are very pleased to begin this international Phase II study as planned, and expect to have interim (six month) efficacy data by mid-2008. ATG3 could be the first topical angiogenic treatment for AMD and if approved, would compliment current therapies which require injection directly into the eye.” Inhibition of the nicotinic acetylcholine (nACh) receptor pathway, which was discovered at Stanford by two of CoMentis’s founding scientists, also down regulates vascular endothelial-derived growth factor (VEGF) dependent angiogenesis. Studies in animal models have demonstrated excellent penetration of the proprietary ATG3 formulation to the retina and choroid following eye drop application as well as reduction of new blood vessel growth in the eye.

  • Targegen développe un inhibiteur de kinases (TG100801) :

    TargeGen Announces Successful Completion of Phase I Clinical Trial Of Topical AMD Drug TG100801
    San Diego, CA – Feb. 27, 2007 – TargeGen, Inc. has announced that the Company has completed a single-center Phase I clinical trial of TG100801 in 42 healthy volunteer subjects. TG100801 is a small molecule, topically applied (eye drop), multi-target kinase inhibitor that is being developed for the treatment of macular degeneration and other debilitating diseases of the eye. Preliminary results from this Phase I study suggest that TG100801 is well tolerated in humans at the low and high doses tested when applied topically twice daily for 14 days. Final study results are expected by the end of April 2007. TargeGen currently plans to initiate Phase II clinical trials in wet age-related macular degeneration (AMD) patients in mid-2007.

    TG100801, applied daily in eye drop form, is designed to suppress disease related edema, angiogenesis and inflammation simultaneously. Edema, angiogenesis and inflammation are pathological hallmarks of AMD, diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Currently approved therapies for macular degeneration require repeated injection into the eye.

    “The successful completion of this ‘first in human’ safety study with TG100801 represents a meaningful milestone for TargeGen and sets the stage for the near term initiation of human efficacy trials. We remain very optimistic about the potential for demonstrating efficacy in humans in the near future,” stated Peter G. Ulrich, President, CEO and Co-Founder of TargeGen.

Sources : http://www.athenagen.com/index.php?/athenagen/press_releases/43/
http://www.targegen.com/news022707.htm