Archives du mot-clé DMLA

Iontophorèse, Anecortave, Radiothérapie : du nouveau…

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’œil, 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

Ophthotech attaque la DMLA sur tous les fronts

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.

Imagerie rétinienne en 3D sur YouTube

Trouvées par hasard sur YouTube, quelques pathologies représentées en 3D grâce à l’un des nouveaux OCT, dits « Spectral-Domain » (Topcon) :

  • Drusen :
  • Décollement de l’épithélium pigmentaire :
  • Syndrome de traction vitréorétinienne :
  • Membrane épi-rétinienne :
  • Trou maculaire :

Si la représentation de l’OCT en 3D ne nous apporte pas forcément grand chose pour porter un diagnostic, ces images sont probablement plus parlantes pour les patients, en plus d’être jolies !

J’en profite pour vous signaler l’existence d’un site en français dédié à la Tomographie en Cohérence Optique : oct-ophtalmo.fr

DMLA et accidents thrombo-emboliques (AVC, infarctus)

Les résultats à un an de l’étude SAILOR et une étude parue dans le British Journal of Ophthalmology apportent de nouveaux éléments quant au risque d’accidents thrombo-embolique des patients atteints de DMLA :

  1. Alors que l’analyse intermédiaire (à 6 mois) de SAILOR faisait craindre une augmentation du risque d’AVC sous Lucentis (notamment pour les patients ayant déjà des antécédents d’accidents de ce type), les données à un an, communiquées récemment, sont plutôt rassurants, avec certes toujours une « tendance » à une incidence supérieure d’AVC sous Lucentis 0.5 mg par rapport à 0.3 (1.2% vs 0.7%), mais la différence n’est pas statistiquement significative (p=0.21) :

    One-year data on the phase 3b SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) trial showed the drug was safe and was not associated with higher rate of stroke, according to principal investigator David S. Boyer, MD, at Bascom Palmer Eye Institute’s Angiogenesis, Exudation, and Degeneration 2008 meeting in Key Biscayne, Florida.

    The study included approximately 4,300 patients with all subtypes of new or recurrent active subfoveal wet age-related macular degeneration (AMD) who were treated with 0.3 mg or 0.5 mg doses of intravitreal ranibizumab (Lucentis, Genentech). Results were based off of information gathered from cohort 1, which included 2,378 patients.

    These data come almost 1 year after Genentech issued a letter to physician-users (a so-called « Dear Doctor » letter) in January 2007, noting safety concerns in the interim safety analysis of SAILOR. That preliminary data showed a four-fold difference in the rate of strokes in the group receiving the 0.5-mg (1.2%) than in the group receiving the 0.3-mg dose (0.3%) at an average follow-up of 230 days. Patients with previous history of stroke appeared to be at higher risk for stroke during the trial.

    One-year results, however demonstrated that although the US Food and Drug Administration (FDA) approved dose of Lucentis (0.5 mg) trended toward a higher incidence of stroke (1.2% vs. 0.7% in the 0.3 mg dose group) the results were not statistically significant (P=.21). The stroke rate in the general US population (65 years of age or older) is 1.4%, according to Anne E. Fung, MD, who presented at the same meeting on the rates of arterial thromboembolic events in Medicare patients.

    « I think that we over-analyzed the 6-month data; perhaps it was blown a bit out of proportion in comparison to all of the other studies out there at the time, » Dr. Boyer said in a telephone interview with Retina Today. « Genentech reported the 6-month data, as it should have. But I think that [the results of SAILOR] are one of the reasons you wait for a year to get the complete data. We now see that there was no probable statistical significance — the numbers just caught up by the end of the trial. If we examined the data for a longer period of time, those numbers for the two dosing groups might even come closer in line to each other. »

    As SAILOR was a 1-year study, there are no further plans to continue the trial, Genentech spokeswoman Krysta Pellegrino told Retina Today. Results for the second SAILOR cohort (approximately 1,900 patients), however, will be available sometime this year.

    Sur MDSupport.org, il est précisé que cette tendance (9.6% vs 2.7% quand même !) est également observée dans le sous-groupe de patients aux antécédents d’AVC, mais qu’il est difficile de conclure en raison du faible nombre d’évènements :

    At one-year, patients with a prior history of stroke had a higher rate of stroke in the 0.5 group (9.6%) compared to the 0.3 group (2.7%). However, this trend was inconclusive, as the number of events was small. These data are consistent with epidemiologic data showing that prior history of stroke predisposes patients to subsequent stroke.

  2. Dans une publication en ligne depuis le 29 février, basée sur les examens de patients 10 ans après leur inclusion dans la Blue Mountain study, les sujets de moins de 75 ans avec des signes de maculopathie liée à l’âge à l’inclusion ont un risque de décéder par AVC ou infarctus du myocarde à 10 ans multiplié par 2, par rapport aux patients sans signe de DMLA.
    Pour ceux qui avaient déjà à l’inclusion des signes de DMLA compliquée, le risque est multiplié par 5 (infarctus du myocarde) à 10 (AVC).

    Background/aims: Age-related macular degeneration (AMD) and vascular disease share similar risk factors. Recent data suggest AMD may independently predict stroke or coronary heart disease. We prospectively assessed the relationship between AMD and risk of stroke- or cardiovascular-related death in an Australian population.
    Methods: Of 3654 baseline participants (1992-4) aged 49+years, 2335 were re-examined after 5-years and 1952 after 10-years. Retinal photographs were graded using the Wisconsin System. History and physical examination provided data on possible risk factors. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Risk ratios (RR) were estimated in Cox models.
    Results: Among persons aged <75 years at baseline, early AMD predicted a doubling of cardiovascular mortality (RR, 2.32; 95% confidence interval (CI), 1.03-5.19), over the next decade, after controlling for traditional cardiovascular risk factors. Late AMD predicted 5-fold higher cardiovascular mortality (RR, 5.57; CI, 1.35-22.99) and 10-fold higher stroke mortality (RR, 10.21; CI, 2.39-43.60) after adjusting for age and sex only. These associations were not present when persons older than 75 were included. Conclusion: AMD predicted stroke and cardiovascular events over the long-term in persons aged 49-75 years. This may have potential implications for new intravitreal anti-VEGF AMD therapies. Tan JS, Wang JJ, Liew G, Rochtchina E, Mitchell P. Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol. 2008 Feb 29 [Epub ahead of print]

Donc, chez les patients traités par anti-VEGF pour DMLA exsudative, il semble que la probabilité de décéder d’un AVC ou d’un infarctus du myocarde soit plus du fait de facteurs de risques partagés entre DMLA et pathologies cardio-vasculaires, que d’un traitement anti-VEGF…
Mais, en raison du (finalement) faible nombre d’évènements, il faudra probablement attendre d’avoir un peu plus de recul pour conclure de manière formelle…

Source : Retina Today eNews

Disponibilité de l’Avastin : accord entre Genentech et ophtalmologistes américains

En cette période de « trêve des confiseurs« , un accord semble avoir été trouvé entre Genentech (le fabriquant de Lucentis et Avastin) et ophtalmologistes américains, qui permettra donc à ces derniers de continuer à s’approvisionner en Avastin.

Les ophtalmologistes pourront en effet le commander directement auprès de grossistes, qui livreront le médicament, au choix, soit à une pharmacie hospitalière, soit à une « compounding » pharmacie, soit au praticien lui même.

Bien que la mise en place de cette « filière » puisse varier selon les états, cette décision marque donc un signe de bonne volonté du laboratoire pour permettre l’accès à l’Avastin.

Source : OSN, New York Times.

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