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Therapeutic development for ocular diseases of aberrant neovasculature, notably macular degeneration and diabetic retinopathy among others, has been lagging in the pharma industry. Only three drugs have been approved for macular degeneration, Visudyne with photodynamic therapy (PDT), MacugenTM and LucentisTM . Visudyne with PDT uses laser light to photocoagulate vessels with the use of Visudyne to enhance the activity of the laser. Although laser photocoagulation can be successful in treating vascular progression, it has significant drawbacks. PDT cannot be used when vessels are in the central or foveal region of the eye due to neighboring photoreceptor damage and inherent retinal scarring resulting in local loss of vision. In addition, in advanced cases of retinal disease, bleeding may occur which makes it difficult to see vessels to use photocoagulation. Therapeutic intervention in diseases of ocular vascularization remains an unmet need.

Pharmaceutical companies developing anti-angiogenic drugs for cancer have been looking at the ocular market. Notably one company, Eyetech/OSI, has met the challenge with its drug MacugenTM, an oligonucleotide VEGF neutralizing agent, developed and approved for macular degeneration in December 2004. This makes the first drug approved for an anti-angiogenesis application for the eye. Later in June 2006, LucentisTM, a monoclonal antibody fragment VEGF neutralizing agent, was also approved by the FDA to treat macular degeneration. Although these two drugs were brought to market under the banner of being an anti-angiogenic agent, it appears their activity in patients revolve around their ability to inhibit vascular permeability. In patients with macular degeneration, aberrant vessels in the eye are leaky hence induce edema and hemorrhage. VEGF antagonists quickly reduce permeability of these aberrant vessels and provide rapid improvement in vision. However, not unlike tumor initiated angiogenesis, a wide variety of angiogenic cytokines have been found in diseases of aberrant vasculature in the eye. For this reason, it is not likely that anti-VEGF modalities inhibit new vessels from forming nor regress existing vessels. In fact, in most cases both MacugenTM and LucentisTM need to be given intravitreal (injection of drug directly into the eye) monthly for activity which gives credence to a vascular permeability mechanism as opposed to an anti-angiogenic one. Furthermore, clinical trials of LucentisTM did not show vessel regression, again lacking direct anti-angiogenic modality. Hence, therapeutic modalities mirroring the history of development in cancer is following in ocular diseases. This has resulted in companies now looking for broad cytokine neutralizing modalities. Again, as discussed for cancer, the Company feels P529 to be a superior drug for diseases of aberrant neovasculature of the eye.

P529 shows both anti-angiogenic and anti-proliferative activity as described above. Ocular diseases of neovasculature, namely of retinal origin (age-related macular degeneration and diabetic retinopathy), create aberrant vessels in a manner not unlike that created in cancer, with two caveats. In cancer, the tumor cell is the initiator of angiogenesis by secreting pro-angiogenic factors to induce the angiogenic cascade of events. In ocular diseases, the cellular initiators of angiogenesis are not entirely clear. However, data supports that a host of pro-angiogenic factors are present in a variety of ocular compartments of identical composition to that shown to induce angiogenesis in cancer. Under these circumstances, what would make an optimal drug for macular degeneration and diabetic retinopathy? As these diseases are chronic, one would need to administer drug for the life of the patient. Hence the drug needs to exert effect over a long term to obviate frequent administration (assuming local administration). The drug would need to inhibit vessel formation and regress existing vessels along with correcting in the short term the vascular leakage. Lastly, as these diseases may form retinal detachment and scarring, it would be beneficial if a drug would have an effect on problems outside of neovascularization. There is data to support all of these needs in P529.

P529 has shown activity in in vitro models of angiogenesis described above as well as animal models of ocular diseases. As the drug is an inhibitor of VEGF (signal transduction and synthesis) it makes a favorable drug to inhibit vascular leakage. In a rabbit model of macular degeneration, a bFGF/VEGF pellet was placed suprachoroidal to induce subretinal angiogenesis. This model induces subretinal capillary growth within 10 days progressing for over 28 days. P529 was able to inhibit angiogenesis in a dose dependent manner completely inhibiting angiogenesis for the length of the 28 day model. As P529 has limited solubility in aqueous medium, it has the ability to remain in the vitreous as a depot thereby limiting the need for multiple intravitreal dosing over time, as shown in this model over the course of the 28 day period. In addition, a six month rabbit intravitreal biodistribution was study was carried out showing that not only does P529 remain in the eye for at least six months, it was able to transport to the retinal and choroid, relevant tissues in macular degeneration and diabetic retinopathy. Of particular interest, placing the drug subconjunctival in another rabbit model showed that the drug could move from the conjunctiva to again the retina and choroid, as well as remain in the eye for at least three weeks. Giving the drug either intravitreal or subconjunctival did not result in overt toxicity. As subconjunctival administration is not invasive (does not penetrate the globe of the eye) toxicity due to mode of administration, compared to intravitreal administration which is invasive, is significantly reduced as is patient acceptance. In a murine laser-induced retinopathy model, P529 was able to inhibit subretinal neovascularization by 65%. In a model of diabetic retinopathy, the retinopathy of prematurity model (also called the oxygen-induced retinopathy model), P529 also showed a 65% reduction in retinal neovascularization. In this model as a comparator, most anti-angiogenesis drugs inhibit angiogenesis in a range of 30-40%. Additionally, P529 was not only able to just inhibit angiogenesis in this model but allowed normal angiogenesis to occur. This suggests that P529 could have a positive safety profile in the clinic relative to the need for normal angiogenesis. Lastly, as retinal diseases of neovasculature can develop retinal detachment leading to retinal scarring, it was of particular interested to determine if P529 could have an effect in a rabbit model of retinal detachment. To this end, P529 was examined in a rabbit model of retinal detachment which showed a reduction of the presence of glial cells at the site of detachment and elimination of retinal scar formation.
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