Ohr Pharmaceutical initiates Investigator sponsored trial of squalamine eye drops in diabetic macular edema

Ohr Pharmaceutical, Inc., a research and development company with a primary focus in ophthalmology, has announced the initiation of a Phase II investigator sponsored clinical trial, OHR-005, testing Squalamine eye drops in patients with diabetic macular edema (DME).

The current standards of care for DME include chronic treatments of VEGF inhibitors administered directly into the eye via an injection. Squalamine eye drops may potentially represent a less-invasive treatment option for patients suffering from diabetic macular edema, as per the investigators of this trial. 

OHR-005 is a randomized, placebo controlled, investigator sponsored, multicenter Phase II clinical trial evaluating the effect of Squalamine Eye Drops in patients with DME. The primary endpoints will measure change in retinal thickness and change in Best Corrected Visual Acuity (BCVA) over 24 weeks. Secondary objectives include additional BCVA measurements, change in foveal thickness, evaluation of the need for rescue injections of ranibizumab (Lucentis®) and an assessment of the safety and tolerability of Squalamine Eye Drops. The trial is designed to enroll up to 30 subjects at 3 sites in the United States. Patients will be randomized to receive a single injection of ranibizumab at baseline followed by treatment with either Squalamine lactate ophthalmic solution 0.2% or placebo ophthalmic solution, administered QID for 24 weeks.

Squalamine is an anti-angiogenic small molecule with a novel intracellular mechanism of action, which counteracts multiple growth factors implicated in the angiogenesis process. Ohr Pharmaceutical has developed a novel eye drop formulation of Squalamine for the treatment of wet-AMD, designed for self-administration, which may provide several potential advantages over the FDA approved current standards of care, which require intravitreal injections directly into the eye. The drug, using an intravenous administration in over 250 patients in Phase I and Phase II trials for the treatment of wet-AMD, showed favorable biological effect and maintained and improved visual acuity outcomes. In May 2012, the Squalamine Eye Drop program was granted Fast Track Designation by the FDA. A Phase II randomized, double blind, placebo-controlled study (OHR-002) to evaluate the efficacy and safety of Squalamine Eye Drops for the treatment of wet-AMD has completed enrolling patients. Three additional investigator sponsored trials (IST) are evaluating Squalamine eye drops for the treatment of proliferative diabetic retinopathy, retinal vein occlusion and diabetic macular edema, with one additional IST expected to be initiated in diabetic macular edema in the second calendar quarter of 2014.

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New technique to determine gene carriers for autosomal recessive retinitis pigmentosa

Scientists from Bascom Palmer Eye Institute and Duke University Medical Center have developed a non-invasive technique to determine if individuals carry a gene for the autosomal recessive type of retinitis pigmentosa. 

The work was being presented at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Orlando, Florida.

The technique involves collecting a patient's urine and measuring the ratio between specific compounds. The non-invasive process makes subsequent testing clinic-friendly, especially for children being screened.

In search of quantitative biomarkers for the disease, the authors checked on the urinary and plasma dolichol profiles in autosomal recessive RP (arRP) patients and carriers with mutations in the DHDDS gene encoding dehydrodolichol diphosphate synthase, a key enzyme in dolichol biosynthesis. Dolichols are long chain polyisoprenoid alcohols composed of 17-21 isoprene units.

Mutations in the DHDDS gene lead to a characteristic shortening of plasma and urinary dolichols, which, as per the authors of this study, can be used as a functional readout of the enzyme. Urinary and plasma D18/D19 ratios reliably determine if a DHDDS genotype is disease-causing. 

D18/D19 ratio is a viable objective functional biomarker and can be readily adapted as a clinical test for arRP diagnosis and carrier screening with DHDDS or other genetic mutations that impair dolichol biosynthesis.

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Coffee may prevent hypoxia-induced retinal degeneration

Retina is one of the most metabolically active tissues in the body, consuming oxygen more rapidly than any other tissues, including the brain. Therefore, it is susceptible to a variety of diseases caused by oxidative stress, including age-related macular degeneration, diabetic retinopathy, and glaucoma - all of which can lead to partial or complete blindness.

One mechanism of retinal degeneration is hypoxia, a reduction in retinal oxygen supply caused by pathologies such as central retinal artery occlusion, ischemic central retinal vein thrombosis, complications of diabetic eye disease, and some types of glaucoma that cause vascular eye diseases. Retinal hypoxia can negatively impact both tissue function and cell viability, and is a potential risk factor for sight-threatening disorders. Hence there has been a great interest in identifying neuroprotective compounds that inhibit hypoxia. Particularly promising in this capacity are natural products and phytochemicals that act as antioxidants and can be taken regularly without causing significant side effects.

One important group of neuroprotectants comprises derivatives of chlorogenic acid (CGA) found in a variety of edible plants, including tea, fruits, and vegetables, with the major source of intake in humans being coffee. Collectively, these phenolic phytochemicals are known to have hepatoprotective, antibacterial, anti-inflammatory, DNA protective, and anticancer activities, among others. Several studies have also suggested that the antioxidant properties of CGA make it a powerful neuroprotectant.

In raw coffee, CGA amounts to about 4–12% of raw coffee, while a 200 mL cup of prepared coffee contains 200 mg of total CGA. Coffee consumption appears to decrease the risk of developing chronic diseases such as Parkinson’s, prostate cancer, and diabetes. It also reduces the extent of cognitive declines associated with aging. The current study was designed to investigate whether coffee and, in particular, its main polyphenol, CGA, has protective effects against the degeneration of retinal ganglion cells (RGC), both in vitro and in vivo.

The researchers found that CGA significantly reduced the negative effect of the hypoxic agent on the cells being studied, with cell viability increasing with more CGA pretreatment. Also in animal models that mimic glaucoma, where the inner plexiform layer appears thinned, pretreatment with CGA reduced the amount of thinning seen. The authors also noted reduction in ganglion cell apoptosis.

This study demonstrates that CGA and coffee extract are responsible for reduction of the RGC apoptosis induced by hypoxia. Thus, coffee consumption may provide additional health benefits by preventing retinal degeneration.

Sources: Journal of Agricultural and Food Chemistry

DENAQ, a new chemical that may restore sight in retinitis pigmentosa and macular degeneration

Scientists from the University of California, Berkeley report on a chemical ‘photoswitch’ named DENAQ that may be a potential drug for treating patients suffering from blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

RP and AMD are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. In the paper published in Neuron, the authors led by Dr Richard H Kramer report about a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight, compared to earlier attempts at photoswitch that required very bright ultraviolet light, making it unsuitable for use in patients. In experiments conducted on three-month to six-month-old healthy mice, and on mice carrying a mutation causing nearly all their rods and cones to degenerate by the time they were a month old, a single intraocular injection of DENAQ has been able to photosensitize the blind retina for about 3 days, restoring electrophysiological and behavioral responses with no toxicity. DENAQ also is able to rapidly turns itself off, allowing rapid repeated stimulation of the retina. The researchers compared the retinae of DENAQ-injected mice to untreated healthy mice and found no signs of toxicity for up to 30 days after the injection.

Retinas with damaged rods and cones are subject to several morphological and biochemical changes, making them different from a healthy retina in more than one way. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated or dead photoreceptors. Apparently, the degenerated outer retinal cells help in DENAQ photosensitization due to changes in electrophysiological characteristics, while the presence of intact photoreceptors possibly prevent this action. This appears to give it significant advantage, since this selective action on diseased tissue alone may potentially reduce side effects on healthy retina.

DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.

The researchers plan on conducting more experiments, including in larger animals before its safety can be established and any clinical trials can be considered.

To watch a video of Dr Kramer explaining his work, click here.

Sources: Neuron, Univ of California, Berkeley, Kramer Lab, The Scientist

Editor's note: The drug appears to have an exciting potential to help patients with retinitis pigmentosa and age-related macular degeneration. There are two thoughts though. 

1. Such a drug may only work in advanced stages of the disease, considering we will have to wait for the retinal cells to die before it can act.

2. We also need to know how long the effect of one injection lasts. Such treatment may require repeat injections over a long-term, something similar to Lucentis or Avastin.

QLT announces clinical & regulatory update for oral retinoid program for inherited retinal disease

QLT announced that, following meetings with the U.S. Food and Drug Administration and the European Medicines Agency, the Company believes that it is close to finalizing a pivotal trial protocol for QLT091001 for the treatment of inherited retinal disease such as Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP) due to mutations in the LRAT and RPE65 genes, both orphan indications.

The Company expects to provide final guidance on its development plans in these indications before the end of the first quarter of 2014 after final feedback from the European regulatory agency.

Additionally, QLT has initiated recruitment of subjects for a Phase IIa proof-of-concept trial of its drug candidate, QLT091001, in adult subjects with Impaired Dark Adaptation (IDA), a condition that results in decreased ability to recover visual sensitivity in the dark after exposure to bright lights.

The Company also announced the launch of a compassionate use program for QLT091001 in LCA and RP, as well as plans for a patient registry and an update on its retreatment study in these indications.

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Govt accepts Ranjit Roy panel report on approval of new drugs, clinical trials & banning of drugs

The Union Health Ministry has accepted the recommendations of the Prof. Ranjit Roy Chaudhury expert committee.  The committee was constituted by the ministry in February this year to formulate policy and guidelines for approval of new drugs, clinical trials and banning of drugs.

According to senior officials in the ministry, the recommendations of the expert committee were discussed in a meeting with its members recently. During the meeting, clarifications on certain recommendations were obtained from the committee. After the meeting, the ministry in-principle accepted the recommendations of the committee. 

Accepting the recommendations of the expert panel for accreditation of ethics committees, investigators and the clinical trial sites, the ministry decided that in order to strengthen the clinical evaluation of new drugs, the clinical trials should be conducted in accredited sites by accredited investigators with the oversight of accredited ethics committees (Ecs). As this is a long term measure, in the meantime, Quality Council of India (QCI) will be considered for creating a system for accreditation of investigators, ethics committee and clinical trial sites. Although the Drugs & Cosmetics Rules, 1945, already provide for registration of ethics committee, accreditation of such committees will be undertaken following a specific procedure. 

As this requires amendments in the Drugs & Cosmetics Rules, as an immediate measure, CDSCO would initiate steps relating to the process of accreditation by constituting an expert body of 20-25 experts. The names of experts will be finalized by CDSCO in consultation with Dr. Ranjit Roy Chaudhury, Dr. Y. K. Gupta, Prof. & Head, Dept. of Pharmacology, AIIMS, New Delhi and Dr. Arun Aggarwal, Prof. of ENT, Maulana Azad Medical College, New Delhi, senior officials in the ministry said. 

Accepting the recommendations of the committee on the procedure for review of applications of clinical trials and new drugs, officials said that the New Drug Advisory Committees (NDACs) will be renamed as Subject Expert Committees. The members for their meetings will be drawn randomly from a large pool of experts. Applications of clinical trials and new drugs will initially be evaluated by the Subject Expert Committees and their recommendations will be reviewed by the Technical Review Committee (TRC). The TRC will be constituted under DGHS and consisting of experts from each areas i.e. clinical pharmacology, regulatory clinical toxicology/ pathology, medicinal/ pharmaceutical chemistry, pharmacy and immunology including clinicians, basic scientists involved in drug development and subjects specialists (drug indication wise). CDSCO will grant approval of clinical trial and new drugs based on the recommendations of TRC.

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UT Arlington researchers exploring better methods for gene therapies to fight the sight-deteriorating disease Retinitis Pigmentosa.

UT Arlington researchers are exploring a better method for initiating certain gene therapies that could better fight the sight-deteriorating disease retinitis pigmentosa. This research is funded by the National Institutes of Health.

Dr Samarendra Mohanty, Assistant Professor of Physics, at UT Arlington, is focused on using near-infrared ultrafast laser beam to deliver genes that allow expression of light-sensitive proteins, called opsins, into specific cells. That proteins’ expression allows researchers to influence neural activity through optical or light stimulation – a technique known as optogenetics.

In the past, the genes have been delivered to cells by virus. That method can have drawbacks, such as immune responses, in addition to the benefits. In Mohanty’s method, a laser beam creates a transient sub-micrometer size hole, which allows for the gene encoding the proteins to permeate through the cell membrane. It can limit the risk of immune response, as well as delivering larger genes than viral methods, he said.

The scientists claim that with the minimally invasive near-infrared method, DNA and other impermeable molecules can be effectively delivered only to the places most required. In retinitis pigmentosa, the peripheral retina begins to lose light sensitivity due to loss of photoreceptors. With this method, a laser can deliver the genes only to the required part of the retina, making those neurons respond to light again. This method will be more effective than a virus, where the genes are delivered everywhere, potentially causing complications in areas that are already working fine.

Optogenetic stimulation also holds promise for influencing neurons in the brain. Scientists, including Mohanty’s research group, are researching ways it could be used to understand how the brain works or to intervene in case of neurological disorders or to affect behavior.

Ultimately, Mohanty’s team has a goal of creating all optical, or light-based, control and monitoring of cell activity. So, in addition to the light-assisted delivery of genes, the researchers also will work on refining methods for stimulating the neural activity using near-infrared and visible light. Some of those methods are described in a recently published paper called “Fiber-optic two-photon optogenetic stimulation,” which appeared in the journal Optics Letters.

Mohanty’s lab at UT Arlington also will use a method called phase-sensitive interferometry, to monitor the changes in neurons that result from the activation by light. The interferometry method is called “label-free” because unlike fluorescence, it uses the change in behavior of light rays, rather than staining, to track changes at the sub-nanometer level.

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