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People in the NorthWest with X-linked retinoschisis

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XLRS Natural History Study Beginning in Portland, Oregon

March 29, 2013 – Oregon Health & Science University (OHSU) is launching a three-year natural history study for people with X-linked retinoschisis (XLRS). Funded by the Foundation Fighting Blindness, the investigation’s primary goal is to identify outcome measures — such as changes in vision or retinal structure — that could be useful in evaluating the effectiveness of potential therapies in clinical trials. The study will also help determine the types of XLRS patients most suitable for future therapeutic studies.

Knowledge gained from the XLRS natural history study will aid in the design of an XLRS gene therapy clinical trial slated to begin in late 2014 or early 2015. The trial will be a collaboration between Applied Genetic Technologies Corporation, OHSU and the Foundation.

X-linked retinoschisis occurs almost exclusively in males. Participants in the natural history study must be of that gender. Otherwise, to qualify, they must:

  • have a clinical diagnosis of XLRS
  • have a disease-causing mutation in the gene RS1
  • be 7 years of age or older
  • be able to provide consent/assent (understand study procedures and risks)
Participants will need to make yearly visits to the Casey Eye Institute in Portland, Oregon. Some travel may be reimbursed.
If study participants are not already using carbonic anhydrase inhibitors (CAI), they will be offered this standard-of-care treatment during the study. If participants start CAI treatment during the study, they will need to travel to OHSU for some additional visits. CAIs are thought to reduce retinal edema (swelling) and other symptoms associated with XLRS.
For more information about the XLRS natural history study, contact the study coordinator at (503) 494-2363.

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Gene Therapy in Ophthalmology Update 18: A RetroSense Update

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I first learned about the potential of using gene therapies in treating ophthalmic disorders back in November 2010. That’s when I was introduced to gene therapy by Sean Ainsworth, the founder and CEO of RetroSense Therapeutics. I haven’t written about this company or the unique approach it is taking to try and treat retinitis pigmentosa and the dry form of AMD since that first article, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD. With several news events occurring with the company recently, I felt it was time to bring readers of this blog up-to-date.
First, a brief review of the approach that RetroSense is taking. The technology that the company is using was developed at Wayne State University by Dr. Zhuo-Hua Pan. It involves using channelrhodopsin-2, delivered via an adeno-associated viral vector (AAV) directly into the retina to restore lost vision. Channelrhodopsin-2 is an “opsin”, derived from green algae which can be used to convert light-sensitive inner retinal neurons into photoreceptor cells, thereby imparting light sensitivity to retinas that lack photoreceptors. This is a process called “optogenetic therapy”.
As reported in Retina Today(1), “We took a new strategy for restoring vision by genetically converting the retina’s second- or third-order cells to become light sensitive to mimic the function of rods and cones,” wrote Dr. Pan. “But critical to this strategy, we needed to find certain suitable light sensors that can be easily inserted into these surviving retinal cells.”
Optogenetics is defined(2) as, “…the combination of genetic and optical methods to control specific events in targeted cells of living tissue, even within freely moving mammals and other animals, with the temporal precision (millisecond-timescale) needed to keep pace with functioning intact biological systems.”
           
In an interesting write-up about both optogenetics and RetroSense, Susan Young writing for MIT’s Technology Review(3), said, “The idea behind Retrosense’s experimental therapy is to use optogenetics to treat patients who have lost their vision due to retinal degenerative diseases such as retinitis pigmentosa. Patients with retinitis pigmentosa experience progressive and irreversible vision loss because the rods and cones of their eyes die due to an inherited condition.”
She went on to say, “Retrosense is developing a treatment in which other cells in the retina could take the place of the rods and cones, cells which convert light into electrical signals. The company is targeting a group of neurons in the eye called ganglion cells. Normally, ganglion cells don’t respond to light. Instead, they act as a conduit for electrical information sent from the retina’s rods and cones. The ganglion cells then transmit visual information directly to the brain.”
“Doctors would inject a non-disease causing virus into a patient’s eye. The virus would carry the genetic information needed to produce the light-sensitive channel proteins in the ganglion cells. Normally, rods, cones, and other cells translate light information into a code of neuron-firing patterns that is then transmitted via the ganglion cells into the brain. Since Retrosense’s therapy would bypass that information processing, it may require the brain to learn how to interpret the signals.”
Before I relate the latest news about the company, I would like to share one further write-up about the company’s technology. This brief appeared in February, as part of an article in Popular Science entitled, “How Neuroscience Will Fight Five Age-Old Afflictions(4)”. One of the “afflictions” noted was blindness, and the writeup described RetroSenses’ approach to curing that affliction.
BLINDNESS

Gene therapy converts cells into photoreceptors, restoring eyesight

Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.

In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.

A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.

The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”

Rewiring The Brain: Blindness: a) An eye diseased with retinitis pigmentosa has damaged photoreceptors, or rods and cones. Doctors inject the eye with a nonharmful virus containing the gene channelrhodopsin-2, or ChR2. b) The virus migrates into the retina at the back of the eye and inserts the gene into ganglion cells, which relay signals from the rods and cones to the optic nerve. The ganglion cells begin expressing the ChR2 protein in their membranes. c) Incoming light activates the ChR2 protein in ganglion cells, stimulating them to fire an electrical impulse. That message travels through the optic nerve to the brain’s visual cortex, which interprets it as a rough image.  Medi-Mation (Used courtesy of Popular Science)
What’s New
Within the past few weeks, the company has made two important announcements relative to its intellectual properties:
On March 5th, the company announced the notice of allowance for a new U.S. Patent Application broadly covering optogenetic approaches to vision restoration. The Patent Application broadly covers methods of restoring visual responses with a variety of optogenetic compounds. Specifically, the allowed application includes claims covering methods of restoring visual responses by delivering channelrhodopsin and variants thereof, as well as halorhodopsin to retinal neurons – with or without the use of cell-type specific promoters, including mGluR6 (Grm6). The subject opsins have been studied extensively and published on as means of vision restoration in retinal degenerative conditions such as retinitis pigmentosa and dry age-related macular degeneration.
The approved patent application is part of the “Pan” patent family, which stems from the novel research of Dr. Zhuo-Hua Pan and others at Wayne State University and Salus University, designed to restore vision in retinal degenerative conditions. Several Pan patent applications are part of RetroSense’s intellectual property estate, which focuses on optogenetic gene therapies and complementary devices for vision restoration.
“We are pleased that the U.S. Patent Office has allowed this patent application, which will substantively expand the coverage of RetroSense’s intellectual property estate. RetroSense continues to develop novel intellectual property in the area of optogenetics. Accordingly, we plan to continue to extend our basic patent protections on our technologies. We have also maintained an ongoing strategy to consolidate key intellectual property required to develop and commercialize optogenetics to restore visual responses,” said Sean Ainsworth, Chief Executive Officer of RetroSense.
And, on March 27th, the company announced an exclusive option to intellectual property covering vision augmentation from Massachusetts General Hospital. This gives RetroSense the right to an exclusive, worldwide license to the patent application “Method for Augmenting Vision in Persons Suffering from Photoreceptor Cell Degeneration”, based on the research of Dr. Richard Masland, director of the Cellular Neurobiology Laboratory in the MGH Department of Neurosurgery.
“This is an exciting development for RetroSense Therapeutics, as Dr. Masland’s work at Massachusetts General Hospital has been tremendous,” stated Sean Ainsworth, CEO of RetroSense Therapeutics. “This intellectual property broadens our reach and strengthens our existing position in optogenetic approaches to vision restoration.”
Dr. Masland stated, “The goal of the work we have done so far is to find a therapy that can help restore some level of vision to people who are now blind from retinal disease. I look forward to moving forward with this work.”
The next step for the company is to begin a Phase I human clinical trial. As noted in the Popular Science article, the company believes that is likely to occur sometime next year.
References:
1. Novel Optogenetic Therapy May Restore Vision After Retinal Degeneration, Callan Navitsky, Assoc. Editor, Retina Today, April 2012.
2.  From Wikipedia.
3 Company Aims to Cure Blindness with Optogenetics, Susan Young, MIT Technology Review, August 28, 2012..
4.  How Neuroscience Will Fight Five Age-Old Afflictions, Virginia Hughes, Popular Science, Feb. 18, 2013.

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Gene Therapy in Ophthalmology Update 17: Hemera Biosciences Obtains Initial Funding

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In December 2011, following that year’s AAO Meeting, I wrote about Hemera Biosciences and its complement regulation therapy via the use of gene therapy to prevent membrane attack complex (MAC), the final stage of the complement cascade that is implicated in both dry and wet AMD. (Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD)

I am now happy to report that Hemera has obtained initial funding, along with the issuance of a US Patent and can now begin manufacturing its drug, soluble CD59 (protectin), perform animal toxicology and initiate a phase 1 clinical study.

To review, HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

The primary focus for the company will be preventing the conversion of the dry form of AMD from progressing into the wet form, however, they think that there’s a role for HMR59 in treating the dry form (drusen and GA) as well as wet (neovascular) AMD.

Here is the company’s news release:
Hemera Biosciences Raises $3.75 Million; Patent Issued for TreatingAge-related Macular Degeneration
BOSTON, MA (March 15, 2013)  Hemera Biosciences announced its Series A financing of $3.75 million and issuance of US Patent 8,324,182 B2 on December 4, 2012, for treating age-related macular degeneration (AMD) with a human protein, soluble CD59 — otherwise known as protectin.
“Human genetic studies and preclinical research have shown that alterations in complement – a significant driver of inflammation — play a key role in the development of both wet and dry AMD,” said Adam Rogers, MD, one of the founders of Hemera. 
Preclinical studies done in the laboratory of Rajendra Kumar-Singh, PhD, another Hemera founder, have shown that intravitreal injection of an adeno-associated virus  that expresses soluble CD59, in an animal model, prevents the development of choroidal neovascularization. Choroidal neovascularization is the leading cause of  severe vision loss due to the wet form of AMD.
“Membrane attack complex (MAC) formation is the last step in the complement inflammation pathway.  Soluble CD59 when expressed in our animal models using gene therapy, prevents the development of MAC, death of retinal pigment epithelial cells and prevents abnormal blood vessel development in the eye.  Use of gene therapy to express soluble CD59 allows for long term treatment for this chronic blinding disease,” said Dr. Kumar Singh.
With the $3.75 million of financing raised in this initial round of funding, Hemera expects to have sufficient resources to manufacture the drug, perform animal toxicology studies and initiate a phase 1 study.
The founders and management team include Elias Reichel, MD, Jay Duker, MD, Rajendra Kumar-Singh PhD , and Adam Rogers, MD who all are on faculty at Tufts University School of Medicine.
About Hemera
Hemera Biosciences, founded in 2010, is a private company headquartered in Boston, Massachusetts that focuses on developing and commercializing gene therapy for age-related macular degeneration and other ocular conditions.
Hemera is developing its proprietary soluble CD59 gene therapy technology as a treatment for age-related macular degeneration for both the dry and wet forms of the disease.  The company’s lead program is the first and only complement therapy that directly targets MAC.  Hemera was started by some of the world’s leading experts in AMD and gene therapy.

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Webinar on Floaters: Uploaded

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I have finally uploaded the webinar on floaters presented on 2/5/13.  There are five parts and it includes the entire presentation and Q & A following. As always, please feel free to leave comments and ask questions. Part 1:  Presentation Part 2:  Presentation Part 3:  Q & A, 1st Portion Part 4:  Q & A, […]

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Oraya IRay Update 2: INTREPID Two-year Results Meet Primary Clinical Endpoint – Results in At Least 35% Fewer anti-VEGF Injections — Oraya Joins with Optegra to Provide Treatments in the UK

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The last time we checked in on Oraya in May 2011, the company had announced it had completed enrollment in its INTREPID clinical trial, being conducted at seven European sites with the enrollment of a minimum of 150 patients. (Oraya IRay Update: Company Completes Enrollment in European Clinical Trial)
The INTREPID trial is the first sham-controlled double-masked study to evaluate the effectiveness and safety of a one-time radiation therapy in conjunction with as-needed anti-VEGF injections for the treatment of wet AMD. A total of 21 sites in five European countries participated in the trial with a total enrollment of 230 subjects.
During the EURORETINA Congress, held in Milan, Italy, at the end of September 2012, Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator for the trial, presented the results during the program’s AMD session. He reported that the trial achieved its primary end point demonstrating a statistically significant reduction in as-needed injections after one year. The actively treated patients required approximately 35 percent fewer injections than the sham group with similar or in some cases, better visual acuity outcomes. No radiation-related adverse events were experienced at the one year end point; including 60 subjects already at two year follow up. In addition, a defined population sub-group comprised of roughly half of the study participants experienced even lower injection rates while exhibiting meaningful vision benefit compared to sham.
Jackson stated that, “The year one results of the INTREPID trial are very encouraging for people with wet AMD—the prospect of fewer eye injections will appeal to all those receiving anti-VEGF therapy, and for certain subsets there is the added advantage of an improved visual outcome. Whilst it will be important to monitor safety over a longer period, the results so far suggest a favorable safety profile.”
Jim Taylor, CEO of Oraya Therapeutics, added, “We are very pleased that the results of the  INTREPID trial have validated the benefits of the Oraya Therapy for patients, clinicians and health  care providers. It is rare to have a new therapy that demonstrates improved patient outcomes while simultaneously offering the potential to significantly reduce treatment burden and costs. To have these benefits validated in a rigorous clinical trial is very rewarding, and we are exceptionally grateful to the patients and clinicians who participated in this important study.”
Then, the following month, at the British and Eire Association of Vitreoretinal Surgeons (BEAVRS) meeting in Dublin, Dr. Jackson presented a further analysis of the INTREPID results, discussing an analysis of the best responders in the INTREPID trial showing that anti-VEGF injections were reduced by 54% in the patient sub-group characterized by the presence of significant fluid and smaller lesion size.
Dr Jackson said: “A post-hoc analysis looked for the best responders to stereotactic radiotherapy and found that they had significant fluid at baseline and a lesion size of 4 mm or less in greatest linear dimension.”
“This dimension corresponds to the diameter of the spot beam (90% isodose) projected onto the retina by the IRay device. The 26% of patients with both of these characteristics not only had a reduction of 54% in the number of PRN injections but also a mean vision superiority of 6.8 ETDRS letters compared to equivalent patients in the control group.”
Dr Jackson added: “The one-year results of the INTREPID study are encouraging for clinicians and for individuals with neovascular AMD. The prospect of needing fewer eye injections will appeal to any patient receiving anti-VEGF therapy, and for certain sub-sets there is the added advantage of an improved visual outcome. The study showed a favorable safety profile for the procedure, and safety review is ongoing to detect any later effects of the radiotherapy treatment.”
Oraya Therapeutics Joins Forces with Optegra Eye Hospital Group
In December 2012, Oraya Therapeutics, Inc. announced that an agreement had been reached with UK specialist eye hospital group Optegra, to establish Optegra as the world’s first clinical centers to offer Oraya Therapy Stereotactic Radiotherapy for the treatment of wet Age-related Macular Degeneration (AMD).
The agreement was reached shortly after Oraya released data from a successfully completed clinical trial (The INTREPID Study) involving 21 sites and conducted in the UK and four other European countries.
Ophthalmic surgeon at Optegra, Andy Luff, commented: “Wet AMD currently affects approximately 260,000 people in the UK2, and it is projected that nearly 40,000 new people will be affected each year. The chronic injection therapies currently in use often require six to eight injections per year placing an unsustainable and costly burden on the National Health Service (NHS), on patients and on their families.”
Gareth Steer, Managing Director for Optegra, said: “Optegra is excited to have been selected to offer the Oraya Therapy as a treatment option that can help to mitigate this critical problem. We are pleased to have the opportunity to work with the innovative and dedicated people of Oraya, and to have the benefit of a scientifically sound clinical trial to support the value and potential of this unique therapy.”
In commenting on the choice of Optegra and the UK for the global introduction of the therapy, Jim Taylor, CEO of Oraya Therapeutics, said: “We are exceptionally proud and pleased to have partnered with Optegra, an organization that shares our values regarding the importance of good science, a focus on services that offer better patient outcomes and greater cost effectiveness, and with a commitment to the highest standards of quality and patient care. Bringing the therapy to the UK also provides us the opportunity to address a recognized and urgent need within the NHS for better therapeutic solutions, and we look forward to working with Optegra and the NHS to expand the access and availability of this important therapy in the months ahead.”
Finally, at the end of February 2013, the company announced that one of the patients who successfully was treated for wet age-related macular degeneration (AMD) with Oraya Therapy during the INTREPID clinical trial has released data showing he has experienced significant, sustained vision improvement more than two years after treatment in his right eye, without any subsequent anti-vascular endothelial growth factor (anti-VEGF) injections or other treatment. The patient, well-known British author Jonathan Gathorne-Hardy, also said he had experienced significantly reduced central vision in his left eye following standard anti-VEGF treatments over the same time period.
Oraya president and CEO Jim Taylor commented, “These life-changing results for patients with wet AMD further underline the efficacy of Oraya Therapy, and are the real source of motivation behind all that we do. With the ability to improve the vision of wet AMD patients with fewer injections – and in this case no injections at all – Oraya Therapy can offer a more convenient, effective and cost-effective treatment for this debilitating disease.”
Mr. Gathorne-Hardy was one of 230 patients enrolled in the multi-national INTREPID study evaluating the 20-minute, non-invasive therapy. He has wet AMD in both eyes, and received he Oraya Therapy at King’s College Hospital, London on his right eye in August 2010. After one year, the visual acuity in his right eye was significantly improved, with a vision gain of nine letters on his visual acuity score, and after two years has stabilized at an acuity better than before the Oraya Therapy. He has not received any subsequent anti-VEGF injections into the eye or any other treatment. In contrast, the central vision of Mr. Gathorne-Hardy’s left eye, diagnosed in 2008 and treated solely with the standard anti-VEGF injections, was significantly reduced.
All patients in the INTREPID trial previously had received at least three anti-VEGF injections in the prior year and required further anti-VEGF treatment. Within two weeks of receiving the injection, one-third of the subjects received a sham exposure and the remainder received a radiation dose of either 16 or 24 Gray (Gy). They were then followed monthly and treated with anti-VEGF (Lucentis) as needed according to specified reinjection criteria.
Results of the trial showed that further injections were reduced by 32 percent in the radiotherapy groups compared with the control group. These radiotherapy groups were twice as likely to receive no injection over the course of a year and were approximately half as likely to need four or more injections over the course of a year. Also, post-hoc analysis looked at the best responders to stereotactic radiotherapy and identified a group of patients which experienced a 54 percent reduction in the number of injections and a mean visual superiority of 6.8 ETDRS letters compared to equivalent patients in the control group.
“The results of the INTREPID study which have been reported to date are encouraging for clinicians and for individuals with wet AMD. The prospect of maintaining vision while needing fewer eye injections will appeal to any patient receiving anti-VEGF therapy, and for certain subsets in the trial there is the added advantage of an improved visual outcome,” said Timothy L. Jackson, PhD, FRCOphth, King’s College Hospital, London, lead investigator for the trial.
The Oraya Therapy is now available at the Optegra Surrey Eye Hospital in Guildford, United  Kingdom, establishing Optegra as the world’s first clinical centre to offer Oraya Therapy.
Tim Clover, CEO of Optegra, said: “Optegra treats many patients with AMD and knows the frustration of managing this disease. We are committed to encouraging new therapies that ill have a positive impact on patients. Oraya Therapy offers a real benefit to patients and Optegra is proud and excited to be selected as Oraya’s launch partner. We are pleased to have the opportunity to work with the innovative and dedicated people of Oraya, and to have the benefit of a scientifically sound clinical trial to support the value and potential of this unique therapy.”
Status of U.S. Clinical Trials:
When asked about progress towards U.S. clinical trials, Jim Taylor, CEO of Oraya responded with this, “On the topic of (the) U.S., the results from the INTREPID trial provide us a clear understanding of the trial design most appropriate and suitable for the FDA process; and with a high probability of success. The company is currently raising the capital needed to support the initial commercialization efforts in Europe, and that funding might also support the implementation of the US trial. Decisions on when to initiate the US trial will be based on the availability of that financing.”
For a full report on the Oraya IRay system and how it works, see my first writeup from November 2009: Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report
Reference Links: 

Company News Releases

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AMD Update 23: DARPins, The Next “Game Changer” for Wet AMD?

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As many of you know, I am now retired and no longer attending ophthalmic industry meetings, the source for much of my writing when I was producing the “Technology Update” columns for Ocular Surgery News for over eleven years. I now scour the web searching for interesting ophthalmic industry news in the field of my current interest –  new technologies for treating retinal diseases, for ideas of stories to write about for this Journal. I also rely on tips from former industry colleagues and new friends that inquire, “Have you heard about…”, which sometimes leads to interesting stories to investigate and write about.
In this case, I received an analyst’s report on Allergan, discussing their involvement with DARPin technology for use in treating wet AMD. (A hat tip to Larry Haimovitch.) This was the  first I had heard about this new technology.
The report was basically an interview with Dr. Elias Reichel, of Tufts University School of Medicine.
After reading the report (from Wells Fargo Securities) I realized that the drug that they were discussing, MP0112 (AGN -150998), has a long ocular half-life and appears to be a vast improvement over both Lucentis and Eylea in terms of dosing for wet AMD, perhaps requiring injections only every 3-4 months compared to bi-monthly for Eylea and monthly for Lucentis and Avastin. I did some further research and also called Dr. Reichel to gain some important perspectives about this drug.
After discussing the Wells Fargo report with Dr. Reichel, and some further web research about the DARPin technology, I realized that the analysts had not told the entire story  – the important element of Allergan’s further work with DARPin as not only an improved anti-VEGF agent (which it appears to be), but the second deal with Molecular Partners (the owners of the DARPin technology), announced last fall, to investigate and commercialize a dual action anti-VEGF/PDGF drug (hello Fovista!) that will be both longer lasting in the eye (fewer injections needed) than current anti-VEGF drugs, but also potentially improve visual acuity in those suffering from wet AMD (and other vascular conditions), similar to the effect shown by the use of Fovista plus Lucentis that I have previously written about. (See AMD Update 19: Combination Therapy May Be A “Game Changer” for Wet AMD, and AMD Update 20: How Fovista Works to Increase Vision in the Treatment of Wet AMD)
In the case of Fovista, Ophthotech demonstrated a 62% increase in efficacy over monotherpay with Lucentis in their Phase 2b clinical study. If the dual drug from Allergan (MP 0260), now in pre-clinical study, shows the same type of results as the dual action of Fovista plus Lucentis, than Allergan will really have a “game changer” – a drug that needs to be injected only perhaps three or fewer times a year, that both stops the progression of wet AMD AND also provides vastly improved visual acuity!
(Caveat – to date, Allergan (and Molecular Partners) have shown only Phase 1 data for its anti-VEGF version of the DARPin (MP 0112/AGN -150998), but Dr. Reichel believes that these results are indicative of what can be expected in their Phase 2b study results, which are expected to be presented at the upcoming AAO Meeting in the fall. Furthermore, a recently published Phase 1/2 dose escalating study of the MP 0112 DARPin drug in treating diabetic macular edema (DME) in the Am. J. Ophthalmology (Jan. 2013) showed safety and bioactivity with improved visual acuities.)

Background
So, what are DARPins, how do they work in the eye and how did Allergan get involved with Molecular Partners?
Basically, DARPins are new protein drugs that, according to Molecular Partners, have “the potential to transform medicine”. The DARPins have very high potency, affinity for a target and strong biophysical profiles. Molecular Partners have developed a  robust process to ensure that DARPins have properties allowing preclinical and clinical development at “unmatched speed”.
Molecular Partners states that each DARPin drug candidate exhibits distinct class behavior, including:
●    very high affinity and potency, often in the low picomolar range
●    exceptional stability and solubility
●    simple and low-cost production
●    tailored PK profile, ranging from minutes to a week
●    formatting for multiple specificities and effector functions
●   high safety and absence of T-cell epitopes for low risk of immunogenicity
DARPin Origin
DARPins (Designed Ankyrin Repeat Proteins) are derived from natural ankyrin repeat proteins which were evolved by nature as versatile binding proteins with diverse functions such as anchoring to other proteins, cell signaling, or receptor binding. Natural repeat proteins are, next to antibodies, the most prominent class of binding proteins in nature. The human genome encodes and expresses more than a thousand ankyrin repeat domains, which are located and restricted to the intracellular space.
MP0112
And in the case of MP0112, the candidate for treating wet AMD, it is a DARPin-based anti-angiogenic drug that specifically binds vascular endothelial growth factor (VEGF). It has completed two separate Phase I/IIa clinical trials in wet age-related macular degeneration and diabetic macular edema, the two most common causes for vision loss.
MP0112 is an antagonist of Vascular Endothelial Growth Factor A (VEGF-A) that inhibits all relevant subtypes of VEGF-A with very high potency (IC50 of < 10 pM). MP0112 was shown to have a very long half-life in the eye (> 6 days). The combination of small size, high potency and long intravitreal half-life offers the potential to drastically reduce the frequency of injections needed as compared to the current standard of care and other approaches. Further, MP0112 also has the potential for higher efficacy. DARPins have also shown efficacy when applied as eye-drops.

Clinical Results
(Data taken from the Wells Fargo Securities report.)
Molecular Partners presented Phase I data from its AMD and DME (diabetic macular edema)
studies at the ARVO (Association for Research in Vision and Ophthalmology) meeting in May 2011. In two parallel trials, 50 wet AMD or DME patients showed that DARPin MP0112 is safe and well tolerated when given as a single intravitreal injection. Therapeutic effect was demonstrated to be dose dependent and to last, for most of the patients of the higher dose cohorts, for 16 weeks and beyond after a single injection. Below is a summary of the data from an abstract presented at 2011 ARVO in wet AMD.
Abstract Title: Phase I MP0112 Wet AMD Study: Results Of A Single Escalating Dose Study With DARPin MP0112 In Wet AMD
Purpose: To report the safety and preliminary efficacy of DARPin MP0112 in patients with wet AMD. DARPins are a new class of small proteins with very attractive therapeutic properties. The clinical study with DARPin MP0112 assessed the safety and preliminary efficacy measured by visual acuity (VA), fluorescein angiography (FA), and color fundus photography during 16 weeks.
Methods: DARPin MP0112 is an extremely potent VEGF inhibitor with very long ocular half-life. Animal studies indicate that dosing frequency in patients may be reduced 3-4 fold compared to current standard therapy. The MP0112 wet AMD study is a Phase I/II, open-label, non-controlled, multi-centre trial. The MP0112 wet AMD study consisted of 5 dose (0.04 mg; 0.15 mg; 0.4 mg; 1.0 mg; 2.0 mg MP0112) ascending cohorts. Eligible patients were aged >50 years with diagnosed wet AMD who are treatment naïve and have a BCVA of 20/40 to 20/320 in the study eye at 4 meters. Four to nine patients were included per cohort and received a single dose of MP0112 as intravitreal injections.

Results: Overall, MP0112 was safe and well tolerated. VA at baseline ranged from 32 to 72 ETDRS letters (median: 64 ETDRS letters). At the end of the 16 weeks follow-up all patients had stable or increased VA. At the 4 week visit, a total of 16 patients (50%) received rescue therapy. In the highest two dose groups, 8 of 10 patients had no disease progression for 8 weeks, and 7 of 10 patients for even 16 weeks. The most frequent adverse effect was a dose-related transient sterile inflammation that resolved without visual consequences.

Conclusions: The results of this Phase I dose-escalation study demonstrate overall safety and efficacy of MP0112. The higher MP0112 doses show potential for quarterly dosing for the treatment of wet AMD. DARPin MP0112 represents a very promising new anti-VEGF treatment option with potential in various retinal diseases and is a showcase for a novel class of therapeutic proteins in ophthalmology.
And, here is the early safety information about MP0112 in the DME clinical trial, as reported in the January 2013 issue of the Am. Jnl. of Ophthalmology:
Abstract Title: Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase 1/2 Study
Authors: Peter A. Campochiaro, Roomasa Channa, Brian B. Berger, Jeffrey S. Heier, David M. Brown, Ulrike Fiedler, Julia Hepp, and Michael T. Stumpp
Purpose: To evaluate the safety and bioactivity of MP0112, a Designed Ankyrin Repeat Protein (DARPin) that specifically binds vascular endothelial growth factor (VEGF) in patients with diabetic macular edema (DME). DARPins are a novel class of proteins selected for specific, high-affinity binding to a target protein.
Design: Phase 1/2, open-label, multicenter dose-escalation trial.
Methods: After a single intravitreal injection of MP0112, the main outcomes were safety assessments, aqueous MP0112 levels, change in best-corrected visual acuity (BCVA), and foveal thickness measured by optical coherence tomography. Six cohorts were planned, but only 3 were enrolled (0.04, 0.15, 0.4 mg), because a maximally tolerated dose of 1.0 mg was identified in a parallel age-related macular degeneration trial.
Results: Median aqueous concentration of MP0112 was 555 nM 1 week and >10 nM in 3 of 4 patients 12 weeks post injection of 0.4 mg. Median BCVA improvement at week 12 was 4, 6, and 10 letters in cohorts 1, 2, and 3. Ocular inflammation was observed in 11 patients (61%) and  as severe in 1. High-resolution chromatography separated proinflammatory impurities from MP0112, resulting in a new formulation.
Conclusions: A single intraocular injection of 0.4 mg MP0112 resulted in levels above the half-maximal inhibitory concentration and neutralization of VEGF in aqueous humor for 8-12 weeks. Despite inflammation in several patients, there was prolonged edema reduction and improvement in vision in several patients. The source of the inflammation was eliminated from a new preparation that is being tested in an ongoing clinical trial.
Allergan and Molecular Partners
The first licensing agreement between Allergan and Molecular Partners occurred in May 2011. Under the agreement, Allergan obtained exclusive global rights for MP0112 for ophthalmic indications. The parties agreed to work together during phase IIb development with Allergan responsible for phase III development and commercialization activities.
The agreement followed closely the presentation of data about MP0112 at the ARVO Meeting earlier that week, stating that MP0112 was well tolerated and had a potentially long lasting effect on vision gain after a single injection. In the studies, for most patients in the cohorts treated with the higher dose of the investigational compound, the potential beneficial effect on visual acuity lasted for approximately 16 weeks.
As noted in the press release about the agreement, both companies commented favorably about both the license agreement and the future of the drug:
Scott M. Whitcup, M.D., Executive Vice President, Chief Scientific Officer of Allergan commented: “This agreement aligns with Allergan’s strategy to become a leader in developing new treatments for retinal disease. The goal of this program is to develop a potentially more effective treatment for diseases like neovascular age-related macular degeneration with the possibility for less frequent intravitreal injections.”
And, Christian Zahnd, Ph.D., Chief Executive Officer of Molecular Partners said: “This is a transformational deal for Molecular Partners, and Allergan is the ideal partner for MP0112 to build the most value out of our lead product. Further, this agreement strengthens our ability to execute on the progression of our substantial internal systemic pipeline.”
Then, this past August, the companies struck a further set of agreements, this time to discover, develop, and commercialize proprietary therapeutic DARPin products for the treatment of serious ophthalmic diseases.
The first agreement is an exclusive license agreement for the design, development and commercialization of a potent dual anti-VEGF-A/PDGF-B DARPin (MP0260) and its corresponding backups for the treatment of exudative age-related macular degeneration (AMD) and related conditions. Under the license agreement, Allergan and Molecular Partners will work together to develop MP0260 through human proof of concept, at which point Molecular Partners has the option to co-fund Allergan’s development costs in exchange for a significant royalty step-up.
The second agreement is an exclusive discovery alliance agreement under which the parties will collaborate to design and develop DARPins against selected targets that are implicated in causing serious diseases of the eye. During the research phase, Allergan has the right to exercise three options to exclusively license collaboration compounds for ophthalmology. Upon execution of each option, Allergan will pay Molecular Partners an option exercise fee and be solely responsible for all downstream development, manufacturing, and commercialization activities.
The first August agreement above is what caught my eye. The development of the dual-action anti-VEGF/PDGF drug will compete directly against Fovista from Ophthotech, which already has shown such impressive results (as noted in my prior writeups).
If MP0260 lives up to its potential, as I mentioned in the introduction, it could indeed become a serious game changer in the treatment of wet AMD and related diseases (DME and CRVO).
In an article about the two companies and the license agreements in BioTuesdays last September, Dr. Zahnd, CEO of Molecular Partners noted, “While Molecular Partners’ lead ocular compound, MPO112, could be ready to enter Phase 3 testing as a treatment for wet AMD and diabetic macular edema (DME) during the first half of 2014, MPO260 is probably a couple of years behind.”
However, MPO260 is a “dual antagonist,” he explained, with one functional group of the molecule blocking VEGF and a second functional group blocking PGDF. “Blocking two mechanisms of action has the potential to lead to a much more stable drying of the eye,” he suggested. “In preclinical studies, MPO260 was shown to strip pericytes from newly formed blood vessels, thus destabilizing these vessels much more than VEGF alone could do and leading to the regression of these blood vessels,” he said. “We expect this to lead to a higher efficacy and longer duration of action.”
Roche’s Lucentis and off-label use of its oncology drug, Avastin, now dominate the wet AMD market, along with Regeneron’s Eylea, which is injected into the eye every two months, compared with monthly injections of Lucentis and Avastin.
Dr. Zahnd said MPO112 could be administered as infrequent as quarterly or less for wet AMD and DME and MPO260 could even beat this dosing frequency for wet AMD.
 “If I had to crystal ball, I’d expect MPO112 to take significant share of the wet AMD market and MPO260 to completely turn the AMD market to DARPins,” he predicted.
And, I agree.
Other Activity with Dual-Action Drugs
It has come to my attention that Neurotech Pharmaceutical is also working on a dual-action system, in this case, a chronic long-term delivery implant of a PDGF-antagonist in conjunction with a VEGF-antagonist. This, as described on the company’s website, is called their NT-506 PDGF antagonist program.
They also have an anti-VEGF implant, NT-503, that is in Phase 1/2 clinical studies.
NT-503 entered dose escalation clinical trials late in 2010 in patients with treatment naïve wet AMD. One year data in the low dose cohort has demonstrated excellent safety to date, with clinically relevant efficacy in some patients lasting for upwards of 12 months. A 5-10 fold higher dose is currently being evaluated in patients for safety and efficacy in a Phase 1/2 trial.
The NT-503 VEGF-antagonist program and NT-506 PDGF-antagonist program are aimed at producing Encapsulated Cell Technology (ECT) implants that treat pathological angiogenesis (choroidal neovascularization) within the retina, associated with the wet form of Age-Related Macular Degeneration (wet AMD).
ECT implants are capable of continuously producing recombinant biotherapeutics for up to two years in the eye. ECT implants secreting PDGF-antagonists are in the pre-clinical stage of development. They will play a major role in conjunction with NT-503 VEGF antagonist, or with anti-VEGF standard of care, in future clinical studies.

Resources and Links:
Wells Fargo Securities;
Equity Research: Allergan, Inc., AGN: DARPin Call Take-Away – High Probability of Success, Larry Biegelsen et al, Wells Fargo Securities, Februay 7, 2013
Fovista Reports:
AMD Update 19: Combination Therapy May Be A “Game Changer” for Wet AMD, Irv Arons’ Journal, June 4, 2012
AMD Update 20: How Fovista Works to Increase Vision in the Treatment of Wet AMD, Irv Arons’ Journal, June 28, 2012
Allergan website:

Molecular Partners website:
DME clinical results
Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase 1/2 Study, Peter A. Campochiaro, et al, Am. Jnl. of Ophth., Jan 2013.
First licensing agreement:
Allergan and Molecular Partners Enter into Exclusive Alliance, May 4, 2011
Second licensing agreement:
Allergan and Molecular Partners Enter into Exclusive Alliance, August 21, 2012

BioTuesdays
Molecular Partners continues to validate DARPin platform
Neurotech website:

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Excercise After PVD is Safe

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I believe exercise after sustaining a posterior vitreous detachment (PVD) to be safe.  Many doctors recommend a “no exercise” period after a PVD to decrease the risk of retinal tear and retinal detachment.  This does not make sense to me. PVD Causes Retinal Tear A retinal tear may occur after a posterior vitreous detachment, but […]

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Locations

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Capital Eye Consultants 3050 Hamaker Court Suite 101 Fairfax, Virginia 22031 703.876.9630 Dressler Ophthalmology Associates 3930 Pender Drive Suite 10 Fairfax, Virginia 22030 703.273.2398 Woodburn Surgical Center 3289 Woodburn Road Annandale, Virginia …

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