|Posted by australiandryeye on June 17, 2018 at 5:50 AM||comments (0)|
University of Michigan researchers have investigated the potential for a natural voltage boost to alleviate the symptoms of dry eye.
New research, published in Cell Physiology, explored how bioelectrical responses of goblet cells in the eye adapt to fluid imbalance.
In a study of rats, scientists found that electrical activity in the goblet cells increases as hyperosmolarity rises in the tear film, allowing the cells to produce more mucin.
However, this increase in electrical activity is temporary. If the salt-to-water ratio in the tear film remains unbalanced, the activity returns to normal levels.
Study author and University of Michigan academic, Professor Donald Puro, highlighted that understanding the bioelectric mechanisms that the ocular surface uses to respond to hyperosmolarity could form the basis for new strategies for treating dry eye.
|Posted by australiandryeye on May 6, 2018 at 5:10 AM||comments (0)|
Ophthalmic medical device company Sight Sciences today announced the launch of a new pivotal trial exploring the safety and effectiveness of its TearCare system in patients with dry eye disease.
The Menlo Park, Calif.-based company’s TearCare system is a wearable therapeutic eyelid technology designed to deliver energy over a specified period to liquify meibum, an oily coating on the eye’s surface which prevents tear film evaporation.
The device allows the patient to blink and for the eye to remain comfortably open during the procedure, Sight Sciences said.
“We need additional treatment options for dry eye. I like several aspects of the TearCare System’s iLid device. It is non-invasive and conforms to the patient’s lid anatomy thereby individualizing and optimizing treatment and allows the patient to blink freely throughout the procedure,” Dr. Edward Holland of the Cincinnati Eye Institute said in a prepared statement.
The randomized, controlled, 200-patient Olympia trial aims to explore the safety and effectiveness of the system in treating signs and symptoms of dry eye disease compared to a daily regimen of warm compress therapy and lid massage, the company said.
“I am excited to participate in the Olympia trial and offer a customized, non-invasive treatment option to my patients. Unlike other dry eye technologies, the TearCare System is a smart and wearable solution that automatically regulates and maintains sufficiently elevated therapeutic temperatures for a sufficient period of time to effectively melt meibum. I can further customize the procedure by using the TearCare specialized instrument to manually, fully clear the meibomian glands of melted meibum,” Dr. Paul Karpecki of Lexington, Ky.’s Kentucky Eye Institute said in prepared remarks.
The trial’s primary endpoint is tear breakup time at one month, and several other endpoints are slated to be evaluated to assess changes in dry eye signs and symptoms. Patients will be followed out to six months, after which patients will be re-treated and followed for another six months.
The study follows a pilot study which showed a significant increase in tear breakup time, reduction in corneal and conjunctival staining and improvement in patient symptoms following treatment, Sight Sciences said.
“Over the past several months, we have worked diligently to select investigational sites for successful completion of the trial. I look forward to working directly with the OLYMPIA sites and completing a trial that will provide a long-term impact in the dry eye space,” clinical and regulatory affairs VP Anne-Marie Ripley said in a prepared release.
“The initiation of this study is a significant milestone for Sight Sciences and our cutting-edge TearCare technology. I am truly proud of our team that has worked obsessively in stealth over the past five years to iterate to a final product design we think will set a new bar for dry eye therapy. Our pivotal trial brings us one step closer to our vision of delivering a first-class dry eye treatment experience for both patients and eye care professionals,” prez & CEO Paul Badawi said in a press release.
Last October, Sight Sciences said it closed a $10 million oversubscribed Series C round to support expanding manufacturing and its US commercial team and the launch of its devices into the dry eye and microinvasive surgery markets.
|Posted by australiandryeye on May 4, 2018 at 5:15 AM||comments (0)|
Sylentis, Pharmaceutical Company belonging to the PharmaMar Group, has presented results from the clinical studies carried out with tivanisiran for the treatment of dry eye syndrome and that has enabled the start-up of the Phase III "Helix" clinical trial. The presentation has taken place within the framework of the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) that has been held from the 29th of April to the 3rd of May in Honolulu, Hawaii.
The purpose if this meeting is to share the latest breakthroughs in research in the area of ophthalmology, to contribute to the progress in basic science and also in cutting-edge clinical research. In this context, Sylentis has participated at this event presenting the pre-clinical and clinical results of various compounds that are being developed for the treatment of ocular disorders. Among these, the abstract "Tivanisiran a new treatment for Dry Eye Disease, that improved signs and symptoms in clinical trials" (Posterboard number: 925 - B0103) is highlighted, the compound improving the ocular inflammatory parameters, tear quality and a reduction in ocular pain associated with dry eye disease is also underlined1.
The novel mechanism of action of tivanisiran, based on genetic silencing through RNA interference (RNAi), is targeted at the treatment of the signs and symptoms of this pathology, making it a firm candidate for the treatment of dry eye disease.
According to Ana Isabel Jiménez, Director of R&D at Sylentis, "we trust in our technology, innovative in this field, and we hope that tivanisiran will soon become a real alternative for the treatment of millions of people that suffer dry eye disease around the world."
In this respect, Jiménez points out that "this is a significant step forward in the development of innovative drugs in different therapeutic areas through a novel technology of genetic silencing based on the RNA."
Sylentis is a pioneer in RNAi research, and is one of the few in Europe that applies this technology to the field of ophthalmology. It also continues with its research on new therapies for ophthalmological and inflammatory illnesses.
It must be empathized that this pathology affects more than 5 million in Spain, between 10% and 20% of the population, mostly women, and almost 100% of these being elderly. In this context, the phase III "Helix" study is being carried out in more than 30 hospitals in Spain, Germany, Estonia, Portugal, Slovakia and Italy, in 300 patients to evaluate the efficacy of this compound in the treatment of the sign and symptoms of dry eye syndrome.
|Posted by australiandryeye on April 17, 2018 at 1:20 AM||comments (0)|
WASHINGTON ― At the Ophthalmology Innovation Summit at ASCRS here, Bernhard Günther, president of Novaliq, discusses the company’s efforts to enter the U.S. market, principally in treating dry eye disease, by establishing an office in Cambridge, Massachusetts.
SiteOne Therapeutics Announces Abstract Presentation At the Association for Research in Vision and Ophthalmology (ARVO)
|Posted by australiandryeye on March 27, 2018 at 6:30 AM||comments (0)|
BOZEMAN, Montana, March 26, 2018 /PRNewswire/ -- SiteOne Therapeutics, Inc., today announced a presentation at the Association for Research in Vision and Opthalmology (ARVO) meeting in Honolulu, Hawaii, April 29 to May 3, 2018.
The abstract will present preclinical research using SiteOne's novel sodium ion channel blockers showing corneal anesthesia, penetration into the ocular structures, and excellent tolerability after topical administration. The study was conducted to inform development of a novel drug candidate to treat ocular pain associated with dry eye syndrome.
Accepted ARVO abstract is listed below:
Delwig, A. et al, "Evaluation of Selective NaV 1.7 Inhibitors for the Treatment of Ocular Pain" Abstract # 2908312, Poster Presentation.
About Ocular Pain Associated with Dry Eye Syndrome
Dry eye syndrome is a clinical diagnosis that encompasses a broad range of distinct conditions with unique etiologies that share signs and symptoms, the most common of which are sensations of burning, stinging, itching or grittiness in the eyes. The objective of our program is to develop a topical ophthalmic analgesic to safely and effectively treat ocular discomfort associated with the diagnosis of dry eye. This product would also be useful for treating other types of ocular pain, such as post-surgical pain and pain associated with acute corneal injuries or abrasions.
Existing therapeutics for dry eye include topical cyclosporine (Restasis) and lifitegrast (Xiidra). Both drugs address the inflammatory component of the disease by inhibiting activation of T-cells, however signs and symptoms of dry eye frequently persist.
The objective of our program is to advance a topical ophthalmic analgesic that reduces ocular discomfort associated with dry eye by targeting a voltage-gated sodium channel in the cornea, NaV1.7, and reducing corneal pain. Our product has the potential to be broadly effective in the ~30 million Americans suffering from dry eye regardless of the etiology because it addresses the discomfort rather than the heterogeneous physiologic cause. The analgesic would complement therapeutics that reduce inflammation or improve tear film, allowing the patient to be comfortable over weeks to months required for these therapies take effect. It would also be a useful treatment for postoperative pain following certain surgical procedure and acute ocular injuries, such as corneal abrasion.
About SiteOne Therapeutics, Inc.
SiteOne Therapeutics is a biotechnology company headquartered in Bozeman, Montana with a research laboratory in the South San Francisco, California. Since its inception, SiteOne has been dedicated to developing novel pain therapeutics to safely, effectively and efficiently treat acute and chronic pain without the limitations of existing pain therapies, such as NSAIDs or opioids. The company's therapeutic candidates are highly selective sodium ion channel 1.7 (Naᵥ1.7) inhibitors based on naturally occurring small molecules. Given the urgent need for new, non-opioid solutions for managing pain, SiteOne is focused on advancing its lead product candidates for multiple therapeutic applications.
SOURCE SiteOne Therapeutics
|Posted by australiandryeye on March 26, 2018 at 8:10 AM||comments (0)|
“Reverse chocolate” — that’s how AesculaTech co-founder and chief science officer Niki Bayat describes the material created by its proprietary technology. Chocolate is solid until heated, when it melts deliciously into liquid. AesculaTech’s material, on the other hand, is a liquid at low temperatures, turns into a gel when heated and then reaches its final, solid state at body temperature. (If you are having a hard time visualizing the process or are distracted by thoughts of dessert, there’s a gif below that shows it being injected into a 37 degree Celsius water bath).
By changing the composition of the material, AesculaTech is able to control the temperature at which it transitions into different states. While the liquid is transforming into a gel, different compounds, including medications, can be added to it. Bayat and co-founder Andrew Bartynski, who are in Y Combinator’s latest startup batch, say it has a wide range of potential applications, including pharmaceuticals, medical devices, cosmetics and textiles.
First, the material is being used in a treatment for dry eye syndrome. AesculaTech’s founders say the condition affects more than 20 million people in America, who collectively spend $3.5 billion a year treating symptoms that can include a burning, scratchy sensation, discharge and impaired vision. Prescription treatments like Restasis and Xiidra can take weeks or even months to reach full effectiveness, while over-the-counter eye drops bring only minutes of relief and need to be reapplied constantly. AesculaTech’s treatment, however, is designed to be administered by a doctor during a quick, in-office procedure and last for about a year. It is slated to be commercially available by 2019.
Bayat and Bartynski, AesculaTech’s chief executive officer, met in 2012 while doing graduate work in chemical engineering at the University of Southern California and discovered a shared interest in unique classes of materials. As graduation drew closer, they began to think of what they wanted to do next.
“One day I was talking to my dad and I heard from him that he’d been diagnosed with glaucoma, but because he’d had heart surgery, he couldn’t have another one,” says Bayat. “I kept thinking there should be a better way to treat glaucoma and so I started working on this project with Andrew and a few other people.”
The team decided to focus on dry eye syndrome first because it is easier to treat, but they plan to work on glaucoma medication in the future. The treatment starts off as an injectable liquid that is inserted into the patient’s tear duct by a doctor. It turns into a solid after raising to body temperature, forming a tiny plug that keeps tears from draining away from the surface of the eye.
AesculaTech has already performed pre-clinical animal trials that show its dry eye treatment creates statistically significant increases in tears on eyes and are preparing for human trials to bring it closer to approval from the Food and Drug Administration.
Because it only needs to be applied once a year, the treatment addresses another important health issue: medication compliance. Many patients don’t stick to drug regimens for chronic conditions as directed by their physicians even though it reduces the efficacy of their medicines. In the case of antibiotics, patient non-compliance can also impact public health by increasing bacterial resistance. As it branches out beyond ophthalmic treatments, Bayat and Bartynski hope their technology will form the foundation of a new way of taking medication that is more realistic for patients to follow.
“To allow people to get the treatment they need without having to interact with medication on a daily basis is hugely valuable because you deliver the treatment to them continuously so they don’t have to interrupt their daily life or be bound to an eye drop or pill pack,” says Bartynski.
“It’s not only about the treatment of dry eye or glaucoma,” adds Bayat. “We are thinking of a platform for drug delivery technology.”
AesculaTech’s founders say the technology can also be used to create materials for a wide range of products, like cosmetics and smart textiles that are temperature responsive. The startup’s plan is to form partnerships with companies, license their technology and help them bring new products to market. The material hasn’t been tested for food products yet, but Bayat and Bartynski say they haven’t seen any indications that it isn’t edible, so reverse chocolate may one day be more than just a simile.
TopiVert Publication Highlights the Potential of Narrow Spectrum Kinase Inhibitors in Dry Eye Disease and Supports Successful Clinical Proof-Of-Concept Study with TOP1630
|Posted by australiandryeye on March 26, 2018 at 8:05 AM||comments (0)|
TopiVert Publication Highlights the Potential of Narrow Spectrum Kinase Inhibitors in Dry Eye Disease and Supports Successful Clinical Proof-Of-Concept Study with TOP1630
London, UK, 22 March 2018: TopiVert Pharma Ltd ("TopiVert" or the "Company"), a clinical-stage biotechnology company developing Narrow Spectrum Kinase Inhibitors (NSKIs) as novel, locally-acting medicines for the treatment of chronic inflammatory ocular and gastrointestinal diseases, today announces the publication of "Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders" in Investigative Ophthalmology & Visual Science (IOVS, March 2018, Vol. 59, 1443-1453), a peer-reviewed journal for the dissemination of results from laboratory and clinical ophthalmic and vision research.
The publication presents the results of a collaboration with the group of Dr Suzanne Hagan, Lecturer in Vision Sciences at Glasgow Caledonian University, which demonstrated upregulated expression of NSKI targets, pivotal enzymes in inflammatory signalling cascades, in DED patients along with key inflammatory cytokines and matrix metalloproteinase-9 (MMP-9). TOP1362, an NSKI specifically designed to inhibit these target kinases, potently reduced cytokine release in cellular models of innate and adaptive immunities. These reductions in inflammatory cytokine release also translated into an in vivo setting, where TOP1362 attenuated the increase in inflammatory cell infiltration and ocular cytokine levels in a preclinical inflammatory eye model with efficacy comparable to that of high potency steroid dexamethasone.
Inflammation is a core driver of DED. TopiVert believes that breaking the inflammatory cycle with NSKIs will provide efficacy superior to that of existing DED therapies with good tolerability. In this regard, in November 2017, TopiVert announced compelling results with TOP1630, an NSKI obtained following optimisation of TOP1362, in a Phase 1/2a proof-of-concept (POC) study in DED. TOP1630 delivered statistically significant improvements compared to placebo across multiple sign and symptom endpoints starting at day 15, the first study assessment point. Importantly, this NSKI provided excellent safety and placebo-like tolerability and comfort profiles, in contrast to currently marketed products, including steroids.
Dr Victor Perez, Professor of Ophthalmology at Duke University, said: "Further to the exciting TOP1630 clinical POC study results announced last year, the IOVS article by Hagan and co-workers highlights the novel NSKI mechanism of action as being one with the potential to provide compelling, steroid-like, efficacy in DED and also reveals biomarker targets for possible evaluation in the Phase 2b/3 study planned for later this year. The ability to block a narrow range of multiple kinases safely with a single compound is very attractive and offers much potential in treating inflammatory and non-inflammatory diseases of the eye."
Steve Webber, TopiVert's Chief Scientific Officer, added: "We have previously shown that targeted multi-kinase inhibition provides broad efficacy in both the innate and adaptive immune responses, giving rise to significant advantages over "single" kinase approaches. The IOVS article highlights the potential utility of NSKIs for treating DED. We are pleased to have translated the preclinical research described in the article into the convincing efficacy seen in the TOP1630 clinical POC study and look forward to commencing late-stage development of this exciting agent in an area of significant unmet medical need."
|Posted by australiandryeye on March 26, 2018 at 8:05 AM||comments (0)|
Yuyu Pharmaceuticals said Thursday that it has received approval from the Ministry of Food and Drug Safety to go ahead with domestic phase 1 clinical trials for YY-101, a peptide-based dry eye treatment.
Dry eye syndrome is a common eye condition, in which the eye surface gets damaged due to insufficient tear production or excessive tear evaporation. The number of patients suffering from the disorder is on the rise because of the increase of computers, smart devices, air conditioners, and heaters.
Inje University Paik Hospital plans to conduct a randomized, double-blind and placebo-controlled phase 1 clinical trials on 28 healthy adult male volunteers to test the drug’s safety, tolerability, and pharmacokinetic properties. The hospital also conducted pre-clinical trials before the approval.
The Korea Evaluation Institute of Industrial Technology under the Ministry of Trade, Industry and Energy selected the drug as a promising bio-IP business promotion project.
“YY-101 is a new peptide-based drug that has confirmed its efficacy and safety in preclinical testing,” said Baek Tae-gon, head of research at the company. “The company plans to accelerate the speed of new drug development with the phase 1 clinical trial approval.”
The ministry also approved phase 3 clinical trials on YY-201, the company’s benign prostatic hypertrophy combined treatment, on March 9.
<© KBR , All rights reserved.>
|Posted by australiandryeye on March 26, 2018 at 8:00 AM||comments (0)|
Reported topline results from two Phase 3 clinical trials of KPI-121 0.25% - STRIDE 1 and STRIDE 2 – in patients with dry eye disease.
Achieved statistical significance for the primary sign endpoint of conjunctival hyperemia at Day 15 in the ITT population in both trials.
Achieved statistical significance for the primary symptom endpoint of ocular discomfort severity at Day 15 in the ITT population in STRIDE 1 with a trend towards a treatment effect in STRIDE 2.
Achieved statistical significance for the second primary symptom endpoint of ocular discomfort severity at Day 15 in patients with a more severe baseline discomfort in STRIDE 1 with a strong trend towards a treatment effect observed for the same endpoint in STRIDE 2.
Positive treatment effects were also observed for symptom endpoint of ocular discomfort severity in the ITT population at Day 8 in both trials, which was a key pre-specified secondary endpoint.
KPI-121 0.25% was well-tolerated in both trials with elevation in intra-ocular pressure, a known side effect with topical corticosteroids, similar to placebo.
Additional analyses of STRIDE 1, STRIDE 2 and Phase 2 data
Kala conducted additional analyses on a post-hoc basis to better understand the data on KP1-121 0.25% for patients with dry eye disease.
Phase 2 ocular discomfort data using the analysis method defined in the Phase 3 statistical analysis plan: Kala observed a positive treatment effect for ocular discomfort at day 15 (p=0.0489) using this analysis method. Additionally, a similar magnitude of effect was observed in the Phase 2 trial as observed in STRIDE 1 (5.27 mm and 5.44 mm differences vs. vehicle, respectively).
Pooled ITT populations from STRIDE 1 and STRIDE 2: A positive treatment effect was observed for the primary symptom endpoint of ocular discomfort at day 15 (p<0.0001) in this pooled population. The pooled results in 2 exploratory analyses in subgroups defined by geographical regions of east and west achieved p-values of 0.0071 and 0.0021 respectively and north and south achieved p-values of 0.0002 and 0.0176, respectively.
Effect on ocular discomfort on each of the days between days 8 and 14 in STRIDE 1 and STRIDE 2 using the analysis that was pre-specified for day 15: P-values of less than 0.002 were observed for all days during that time period in STRIDE 1, and p-values less than 0.05 were observed on 6 of the 7 days during that time period in STRIDE 2.
|Posted by australiandryeye on March 24, 2018 at 8:00 AM||comments (0)|
The first patient has been enrolled in the SEECASE phase 2 trial of NOV03 for the treatment of dry eye disease, Novaliq announced in a press release.
The multicenter, randomized, double-masked, saline-controlled study will evaluate the effect of NOV03 at both twice daily and four times a day.
NOV03 is designed to penetrate further into the meibomian glands, potentially dissolving meibomian lipids and helping to improve gland functionality, the release said.
“Earlier studies have demonstrated a highly favorable safety and efficacy profile in patients with DED, particularly for evaporative DED and [meibomian gland dysfunction],” Sonja Krösser, PhD, vice president of clinical development at Novaliq, said in the release.
Top-line data are expected in the second half of the year.
|Posted by australiandryeye on March 24, 2018 at 8:00 AM||comments (0)|
Biotech startup Ocunova, a spin-out from the Penn State University College of Medicine, has closed a fresh round of seed funding to support clinical trials for a treatment aimed at a chronic dry eye condition related to diabetes.
The treatment enlists a drug already approved by the FDA to manage alcohol and opioid dependence called Naltrexone. The company noted on its website that more than 3 million diabetic patients experience chronic dry eye in the U.S.
The $500,000 seed round comes from two funding sources supported by Pennsylvania: Life Sciences Greenhouse of Central Pennsylvania (LSGCP) and a branch of the state economic development arm Ben Franklin Technology Partners/Central and Northeastern Pennsylvania. Based in Harrisburg, LSGCP functions as a technology transfer group and also works with research institutions, medical centers, economic development agencies, and companies to identify needs and opportunities in life sciences. It is one of three regional biotechnology research centers that were created using funds from the state’s Tobacco Settlement Fund.
In a statement, CEO Michael Shine explained why he regards his company’s treatment as a gamechanger for the disease.
“Current treatments are limited to either over-the-counter eye drops that provide temporary relief to the eye or two prescription, anti-inflammatory medications which have delayed onset of action, variable efficacy and side effects which limit compliance. There are no treatments approved for diabetic DES. Ocunova’s drug candidate, OCU-001, is designed to affect the underlying cause of DES, which is a novel approach.”
Another group that focused on treatments for dry eye disease related to specific condition is TearSolutions. Founded by cellular biology professor Gordon Laurie with the University of Virginia and led by Tom Gadek, the company is developing a treatment called Lacripep. The first indication is for people with the autoimmune disease Sjögren’s syndrome. The drug, currently in clinical trials, is a topical eye drop that seeks to eliminate inflammatory triggers by restoring the natural basal tearing mechanism and health of cells in contact with tears, according to a description on the group’s website. This includes restoration of the nerves on the cornea of the eye, which signal the brain to produce more tears. It also stabilizes the tear film that in dry eye is very unstable. Last month, TearSolutions received backing from UVA Licensing and Ventures Group‘s Seed Fund.
There are also a fair few life science companies that have developed dry eye disease treatments for the wider population. One, TearScience, was acquired by Johnson & Johnson last year.
Aldeyra Therapeutics Inks Collaboration Deal with Johnson & Johnson to Develop Anti-inflammatory Therapies
|Posted by australiandryeye on March 24, 2018 at 7:55 AM||comments (0)|
By Mark Terry
Based in Lexington, Massachusetts, Aldeyra Therapeutics just signed a collaboration research deal with Janssen Research & Development, a Johnson & Johnson company.
The companies will work together to develop drugs that sequester pro-inflammatory aldehyde mediators. This is a new class of therapeutic targets. Aldeyra’s lead program is reproxalap, a first-in-class drug candidate that has shown anti-inflammatory activity in four Phase II clinical trials. Reproxalap is being evaluated for dry eye disease and other types of ocular inflammation. The agreement will advanced the existing analogs of reproxalap to treat inflammatory diseases.
Aldeyra will work with Janssen on research activities, which will be overseen by a joint scientific review committee. For a limited but unannounced period, Janssen will keep an option to negotiate an exclusive license to compounds that come out of the relationship.
“As we are committed to the development of novel therapeutic product candidates for autoimmune and other diseases characterized by systemic inflammation, we are pleased to partner with Janssen, a world leader in the discovery and development of therapeutics for inflammatory diseases,” said Todd Brady, president and chief executive officer of Aldeyra, in a statement.
No specific financial details for the agreement were released.
On November 29, 2017, the company presented new statistical analyses of its Phase II trial of reproxalap to the American Uveitis Society held at the American Academy of Ophthalmology 2017 Annual Meeting. The data showed formal statistical non-inferiority of 0.5% reproxalap ophthalmic solution compared to Pred Forte, a topical ocular corticosteroid, in reducing anterior chamber inflammatory cell count. The combination of reproxalap and twice-daily Pred Forte also was non-inferior to Pred Forte monotherapy four times a day.
“The use of corticosteroid therapy for the treatment of ocular inflammation is hampered by ophthalmic toxicity, including cataract formation, secondary infection, viral reactivation, delayed wound healing and elevated intraocular pressure that can cause irreversible glaucomatous optic atrophy,” said John Sheppard, professor of Ophthalmology, Eastern Virginia Medical School, who gave the presentation, in a statement. “Reproxalap could represent a welcome addition to the topical therapeutic options available to practitioners who treat noninfectious anterior uveitis, a severe inflammatory disease which can lead to permanent vision loss.”
And on January 30, 2018, Aldeyra announced that it had enrolled its first patient in a Phase IIb trial of reproxalap for dry eye disease. The trial will test two concentrations of the drug over 12 weeks in 300 patients with moderate dry eye disease.
“Existing therapy for dry eye disease, a common inflammatory condition that leads to persistently disturbing ocular irritation, is generally considered by physicians and patients to be inadequate, but represents one of the largest ophthalmic markets worldwide,” said Brady, in a statement. “Based on the positive results from the Phase IIa dry eye disease clinical trial with our topical ocular product candidate reproxalap announced in September 2017, we are pleased to begin enrolling our Phase IIb clinical trial, and expect to report results in the second half of this year.”
It seems that the work and results with reproxalap is what attracted J&J to the company and that category of drug.
|Posted by australiandryeye on March 24, 2018 at 7:55 AM||comments (0)|
ROCKVILLE, Md., Feb. 22, 2018 /PRNewswire/ -- RegeneRx Biopharmaceuticals, Inc. (OTCQB: RGRX)("the Company" or "RegeneRx"), a clinical-stage drug development company focused on tissue protection, repair and regeneration, today announced that the U.S. Patent and Trademark Office (USPTO) has issued a patent for Thymosin beta 4 (Tβ4) for use in the treatment of dry eye syndrome. Tβ4 is the active pharmaceutical ingredient in RegeneRx's proprietary drug candidate, RGN-259, a first-in-class, preservative-free, eye drop designed for patients suffering from moderate to severe dry eye syndrome.
Dry eye syndrome is a multifactorial disease of the eye and its treatment with Tβ4 would represent a major step forward from current treatment options by promoting cell migration and proliferation, reducing inflammation and accelerating corneal epithelial growth, while offering a rapid patient response with no side effects.
Two Phase 3 dry eye trials (ARISE-1 and ARISE-2), sponsored by the Company's U.S. joint venture, ReGenTree LLC, have been completed in over 900 dry eye patients with clinically significant results. ReGenTree has scheduled a meeting with the FDA in April to discuss its clinical development and regulatory plans for RGN-259.
"This patent is very significant in that it is specifically focused on administering RGN-259, consisting of Tβ4 or certain of its fragments, for the treatment of dry eye syndrome in the U.S. This, as well as additional patents we expect to receive, further enhances our unique and proprietary position in this area," stated J.J. Finkelstein, RegeneRx's president and chief executive officer.
|Posted by australiandryeye on March 24, 2018 at 7:50 AM||comments (0)|
Shire has agreed a licencing deal with Parion Sciences for a dry eye disease drug that bolsters its ophthalmic portfolio, a priority area for the Irish group.
Shire is paying $20m upfront for rights to P-321 a sodium channel (ENaC) inhibitor that is currently heading into a phase II trial, with another near-term development milestone of $20m on the cards in the near future. All told the deal could be worth up to $535m for North Carolina biotech Parion, while Shire adds to the pipeline behind its recently-approved dry eye disease therapy Xiidra (lifitegrast).
Xiidra became the first and only product approved in the US to treat both the signs and symptoms of dry eye disease when it got the go-ahead from the FDA last year, challenging a market for drug treatments currently dominated by Allergan’s $1.4bn product Restasis (cyclosporine). Shire’s drug was launched in August and had turned over $54m by the end of the year, adding another $39m in the first quarter with Shire claiming its product is now capturing 22% market share in the US.
P-321 is a topical formulation that is thought to work by blocking the absorption of tears, helping to keep the surface of the eye hydrated. That is a different mechanism of action to current drugs including Xiidra, which work by reducing inflammation in the eye. In a statement the two companies said the hope was that the drug could “address tear volume deficiency and promote ocular surface healing”.
Parion has already completed a phase I/II trial in 53 patients with mild-to-moderate dry eye disease with preliminary signs that it could improve symptoms.
“Ophthalmics is a continued focus for Shire, and the programme for P-321 will benefit from our development and commercial infrastructure and expertise,” said Shire’s CEO Flemming Ornskov. “This is an opportunity to apply our knowledge and experience from ophthalmics and dry eye disease for further innovation in this space.”
Dry eye is widespread but hard to define - in part because it can be caused by a range of factors and patients report symptoms from mild, temporary irritation through to chronic illness that can dramatically affect quality of life and even threaten sight.
Eyecare market research firm Market Scope estimates that new drugs will help drive the dry eye market from $3.4bn last year to nearly $4.5bn in 2021, with drugs taking a share alongside over-the-counter eyedrops and surgical devices.
In 2015 Shire bolstered its eyecare pipeline with the acquisition of Foresight Biotherapeutics for $300m, adding a late-stage treatment for bacterial and viral conjunctivitis.
|Posted by australiandryeye on March 24, 2018 at 7:40 AM||comments (0)|
The pharmaceutical company Sylentis (PharmaMar Group) has announced the start of the first Phase III study, HELIX, with the investigational new drug, SYL1001 for the indication of dry eye syndrome. The company has agreed with the U.S. Food and Drug Administration (FDA) on plans for the Phase III clinical program, which is designed to support the submission of a New Drug Application (NDA). The company has received final, End-of-Phase II meeting minutes from the FDA.
SYL1001 is an advance in the development of innovative compounds in different therapeutic fields, through the novel technology of gene silencing, based on RNA interference (RNAi). In the HELIX study, more than 30 centers from 5 European countries (Spain, Germany, Estonia, Portugal and Italy) will participate with the objective of evaluating the effect of the ophthalmological solution SYL1001 for improvements in the signs and symptoms of dry eye syndrome in about 300 patients an area in which few therapeutic options exist today. SYL1001 is a compound based on RNAi being administered in the form of eye drops that block the synthesis of a receptor implicated in the pathology of dry eye syndrome.
Patients with dry-eye syndrome suffer the chronic loss of lubrication and hydration on the ocular surface. The risk of developing this disorder increases in 35% every decade thereafter. Around the world, 344 million people suffer from this syndrome.
Dry eye syndrome is characteristic in people that live in developed countries and is caused by pollution, air conditioning, the use of contact lenses, refractive eye surgery or the continued use of computers. The most common symptoms of this pathology are burning, a constant itching, eye fatigue, dryness, blurred vision, the sensation of having a foreign body or eye pain, are some of the symptoms
As explained by Dr. Ana Isabel Jimenez, COO and Director of R&D at Sylentis, "the RNA interference on which we are working, could improve the signs and symptoms for patients that suffer from this syndrome, given that this compound could reduce the inflammatory parameters of the eye´s surface, could improve the quality of the tear and could reduce the ocular pain associated with dry eye syndrome. We consider that our molecule SYL1001 could be a very effective and important therapeutic alternative for these patients".
The company is working on the investigation of new treatments for ophthalmological and inflammatory illnesses. "Up to today, the line of work in which we have more rapidly advanced in is in ophthalmology, for the treatment of illnesses such as dry eye syndrome, glaucoma, ocular allergies and illnesses of the retina", added Jimenez.
What is RNA Interference?
RNA interference is an innovative technology that looks for a reduction in the anomalous production of protein, silencing the RNA Messenger. The RNAi provides a step forward, as it provides a new mechanism of action to confront numerous pathologies. Nowadays there are two marketed products based on this technology and there are several drugs in different phases of clinical development.
Pathologies, such as dry eye syndrome, are produced by an alteration in certain proteins. Through this technology, the production of proteins that take part in various pathologies could be decreased or very specifically controlled.
HELIX: A Clinical Trial Study
With the purpose of progressing in this field, Sylentis has begun the multicenter, random, controlled and double blind Phase III clinical trial in more than 30 hospitals in Spain, Germany, Estonia, Portugal and Italy. The trial, in which 300 patients are going to be enrolled will evaluate the efficacy of the product patented by Sylentis, SYL1001, in the treatment of the signs and symptoms of dry eye disease.
For more information about the clinical trial, click here.
The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf, 2007. 5(2): p. 75-92
Martínez T, Jimenez AI, Pañeda C. Short-interference RNAs: becoming medicines. EXCLI Journal, 2015;14:714-46
Pañeda C, González V, Martínez T, Ruz V, Vargas B and Jimenez AI. RNAi based therapies for ocular conditions. In Proceedings of the 11th ISOPT,2014, 25-30, Medimond, Bologna, Italy
Benitez-Del Castillo JM [https://www.ncbi.nlm.nih.gov/pubmed/?term=Benitez-Del-Castillo%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=27893109], . Protocol No.: SYL1001_IV. EUDRACT No: 2016-003903-79. A double-masked study of SYL1001 in patients with moderate to severe dry eye disease (DED). HELIX Study (Phase III). Version 1.1: December 14th, 2016. Sylentis SAU-Pharma Mar Group
(Source: PR Newswire)
|Posted by australiandryeye on March 24, 2018 at 7:40 AM||comments (0)|
March 21, 2018
A phase 2 proof-of-concept clinical trial of OCU310, a combination of brimonidine tartrate and loteprednol etabonate, has shown meaningful improvements in patients with dry eye disease, according to an Ocugen press release.
Over a 12-week period, the randomized, multicenter, double-masked, placebo-controlled study met its primary endpoint of tolerability, the release said. In addition, it showed meaningful improvements related to dry eye signs and symptoms compared with placebo.
“We believe OCU310 can provide significant benefit to those suffering from dry eye disease, and we look forward to presenting the full results at a future academic meeting and discussing with the FDA in the coming months,” Daniel Jorgensen, MD, MPH, Ocugen chief medical officer, said in the release.
Phase 3 clinical studies of OCU310 are expected to begin in the third quarter of this year.
|Posted by australiandryeye on December 12, 2017 at 6:30 PM||comments (0)|
TopiVert has released the results of a clinical trial that the company believes yielded “the best proof of concept data in dry eye syndrome.”
Based in London, the biotech company TopiVert is trying to enter the $3Bn market of dry eye syndrome with a drug with the potential to work better than the options currently available for patients with this condition.
“Most people are just not aware of the huge unmet medical need there is,” told me Ajay Duggal, CMO of TopiVert. “There are 40 million people with the disease in the US alone, and research has revealed dry eye syndrome impacts quality of life as much as angina.”
As he explains, many patients use over the counter eye drops to address the symptoms. But they do not target the cause of the disease, which is an inflammatory process. The leading prescription medicines are Allergan’s Restasis and Shire’s Xiidra, but both have limited efficacy and come with several side effects, including irritation of the eyes.
To address this situation, TopiVert is using a technology called narrow spectrum kinase inhibitors (NSKIs). “They work by targeting a range of kinases, which are molecules involved in the inflammatory response,” explains Nick Staples, CBO.
Kinase inhibitors are commonly used in cancer therapy, but they often cause side effects because kinases are involved in many other physiological processes. To avoid that, TopiVert targets a narrow selection of kinases and delivers the drug locally to the eye.
In a first, Phase I/IIa clinical trial where 60 patients were treated with either placebo or TopiVert’s therapy for dry eye syndrome, TOP1630, the company’s strategy seems to have proved successful. The therapy was as safe and well tolerated as the placebo. But most importantly, the efficacy data indicates the drug might be superior to what is currently on the market.
After 15 days, TOP1630 proved to show a significant improvement in several symptoms, including dryness, grittiness, ocular discomfort and pain, as well as on the signs physicians use to diagnose the disease, including measuring the deterioration of the cornea. These effects were further improved after 29 days on many of the measurements.
Duggal remarks that the results are particularly impressive given the consistency of effects across multiple symptoms and clinical signs. Furthermore, all these analyses were specified before running the trial, whereas most competitor studies have relied on post-hoc analysis to demonstrate an effect. Duggal is therefore confident that TopiVert will be able to reproduce these results in the next clinical trial. If the results are confirmed there, it would allow the company to seek approval. Something that could happen as soon as 2021.
|Posted by australiandryeye on December 4, 2017 at 10:15 PM||comments (0)|
Melbourne, October 11, 2017 – Azura Ophthalmics has received US$16 million in Series B funding to develop treatments for Meibomian Gland Dysfunction (MGD) – the number one cause of Dry Eye Disease.
The funding from Brandon Capital’s Medical Research Commercialisation Fund (MRCF), TPG Biotech, OrbiMed and Ganot Capital, will allow the Israeli-Australian company to move into its next clinical stage in the development of novel treatments for MGD – an eye condition where the Meibomian Glands becomes dysfunctional which results in rapid evaporation of the tear film.
Meibomian glands reside in the upper and lower eyelids and are responsible for producing the oily layer that forms the outer most layer of a person’s tear film. This oil (lipid) layer, in conjunction with the watery layer of the tear film work together to maintain clear vision and ocular health. An intact lipid layer ensures tears do not evaporate and keeps the eyes moisturised and nourished. If this layer is disturbed, it leads to tears evaporating too quickly, drying out the ocular surface and resulting in damage to the front of the eye, discomfort, and a significant reduction in both quality of life and productivity.
As Azura Ophthalmics Chief Executive Officer Marc Gleeson explained, “Meibomian gland dysfunction is responsible for at least 70 per cent of dry eye cases and affects about 300 million people worldwide, yet despite significant efforts there are no pharmaceutical treatments available for this condition. Using our novel therapy, Azura has generated promising results in a phase 1 study in MGD sufferers. We are therefore optimistic that Azura’s treatment could one day provide the first effective treatment for MGD sufferers.”
MGD sufferers represent one of the largest and most underserved patient segments in ophthalmology. If left untreated MGD will alter the tear ﬁlm, causing eye irritation, inﬂammation, and severe Dry Eye Disease (DED). Following initial clinical success with their lead compound, Azura Ophthalmics will undertake Phase 2a clinical testing of this new formulation in approximately 120 patients with MGD.
The Israeli-headquartered company was founded in Tel Aviv in 2014. All further research, clinical trials and the development of Azura’s Ophthalmics drug treatment will be undertaken in Australia.
MRCF Chief Executive Officer Dr Chris Nave noted, “Australia is an accepted world leader in medical research. However, historically a lack of investment funding in the life sciences sector has resulted in Australian medical discoveries leaving our shores to gain access to the capital required for further development. The government’s R&D tax incentive and the introduction of the $500 million-dollar Biomedical Translation Fund are addressing this problem and are attracting foreign life science companies like Azura Ophthalmics to Australia, stimulating the industry locally, creating jobs and keeping our talented clinicians and scientists, and their research, in Australia.”
Indeed, Sydney-based CEO, Marc Gleeson, is leveraging these incentives to bring innovation home. As Gleeson noted, “Australia has an attractive regulatory environment for early-stage clinical trials and the government’s R&D tax incentive, which sees eligible companies undertaking research and development in Australia, receive a refundable tax offset, helps preserve valuable capital. Azura Ophthalmics was established in Israel, which is highly-renowned for its innovation ecosystem. The Company is now looking to take advantage of Australia’s clinical research excellence and the incentives that support investment in Australian innovation”.
Through a combination of innovation from Azura Ophthalmics, the Australian government’s R&D tax incentive, and the Biomedical Translation Fund, Australia is now positioned to be at the forefront in developing innovative treatments for Meibomian Gland Dysfunction, the leading cause of dry eye disease, offering hope to hundreds of millions of people worldwide.
|Posted by australiandryeye on November 20, 2017 at 8:15 PM||comments (0)|
Cannabinoids could have potential in a novel topical drug delivery vehicle to treat neuropathic dry eye pain.
The disconnect between signs and symptoms in dry eye disease is an intriguing clinical problem. Although we know quite a lot about the etiology of dry eye, the ideal structure of the tear film and how to diagnose and treat dry eye disease, there are still some patients who do not respond to treatment or who present complaining of severe symptoms that seem to be poorly correlated with clinical signs. Complaints may include a burning or stabbing sensation or a feeling of pressure in the eyes.
Many clinicians find these patients—and the chair time they consume—frustrating. But before dismissing them as “crazy,” it may help to consider whether they could be suffering from a different form of dry eye that is difficult to detect by traditional methods.
In 2009, Perry Rosenthal and colleagues observed what they presumed to be corneal neuralgia, which they termed “pain without stain” because of the paucity of corneal staining or other clinical signs.1 They speculated that the pain symptoms could be related to a neuropathic disorder, rather than to qualitative or quantitative tear film factors.
Later work by Rosenthal further elucidated how the nociceptive system—critical to vision when functioning properly, because it monitors and restores the optical tear film—could become dysfunctional.2 When this happens, the corneal nerves, the central trigeminal sensory network, and/or the pain organising centres in the brain escalate the eye’s natural ‘alarm system’, sending pain signals that are out of proportion to the physical insult (if indeed there is any injury at all).
Neuropathic dry eye pain may be triggered or exacerbated by ocular surgery, systemic conditions or even psychological distress.
The dry eye community has been increasingly interested in neuropathic dry eye. In fact, the new DEWS II definition of dry eye explicitly includes “neurosensory abnormalities” in the list of etiological factors in dry eye.3
A DEWS II subcommittee report on pain and sensation notes that long-term inflammation can alter neuron excitability, connectivity and impulse firing and that disturbances in ocular sensory pathways may ultimately lead to neuropathic pain.4 However, as yet, there are no dry eye therapies that specifically target neuropathic pain.
The role of cannabis
Cannabinoids and, in particular, tetrahydrocannabinol (THC, the main active ingredient in recreational marijuana) is of great interest in the treatment of neuropathic pain. Cannabinoid receptors are known to modulate pain and inflammation and are located throughout the eye, including the corneal epithelium and the retina; they are present on immune cells and may be involved in wound healing, as well.5 So, from a theoretical perspective there are a number of reasons to pursue the use of cannabinoids to treat dry eye.
And the time may be right to conduct such research now. Regulatory restrictions around the use of cannabinoids are being loosened, with more than half of U.S. states and several European countries now permitting the use of THC for medical purposes.
In Germany, where I practice, a special permit is required and the drug must be used in a controlled research setting as part of a clinical trial, which seems to be a reasonable way to open the doors to research on cannabinoid compounds while still limiting the potential for abuse.
In my laboratory, we have been actively investigating what the best targets for treating neuropathic pain might be and how THC could be safely and effectively delivered to those targets.
There are a number of challenges in using THC therapeutically. Smoking marijuana or consuming THC in edible form is impractical for the treatment of ocular disease; these systemic applications deliver an unpredictable dose with unwanted systemic side effects.
Sublingual and dermal administration have similar effects and are probably not appropriate for ocular conditions. For these reasons, and due to a lack of evidence of predictable, long-lasting therapeutic effect, a number of professional organisations, including the Canadian Ophthalmological Society and the American Academy of Ophthalmology, have taken positions against the use of systemic THC treatment for ocular conditions.
Local application of THC is considerably more compelling. Cannabinoid eye drops have been investigated and are available for glaucoma from at least one small manufacturer. But noone yet has been particularly successful with this approach due to the challenges of formulating the drops appropriately.
THC and most other pain-relieving or anaesthetic compounds are quite lipophilic. Like oil with water, they do not mix well with the aqueous solutions in most eye drops, making it difficult to get THC into the target ocular tissues.
Enhanced topical drug delivery
Recently, we have been investigating the use of a novel semi-fluorinated alkane (SFA) drug delivery technology (EyeSol, Novaliq) as a vehicle to deliver cannabinoids to the ocular surface. This class of molecules has a number of advantages as an eye drop.
EyeSol-based drops contain no water, so they mix well with lipophilic substances, including cyclosporine and THC, and allow them to remain solubilised instead of separating out in the bottle. They have a very low surface tension so a drop on the eye rapidly forms a very thin layer, giving it spreading properties that are far superior to an aqueous eye drop (Figure 1).
These properties should help to distribute a drug across the uneven ocular surface without the drug being immediately drained or spilling out of the eye as excess aqueous. SFA molecules are metabolically inert and do not interact with the immune system. Finally, they have a refractive index similar to water, so they do not disturb vision the way oil emulsions of lipophilic ingredients can.
In several observational trials we conducted, q.i.d. treatment with an EyeSol delivery vehicle alone resulted in a highly significant reduction in corneal staining and a 20-point improvement in OSDI scores after just six weeks.6 We thought that if this vehicle could be combined with a compound like THC for pain and inflammation, it could be very beneficial in dry eye treatment.
We began to conduct experiments using an established mouse model for dry eye disease that relies on behavioural testing methods to determine pain levels, as well as other testing methods (Figure 2). We compared a group treated with EyeSol THC eye drops to a control group treated with topical cyclosporine.
One-year results of these preclinical studies suggest that the drop is at least as effective as cyclosporine and may have dual or even triple mechanisms of action, including lubrication, anti-inflammation and pain reduction. Although we continue to evaluate various parameters, the pharmacodynamics thus far are very promising.
We are fairly confident that topical application of THC dissolved in EyeSol will not result in any measurable systemic effects. The first human clinical trials in dry eye disorder are expected to begin in the second half of 2018.
Understanding neuropathic pain
Even as research into THC delivery to the ocular surface continues, we have also been seeking to gain a better understanding of neuropathic pain and the characteristics of patients who may suffer from this form of dry eye. To do this, we in the dry eye clinic have been working closely with experts from the University of Cologne’s pain clinic.
We retrospectively evaluated 52 patients seen in our dry eye clinic who fell into the ‘pain without stain’ category. These subjects had normal Schirmer’s, no corneal staining and no signs of blepharitis, but they had OSDI scores >40, in the ‘severe’ symptom range (median score 77).
In addition to a very thorough history and examination in our clinic, many of the patients also underwent a full pain inventory and Hospital Anxiety and Depression Score (HADS) questionnaire. Comorbidities included depression (n=9), chronic pain syndrome (9), anxiety disorders (4), and prior eye surgery (17).7 Other researchers have also recently shown that severe dry eye pain is correlated with antidepressant use but not with corneal staining.8
For ophthalmologists, these are exactly the sort of patients who are mystifying at best, and often get dismissed as people whose symptoms are “just” psychological. To the pain experts we consulted, however, it was very clear that these were typical pain patients, with the same types of concomitant psychosomatic conditions they often see among patients who suffer from chronic headache or back pain.
A typical patient in our study, for example, might have fibromyalgia and rheumatoid arthritis, with an OSDI score of 65 but no clinical signs of dry eye. Upon questioning, she might have first noticed the dry eye pain following LASIK or around the time of a particularly stressful life event, such as the death of a close family member.
In some cases, the patients had no response to topical anaesthesia or to systemic pain medications, which was quite interesting, since it indicates there is something very unusual going on with regards to their pain response. It seems that these individuals may be predisposed to systemic neuropathic pain, of which ocular pain is but one manifestation.
These insights have changed the way I practice in a number of ways. For example, I have started using the HADS questionnaire more frequently for patients with severe symptoms. I ask broader questions about fatigue, anxiety and depression as part of my history taking.
Recognising that ocular surgery can trigger an underlying pain syndrome, I am more thoughtful about evaluating postoperative patients with unexplained symptoms to determine whether they might be most appropriately managed as a pain patient. As medical doctors, it is our responsibility to see the whole patient and, when appropriate, help them to seek treatment for systemic autoimmune disorders, psychosomatic illnesses and other pain syndromes.
‘Pain without stain’ patients provide us with a model to understand the process of neuropathic dry eye. Because they do not have significant meibomian gland dysfunction or aqueous deficiency, we are able to isolate the neuropathic disease and hopefully identify new therapies to relieve their symptoms.
While these patients represent what is probably a very rare subtype of dry eye, it is likely that many more dry eye patients who do have clinical signs also have neuropathic pain as a component of their dry eye. In fact, I believe that most of the patients who fail, even partially, to respond to stepwise, appropriate dry eye therapy or for whom resolution of signs does not lead to significant improvement in symptoms, might also have an additional neuropathic disorder.
What we learn from treating the extreme form, therefore, has the potential to benefit a much broader range of patients whose pain is inadequately addressed with current therapy.
It has become clear to me that there is a strong unmet need for treatments that specifically address ocular surface pain. Although much research remains to be undertaken, I am optimistic about the potential for cannabinoid therapies, particularly if we are able to confirm that use of an SFA drug delivery technology is effective in reaching the target tissues without systemic side effects.
Rosenthal P, Baran I, Jacobs DS. Corneal pain without stain: Is it real? Ocul Surf. 2009;7(1):28-40.
Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100(1):128-134.
Nelson JD, Craig JP, Akpek EK, et al. TFOS DEWS II introduction. Ocul Surf. 2017;15:269-275.
Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017;15(3):404-437.
Toguri JT, Caldwell M, Kelly MEM. Turning down the thermostat: modulating the endocannabinoid system in ocular inflammation and pain. Front Pharmacol. 2016;7:304.
Steven P, Scherer D, Krösser S, et al. Semifluorinated alkane eye drops for treatment of dry eye disease—a prospective, multicenter noninterventional study. J Ocul Pharmacol. Ther 2015;31(8):498-503.
Steven P, Schneider T, Ramesh I, et al. Pain in dry eye patients without corresponding clinical signs—a retrospective analysis. Association for Research in Vision and Ophthalmology. 2016, Abstract 2848-A0057.
Satitpitakul V, Kheirkhah A, Cmej A, et al. Determinants of ocular pain severity in patients with dry eye disease. Am J Ophthalmol. 2017;179:198-204.
Professor Philipp Steven, MD
Prof. Steven is principle investigator for the Ocular Surface Group in the Department of Ophthalmology at the University of Cologne, in Germany. He consults for and receives research funding from Novaliq and has a patent pending related to the work described within this article.
|Posted by australiandryeye on October 31, 2017 at 10:35 PM||comments (0)|
The possible causes are many and prescription treatments few, but new and potential dry-eye therapeutics keep coming.
The update reflects the most current understanding of dry-eye disease as a disruption in homeostasis and emphasizes the importance of hyperosmolarity in dry-eye tears and the role of inflammation in DED. Inflammatory mediators are frequent therapeutic targets. As things stand, Restasis and Xiidra (Allergan and Shire, respectively) are the only prescription eye drops approved by the Food and Drug Administration for the treatment of dry-eye disease. Both medications are thought to inhibit T cells by different mechanisms of action. The heterogeneous nature of dry-eye disease is one of the things confounding new drug development: Drug makers have multiple potential molecular and tissue targets to consider and DED is notorious for a lack of overlap between signs and symptoms.2 With an estimated global prevalence ranging from 5 to 50 percent3 and the potential for corneal surface damage and diminished quality of life absent good treatment, DED’s therapeutic pipeline is unlikely to run dry anytime soon.
Four dry-eye treatments at various stages follow: a freshly FDA-approved medical device; a drug in the middle of the investigational stage; a patented topical solution/gel formulation; and a protein-fragment-based drop beginning a human trial.
Approved by the Food and Drug Administration in the spring of 2017, Allergan’s TrueTear Intranasal Tear Neurostimulator device relies on an old idea—nerve stimulation—to address the problem of dry eye. Oculeve, the startup that invented the device before being purchased by Allergan, based TrueTear on technology used in TENS units and for the treatment of movement disorders. The TrueTear stimulates the trigeminal nerve and, in turn, the seventh cranial nerve with small electrical pulses that ultimately trigger the lacrimal gland to produce tears.
To reach the ophthalmic branch of the trigeminal nerve, this small handheld device has two prongs covered in disposable hydrogel tips that go up the patient’s nostrils. Patients can choose from five levels to control the intensity of electrical stimulation. According to patient information for the TrueTear,4 patients should
The TrueTear is an intranasal device that uses neurostimulation.
aim to use the device at least twice a day for no more than three minutes per session; the TrueTear automatically shuts off after 30 minutes of use in a 24-hour period. Allergan lists a tendency for nosebleeds, a history of clotting disorders, the use of pacemakers or wearable defibrillators, as well as the presence of metallic or electronic implants in the head or neck as contraindications to TrueTear use. The device is currently approved for patients 22 years of age and older.
Supportive data released by Allergan4 consist of two studies: OCUN-009, a look at one-day correct use of the device versus one-day sham control treatments, and OCUN-010, a six-month trial comparing tear production at six months to baseline. Forty-eight dry-eye patients at two sites underwent three applications of neurostimulation in OCUN-009: correctly applied intranasal stimulation treatment with an active TrueTear; intranasal application of an inactive TrueTear; or extranasal (incorrect) application of an active TrueTear. The average Schirmer’s score for the treatment group was 25 mm during treatment, versus 9 mm for both sham groups. OCUN-010 was an interventional open-label study looking at tear production in 97 dry-eye patients at treatment days one, seven, 30, 90 and 180. Patients were told to use the TrueTear anywhere from two to 10 times per day for a maximum of three minutes per session. At each follow-up visit, Schirmer’s testing without stimulation was compared to scores with stimulation; tear production was consistently significantly greater with active TrueTear stimulation than without. The effect appeared to decrease from the first-day results but then plateaued over time (still remaining higher than without stimulation). The average differences in Schirmer’s scores (with stimulation versus without) were 18 mm on day one, 13.1 mm at seven days, 8.1 mm at 30 days, 8.3 mm at 90 days and 9.4 mm at 180 days. In both studies, adverse events were minor and included nasal complaints such as irritation.
“Crazy,” is how John Berhdahl, MD, of Vance Thompson Vision in Sioux Falls, S.D., sums up his first impression of the TrueTear upon getting the chance to try it out a couple of years ago. “But I love outside-the-box ideas, and as I thought about it more deeply, it made sense,” he says. “We know that reflex tearing can occur when you stimulate nerves, and it’s not so different from other electrotherapies that we use to stimulate nerves in other parts of the body. I believed that it would be safe, so I thought, ‘Let’s try it. Let’s see if this crazy idea turns out to be legit,’” he recalls.
So far, Dr. Berdahl reports that patients are having “a very good response” to the TrueTear since it has become generally available. “I like that we’re using concepts outside of ophthalmology like electrostimulation and applying them to ophthalmology to see if we can control the pathophysiology of the eye: I think that’s great,” he says. He thinks that the high degree of control over treatment that the device affords patients is one factor in its success to date. “One of the things that’s really nice about it is that we allow them to try it in the office so that they can experience the increased tearing,” he notes. “Then they can try it for a month, and if it’s not working for them, it can be returned. Those two steps allow people to climb the learning curve in a noncommittal way.”
Dr. Berdahl also values the safety and flexibility of the TrueTear, since it fits well into comprehensive treatment plans that include other modalities. “I believe in treating severe dry eye by hitting it really, really hard to get it under control and then backing off the things that you no longer need, or that the patient likes the least,” he says. Using the TrueTear is part of that treatment philosophy for dozens of patients in his practice.
Surgeons say that the base price of the TrueTear is $750 and a month’s supply of disposable tips costs $250, although Allergan does offer some rebates to help defray costs.
In addition to stimulating the lacrimal gland in aqueous-deficient dry eye, Dr. Berdahl says that there is evidence that using TrueTear improves the tear film in dry eye as well. “They have done some work to show that it improves meibum secretion, so it would improve tear-film quality,” he says. A small study5 suggests that use of the neurostimulator can promote degranulation of conjunctival goblet cells in both dry and healthy control eyes.
Since its launch in 2003, Restasis (0.05% cyclosporine A emulsion), has been a dry-eye treatment mainstay, thought to inhibit the action of inflammatory T-cell mediators. Cyclosporine eye drops, however, present the same roadblocks to efficacy and compliance as other topical drops: Many patients have difficulty getting them into the eye without blinking as soon as they reach the cornea, which results in spillover and drainage into the lacrimal system before the drug can provide much therapeutic benefit.
Novaliq GmbH (Heidelberg, Germany) has combined cyclosporine A with its Eyesol drug-delivery platform, which is made up of semifluorinated alkanes, in a bid to create a more bioavailable and user-friendly alternative to aqueous drops.
Semifluorinated alkanes aren’t new to ophthalmology because they possess characteristics that make them suitable tamponades in vitreoretinal surgery, including good solubility in silicone oils, perfluorocarbon and hydrofluorocarbon liquids; a refractive index of 1.3; and a specific gravity of 1.35 g/mL.6 Those attributes also make semifluorinated alkanes good for mixing with cyclosporine A—a drug with poor water solubility—to make a slick, clear, preservative-free solution with low surface tension that spreads rapidly over the ocular surface.
One drop of a 0.05% aqueous emulsion has a volume of 40 to 50 μL: a drop of that size triggers reflexive blinking in many patients when it contacts the eye. To create a cyclosporine A drop that will more successfully reside on the cornea, Novaliq has developed CyclASol, a preservative-free cyclosporine A solution with Eyesol. Novaliq says that a drop of CyclASol is only about 10 μL in volume, so it doesn’t trigger a blink reflex and accompanying spillover in the eye, and its low surface tension allows the drop to spread over the cornea more quickly and evenly than aqueous eye drops. Alternate dry-eye treatments include gels and ointments, but these are often limited to nighttime use because they blur and distort vision, even though they reside on the cornea better than aqueous drops. The company claims that CyclASol’s refractive index is very close to that of the crystalline lens, so it will not blur or distort vision.
A Phase II study (Trial Identifier: NCT02617667) comparing two dose levels of CyclASol (0.05% and 0.1%) solution with cyclosporine A 0.05% emulsion and a placebo followed 207 randomized patients with moderate-to-severe dry-eye disease for four months. Novaliq released topline data from this study in early 2017.7 Although patients in all treatment arms showed reduced corneal fluorescein staining, patients enrolled in both CyclASol groups showed significantly more disease-sign improvement than patients in the vehicle (placebo) group. Novaliq says that its data also demonstrated that CyclASol patients began showing reduced corneal and conjuctival staining as early as 14 days into treatment. It reports that the drops were well tolerated with no serious adverse events. Novaliq added that improvement was most marked in the central area of the cornea and noted that area’s importance to good visual functioning.
Upon release of the topline data, a company press release7 quoted Claus Cursiefen, MD, PhD, FEBO, professor and chair of the ophthalmology department at University of Cologne, Germany, and member of Novaliq’s scientific advisory board, on the therapeutic benefits of CyclASol: “Consistent improvements in several measures of ocular inflammation of dry-eye disease, particularly the improvement in central corneal staining, is a very important feature of the formulation because it positively influences visual function. This, combined with the early onset of action and an excellent tolerability profile, represents a highly relevant improvement over currently available therapies.”
In the spring of 2017, Imprimis Pharmaceuticals (San Diego) announced that it had purchased the exclusive worldwide rights to Klarity, a patented topical ophthalmic solution created by Richard L. Lindstrom, MD, to protect and heal the ocular surface in moderate-to-severe DED. Klarity is also intended for dry eye and corneal irregularities arising from intraocular surgery or contact lens wear.
The preservative-free Klarity solution contains chondroitin sulfate, thought to have protective and healing effects on the corneal epithelium,8 and established as safe for intraocular use in viscosurgery. It also contains dextran and glycerol. Imprimis says that the solution can be formulated to vary in viscosity, making it suitable as a topical drop, a gel or even a dispersive OVD.
The company plans to make Klarity part of its emerging dry-eye program. According to the Imprimis website, another upcoming addition is the compounding of autologous serum tears at the company’s 503A PCAB-accredited pharmacies.
Lacripep (TearSolutions, Inc.) is a synthetic protein fragment incubated in the Laurie Cell Biology Laboratory at the University of Virginia in Charlottesville. Its inventor, Gordon W. Laurie, PhD, professor of cell biology, biomedical engineering and ophthalmology at UVA and co-founder and CSO of TearSolutions, and colleagues say that Lacripep is potentially the first therapeutic agent capable of improving dry-eye disease regardless of etiology.
“Lacripep is a synthetically generated 19-amino-acid fragment of lacritin,” Dr. Laurie explains. “Lacritin is a naturally occurring protein in tears, first identified in 2001 by the Laurie Cell Biology Lab out of an unbiased discovery screen for factors that regulate basal tearing.” He notes that Lacripep-like lacritin fragments occur naturally in tears secreted by healthy eyes—and that they are deficient (as is lacritin) in dry-eye tears. “Lacripep and lacritin have been studied in several dry-eye animal and human cellculture models, and have been found to restore ocular surface health by: promoting tear protein release and tearing, even under conditions of inflammation; transiently stimulating a cellular lysosomal pathway known as autophagy to rid cells of damaged proteins and organelles that accumulate under conditions of stress; and restoring mitochondrial oxidative phosphorylation. In unpublished data, both also appear to stimulate and benefit sensory nerves at the ocular surface that in dry eye are disrupted and diminished,” he says.
This neural stimulation may bring relief for both aqueous-deficient and evaporative dry-eye patients. “By apparently targeting corneal sensory nerves that in turn regulate all glandular and secretory elements of the ocular surface, Lacripep is expected to benefit both evaporative and aqueous-deficient dry eye,” Dr. Laurie explains.
With support from the National Eye Institute,
A molecular model of lacritin, a protein that is selectively deficient in dry-eye tears. Lacripep is a synthetic lacritin fragment.
Dr. Laurie and colleagues focused on the causes of dry eye rather than the effects of the disease. “With NEI R01 support, we were the first to explore the cell biological basis of dry eye using an unbiased biochemical screen. This differs from others who have largely employed a candidate approach, in most cases focused on downstream inflammation,” says Dr. Laurie. “It took years, but we succeeded in identifying a natural tear activity, encapsulated in Lacripep, that appears to be fundamental for the maintenance and restoration of ocular surface homeostasis. Yet, dry-eye tears are selectively deficient in lacritin and natural Lacripep-like fragments. This draws a parallel to type I diabetes and insulin, and offers a new way to think about dry eye with Lacripep as a replacement therapy, that based on the biology, could be a game changer.”
“A shout-out to the National Eye Institute for their many years of support, without which this discovery would not have been possible,” says Dr. Laurie. “We also wish to acknowledge the Lacritin Consortium of labs in the U.S. and outside, who have contributed fundamentally to our understanding of Lacritin,” he says.
Dr. Laurie, Marc G. Odrich, MD, associate professor of ophthalmology at University of Virginia and medical director of TearSolutions, Inc., and colleagues have recently begun an attempt to transition from the laboratory to the marketplace with a double-masked, randomized, placebo-controlled Phase II study of topical Lacripep in more than 200 patients with Sjögren’s-associated dry-eye disease at 27 U.S. sites (Trial Identifier: NCT03226444). Enrolled patients receive one of two concentrations of Lacripep eye drops or a placebo three times a day for four weeks. Improvement in fluorescein corneal staining is the primary endpoint.
Dr. Odrich says that they selected Sjögren’s patients for the first study because primary dry eye associated with the disorder “is the most homogenous form of dry-eye disease, with diagnosis aided by blood tests and salivary gland biopsy.” He adds, “Second, lacritin deficiency in Sjögren’s syndrome correlates with reduced corneal nerve fiber density and length, tear insufficiency, increased ocular staining and reduced corneal sensitivity. Third, in two different mouse models of Sjögren’s syndrome, lacritin promoted rapid resolution of corneal staining and/or tearing. Fourth, Sjögren’s syndrome patients are highly motivated.”
Dr. Odrich estimates that data will become available in the first half of 2018. Should Lacripep garner FDA approval in the future, he believes that patients could titrate the number of daily doses down from three once their condition stabilizes. “There appears to be a lasting effect with repeated dosing,” Dr. Odrich says of his team’s studies in rabbits that were dosed three times daily for two weeks. “Basal tearing steadily increased and remained elevated one week after washout.The molecular basis is under study. At least two different mechanisms are likely involved,” he says.
The dry-eye pipeline is tricky for a variety of reasons: the heterogeneity of the target disease; the lack of overlap between signs and symptoms; and the costly path to FDA approval, to name a few. As the most prevalent ocular surface disease globally, however, DED will never be without therapeutic contenders.
“Dry eye is a disease that has real unmet needs because we can’t get everybody better right now,” Dr. Berdahl observes. “So I’m excited about all of it, but it remains to be seen which things will be the most clinically useful.” REVIEW
Dr. Berdahl is a consultant to Allergan. As mentioned in the article, Drs. Laurie and Odrich are the CSO and medical director, respectively, of TearSolutions, Inc.
1. Craig JP, Nichols KK, Akpek EK, Caffery B, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15;3:276-83.
2. Novack GD. Why aren’t there more pharmacotherapies for dry eye? Ocul Surf 2014;12;3:227-29.
3. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf 2017;15;3:334-65.
4. Allergan. Patient Guide to the TrueTear intranasal tear neurostimulator. https://allergan-web-cdn-prod.azureedge.net/actavis/actavis/media/allergan-pdf-documents/labeling/ifu_truetear_patient.pdf. Accessed August 28, 2017.
5. Gumus K, Schuetzle KL, Pflugfelder SC. Randomized controlled crossover trial comparing the impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation. Am J Ophthalmol 2017;177:159-68.
6. Alovisi C, Panico C, de Sanctis U, Eandi CM. Vitreous substitutes: Old and new materials in vitreoretinal surgery. J Ophthalmol 2017;2017:3172138. doi: 10.1155/2017/3172138. E-pub ahead of print.
7. Novaliq, “Novaliq announces positive topline results of Phase 2 clinical trial evaluating CyclASol in adults with moderate to severe dry eye disease,” (2017). Available at: http://bit.ly/CyclASol. Accessed August 28, 2017.
8. Sandri G, Bonferoni MC, Rossi S, Delfino A, Riva F, et al. Platelet lysate and chondroitin sulfate loaded contact lenses to heal corneal lesions. Int J Pharm 2016;25;509(1-2):188-96.