Stem Cells in Ophthalmology Update 28 First Ophthalmic Stem Cell Treatment Recommended for Approval

On December 19th, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) recommended the stem cell product Holoclar (Chiesi Farmaceutici S.p.A.)  as a first-ever medicinal treatment for severe limbal stem cell deficiency, a condition caused by physical or chemical burns to the eye or eyes in adults, which can result in blindness.

The EMA has designated Holoclar as both an orphan medicine and an advanced therapy medicinal product, which enabled the manufacturer to receive free scientific advice and protocol assistance for drug development. The CHMP recommendation was based on an assessment by the expert Committee for Advanced Therapies. Such steps are taken to promote the development of medicines for rare diseases and to encourage innovative medicinal products, according to the EMA statement.

Holoclar is produced by Chiesi under an agreement with Holostem Terapie Avanzate, an Italian biotechnological company devoted to the development, manufacture, registration and distribution of Advanced Therapy products based on cultures of epithelial stem cells both for cell therapy and gene therapy. Holoclar was designed specifically for the treatment of severe limbal stem cell deficiency (LSCD).

The transparency of the cornea is essential to ensure the ability to see properly. Corneal cell renewal and repair are dependent upon the cells present in the limbus, which is found in a small area of the eye between the cornea and the conjunctiva.

Thermal or chemical burns to the eye can destroy the corneal surface (epithelium) and the limbus, causing a deficiency of limbal cells. If this happens, the cornea is covered by a different epithelium following an invasion of cells from the conjunctiva. This process leads to neovascularization, chronic inflammation and stromal scarring, rendering the cornea opaque and results in subsequent loss of vision. Conventional corneal transplants are an ineffective treatment in such cases.

Fig 1 Damaged eye before treatment

The therapy is based on cultures of limbal cells taken from the patient, which, once they have successfully grafted, regenerate the corneal epithelium and restore its functions. Limbal cell cultures even allow the possibility of treating patients with a loss of corneal epithelium in both eyes, provided that a small portion of limbus remains in one of the eyes.

Holoclar, is an autologous culture of limbal stem cells. It is made from a biopsy taken from a small undamaged area (minimum of 1-2 mm2) of the patient's cornea and grown in the laboratory using cell culture, and transplanted in the affected eye or eyes after removal of the damaged area. Such cultures engraft and permanently regenerate a functional corneal epithelium allowing recovery of visual acuity. replacing damaged limbal stem cells.

Fig 2 A cultured sheet of corneal epithelium

Holoclar can offer an alternative to corneal transplantation for replacing altered corneal epithelium in some cases, and it has been shown to increase the chances of a successful corneal transplant where the injury has caused extensive eye damage. It reduces the risk of rejection compared with transplanting tissue from a donor and does not require surgery on the patient's other eye as only a small biopsy is performed to collect the cells, thus reducing the risk of damage to the healthy eye. Therefore, Holoclar may also be suitable where both eyes are affected by moderate to severe LSCD.

Limbal stem cell deficiency is estimated to affect about 3.3 per 100,000 people in the EU, causing pain, photophobia, inflammation, corneal neovascularization, loss of corneal transparency, and eventually blindness.

The recommendation was made by the Committee for Medicinal Products for Human Use (CHMP) based on a robust assessment carried out by the Committee for Advanced Therapies (CAT), the Agency's expert committee for ATMPs.

“This recommendation represents a major step forward in delivering new and innovative medicines to patients,” says Enrica Alteri, Head of EMA's Human Medicines Evaluation Division. “EMA has used all available support tools to facilitate the development and assessment of Holoclar. It is an advanced therapy medicinal product that has been designated as an orphan medicine. This allowed the Agency to provide support including several rounds of free scientific advice to the applicant during Holoclar's development.”

The Committee for Advanced Therapies and the CHMP panels determined that although the product's benefits outweigh its risks, the marketing authorization should be conditional because the data thus far are retrospective and not yet comprehensive. Therefore, the EMA says, "an additional study on the use of Holoclar should be conducted."

The opinion adopted by the CHMP at its December 2014 meeting is an intermediary step on Holoclar's path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. After that, decisions about price and reimbursement will take place at the level of each member state,  taking into account the potential role/use of this medicine in the context of the national health system of that country.

Update: On February 20, 2015, the EMA approved European marketing for Holoclar. Chiesi said that Holclar would be available to all suitable patients in Europe "in the near future".

References:

1. First stem-cell therapy recommended for approval in EU, European Medicines Agency Press Release, December 19, 2014

2. First-Ever Stem Cell Therapy Recommended in EU, Miriam E. Tucker, Medscape, December 19, 2014

3. Chiesi website

4. Holostem website

5. Europe approves Western world's first stem-cell therapy for rare eye condition, Reuters Press Release, February 20, 2015

Another Word for Stubborn Tapas Maybe

by Nina

Leaf in a Grid by Melina Meza

Baxter and I had an interesting discussion yesterday about what “yoga for healthy aging” means. He said that he felt that essentially it was an attitude, you know, the combination of acceptance and active engagement we’ve been talking about since the early days of the blog (see What We Need to Practice  and Acceptance, Active Engagement, and the Bhagavad Gita). Then our conversation—as so often happens—wandered off track and we started talking about various older yoga teachers we know, how some of them were still very physically capable while others had lost a lot of abilities due to injuries and other physical problems. 

In reference to one particular teacher we knew, Baxter said he thought her injuries and physical problems were due to over-practicing asana over the years. 

I shook my head and said, “I think that some people are just more physically robust than others.” And then I mentioned another older teacher who was a very dedicated practitioner of asana who still seemed to be very good physical condition. 

“That’s also true,” Baxter said.

“Like me,” I sighed. “I not very physically robust.” 

“Yes, you are, Nina!” he said. “You’re very robust! Look at you, you recovered completely from two different bouts of frozen shoulder.”

I laughed. “I’m not robust. I’m just very stubborn. I remember once when someone was commenting on how I was practicing during class even while I had a frozen shoulder, Donald said, “Nina never gives up!”

Baxter laughed, too. “Maybe you should write about that—being stubborn.” 

“Good idea! I always need more topics....” 

“But the thing about you,” Baxter went on, “is that even while you’re being stubborn, you also know when to stop practicing poses that aren’t working for you.”

“Yes,” I said. “You need to practice only what is serving you.”

So this morning I’m sitting down to write the blog post on “stubbornness” that Baxter requested, and I’m thinking that “stubbornness” doesn’t really sound very yogic, if you know what I mean. But, really isn’t the term “stubborn” was just my humorous way of describing tapas, the niyama that Ram defined in his post The Second Branch of Yoga: Niyamas as “a burning desire or a disciplinary approach to achieve one’s aims and aspirations.” Yes, a “disciplinary approach” is a much nicer way of saying that when I was recovering from my frozen shoulders than I practiced stretching them every single day, even though it was quite painful, because, yes, I was stubbornly committed to trying to recover as much as could (see Living Proof). And I've actually already written about tapas as an important aspect of healthy aging in my post Tapas: Working with Dedication, where I used my mother’s determination to recover from a broken hip as an example of tapas and healthy aging. (Thank you, Mom, for setting me such a good example!)

Thinking about it now, I decided that the “active engagement” part of our yoga for healthy aging attitude really is tapas, which means practicing for physical, emotional, and spiritual health with dedication and persistence. What do you think, Baxter?

I’m also thinking that when Baxter said that I was good at practicing only what served me and giving up what didn’t, he was referring to the other side of the coin, acceptance. I used to believe—and even teach—that acceptance was primarily about santosha, or, as Desikachar put it, “the ability to be comfortable with what we have and what we do not have.” But this morning I’m wondering whether another big part of acceptance isn’t satya, or truthfulness (see Satya: The Truth About Lies and Healthy Aging). Perhaps I’m focused on truthfulness because I’m still mulling over what I wrote about Tama and how she faced her death with honesty (see The Death of a Friend). But it seems to me that to practice the yoga that serves you, you need to be able to look honestly at the aging process and how it is affecting you. Rather than practicing for the body you wish you had—or used to have—when you step on your mat, you need to meet yourself as you are at this moment, on this day. And adjust accordingly. Hmmm, I think I found a topic for my next blog post!

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How its possible for you to increase muscle without overexerting yourself

By Barry Lang

Regardless of whether you are a man or a woman, muscle building is an entertaining and beneficial technique to get in top form. It is not just a matter of 1 or 2 bench presses and squats nonetheless , you have to do it properly! Be aware of the following pointers to discover how to do muscle development right and get yourself in good shape!

It looks a lot of people that work out go for speed over methodology. It is usually better to perform exercises slowly and focus on correct technique. This gives much better results than merely attempting to pump out reps as fast as possible. Slow down and double check that you are doing the exercise properly.

Do more repetitions, not heavier. The perfect workout to increase muscle contains a high number of repetitions at a medium level of intensity. Keep your breaks between sets under a minute. This continuing repetition causes a buildup of lactic acid in your muscles, which has been noted to stimulate muscle growth.

Massage your muscles frequently. You can do this on your own by making use of a froth roller, tennis ball or any other tool that will provide help to relieve the rigidity of sore muscles. You could even think about going for regular massages at the parlor. Whatever means you use; you need to be bound to relax those muscles frequently.

You have to consume a bit of protein in order to build up muscle. Getting plenty of protein is easier if you use protein supplements and shakes. Such beverages are particularly handy following exercise and just before bedtime. If you would like to drop fat and build muscle at the exact same time, you should just consume one every day. If you want to gain mass with muscle, from a different perspective, you can consume up to 3 every day.

In order to add muscle, it is important to maintain detailed records of your progress, and how you got there. By making the effort to jot down 1 or 2 notes on the exercises and repetitions performed in each workout session, you will be ready to consistently build on what you have just done, and keep growing stronger and build more muscle.

When you become more experienced in working out, your muscles will start to resist any growth on exercises that are familiar to them. Different grip strengtheners may help to make these familiar exercises different, which can cause extra muscle tissue growth. Examples of exercise where you can change the grip are barbell rows, barbell curls, pull-ups, and bench presses. Try utilising wide grips, close hand grips, reverse grips, and even mixed grips that include having one hand up and one hand down.

Use variety in your gripping when targeting the back. Perform deadlifts and rack pulls with a mixed or staged grip, in order to achieve more strength. Staggered grips help twist the weight bar in one specific direction, working your muscles a certain way, while a underhand grip twists the weight bar in the other direction, working your muscles differently. This type of grip will forestall the bar from moving during lifts.

Hopefully you have found the tips contained in this post to be highly advantageous to your muscle development efforts. Incorporate them into your fitness program to build and condition your muscles smartly and efficiently. With time and commitment you'll have the amazing body you would like and are battling for, so get going shortly!

About the Author:

my name is barry lang I've been helping folks about grip strengthener and hand strengthener for over a decade. In that time, I have gained a big amount of knowledge about grip strength and the way to best achieve an abiding increase in gripping power feel free to get your free e-book here on grip strengthener here thanks

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

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

Neurotech Pharmaceutical

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.

Allegro Ophthalmics, LLC

After posting this article online, I learned of another potential class of drugs that might be useful in treating wet AMD and DME. These are the Integrin Peptide therapies from Allegro Ophthalmics.

Integrin Peptide therapy is an emerging new class of treatment for vascular eye diseases. By utilizing a small molecule discovered by Allegro Ophthalmics' founders in collaboration with CalTech, ALG-1001 works from a different mechanism of action than current anti-VEGF treatments, by binding to multiple integrin-receptor sites and affecting multiple angiogenic pathways.

"Integrin Peptide therapy is an emerging new class of treatment for vascular eye diseases based on our discovery of ALG-1001, an anti-integrin oligopeptide. Introducing a new class of treatment that works with a different mechanism of action from current anti-VEGF treatment (but that) can provide additional options and benefits to patients," said Vicken Karageozian, M.D., Co-Founder and Chief Technology Officer, Allegro Ophthalmics.

Integrin Peptide therapy works by delivering a small, anti-integrin oligopeptide with a unique method of action that shuts off VEGF production directly at its source, blocking activation of VEGF receptors, inhibiting tyrosine kinase, and causing a posterior vitreous detachment (PVD) and vitreous liquefaction to increase VEGF turnover.

By contrast, therapies in the current standard of care for patients suffering from neovascular eye diseases (such as DME, Wet AMD and Diabetic Retinopathy) bind and inhibit vascular endothelial growth factors (VEGFs) that cause bleeding and fluid leakage into the eye.

By utilizing a small molecule, Integrin Peptide Therapy with ALG-1001, uniquely approaches these indications by collectively turning off the production of aberrant blood vessels, reduces the leakage of aberrant blood vessels, and inhibits the growth of aberrant blood vessels. This novel approach has the potential to be both an effective stand-alone treatment as well as complementary to existing standard of care due to its unique mechanism of action.

The company recently announced that it has completed enrollment of its phase 1b/2a study in wet AMD in addition to commencing its second diabetic macular edema study. This second DME study is masked and will observe the additional clinical benefit of therapy with ALG-1001 in combination with bevacizumab (Avastin) versus bevacizumab alone. 

The results of the wet AMD trial will be presented at the upcoming ARVO Meeting in May 2013.

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

http://tinyurl.com/AMD-Update19

AMD Update 20: How Fovista Works to Increase Vision in the Treatment of Wet AMD, Irv Arons’ Journal, June 28, 2012

http://tinyurl.com/AMD-Update20

Allergan website:

www.allergan.com

Molecular Partners website:

www.molecularpartners.com

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.

www.molecularpartners.com/public/files/pdfs/20130116_mp_press_release_dme_study.pdf

First licensing agreement:

Allergan and Molecular Partners Enter into Exclusive Alliance, May 4, 2011

http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=574486

Second licensing agreement:

Allergan and Molecular Partners Enter into Exclusive Alliance, August 21, 2012

http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=701294

BioTuesdays

Molecular Partners continues to validate DARPin platform

http://biotuesdays.com/2012/09/11/molecular-partners-continues-to-validate-darpin-platform/

Neurotech website:

http://www.neurotechusa.com/PDGF-antagonist.html

Allegro website:
http://www.allegroeye.com

Friday Q A Yoga for a Sprained Ankle

Q: Nina—how bout yoga for a sprained ankle...got some ideas?

A: Why, yes, thank you so much for asking! Last year Baxter did a three-part series on the ankle that is worth revisiting or visiting for the first time if you’ve never read these posts. So check out Getting to Know Your Ankles, Ankle Sprains, and Recovering from Ankle Injuries.

In part 2, Baxter says that a typical recommendation from your doc is to elevate your foot and leg above the level of your heart, and because there are lots of yoga poses that are done lying on your back with the legs elevated, these poses could assist in the healing process. So in the acute phase of injury, try supported inverted poses such as Legs Up the Wall pose, Chair Shoulderstand, and Easy Inverted pose. See All About Supported Inversions for some other possibilities, and links to instructions for them.

Naturally, while you are recovering and need to keep the weight off your ankle, you will need to avoid standing poses. But there are so many other poses you can still do, including seated and reclined poses. If I were in your situation, I’d continue to practice what I could to maintain my flexibility while my ankle was healing. So try some seated poses, such as hip openers, twists, and forward bends, while keeping your ankle in a neutral, pain-free position. Of course, you’ll want to avoid poses that put pressure on the ankle, such as any variation of Hero pose (Virasana) or Half Lotus (Arda Padmasana). Also, many of our office yoga poses, which you can do seated in a chair, will be suitable for you. Reclined poses, including passive backbends as well as restorative poses, can be very effective at opening your body without putting any stress on your ankle. Again, just be sure to keep your ankle in a neutral, pain-free position. It’s kind of an interesting to challenge to figure out how to practice when you need to avoid aggravating an injury (right now I have a plain old skinned knee, so I need to avoid kneeling—it turns out that comes up more frequently in practice that you might imagine).

If the pain and inconvenience of having a sprained ankle is causing you to stress out—which I imagine it would—add in some stress reduction practices, such as meditation, yoga nidra (see the Relaxation Tracks tab at the top of our page), breath awareness or pranayama, or even just a nice long Savasana. Check the index on the right side of our blog for posts on all these topics.

Once the acute phase symptoms have diminished, Baxter says that you can turn your attention to a more typical asana practice, adding in his seated ankle rolls and alphabet spelling exercises (see Ankle Circles). At this point, you can focus on the strengthening aspects of the poses for the ankle and foot area, so add special attention to activating as many of the muscles surrounding your ankles and feet as you do your standing poses.

—Nina

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Yoga for Healthy Eating Rerun

by Nina

Seeing that it’s the holiday season—when people often make resolutions regarding healthy eating—I thought now would be a good time to rerun our overview of yoga for healthy eating. Basically, between the two of us, we’ve come up with a four-pronged approach to support healthy eating:

• Understand your digestive system

• Practice stress management
• Cultivate mindfulness
• Strengthen Will Power

1. Understanding Your Digestive System

Baxter has recorded a short audio tour of the digestive system (see Audio Tracks) that you can use to learn about how your digestive system works and what happens to your food as and after you eat it. It’s especially helpful for you to learn about how your digestive system interacts with your Autonomic Nervous System and higher brain function. When you’re in a state of stress (see Stress, Your Health and Yoga), your nervous system diverts your body’s resources away from your digestive system (you don’t need to be eating or digesting your food when you’re running away from that tiger or that car that looks like it’s not going to be stopping before the crosswalk!). So chronic stress can cause digestive problems. In addition, even thinking about stressful situation can have a potential negative impact on digestion!

2. Practicing Stress Management

Chronic stress may not only cause digestive problems as I mentioned above, but the cortisol that is released can cause weight gain by stimulating your appetite (Yoga, Stress and Weight Management). So one of the most important things you can do to improve digestion and move toward healthy eating is to use your yoga practice to reduce your stress levels. See The Relaxation Response and Yoga for basic information on using yoga to switch your nervous system from the Fight or Flight response (stress mode) to the Rest and Digest response (relaxation mode). It’s not called the Rest and Digest mode for nothing!

3. Cultivating Mindfulness

Many poor eating habits are just that—habits! Practicing yoga asana with mindfulness and meditating will help you tune into your body, and not to ignore it. And as you tune into your body, you may learn about foods you are currently eating that are compromising your health (see Got Mindfulness?) or notice poor eating habits, such as eating beyond satiety (see Meditation and Healthy Eating). Cultivating mindfulness can teach you to recognize:

• which foods are good for you and which are not (not just junk food, but maybe food intolerances or allergies) 
• when you are full and don’t need to eat more
• when you are thirsty instead of hungry
• when you are eating for stress, not for hunger

See Yoga for Healthy Eating for more information.

Mindfulness will also help you start to recognize habitual thoughts that are getting in the way of healthy eating. You can then work on changing your perspective (see Cultivating the Opposite).


4. Strengthening Will Power

Once you’ve identified your habits or have decide to eliminate or cut back certain foods, it takes will power to change! According the Dr. Kelly McGonigal, being in a state of stress can increase impulsive behavior and decrease will power. So practicing stress management as we describe above will help with your will power (see Healthy Eating, Stress and Self Control). However, you can also use a meditation practice to intentionally strengthen your will power.  Meditation teaches you to return to your object of meditation (your focus) and tune out distractions (temptations):

“Neuroscientists have discovered that when you ask the brain to meditate, it gets better not just at meditating, but at a wide range of self-control skills, including attention, focus, stress management, impulse control, and self awareness. People who meditate regularly aren’t just better at these things. Over time, their brains become finely tuned willpower machines. Regular meditators have more gray matter in the prefrontal cortex, as well as regions of the brain that support self-awareness." —Dr. Kelly McGonigal

See Meditation and Healthy Eating for more information. 

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Why go for the ketogenic diet program

By Todd Smith

The ketogenic diet suggests consumption of foods that have a greater fat content and much less carbs and proteins. It is said of having really been great at managing illnesses like epilepsy, cancerous cells among others. It's actually a extremely helpful method which often burns unnecessary fats within the body even while delivering it with energy helping it to be stable even if one is failing to take on food.

The aim of a ketogenic diet is actually to assist our bodies enter into a ketosis, a condition in which it works by using body fat to provide energy rather than the typical carbohydrates. This is actually the method it uses to regulate seizures in epileptic people and particularly kids.

The ketogenic diet plan is a diet plan which is used across the world and started to realize recognition from the 90's.This diet advocates three quarters of fat in the diet along with a quarter of a mixture of proteins along with carbs. Most people can then again question the reason why the need for replacing carbohydrates with fats reducing the consumption of proteins. Dietary fats don't have any effect on blood sugar levels whilst proteins do whenever a great deal of it is taken.

Fifty six per cent of the excessive proteins will likely be changed into glucose along with the left over element going to insulin. This will prevent the body from burning too much fats and it therefore could not go into a ketosis. Foods proven to have a great content of carbs like potatoes, breads and many others will have to be omitted from the diet.

The diet is not however very simple to begin and become used to since your body will likely need to adapt to a lot of adjustments. Start by reading ebooks on ketogenic diets to find information on how it functions and in addition consult your physician in case you have several concerns. This diet plan isn't as pricey as most people think. As a matter of truth, you might typically think it is less expensive than ones own regular eating habits. Ketogenic diet make use of every single drop of water inside you. Therefore, it is recommended that you remain hydrated by taking in a lot of water.

The dietary plan is not very popular with people as the story goes against just what many think. It doesn't offer a provision with regard to fruits and vitamins which many people feel are effective in preventing illnesses, despite a typical saying 'an apple a day keeps the doctor away'. Many medical doctors have little knowledge on our bodies and diet and for that reason have recommended people that enjoying a great deal of fats may result in conditions such as high blood pressure, because fat is not digestible and therefore blocks the arteries.

They nevertheless neglect to understand that whenever fat is actually consumed along with low energy delivering meals, it will be made use of as the source of energy for the human body and for that reason there aren't any chances of gathering and blocking blood vessels. Numerous weight conscious folks, in particular females, will be hesitant around attempting this diet plan for fear of gaining weight.

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Menu Part 4 A Fourth List of Publications for Potential Posting

First, two updates on previously published items:

Avastin Update: Medicare not Likely to Cover its Use

Following posting of the original article – Avastin: A New Hope for Treating AMD, I found an online article that clarifies the Medicare position on “off-label” usage of this drug.

Inlays, Onlays, Rings & Things - Part 2

The original article was written in 1990. Following the 2000 ASCRS meeting, I updated my findings on these types of devices.


As part of my coverage of both the AAO and ASCRS annual meetings, I sat in on the technical presentations and also spent several days walking the vast exhibit halls, gleaning information on new developments in both lasers and other ophthalmic technologies.

Customized Ablation/Custom Cornea: Wavefront Driven LASIK (WFL)

Before presenting my reports on several of these meetings, I would like to showcase two important technologies that I was among the first to write about: Customized Ablations (or Wavefront Driven LASIK), and LASEK, the technique of pushing aside the epithelium and performing PRK on the surface of the cornea – as opposed to first making a flap with a microkeratome or laser, and then zapping the cornea to reshape it.

Here, in chronological order, is a series of writeups on these techniques:

1. I’ve Seen the Future....and its Custom Cornea, OSN, June 15, 1999.

I first learned about custom ablation at the 1998 AAO meeting, but it was at the 1999 ASCRS meeting that I came to realize that it was the future of refractive surgery.

2. Customized Ablation: the Future is Close, OSN, February 15, 2000.

My first encounter with wavefront and ray tracing diagnostics as a pre-cursor to customized ablation.

3. Customized Ablation: Getting Closer Yet, OSN, August 1, 2000.

At the 2000 ASCRS meeting I learned first-hand of the early results on the initial human clinical trials using wavefront combined with LASIK.

4. Customized Ablation: The Wave Moves Forward.....but Keep an Eye on a Newly Developed Technique....LASEK!, OSN, January 1, 2001.

My first exposure to LASEK – laser epithelial keratoplasty, as I explained it in detail.

5. AAO Report: LASEK, Customized Ablation Draws Interest, OSN, January 1, 2002.

More results from ongoing custom LASIK trials and a new technique for performing LASEK.

6. AAO Refractive Pre-Meeting Focuses on LASIK, LASEK, OSN, January 15, 2002.

An overview of what was reported at the RSIG pre-AAO meeting.

7. ASCRS Report: Customized Ablation, Hyperopia & More, OSN, August 1, 2002.

An overview from the 2002 ASCRS meeting.

8. An AAO 2002 Update: Classic vs. Custom LASIK -- The Battle Continues, OSN, January 1, 2003.

And finally, my last report for OSN, reviewing the latest developments occurring at the 2002 AAO meeting.

9. Custom Ablation #9: Questions......and Answers (May 5, 2006)

An update and answer on the question – Custom vs Classic Lasik.

Iluvien Update 3 Alimera Files Resubmission for Approval of Iluvien

Following up the good news released at the recent ARVO Meeting (Iluvien Update 2: New Safety and Efficacy Data Presented at ARVO), Alimera Sciences Inc. filed a resubmission of its New Drug Application (NDA) for the use of Iluvien in treating diabetic macular edema (DME). This resubmission addresses the questions raised in the Complete Response Letter (CRL) received in December 2010. (See Iluvien Update: FDA Marketing Approval Delayed)

As noted by Alimera, according to the FDA's classification, this will be a Class 2 resubmission. Under the Prescription Drug User Fee Act (PDUFA), FDA review of a Class 2 resubmission is expected to be completed within a six-month period beginning on the date that the resubmission is received by the FDA.

This resubmission addresses the FDA's request for further analyses of the safety and efficacy data through month 36 of Alimera's FAME Study, and includes the data from the subgroup population that was presented last week at the ARVO Meeting. In addition, the resubmission includes further information regarding controls and specifications about the manufacturing, packaging and sterilization of Iluvien, which was requested by the FDA.

"We believe that the resubmission package sent to the FDA will demonstrate the safety and efficacy of Iluvien and address the FDA's additional issues," said Dan Myers, Alimera's president and CEO. "We look forward to working with the FDA for a prompt review and response."

In the CRL, the FDA also indicated that it had observed deficiencies in current good manufacturing practices (cGMP) during its facility inspections of two of Alimera's third-party manufacturers. Alimera believes the deficiencies have been resolved and no further action is required because the FDA has issued letters to both of these third-party manufacturers indicating that the inspections are now closed.

"We look forward to the FDA's response to Alimera's resubmission of the NDA for Iluvien for DME, which if approved, would be our third FDA-approved product," said Dr. Paul Ashton, President and Chief Executive Officer of pSivida.  "We are also working on several earlier stage technologies including bioerodible systems to deliver proteins and small drug molecules for macular degeneration and glaucoma." (pSivida licenses the Iluvien delivery system to Alimera.)

Upon approval of Iluvien, pSivida is entitled to receive a $25 million milestone payment from Alimera and 20 percent of net profits, as defined, on sales of the drug made by Alimera.