Thursday, February 28, 2013

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.)


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.


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

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

Allergan website:

Molecular Partners website:

DME clinical results
Treatment of Diabetic Macular Edema With a Designed Ankyrin Repeat Protein That Binds Vascular Endothelial Growth Factor: A Phase 1/2 Study, Peter A. Campochiaro, et al, Am. Jnl. of Ophth., Jan 2013.

First licensing agreement:
Allergan and Molecular Partners Enter into Exclusive Alliance, May 4, 2011

Second licensing agreement:
Allergan and Molecular Partners Enter into Exclusive Alliance, August 21, 2012

Molecular Partners continues to validate DARPin platform

Neurotech website: