What is wet AMD?
Age-related macular degeneration (AMD) is a leading cause of severe vision loss with worldwide incidence of 30-50 million affected with roughly 8 million in the United States. Associated with aging, it occurs when metabolic waste products in the eye are no longer efficiently removed and accumulate in the macula. This buildup restricts the flow of nutrients and oxygen to the cells of the retina and causes them to slowly die. In dry AMD, light-sensitive cells in the macula slowly deteriorate, gradually blurring central vision. As the disease progresses, central vision can gradually become lost completely in the affected eyes. Dry AMD progression is usually painless and slow, and affected persons may not seek medical attention until the disease is fairly advanced. The condition advances in stages and may ultimately become wet AMD. Wet AMD occurs when abnormal blood vessels beneath the retina leak blood and fluid. It is more aggressive, and if left untreated, can lead to irreparable loss of sight within months. Wet AMD accounts for only 10% of all AMD cases but is responsible for 90% of blindness associated with AMD. It is estimated that approximately 200,000 new cases of wet AMD are diagnosed in the United States annually. In people over 50, the global incidence of wet AMD is approximately 1.5 million, with approximately 600,000 new cases of wet AMD diagnosed annually. With the aging baby boomer population in the United States and average longevity in the world increasing, the number of wet AMD victims will likely continue to trend upward.
The Wet AMD Treatment Target
The current focus for treating wet AMD is the abnormal blood vessels (lesions) that form behind the retina. These blood vessels form as a result of the body’s angiogenic response to other neighboring vessels clogging or compressing creating flow restrictions. The newly formed vessels in wet AMD are abnormally fragile and often leak blood and fluid. This liquid raises the macula from its usual position at the back of the eye and causes damage rapidly.
Chronology of Treatments
Pre-2004 - Thermal Lasers and Photodynamic Lasers with Visudyne
Earlier treatments involved thermal lasers that were aimed at the abnormal vessels effectively stopping the leaking and sealing or destroying the non-leaking vessels before they became an issue. Although an effective treatment for some, the prognosis was often poor because only those with abnormal vessels forming away from the fovea (central part of the macula) were good treatment targets. The procedure was also risky because surrounding tissue may be destroyed or damaged. The 2000 approval of QLT Incorporated’s (QLTI) photodynamic therapy for treating wet AMD was a huge advance relative to the earlier thermal laser treatment. It incorporated the drug Visudyne that was administered intravenously. The drug attached to lipoproteins that selectively carried the drug to the abnormal vessels in the eye in minutes. Focusing a non-thermal laser light into the patient’s eyes for 83 seconds activated the drug, which caused it to releases singlet oxygen, a reactive molecule that effectively destroyed the abnormal blood vessels and stopped the leaking. The most reported side effects of the treatment, occurring in 10-30% of patients, were injection site reactions and visual disturbances including blurred vision, flashes of light, decreased visual acuity and visual field defects. Although stabilizing vision degradation, this procedure also did nothing to restore lost vision. It was a treatment that needed be repeated on an as-needed basis as the formation of new abnormal vessels continued.
2004 – VEGF Inhibition as Wet AMD Treatment
In December of 2004, the FDA approved Macugen ushering in a new era for wet AMD treatment. Macugen was co-developed by Pfizer (PFE) and Eyetech Pharmaceuticals and was the first of a new class of drugs binding and/or inhibiting vascular endothelial growth factor (VEGF)-A. VEGF is a signal protein that is thought to play a critical role in the formation of new blood vessels and their hyperpermeability (leakiness). Macugen was injected directly into the eye every six weeks and was proven effective in trials. Side effects, though typically minor, occurred in 10-40% of patients. The drug was effective in slowing the progression of the disease but did not repair damage that had already occurred and therefore did little to improve lost vision.
2006 – VEGF Inhibition Improvement as New Standard of Care
In 2006, the FDA approved Lucentis for wet AMD. Produced by Genentech [acquired by Roche Holding, Ltd. (OTCQX:RHHBY)], Lucentis was also designed to bind and inhibit vascular endothelial growth factor (VEGF)-A. Like Macugen, the treatment procedure is unpleasant requiring monthly to bimonthly injections of the drug intravitreally. Side effects of the treatment are not as serious with vitreous floaters and intraocular pressure increase being the most common. The treatment is costly with a tag of about $1950 per treatment. With injections roughly 5.5 times annually, this adds up to almost $11K annually. The phase III trials did show superiority over the two laser therapies and Macugen with roughly 1/3 of patients in the phase III trials experiencing vision improvement, not just simple cessation of vision loss.
Approved by the FDA for treating colon and other cancers, Genentech’s Avastin has also shows promise for treating wet AMD. With a similar mechanism, Avastin also binds/inhibits VEGF and has shown promise to stop the formation of the abnormal vessels and also improve vision after treatment. However, use of Avastin for this indication is strictly off-label which brings in its own regulatory and insurance issues. For patients having poor or no insurance coverage, the key difference between Avastin and Lucentis is price with Avastin treatments costing less than $150 (conflicting prices in literature on the web) per treatment.
2011 – VEGF Inhibition but With Fewer Injections
On November 18th of this year, Regeneron Pharmaceuticals (REGN) announced FDA approval of its wet AMD drug EYLEA. Similar to Lucentis and Avastin, Eylea blocks the action of VEGF. However, the drug is administered less frequently with one dose every 4 weeks for the first 12 weeks, followed by a dose every 8 weeks thereafter. The price tag, although cheaper than Lucentis, is still $1850 per treatment and still much greater than Avastin’s.
Next? – Lipid Signaling Inhibition as Much Improved Treatment Regimen
Advancing from the two different laser treatment techniques to VEGF inhibition was a huge step for treating wet AMD and raised the bar considerably for any other treatments coming to market. However, there is still much room for improvement. Administration techniques and frequency, vision improvement as opposed to simple vision loss cessation, elimination of the lesions as opposed to stopping their formation, and safety profiles are key areas that need to be addressed. A new class of drugs being tested in trials is showing tremendous promise in these areas. Lpath Incorporated (LPTN) is the class leader in this new class of drugs, lipidomics-based antibody therapeutics, in which lipid signaling is the targeted mechanism. Lipid signaling refers to any physiological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the actions of these lipids on specific cellular responses. Lpath’s proprietary platform, Immune Y2 technology, has a range of applications on these cellular responses including inflammation, cancers, autoimmune as well as the wet AMD application. They have had a great deal of success generating and advancing therapeutic antibodies against specific bioactive lipids. These antibodies “sponge up” the targeted lipids and bind the receptor sites, effectively stopping the specific pathway signal.
Most Advanced Lipid Signaling Candidate for Wet AMD - Lpath’s iSONEP
The lead product in Lpath’s pipeline is iSONEP, a monoclonal antibody targeting Sphingosine 1 Phosphate (S1P). S1P is a bioactive lipid that is a key component of the sphingolipid signaling cascade. In the wet AMD application, S1P has many actions that promote inflammation and dysregulated angiogenesis. It additionally supports the survival of multiple cell types including fibroblasts, endothelial and inflammatory cells that participate in the dysfunctional processes of wet AMD and other eye diseases. What of the VEGF protein implicated in wet AMD and the target of EYLEA, Avastin and Lucentis? iSONEP takes the target a step farther because S1P is linked to the production and activation of VEGF, FGF, PDGF MCP-1 IL-6, IL-8 and other growth factors implicated in the pathogenesis of wet AMD. If this pathway is neutralized, the angiogenesis, leakiness, fibrosis (scarring) and inflammation due to AMD should be effectively eliminated because a larger portion of the factors involved will be targeted, not just those pertaining to the VEGF pathway.
In its phase I trial, iSONEP trial subjects with wet AMD received only one injection of iSONEP. The trial met its primary endpoint of being well tolerated in all 15 patients with a maximum tolerated dosage not reached (enter the safety potential of the drug relative to the profiles of the afore-mentioned) and also met a key secondary endpoint of positive biological effects in most patients. Of special note is the patient set contained several patients who had failed to respond to Lucentis and/or Avastin treatment, a difficult patient set. Like Lucentis and Avastin, the iSONEP data appeared to stop the abnormal blood vessel growth, reduced the retinal thickness and also controlled the leakiness of the existing vessels. However, additional responses also indicated that iSONEP mitigated the fibrosis (scarred tissue) and inflammation, two key areas which would actually improve vision rather than only stopping its regression. There was also significant reduction of more than 38% in the size of the choroidal neovascular lesion in many of the test subjects. One subject experienced a 100% reduction in lesion size as of day 45, as well as complete flattening of his RPE detachment. This subject did not have to be re-injected with the one of the VEGF inhibitors for a year following the iSONEP injection. If this patient set is any indication of the efficacy of the drug, phase 2 data could be very exciting. Remember, this is after a single injection of iSONEP. If a single injection can simply reduce the number of injections of Avastin or Lucentis to once or twice a year, imagine the anxiety and side effects that will be reduced as well as the cost savings.
iSONEP’s Current Status
Lpath has recently initiated two proof-of-concept phase 2 trials for iSONEP. The first of these trials is the PEDigree trial in which iSONEP is being studied as a treatment for retinal pigment epithelium detachment (PED), a prominent feature of wet AMD. Lpath plans to dose 32 subjects that have PED secondary to either wet AMD or PCV. Subjects in this trial will receive up to three monthly intravitreal injections of iSONEP. The primary safety endpoint will be the tolerability of the injections, and the primary efficacy endpoint will be the percentage of subjects that experience complete flattening of their PED. In October 2011, Lpath initiated its Nexus phase II trial on iSONEP as a treatment for wet AMD. The subjects for this trial will be wet AMD patients who have not responded positively to the VEGF inhibitors Lucentis or Avastin. The subject sets will determine potential paths to approval (whether as a stand-alone treatment or synergistically with a VEGF inhibitor), dosage, safety and efficacy. The patients will be randomized into four arms: 1) VEGF inhibitor only 2) combination of VEGF inhibitor and lower dose of iSONEP 3) combination of VEGF inhibitor and a higher dose of iSONEP and 4) iSONEP alone. The endpoints of the study include changes in visual acuity, change in retinal thickness and change in lesion size.
Lpath and iSONEP’s Legitimization
The phase I trial was a small sample set and cannot be fully relied upon to ascertain future phase II and III trial results. However, it is a positive indication of what is possible for iSONEP and Lpath’s remaining pipeline. Lpath is a biotech company with no product marketed and, as typical with a modern biotech, could be construed as a very risky investment. However, a partnership announced in December 2010 with Pfizer helps legitimize Lpath as a solid company and strongly validates its Immune Y2 technology pipeline, in particular its iSONEP drug. The partnership already netted Lpath $14 million in January of 2011. Per current plans, this will help provide cash through June 2013, minimizing the risks associated with stock dilution seen in many biotechs in the development stage. Additional agreements in the deal could net Lpath regulatory and commercial milestone payments that could total up to $497.5 million plus double-digit royalties to iSONEP pending marketing.
It is the author’s opinion that Pfizer could be either paying these royalties potentially to its own subsidiary or to another company that might have already stepped in to purchase Lpath and its valuable platform and portfolio of patents. Lpath’s technology would have long since been legitimized and its potential in other applications such as cancer, autoimmune diseases, inflammation and other eye diseases fully realized. The blockbuster potential could become self evident as the Nexus and PEDigree trial data begins to come to light and the Immune Y2 platform is either validated or denied. The biotech arena is ripe with merger and acquisition activity as Big Pharma’s patents expire and new first-in-class drugs become available through biotechs. Gilead Sciences’ (GILD) recent acquisition of Pharmasset (VRUS) for its next generation hepatitis C treatments at a 89% premium is a prime example of the price Big Pharma is willing to pay for the “next big thing” in pharmaceuticals. Lpath’s Immune Y2 platform and its potential applications treating a host of diseases places it in investors’ and Big Pharma’s spotlights. Will Big Pharma wait until the iSONEP phase 2 data is presented before attempting to grab their prize? Or will there be an earlier press release soon stating “XYZ Pharmaceuticals Pays Big Premium for Lpath and Its Immune Y2 Platform”? The potential payoff could be a big piece of the ever-growing $3 billion Lucentis pie as well as a host of other potential applications.