Lpath Incorporated (LPTN.OB), headquarted in San Diego, California - a city once ranked as the top biotechnology cluster in the United States and home to over 400 biotechnology companies – has a small market capitalization of 70 million dollars, but big aspirations for their technology platform, ImmuneY2. With a robust pipeline and over 50 issued or pending patents, Lpath serves as a leader in the space of bioactive-lipid research and drug development. The rapidly expanding field of bioactive lipids has provided researchers and biotechnology companies with novel therapeutic mechanisms and targets to improve disease states. Many, if not most, of the drugs on the market are protein-based and target receptors as either an agonist and/or an antagonist and enzymes in a pathway that halt metabolic cascades. Although bioactive lipids will not replace protein-based targets in medicine, lipids will provide other avenues and legitimate options for researchers and companies such as Lpath to discover novel compounds to offer additional therapeutic options and in some cases, better treatment.
Clinical Trial Status
Sphingosine 1 Phosphate (S1P)
Wet AMD, PED
Diabetic Retinopathy, Dry AMD, Glaucoma
PED: Phase 1
Wet AMD: Phase 2A
Inflammation, Multiple Sclerosis
Entering Phase 2
Lysophosphatidic Acid (LPA)
Projected IND in 2012/2013
Projected INDs starting in 2013
iSONEP, the compound that generated positive Phase 1 data and a lot of excitement, is one of the lead antibodies in clinical trials for wet age-related macular degeneration (wet AMD) and pigment epithelial detachment (PED) in the pipeline. Vision loss from wet AMD occurs in two forms: neovascularization, the abnormal proliferation of new blood vessels, and pigment epithelium detachment. It is estimated that 1.2 million individuals are afflicted with wet AMD and another 200,000 of new cases are diagnosed annually.
Wet AMD: Vision Loss Due to Neovascularization
Wet AMD begins as a process in which there is an excess and abnormal blood vessel formation in the choroid layer or the vessel layer of the eye. This new formation is often referred to as choroidal neovascularization (CNV) and results from the breaking of the membrane below the retina. This breach deprives the macula of oxygen and in response, the body compensates for this by generating new blood vessels. These newly formed blood vessels are immature, fragile, and tend to leak fluid into the space under the macula, causing damage to the macula and left untreated, eventual vision loss. A better way to picture this is to “imagine the roots of a tree growing and spreading until they actually uproot a sidewalk. Then imagine rainwater seeping up throughout the cracks. These abnormal blood vessels (the roots) tend to be very fragile. They often grow, leak or bleed, causing scarring of the macula.” Leakage of fluid or edema from neovascularization is only part of the picture in the pathology of wet AMD. Equally important to consider are factors such as fibrosis and inflammation.
PED: Vision Loss Due to Excess Fluid Buildup
There are different forms of PED. Notable here, in this report, is the potential manifestation of PED from neovascular wet-AMD. PED can also result from fluid buildup, but without the abnormal growth of blood vessels. The leaking and accumulation of fluid from vessels in the choroid between the retinal pigment epithelium and choroid causes the retina to detach.
Current Treatments in Wet AMD: Mechanism of Action, Sale Figures, and Dosing
- Lucentis (ranibizumab)
o Vascular endothelial growth factor inhibitor (anti-VEGF)
o Sales of 2.9 billion in 2010
o Dosing Regimen: Administer 0.5 mg (0.05 mL) by intravitreal injection once a month (approximately every 28 days).
- Macugen (pegabtanib)
o Vascular endothelial growth factor inhibitor (anti-VEGF)
o <20 million in 2009
o Dosing Regimen: 0.3 mg once every 6 weeks by intravitreous injection into the eye to be treated.
§ A course of verteporfin therapy is a 2-step process requiring administration of both drug and light. The first step is the intravenous infusion of verteporfin. The second step is the activation of verteporfin with light from a nonthermal diode laser.
§ IV Infusion: 6 mg/m2 body surface area (BSA) administered IV over 10 minutes at a rate of 3 mL/min.
§ Light: 50 J/cm2 of neovascular lesion administered at an intensity of 600 mW/cm2. This dose is administered over 83 seconds.
§ Patient should re-evaluated every 3 months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.
- Eylea (aflibercept)
o Vascular endothelial growth factor inhibitor (anti-VEGF) by binding to vascular endothelia growth factor-A and placental growth factor (PIGF)
o FDA approved in November 2011
o Estimated to hit peak sales of 1.1 billion in 2021
o Dosing regimen: Intravitreally in the eye monthly for the first 3 months, followed by an intravitreal injection in the affected eye every 2 months thereafter. If necessary, aflibercept 2 mg may be administered every month.
- Avastin (bevacizumab)
o Not FDA approved for wet AMD, used off-label
o Vascular endothelial growth factor inhibitor (anti-VEGF)
o Estimated anywhere from $20 to $50 per injection.
iSONEP, Novel Approach with Significant Advantages
The target of iSONEP, Sphingosine 1-phosphate (S1P), has many roles in the human body. In vasculature, S1P is important in the regulation of angiogenesis, vascular permeability and vascular tone, and promotes vascular inflammation by releasing vasoactive substances that causes vascular thrombosis and inflammation. iSONEP, an antibody that is designed to bind S1P, fuses with Sphingosine 1-phosphate and renders the compound inactive. Essentially, iSONEP “mops” up and neutralizes Sphingosine 1-phosphate to prevent the deleterious effects of S1P. By shutting off the growth and survival factors to pericytes, fibroblast, vascular endothelial, and inflammatory cells, iSONEP addresses all of the components involved in the pathogenesis of wet AMD - angiogenesis, edema, fibrosis, and inflammation. Standard of care therapies such as vascular endothelial growth factor inhibitors (i.e. Lucentis) only addresses the angiogenesis component of wet AMD. Currently, Lucentis is considered the standard of care for wet-AMD. Avastin (Bevacizumab) is not FDA approved for this condition, but is used off-label because of the significant cost savings relative to Lucentis.
Data generated from Phase 1 study was impressive and encouraging. The most significant finding in the study was a reversal of CNV. Out of the seven patients that began the study with a CNV lesion, four or 57 percent of the patients experienced a decrease in lesion size greater than 5 mm2 and three or 43 percent experienced a decrease in lesion size greater than 75%. These numbers were achieved with only a single dose of iSONEP-a feat not attained by other treatments. Lucentis, the FDA approved wet AMD treatment, did not show any significant regression of the CNV in studies. Furthermore, a single dose of iSONEP completely or near-completely resolved the symptoms of two patients that were determined to have PED. A single dose of iSonep elicited a “strong” positive response from the 5 patients with occult CNV 30-45 days post dose.
The data coming out of Phase 1 was extremely positive. However, it is important to note the limitations of the data. This study was performed with a small sample size and may not truly reflect how this drug will perform in a larger patient population. The comparisons with Lucentis and their studies may not be a fair conclusion as Lucentis performed their studies with many more patients in their MARINA and ANCHOR trials. With a larger sample size, the numbers coming out of these trials - MARINA and ANCHOR - are more statistically significant and greater confidence can be placed in the results. In other words, the results did not occur by chance. The MARINA and ANCHOR trials enrolled 716 and 423 patients, respectively. Furthermore, the Phase 1 iSonep trial was not randomized and/or blinded and bias may not of been minimized.
iSONEP: Market Potential Beyond Wet AMD
The market potential for iSONEP extends beyond wet AMD. Diseases such as diabetic retinopathy, dry AMD, and glaucoma share many pathogenic features of wet AMD - inflammation of blood vessels, leakage of fluid, angiogenesis. In theory, iSONEP can be efficacious in the treatment of these disease states.
In diabetic retinopathy, the blood vessels are inflamed, edema is present, and angiogenesis occurs. The potential market for diabetic retinopathy far exceeds that of wet AMD. It is estimated that in 2005-2008, 4.2 million diabetic patients aged 40 years or older had diabetic retinopathy, with 0.7 million having late stage diabetic retinopathy. There is a 3 fold increase in market potential when comparing this figure to those afflicted with wet AMD. With the current trends in diabetes, this number is expected to climb significantly. In fact, the Center for Disease Control and Prevention (CDC) predicts that diabetes cases can double or triple by 2050.
Other areas of interest for iSONEP that are being explored are dry AMD and post glaucoma filtration surgery. In the latter condition, iSONEP will exert it anti-fibrotic effects to prevent complications from the procedure.
The large volume of data generated in the research community and Phase 1 data of iSONEP confirms that bioactive lipids such as S1P play a role in disease. iSONEP is a novel antibody that employs a unique mechanism to treat ocular disorders such as wet AMD. Most of the products on the market utilize the same mechanism and that is to target VEGF. This approach only targets angiogenesis and does not address the other factors involved in wet AMD - inflammation, fibrosis, and edema. The phase 1 data suggest that iSONEP potentially can be a superior treatment to Lucentis, a $2.9 billion dollar drug, and become the standard of care for patients with wet AMD. The data generated also offers a small suggestion that iSONEP can offer a better dosing regimen. Everything equal, a better dosing scheme will offer significant advantages to iSONEP.
The market potential for iSONEP extends beyond wet AMD. Other indications such as dry AMD, post glaucoma filtration surgery, and diabetic retinopathy are viable options to explore. Diabetic retinopathy seems the most logical to pursue first considering the large market potential and shares many of the features of wet AMD. If approved, iSONEP will be a first-in-class treatment and add credence to the drug-discovery/treatment platform of Lpath.
This potential did not go unnoticed as Pfizer (NYSE:PFE), in December 2010, entered into an agreement with Lpath to gain exclusive rights to iSONEP. Pfizer will provide an upfront payment of 14 million dollars and share the costs of two trials, phase 1b and 2a trials. If, after these two trials, Pfizer exercises their option, Lpath will receive additional milestone payments and fees. Furthermore, if iSONEP is approved, Lpath will receive tiered-double digit royalties.
ASONEP, the Systemic Twin of iSONEP
ASONEP, the second candidate in the pipeline, is demonstrating promise in treating cancers. Like iSONEP, ASONEP also targets Sphingosine 1-phosphate, but systemically or in the body. There is an overwhelming amount of evidence that indicates that Sphingosine 1-phosphate is involved in cancer processes. S1P regulates processes such as inflammation, tumorigenesis, and angiogenesis, which all supplies nutrients and oxygen to cancer cells to promote cell survivability and proliferation. The data from phase 1 studies of ASONEP in advanced solid tumors are encouraging. The drug was well tolerated up to 24 mg/kg and some patients had “long-term” stable disease. The types of patients had the following cancers: ovarian (5 patients), renal (4), colorectal (4), breast (2), prostate (2), melanoma (2), head and neck (2), and other (7). Eight patients had stable disease for greater than 2 months including one with carcinoid (15+ months) and one with adenoid cystic (8+ months), treated with 3 and 17 mg/kg, respectively. Currently, phase 2 studies are underway with no specified tumor type.
Lpathomab: Lysophosphatidic Acid (LPA)
It is well documented that Lysophosphatidic Acid is involved in areas such as pain and fibrosis. The market potential for these indications is significant as there are still great challenges in finding satisfactory treatment for areas such as neuropathic pain and pulmonary fibrosis. For example, in most cases, the treatment of choice for neuropathic pain is protein-based, small molecule drugs such as gabapentin and tricyclic antidepressants. Both therapeutic options, especially tricyclics, were created years ago with potentially intolerable side effects. Lpath is the first of a number of companies to create an antibody directly targeted at LPA. Currently, Lpath is deciding on one of two candidates to move into the Investigational New Drug phase and if successful, clinical trials. The anticipated IND file period is 2012/2013. Although further ahead in clinical trials, it is important to note that AM152, the lead compound from Amira that targets LPA1 receptors, was purchased by Bristol-Myers Squibb for $325 million in cash and $150 million in milestone payments.
Lpath: Company Outlook
Lpath incorporated is on the verge of discovering breakthrough treatments for a spectrum of diseases with limited treatment options. As a pioneer in the field of bioactive-lipid therapies, Lpath is many years ahead of the competition. The current compounds in the pipeline are promising and demonstrate great efficacy and potential in significant markets. With a strong management team and intellectual property portfolio (over 50 issued or pending patents), Lpath has created a barrier to entry in the field of bioactive-lipid antibodies and has significant competitive advantages. Including current cash, grants, and payments from Pfizer, Lpath has a cash position that will carry them into the year 2013.
Disclaimer: All information is provided for informational purposes only and does not serve as investment advice or an offer of management services. There is no guarantee that the information is accurate. All information is subject to change, amendment, and correction without any notice. Any mention of current and past results does not indicate any future expectations or results. All investments are associated with risks and loss of money. Consult with a professional tax, accounting, legal, and/or investment advisor before making any investment decision.
Disclosure: I am long LPTN.OB.