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A phase I/II trial enrolling patients with Sjögrens syndrome dry eye will be investigating a synthetic fragment of a naturally occurring tear glycoprotein. Findings from extensive laboratory and preclinical research suggest that it is a promising novel therapy.
A first-in-class topical synthetic peptide being developed as a treatment for dry eye disease (Lacripep, TearSolutions Inc.) is set to enter into clinical development.
The novel proprietary agent, planned to enter a phase I/II trial in March 2017, is a fragment of lacritin, a naturally occurring, eye-selective tear glycoprotein. The agent was discovered in 2001 by Gordon W. Laurie, PhD, professor of cell biology and ophthalmology, University of Virginia, Charlottesville, and chief scientific officer and cofounder, TearSolutions Inc., Charlottesville, VA.
“Lacritin is largely released into tears by acinar cells of the lacrimal gland, although it is also produced by other cells, including those of the meibomian gland,” Dr. Laurie said.
Findings from laboratory and preclinical research have included collaborators from James Madison University; Eastern Virginia University; Cornell Univesity; University of California, San Francisco; University of Southern California; and University of Western Ontario.
Their research has found that the treatment topically stimulates basal tear secretion and wound healing, helps restore ocular surface cells to normal, and is deficient in the tears of persons with various kinds of dry eye disease.
“[The agent] has the same properties as the parent molecule, and unlike all existing therapies for dry eye disease, appears to address an underlying cause of the disorder rather than a downstream consequence,” Dr. Laurie explained. “Analogous to insulin treatment for diabetes, [lacritin] essentially represents a replacement therapy to correct an existing deficiency. For that reason, we believe it holds exciting promise as a very safe and effective therapy.”
The development history of the agent dates back to 1991 when Dr. Laurie was searching for a research topic at the University of Virginia.
“I was struck by the fact that no one seemed to be addressing the biological basis of dry eye disease other than downstream inflammation,” he added.
Dr. Laurie approached the National Eye Institute with his ideas. He submitted and received funding to biochemically screen for natural regulators of tear secretion.
“Trying to identify this natural tear stimulatory activity was like looking for a needle in a haystack,” he said. “The needle was the novel protein that we named lacritin.”
The first lacritin experiments showed it was released by lacrimal acinar cells and promoted tear secretion. In addition, lacritin was found to be important for the health and homeostasis of the ocular surface epithelium as evidenced by its ability to rescue cultured corneal epithelial cells stressed by exposure to inflammatory cytokines.
No other tear protein appears to share these properties because the capacity of healthy control tears to rescue inflamed cells was lost when tears were depleted of lacritin,” Dr. Laurie outlined. “Furthermore, tears from persons with dry eye lack lacritin and failed to promote health, but gained this benefit when spiked with lacritin.”
Mechanistic studies revealed mitochondrial function was restored. Lacritin was also found to transiently stimulate autophagy, the physiological process that maintains homeostasis by removing damaged proteins and cell organelles which accumulate when cells are stressed, such as by inflammation.
“By restoring a more normal ocular surface condition, lacritin appears to remove triggers that give rise to inflammation, thereby breaking the vicious cycle that perpetuates inflammation in dry eye disease,” Dr. Laurie said.
Results of preclinical studies in animal models showed lacritin was effective in promoting tear secretion, restoring ocular surface integrity, and reducing focal infiltration of inflammatory CD4+ T cells in lacrimal glands.
“In the animal studies, we found these benefits were achieved quickly and were persistent,” Dr. Laurie said.
In order to translate lacritin’s benefits into clinical use, the focus turned to creating a synthetic lacritin peptide which is smaller, easy to manufacture, and retains all of lacritin’s known activities. The final therapeutic agent consists of the lacritin C-terminal fragment.
Phase I/II trial plans
Phase I/II trial plans
The first in-human study aims to enroll 201 patients with Sjögren’s syndrome dry eye. Patients will be randomly assigned into 3 groups to receive 1 of 2 doses of the lacritin agent or placebo for 4 weeks at a frequency of 3 times per day.
The initial clinical trial is focusing on Sjögren’s syndrome because clinical features are better defined in Sjögren’s dry eye compared with other forms of dry eye, Dr. Laurie said. Therefore, variability that commonly plagues dry eye studies will be reduced.
“We expect [the agent to] have benefit across the full spectrum of the condition because lacritin deficiency is apparent in all forms of dry eye,” Dr. Laurie added.
He also noted that although the therapy is administered 3 times daily in the first clinical trial, findings from preclinical studies suggest that once-a-day dosing may be feasible.
“We found that [lacritin] remained stable in rabbit tear film for 24 hours,” Dr. Laurie said. “Thus, it may have long acting activity.”
Safety is not expected to be a concern because no dose-limiting toxicity was observed in animals, he added.
“That is not surprising considering [the agent], like lacritin, is naturally occurring in human tears,” Dr. Laurie said.
Gordon W. Laurie, PhD
Dr. Laurie is co-founder and chief scientific officer of TearSolutions Inc. He is also an inventor on a number of issued and pending lacritin patents licensed by TearSolutions.