A cure for Parkinson’s disease may be possible if the research at Lysosomal Therapeutics, Inc. (LIT) advances as expected. Unlike therapies that treat the symptoms of this disease, LTI is developing a novel platform that addresses the root cause of the disease by working at the intersection of lysosomal storage disorders and neurodegenerative diseases.
As a small startup, it is leveraging the Boston biotech community to grow. The company spun out of research conducted by Dimitri Krainc, MD, PhD and Joseph Mazzulli, PhD, at nearby Massachusetts General Hospital, and enzyme replacement research conducted years ago at Genzyme. The science attracted Henri Termeer, the former chairman, president and CEO of Genzyme Corp.
“Henri brought in Genzyme veterans Bob Carpenter, founder of VacTex, which merged with Genzyme, and Peter Wirth, the current chairman of FORMA Therapeutics,” CEO Kees Been said, along with other respected biotech veterans. Been himself was CEO of EnVivo Pharmaceuticals, after a stint at Biogen Idec. He’s also contributing his expertise as part of the program advisory committee for BioPharm America™, returning to Boston this September.
First, the science
Parkinson’s disease is the first target in a platform approach that potentially could target each of the 60 known lysosomal storage disorders (genetically inherited diseases characterized by particular deficiencies of vital enzymes).
As Been explained, research found that persons with a dual allele mutation in the gene that encodes for glucocerebrosidase (GCase) exhibit enzyme activity that is 10 percent of normal. They develop Gaucher disease. Carriers, who have a one allele mutation, have about 70 percent of the normal enzyme activity. They are at high risk of developing Parkinson’s disease. Therefore, lowered GCase levels indicate a predisposition toward Parkinson’s.
The many linkages between lysosomal storage disorders and other diseases enables LTI to become a platform company. To do that, Been said, “We’re working on additional targets,” implicated in underserved orphan and neurological disorders. Early work suggests that rare diseases, like Gaucher disease, can be models through which therapeutics for common neurodegenerative disorders may be developed.
“In general, when a particular enzyme in the lysosome doesn’t function properly, cell health is compromised,” Been explained. Now that certain lysosomal storage diseases are effectively treated with enzyme replacement therapy, patients live longer and have the time, in a perverse manner, to develop other diseases that share the same genetic underpinnings as their lysosomal storage disease. For example, Gaucher patients exhibit a higher than 20% chance of developing Parkinson’s than people without the mutation. Therefore, “we can use a lysosomal disorder like Gaucher disease as a model system for Parkinson’s disease.”
LTI’s immediate goal is to develop a therapeutic for Parkinson’s disease. “There is high unmet need and no innovation,” beyond variations of dopamine, Been said.
Rather than deliver the depleted enzyme, however, “we’re developing small molecule brain penetrant compounds,” he explained. These molecules cross the blood-brain barrier and can be delivered orally, perhaps once daily, to increase GCase activity and thereby restore normal lysosomal function in human neurons.
LTI currently is optimizing the pharmacological parameters of lead candidate molecules that activate GCase enzyme production. “We expect to begin tox studies in 2016 and enter Phase I trials in the first half of 2017,” Been said.
Biomarker initiative underway
“Because of the genetics, we’re also pursuing a biomarker initiative for Parkinson’s under a USD 230,000 grant from the Michael J. Fox Foundation,” he said. “Low GCase levels indicate an increased risk of developing Parkinson’s disease, much as high cholesterol indicates an elevated risk of heart disease.”
The initiative is designed to establish GCase enzyme activity as a biomarker and to correlate the rise in damaging alpha-synuclein protein to the decrease in GCase in diverse populations of Parkinson’s patients. This is the first stage of a large-scale study.
Biomarkers uncovered through this initiative are expected to predict patients’ responses to drugs, which in turn may help researchers select patients for clinical trials. Eventually, by identifying these persons early and treating them to activate the deficient enzyme, risk could be reduced or onset delayed,” Been said.
The company also is exploring additional targets with genetic links between lysosomal storage disorders and neurodegenerative disease.
Boston: The center of the universe
A good idea, no matter how brilliant, isn’t enough to assure success. The surrounding ecosystem of expertise, infrastructure and resources also contributes.
For LTI, “Cambridge is the hub of the universe,” Been proclaimed. While other biotech hubs may contest that, “the Boston-area cluster is the most condensed,” he said. “Everything—venture capital, universities, biotech and pharmaceutical companies and consultants—is available within a few square miles. It’s an incredibly resource-rich environment.”
The early involvement of many of the leaders who had guided Genzyme toward its 2011, USD 20.1 billion acquisition by Sanofi, shortened LTI’s start-up curve. The reason is obvious. Because these leaders already had built successful companies, their networks were filled with the right contacts to help a startup company grow, and they had the expertise to avoid the missteps so many new entrepreneurs make.
Through the leadership of these serial entrepreneurs, LTI raised USD 4.8 million in seed funding in early 2014. A USD 20 million Series A round followed in January 2015. This round expanded the initial funding commitments of the original investors, including Atlas Venture, Hatteras Venture Partners, Lilly Ventures, Partners Innovation Fund, Roche Venture Fund, Sanofi-Genzyme BioVentures and Orion Equity Partners LLC.
Strong local networks
Having a strong local biotech ecosystem doesn’t guarantee such outcomes, but it does make them easier and faster to achieve. Networking is one of the reasons.
“Being able to actually meet and create relationships is powerful,” Been said. “When biotech evenings are organized, many people attend because it’s easy to be there. You can walk or even bike to an after-work event, so you’re constantly meeting people and expanding your network.”
The tight-knit Boston biotech ecosystem is a boon for employees, too, aiding recruiting. “People like to make the move here,” Been said. The presence of a few hundred biotechs and a strong presence from big pharma removes some of the risk of joining a startup, and helps companies attract top talent. “The variety of options is what makes the Boston/Cambridge environment so vibrant,” Been said.
This critical mass of life sciences companies also helped LTI lower its startup costs by reducing immediate capital costs. For example, Been recalled, “for our first several months we sub-leased space from another biotech.” Other small companies have similar arrangements, leasing scientific suites or lab benches. “That availability is critical to getting a company off the ground,” he said.
As a startup with 13 employees, LTI works closely with a CRO. “We run our assays, but our CRO makes the molecules, performs ADME/TOX analyses and synthesizes the compounds.” The CRO, while not in Boston, was part of LTI’s network. “Our project head had worked with this organization while at Genzyme and was able to secure the same team.”
Such connections are vital to young companies seeking to grow. Achieving success depends upon more than good science. It depends upon a plethora of elements—experienced managers and advisors, access to funding entities that are accustomed to biopharma’s lengthy development times, access to the physical resources and intellectual capital to transform ideas into products, and a like-minded professional community to provide synergy. All of that, Been said, Boston has in abundance.
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