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How Hierotope works. Courtesy of Visterra Inc
A Cambridge, Massachusetts-based biotech startup has unveiled a slew of new announcements over the past few weeks.
Visterra Therapeutics announced on October 5 it had completed a $46.7 million series C financing with prominent investors, including the Bill & Melinda Gates Foundation, MRL Ventures Fund, as well as Flagship Pioneering. The funding will help the venture continue its development efforts for two lead candidates, labeled VIS410 and VIS649, along with continuing refinement of its technology platform for antibody Fc engineering capabilities.
Furthermore, the company recently revealed a new partnership with Vir Biotechnology. Both firms agreed to an exclusive research collaboration, license, and option agreement covering up to six antibodies that can target infectious diseases. Vir will make a significant upfront payment to Visterra in addition to receiving an estimated $1 billion in total royalty payments.
Both of these developments could help usher in a new approach to treating certain disease by identifying unique disease targets that can’t be addressed with traditional clinical approaches.
Hierotope: What it is and how it works
A unique platform sits at the center of this process.
The proprietary technology owned by Visterra is called Hierotope. Researchers use this tool to design and engineer antibody-based biological product candidates—each of which binds to an epitope. Epitopes serve as a key component of larger molecules known as antigens.
“We are targeting epitopes that are composed of highly networked amino acids and that we believe are important for the function of the antigen,” explained David Arkowitz, the chief operating officer and chief financial officer of Visterra in an interview with Drug Discovery & Development (DDD).
“We refer to these specific epitopes, which we believe are highly attractive targets, as Hierotopes. The term Hierotope is derived from “hiero,” the Greek term for sacred, and “tope,” the Greek term for site.”
“In the case of infectious diseases, these Hierotopes are critical to the structural and functional integrity of the pathogen, are common across all strains of the pathogen and resistant to mutation,” explained Arkowitz.
Other aspects that make these Hierotopes intriguing objectives is that they also are not normally targeted by the immune system when it comes to infectious diseases.
This method differs from traditional antibody engineering efforts which typically focus on altering amino acids within an antibody to enhance the strength of the interaction between the antibody and its target.
Visterra’s approach involves using a mix of computational tools and technologies to first identify these Hierotopes. Engineers can then characterize each amino acid in a protein in terms of interactions with other amino acids leading to the identification of the most interconnected ones.
Next, scientists can then create a new antibody scaffold or select from an antibody scaffold residing in an existing antigen-antibody database with the best matches the Hierotope Visterra is targeting.
The end result involves deploying the platform to design and engineer an optimized antibody-based drug candidate with the ability to perform selective targeting.
Attacking influenza
VIS410 and VIS649 are the first two products to emerge from this experiment.
The former is a monoclonal antibody specifically designed and engineered to treat all strains of influenza A with the intent of being administered as a single-dose administration.
“VIS410 is designed to terminate the viral replication cycle and is directed against a Hierotope on hemagglutinin, which is a surface protein of influenza viruses used for binding and entry into cells,” said Arkowitz
Investigators performed a randomized phase placebo controlled phase IIa clinical trial with healthy subjects inoculated with a pandemic strain of the influenza A virus. Results had shown a single dose of this therapy administered over 24 hours after viral inoculation contributed to a statistically significant reduction in the amount of viral traces found in nasal secretions of treated subjects versus healthy ones.
“Antibiotics have been the mainstay for years for treating infections, however, in addition to side effects, small molecules (antibiotics) are handicapped by growing multi-drug resistance and alteration of the microbiome and its consequences,” said Arkowitz.
The company explained since VIS410 is a precision therapeutic that only kills the targeted pathogen through a single-dose curative solution therefore potentially limiting the risk of resistance forming.
Treating a common kidney disease
VIS649 is intended to treat Immunoglobulin A nephropathy, or IgAN. It’s a kidney disease that currently has no specifically approved therapy. The condition is the most common cause of primary kidney disease all over the world with the incidence rate estimated to be 25 cases per million individuals worldwide.
IgAN is associated with symptoms like kidney inflammation, blood in the urine, or hematuria.
“Patients ultimately progress to kidney failure, or end-stage kidney disease, and require dialysis or kidney transplantation in up to 50 percent of cases over the course of the disease. Currently, there is no specifically approved therapy for IgAN,” added Arkowitz.
VIS649 is a monoclonal antibody that binds to and blocks the actions of the protein A Proliferation-Inducing Ligand, or APRIL.
“In IgAN, immune complexes containing ‘a-g’ IgA are deposited in the kidney. Epidemiological studies have shown that high serum levels of aberrantly glycosylated (‘a-g’) IgA are associated with faster progression to kidney failure,” elaborated Arkowitz.
APRIL levels are elevated in patients with IgAN whereas epidemiological studies have shown that high serum levels of APRIL are associated with faster progression to kidney failure and that “a-g” IgA and APRIL levels are correlated, according to the company.
VIS649 has produced a strong safety profile and demonstrated a strong reduction in serum IgAN in a test on non-human primates. An animal model of IgAN also had shown a reduction in immune complex deposition in the kidneys along with a reduction in markers of kidney damage.
Moving forward
Visterra’s next steps will involve using its recent financing to prep for further clinical development.
Arkowitz said his company plans on initiating a global phase 2b clinical trial for VIS410 in early 2018 for hospitalized patients diagnosed with influenza A that need oxygen support. Intern results from this study are expected in 2019 followed by top-line results in early 2020.
“We expect to initiate Phase 1 clinical trials of VIS649 in 2018 and to seek orphan drug designation from the FDA and EMA for VIS649 for the treatment of IgAN,” he added.
