Verge puts ALS target through COVID-19 paces, leaning on preclinical partners
Neuro company Verge aims its PIKFYVE inhibitors at COVID-19
After a drug repositioning screen flagged Verge’s ALS target PIKFYVE as an Achilles heel for COVID-19, the neurodegeneration-focused biotech jumped into infectious disease by tapping the growing ecosystem of partners with industrialized SARS-CoV-2 assays.
That infrastructure, combined with the urgency of the pandemic, could enable Verge Genomics Inc.’s new COVID-19 program to leapfrog its lead candidate into the clinic.
Verge’s original PIKFYVE inhibitor is slated to enter the clinic in early 2021 for amyotrophic lateral sclerosis (ALS). CEO Alice Zhang said the company is aiming to get a different PIKFYVE inhibitor, optimized for antiviral activity, into patients within the next six months.
The AI-based neuro company’s path to a COVID-19 candidate reflects biopharma’s all-hands-on-deck response to the pandemic, which has generated more than 600 preclinical and clinical COVID-19 vaccines and therapeutics in less than six months (see “COVID-19 Resource Center”).
Sifting through this glut of candidates requires systematic clinical trials and preclinical experiments, using the same protocols, readouts and controls to enable apples-to-apples comparisons. A handful of companies, institutes and labs have emerged as go-to sources for harmonizing specific types of experiments (see “Modeling Harmony”).
Verge has six partnerships with such groups, and is running similar assays with multiple partners to build more confidence in the results (see Table: “Verge’s COVID-19 Partnerships”).
“We haven’t wanted to launch into anything too quickly that’s going to give equivocal data that we could spend months deconvoluting.”
“We opted to recapitulate the results in three different independent settings to get a clearer picture of how the assay performs and make sure the data is really compelling before moving forward,” said Verge CBO Jane Rhodes.
Verge had not yet disclosed its ALS target when an April 17 bioRxiv study showed an older PIKFYVE inhibitor apilimod was the most potent inhibitor of SARS-CoV-2 replication in a screen of 13,000 clinical-stage compounds -- about 26 times more potent than remdesivir, which received FDA emergency use authorization (EUA) on May 1.
At least two other recent studies have shown inhibiting PIKFYVE’s function interferes with the ability of SARS-CoV-2 to enter human cells; previous papers had shown the target is also involved in cellular entry by Ebola and other viruses.
Zhang thinks the host-targeting program could be broadly applicable to a wide range of viruses, including ones that have not yet emerged as threats. “The most promising aspect of this molecule is its ability to fight new viruses,” she said.
Table: Preclinical partners
PIKFYVE’s role as a lipid kinase in the endolysosomal system is central to its mechanism in both ALS and viral infection.
Verge homed in on PIKFYVE as a target for ALS via its machine learning platform, which searches for disease-driving gene networks by combing genetic, epigenetic, RNA and protein readouts from tens of thousands of patients (see “Network Intelligence”).
According to Zhang, blocking PIKFYVE helps prevent accumulation of cellular “junk” that often builds up in the CNS of neurodegeneration patients. In the context of viral infections, PIKFYVE inhibition stops viruses from escaping endosomes and replicating in the cytosol.
Because endosomal release is downstream of the binding interaction between viral capsid proteins and their host receptors -- such as the SARS-CoV-2 spike protein and the host ACE2 receptor -- the mechanism works the same regardless of how the virus first binds to the cell, Zhang said.
Figure: Mechanism of action
Disrupting endosomal trafficking of viruses is one of multiple mechanisms proposed for hydroxychloroquine’s effects on SARS-CoV-2 infection, but Zhang thinks PIKFYVE inhibition’s antiviral mechanism is more precise and well-validated than hydroxychloroquine’s.
She told BioCentury cell-based studies conducted by two of Verge’s partners showed the company’s PIKFYVE inhibitors have more potent antiviral effects against SARS-CoV-2 than apilimod, and have a larger therapeutic window. “The trick is to find the right dose that blocks the virus without harming the host cell.”
Zhang said Verge’s compounds also have a longer half-life in blood than apilimod, which could enable once-daily oral delivery and lower the dose needed for therapeutic benefit.
Because the company’s programs were geared toward neurological indications and have CNS penetrance, they may be able to address neurological aspects of COVID-19, she added.
Originally brought to the clinic for autoimmune diseases by Synta Pharmaceuticals Corp. before its direct molecular target was known, apilimod was acquired by LAM Therapeutics and renamed LAM-002. That company, now dubbed AI Therapeutics Inc., has the compound in Phase II testing for B-cell non-Hodgkin lymphoma (NHL) and in preclinical testing for ALS. AI Therapeutics did not return requests for comment.
It takes a village
Verge’s partners are testing its compounds in a handful of preclinical systems that are emerging as the best-validated models for modeling SARS-CoV-2 infection and treatment with antivirals.
“We haven’t wanted to launch into anything too quickly that’s going to give equivocal data that we could spend months deconvoluting,” Rhodes said.
The compounds are first being screened in Vero E6 cells, an African green monkey kidney cell line, by researchers at the Rega Institute at KU Leuven, the Harvard Therapeutics Initiative, and an undisclosed pharma.
“We were conscious about Vero assay platforms being variable across different labs,” Rhodes said.
The next layer of screening involves testing the compounds’ antiviral activity in human lung and intestinal cell lines at Institut Pasteur and NIH’s National Institute of Allergy and Infectious Disease (NIAID).
The company is also partnering with NIAID and the CRO IIT Research Institute to test the compounds in hamster and ferret models of SARS-CoV-2 infection. But Zhang said the compounds could enter the clinic without in vivo data given the urgency of the pandemic and remaining uncertainty about the models’ relevance to human infection.
Verge is also in discussions to test the compounds in human cell-based models that are less established but might capture COVID-19 biology better than cell lines: a lung-on-a-chip model from Emulate Inc. and an induced pluripotent stem cell (iPSC)-derived lung stem cell model from Newcells Biotech Ltd. and the Liverpool School of Tropical Medicine.
Rhodes said all of Verge’s assays are benchmarked to remdesivir, and the partnerships are also giving a “good picture” of the PIKFYVE inhibitors’ effectiveness relative to other classes of compounds.
She said the partners have also helped Verge map out its development and regulatory strategy. “One thing we’ve noticed across the board is the unbelievable appetite for collaboration.”
ACE2 - Angiotensin-converting enzyme 2
PIKFYVE - Phosphoinositide kinase FYVE finger containing