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SfN: Estradiol Analog May Lead to New MS Therapy

SfN: Estradiol Analog May Lead to New MS Therapy

Early data suggest NDC-1308 may have remyelinating properties

by Kristina Fiore 
Associate Editor, MedPage Today
November 17, 2016

SAN DIEGO — An investigational estrogen-like compound induced oligodendrocyte differentiation in vitro, and upregulated oligodendrogenesis genes, making it a potential candidate for a remyelinating therapy in multiple sclerosis (MS), researchers reported here.

Among several compounds that were investigated, NDC-1308 was most potent at inducing oligodendrocyte progenitor cell (OPC) differentiation in vitro, according to Steven Nye, PhD, and James Yarger, PhD, of Endece, the Mequon, Wis.-based company that is developing the drug.

The compound also turned up expression of genes commonly associated with oligodendrogenesis, they reported at the Society for Neuroscience (SfN) meeting.
“NDC-1308 is an agonist of nuclear receptors that upregulate key genes for OPC differentiation and myelination,” Nye told MedPage Today. “We know from studying the mechanism of action at the cellular level that it activates oligodendrogenesis, the body’s natural process of remyelination. It activates this process by upregulating key genes. It induces OPCs to differentiate.”

Researchers have been interested in developing remyelinating therapies to treat MS. The major player in the space has been Biogen’s opicinumab (anti-Lingo-1), but that drug failed in the phase II SYNERGY study, the results of which were reported at the 2016 European Committee for Treatment and Research in Multiple Sclerosis congress. Hopes were high after positive results from the RENEW trial were reported at the 2015 American Academy of Neurology meeting, but Biogen researchers are going back to the drawing board.

Nye said NDC-1308 takes a different approach by getting away from the monoclonal antibody strategy and instead focusing on driving oligodendrogenesis, since these mature cells can repair damaged myelin sheaths. The compound is an estradiol analog that incorporates a long tail to reduce unwanted estrogenic effects.

“It’s analogous to a parked car,” Nye told MedPage Today. “Anti-lingo therapy removes the parking brake, but our strategy is to step on the accelerator and drive the remyelination process.”

At the 2015 SfN meeting, the group reported that NDC-1308 produced remyelination in the cuprizone mouse model of demyelination. This year, the team investigated how NDC-1308 repairs demyelinated axons via in vitro experiments.

They showed that the compound can induce oligodendrocyte progenitor cells from transgenic mice into mature oligodendrocytes — something that did not happen with estradiol or estriol alone.

Using real-time qPCR analyses, the drug also upregulated several genes tied to oligodendrogenesis and remyelination, including OLIG2, DNER, MOG, and MBP.
The drug was also rapidly absorbed into central nervous system tissues in mice, they showed.

In another cuprizone mouse model, the drug induced remyelination, they found, and it also showed functional improvement in these animals, which had significantly higher forelimb grip strength compared with untreated animals.

Safety concerns surrounding potential estrogenicity were assessed in a mouse uterotrophic assay, as estradiol treatment is known to cause a rapid and dramatic increase in uterine weight — but that turned out not to be the case, they reported.

Nor was the compound mutagenic, as assessed in the Ames assay, or genotoxic, as measured by the micronucleus assay, they reported.

They also found that the oligodendrocyte progenitor cell pool remained intact after 6 weeks of chronic NDC-1308 treatment, suggesting that it can serve as a renewable source for sustaining oligodendrogenesis, the researchers said.

They concluded that NDC-1308 is a potential first-in-class remyelinating therapy that possesses many key qualities needed to effectively treat both secondary progressive and relapsing remitting MS.

“We’re currently planning for large animal toxicology and safety studies in 2017, when we also plan to file our [investigational new drug application with the FDA],” Nye told MedPage Today.”That puts us on a timeline to start phase I, first-in-man studies in 2018. We’re also planning phase IIa studies for 2019 that would be our initial evidence for efficacy.”

Asked if remyelinating therapies are still the future of MS therapy, Nye affirmed the strategy and said the company hopes “to bring a functional cure to MS patients, particularly progressive MS patients.”