Stoke Therapeutics Inc. CEO Edward Kaye told BioWorld that the company cranked its quest "into turbocharge mode, once we had the animal data [in June] that suggest we were having some pretty significant efficacy results," and clinical work is expected to begin by 2020.
The Bedford, Mass.-based firm finished a $90 million series B financing to advance antisense oligonucleotide medicines for Dravet syndrome (DS) and other severe genetic diseases. The company has identified thousands of genes that could be addressed by its TANGO (Targeted Augmentation of Nuclear Gene Output) technology, which takes aim at non-productive RNA splicing to increase gene expression and address the root cause of monogenic diseases caused by loss or reduction of gene function.
In January, Stoke raised $40 million in a series A round. Since then, the firm has been "working hard to determine lead a candidate," Kaye said. "We've set up all of our CROs for our IND-enabling toxicology studies" next year, when an observational study will start in DS in order to understand the natural history. "We're setting up the clinical trial design, which we hope to start in early 2020, not only looking at seizures but also looking at intellectual-outcome measures, looking at the ability to walk. All of these children have significant problems other than seizures," he said. Officials are talking to potential trial sites in the U.S. and internationally. (See BioWorld, Jan. 5, 2018.)
DS is an autosomal dominant severe epileptic encephalopathy affecting more than 30,000 patients in the U.S., EU and Japan. It's characterized by febrile seizures within the first year of life, then frequent, uncontrolled afebrile seizures and stagnation of mental development. Though the genetic mechanism is known – haploinsufficiency of SCN1A – there are no genetic therapies in development for DS, until now.
Amy Brooks-Kayal, president of the American Epilepsy Society – with whom Kaye once worked at Children's Hospital of Philadelphia – has said the age of genetic therapy in epilepsy is upon us, and Stoke hopes to lead the charge. Twenty-five years ago, Kaye said, "we thought that these were just idiopathic; we didn't know why children had intractable seizures." It's known today that many stem from genetic disorders with which some 200 genes are associated, and genetic testing has become more common.
Previous anti-epileptic drugs "suppressed brain activity. We knew that these were all neurotoxins, but they controlled the seizures, and that was very important for the children," he said. The push now is to "prevent abnormal electrical activity from beginning in the first place," while addressing the added neurological problems.
Gene therapy runs into trouble in DS because the genes are often quite large, and current adeno-associated virus (AAV) technology can't do the job, said Kaye, who explored gene therapy at Massachusetts General Hospital in the early 1990s. "The other problem is that gene therapy is a little bit of a blunt instrument," he said. "If you think about AAV, you need to get it into the cells and it needs to be expressed, [but] it won't necessarily go into a specific cell where you need to have that sodium channel expressed. Also, you can give way too much of the gene, and then you would have too much protein, and that could result in another disease. Right now, this [TANGO] platform seems to be the best approach."
To partner 'big targets'
Antisense has been around for more than 25 years, but most researchers have been trying to down-regulate proteins, Kaye said. "What's been very helpful is that these signatures that allow us to up-regulate the gene and increase the protein are often present in 150 different species, so we can use the same model in the mouse, nonhuman primates and the human. That helps us accelerate the program because we're not having to generate three different sequences for each animal model to test safety."
In biodistribution, much has been done already by Biogen Inc. and Carlsbad, Calif.-based Ionis Pharmaceuticals Inc., "and we're kind of dovetailing [with] that work," he said. "Obviously, we're confirming everything that they did in spinal muscular atrophy [SMA]."
With the five-year neuroscience deal that spawned SMA blockbuster Spinraza (nusinersen) set to expire in the next year, Biogen, of Cambridge, Mass., sweetened the pot by paying $1 billion for a 10-year extension in the spring of this year. (See BioWorld, April 23, 2018.)
Kaye said another factor that might help speed development along is that Stoke's drug stays in the central nervous system for a long time, since it's a synthetic structure and nothing breaks it down. Specifically, the therapy lasts four to six months in the brain, "which means that, if we have the right dose, a single-dose study should allow us to see whether or not we have efficacy very early."
The company will move another candidate into the clinic as soon as possible after the DS prospect, he said.
Stoke plans to keep the rare diseases projects in the company. "With this platform, however, the signature is present in about 25 to 30 percent of all genes, so we have the potential to go after really big targets" – targets that the company likely would partner. Possible indications include diseases that cause epilepsy as well as separate disorders in neurology, the kidney and liver. "We're having those discussions now," he said. "We'll have to wait and see where we end up with this, but it has huge potential."
The financing round was led by RTW Investments with participation from founding investor Apple Tree Partners. New investors include RA Capital Management, Cormorant Asset Management, Perceptive Advisors and funds managed by Janus Henderson Investors, along with Redmile Group, Sphera Funds Management and Alexandria Venture Investments. Roderick Wong from RTW, Matthew Hammond from RA, and Bihua Chen from Cormorant are joining the board as observers.