Stoke Therapeutics Inc. is marching ahead in the second half of this year with its phase I/IIa study with STK-001 in Dravet syndrome (DS), one of the more abysmal forms of epilepsy, although the FDA has temporarily hobbled part B of the test, pending preclinical data that will more fully characterize the safety profile of the antisense oligonucleotide (ASO).

Shares of the Bedford, Mass.-based firm (NASDAQ:STOK) fell 11.7%, or $2.59, to close at $19.62 on word of the snag with part B of the experiment called Monarch evaluating STK-001, designed to increase levels of SCN1a mRNA in the cell to boost the NaV1.1 protein. U.S. regulators want preclinical data with the compound at doses higher than the current no-observed-adverse-effect-level (NOAEL), Stoke said as part of its earnings report.

The NOAEL was determined using data from a pivotal nonhuman primate study that tried intrathecal delivery of single-dose levels of STK-001. The highest dose given was equivalent to a human dose that is higher than what Stoke plans to give in Monarch’s part B, yet did not turn up effects considered adverse. Stoke has started single-dose toxicology studies to more fully characterize the safety profile of STK-001 at higher doses to satisfy the FDA. Once dosing is done in part A, and with the FDA’s blessing, Stoke will proceed with the higher-dosing cohorts planned in part B. The company said it still expects preliminary data to roll out from the study in 2021.

Between 10% and 20% of those afflicted with DS will die well before adulthood, with most of that percentage passing away before they reach age 10. On average, they die at about 8 years old; the span ranges from infancy to 18, with the most common cause sudden unexpected death. Life for such patients is miserable in the meantime; as DS – which typically appears during the first year as febrile seizures – moves ahead, other types of seizures take hold, including myoclonus and status epilepticus. Intellectual development begins to falter around age 2, with DS patients showing a lack of coordination, poor development of language, hyperactivity and difficulty relating to others, according to the NIH’s Genetic and Rare Diseases Information Center. A family history of either epilepsy or febrile seizures is recorded in 15% to 25% of cases, and about 85% are due to a mutation in the SCN1A gene. In about 10% of cases, the cause is unknown, though researchers suspect other genes are implicated.

Stoke deploys TANGO (Targeted Augmentation of Nuclear Gene Output) technology, which makes use of the cell’s endogenous reservoir of nonproductive mRNA sequestered in the nucleus to restore protein expression in patients with a genetic deficiency. TANGO is the first ASO approach that allows for targeted up-regulation of transcripts known to be insufficiently expressed in the cell – a strategy that Cowen analyst Yaron Werber called “innovative” and “highly differentiated,” with the potential for “unlocking a host of indications with no disease-modifying therapies currently on the market.” The firm, he wrote in a Feb. 24 report, has “wisely positioned their early stage pipeline to target autosomal dominant haploinsufficiences with underlying mutations in genes too large to be effectively treated with traditional gene therapy approaches.” First up: DS. In a report reacting to the more recent news, Werber saw no cause for alarm. “[The] FDA’s request demonstrates an added level of precaution given the severity of the patient population and novelty of the TANGO platform, but we do not expect any problems with Stoke’s current clinical plan and anticipate the hold will be lifted as the ongoing preclinical toxicology studies complete in the coming months.”

BTIG analyst Thomas Schrader had a similar take. He opined in a report that “caution on the part of the FDA is interpreted by management to reflect the frailty of DS patients more than anything else. In a perverse sense, the worst case looks like no maximum tolerated dose is discovered and a handful of cohorts are required to show that drug is safe at its formulation limit (well above the expected maximal dose).”

Roche’s NMDA mouse data promising

Another high-profile player in the space is Zogenix Inc., of Emeryville, Calif., with Fintepla, formerly known as ZX-008, consisting of the serotonin reuptake blocker fenfluramine. The candidate bears a June 25 PDUFA date, but its path with U.S. regulators has proved rough. In April 2019, the FDA smacked Zogenix with a refusal to file letter, which complained that the firm did not include nonclinical data related to chronic use of Fintepla, and that the company's NDA contained an incorrect version of the clinical package, which meant regulators could not complete the review process. As half of the weight-loss drug known as fen-phen, fenfluramine itself owns a checkered past. It was withdrawn from the market in 1997 after cases of heart valve defects and pulmonary hypertension were reported in people who had taken the compound with phentermine.

With Fintepla, gatekeepers said they wanted sensitivity analyses on phase III results – a situation on which Zogenix offered more perspective during its earnings call March 2. “The data are incredibly robust to any sensitivity analysis we have conducted, to the point where we're not seeing any shift in ‘p’ values and very, very small differences in endpoint estimates,” CEO Stephen Farr said. “We don't think there's really anything that the FDA is going to uncover here that we have not already seen.”

SVB Leerink analyst Marc Goodman sounded convinced. “Even with the latest DS ‘speed bump,’ we believe this product will get approved midyear,” he wrote in a March 3 report. “We updated our model to modify launch timing assumptions given the PDUFA delay and a slight EMA approval delay relative to our previous expectations, which brings our Fintepla U.S. sales [estimate] in DS to about $22 million in 2020 and about $83 million in 2021.” In another rare epilepsy, Lennox-Gastaut syndrome, Fintepla has yielded positive top-line results from Study 1601, a global, pivotal phase III experiment.

For DS, doctors for the moment use anticonvulsants such as valproate and clobazam. Other options include stiripentol, topiramate, levetiracetam and potassium bromide. Vagus nerve stimulation by way of electrical impulses may help – a ketogenic diet can, too – but the field badly needs a specific new therapy. In January, Cell Reports published preclinical findings by scientists at Basel, Switzerland-based Roche Holding AG and the Gladstone Institutes with GNE-0723, a small molecule found to increase the activity of a subset of neurotransmitter receptors at synapses. In mouse models, N-methyl-D-aspartate receptor enhancement was shown to improves brain oscillations, synchrony and cognitive function in DS and Alzheimer’s disease, researchers said.

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