A Promising Case Study of Ultra-Rare, AI-Guided, ASO Development

This is the second part of an interview with David Dimmock, MBBS. For the first part, click here.

David Dimmock, MBBS

Creyon Bio has been treating a child with a de novo heterozygous pathogenic variant causing a missense change in TNPO2 with an antisense oligonucleotide (ASO) therapeutic created using the company's AI discovery platform. Creyon presented data from this proof-of-concept case study at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.

At the conference, CGTLive® sat down with David Dimmock, MBBS, chief medical officer at Creyon, to get his insight on the findings from the case study so far. Dimmock went over the increasing doses of the ASO that were administered to the child and the changes reported after each dose, emphasizing that the findings so far seem to indicate that more frequent redosing would be beneficial.

CGTLive: Can you go over the data from the case study?

David Dimmock, MBBS: As with every new therapy, there are ways that we need to convince ourselves and we need to convince the regulators and the family that the ASO is safe enough. It's a real challenge because you've got a child who's getting worse in front of your eyes and you're sitting waiting for good lab practice animal studies. You're waiting for all of the drug manufacturers to sign off on all of the lots demonstrating the drug is safe. So unfortunately, from the point of actually having a drug made to being ready to dose the patient took about 6 months. After the first 5 mg dose, really nothing happened. That wasn't a surprise, we thought it was going to be too small a dose, but we wanted to make sure we started at the low dose and made our way up because we didn't want to give too much. So we then gave 10 mg, 20 mg, and then 40 mg, which was our target dose. Within a few days of giving the 10 mg dose, the parents called us saying their child was doing better. I think all of us are very concerned about a placebo effect. We hadn't seen that after the 5 milligram dose, but [we had to find out whether] there is robustness and durability to this?

Once we gave the 20 mg dose, the parents reported that for the first time really in about a year, the child was actually rolling over. The child had pretty significant cross eye, which we thought might be part of the disease. One of the other really surprising things was, after we gave the 40 mg dose of the ASO, the child's cross eye actually corrected itself, and the eyes turned back to being at a point where they were both looking. We saw a dramatic reduction in the how often the baby was seizing. This child was having such bad seizures on the day before we gave the first dose that the doctor that's treating this child, Dr. Nicole Coufal, who really is the person who's made this all happen, had actually breathed for the child for a little bit in clinic, because the seizure was so bad, the child had stopped breathing for long enough that they actually had to intervene.

So we went from the point where the cyanotic seizures were happening multiple times a day, to being at a point where, after the 20 mg dose, for a couple of weeks, the child had no seizures. All the more remarkably, over Thanksgiving, the child had a viral infection that actually was bad enough to put them in the ICU. Every time prior, when the child got a minor infection, as with most kids with seizures, the seizures got dramatically worse. Instead at this point, the child was in the ICU, sick with a respiratory infection, but not having any seizures at all.

As we've progressed, we didn't know what the half-life of the drug would be, and so there was an extent to which we just had to figure this out empirically, unfortunately, in the child. We initially planned dosing once every 3 months, or once every 90 days. What we found was that we saw a dramatic response at the first 40 mg dose, but after about 5 or 6 weeks, the child started to go backwards again and had an increase in seizures. Some of the skills that had been acquired started to get lost. We gave the next 40 mg dose and within about a week, the child was back doing all of these skills again, and then some more as well—actually we'll show the video on Friday showing the child actually being able to sit up—with some help and with some support, but nonetheless, sitting up. And I think more importantly, the parents have been really interactive with them. Again after the second dose, and after about a month and a half, the drug seemed to wear off and the child stopped interacting with parents, again. We gave the third dose in January, and we saw the same thing again, the child dramatically better... We gave the [next] dose in April of this facing out, and again, we saw the same thing: the child got dramatically better within 3 or 4 days, and actually, the video we're going to show of him sitting up was about 3 days after that dose in April.

So we're all kind of sitting nervously now as we're expecting the drug's going to wear off again in the next few weeks... We’re at the point now where we're very confident that the drug is working, because every time we give the drug, the child gets dramatically better, but unfortunately, it seems to be wearing off. So we're in the process of working out what safety data we need to persuade everybody that it would be more appropriate to dose this child more frequently.

This transcript has been edited for clarity.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

REFERENCE
Dimmock DP, Bird L, Bouck A, et al. AI Enabled ASO Design Can Lead to Rapid Initiation of Treatment for an Ultra-Rare Disorder Leading to Allele Selective Knockdown of a Toxic Protein and Consequent Clinical Improvement. Presented at: ASGCT 27th Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #309