I'm Pratik Shah, Chief Executive Officer of Design Therapeutics. During this presentation, we will use forward-looking statements with regards to our business, R&D activities, and financial conditions, which are subject to known and unknown risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factor section of our most recent Form 10-Q filed with the SEC. Given the nature of the interest in the FA program and the design of the RESTORE-FA trial, we're delighted to provide a general update on our FA program, the key objectives of the RESTORE-FA study, and the multiple biomarker endpoints being evaluated. We're using this quarter's update to provide further context on how we're thinking about the study. The trial is proceeding well, and we're looking forward to data in the second half of 2026.
As a reminder, FA is a debilitating condition which is caused by a mutation in a single gene called a frataxin gene. The mutation causes low levels of production of frataxin, which causes all kinds of downstream dysfunction in multiple organs. There is an approved drug for FA called omaveloxolone, which targets Nrf2 and not frataxin. The mutation causing FA is a GAA-GAA repeat expansion in the first intron of the frataxin gene, which causes the level of normal mRNA to be low and therefore levels of protein to be low. DT-216 is a heterobifunctional gene-targeted chimera or GeneTAC molecule that is designed to recognize these long GAA repeat expansions and dial up normal frataxin RNA transcription. Cellular data suggests a hypothesis that 10 nanomolar levels may be sufficient to increase frataxin as long as there is sufficient duration of exposure.
Green bar is 10 nanomolar of drug on iPSC, patient-derived terminally differentiated neuronal cells, and it shows that these levels increase mRNA and protein. The orange bar shows 100 nanomolar while 100 nanomolar looks better initially. As long as there is sufficient duration, 10 nanomolar appears to give full pharmacology in cells. What do we know about what drug levels may be sufficient in humans? From our previous clinical studies from 2023, plasma exposures at day two are approximately 40 nanomolar-75 nanomolar and correspond to approximately 8 nanomolar-10 nanomolar drug levels in muscle. A day two response, data show that this results in an unmistakable increase in frataxin RNA expression. The frataxin levels drop off after day two because the drug is gone. What we see here is a single-dose pharmacokinetic profile from the current drug product, DT-216P2.
In the purple curve, approximately 40 milligrams gives us sustained levels of 40 nanomolar- 75 nanomolar all the way till the end of one week, supporting weekly dosing, in which with multiple doses, it would be expected to build to a higher steady-state level. Based on these exposures, we started a multiple ascending dose study in FA patients called RESTORE-FA. The trial is proceeding well, and we are looking forward to data in the second half of 2026. Accordingly, with this quarter's update, we're using the following slides to walk through additional elements of the trial design ahead of sharing data in the second half of this year. This is the dosing design in the RESTORE-FA study in patients with FA. When we began the study, we had four weeks of non-clinical tox coverage. This was mid last year.
For both that reason and in order to get to the target exposures more quickly that we showed two slides ago in the purple line, the escalations go from 0.1 mg per kg- 0.3 mg per kg to 0.6 mg per kg in the four-week context. As a reference, the approximately 40-milligram single-dose PK from the single ascending dose trial in healthy volunteers is the 0.6 mg per kg dose level. In order to generate additional exposure, we have started a 1 mg per kg group in four weeks, and to enable 12-week data update in the second half, we have also incorporated 12-week treatment cohorts, including the 1 mg per kg group. We expect additional cohorts in the 12-week dose group because the PK projections do support additional dose levels within the non-clinical safety exposures.
The subcu infusion dosing details are still being determined. The IV is fully bioavailable, we preferred using the IV first to determine dose levels ahead of subcu cohorts. As we have mentioned before, we are evaluating endogenous frataxin levels in both blood and muscle by looking at mRNA and protein. As is customary in clinical trials involving patients, we have included clinical exploratory endpoints, including mFARS or the Modified Friedreich's Ataxia Rating Scale, which is commonly used in studies with FA patients and was used by the omaveloxolone trials for initial approval.
Upright Stability Score, or USS, is a component of mFARS that's being used by the approved drug as a primary endpoint in the BRAVE study. Fatigue is an important complaint for patients living with FA, and in particular, we're using a PROMIS Fatigue Scale, which is considered a validated patient-reported outcome and has been used in a variety of disease areas and multiple regulatory submissions. The purpose of the RESTORE-FA study for us is, you know, threefold. One, to provide a go, no-go on the FA program. Two, to hopefully establish a clinical proof of concept. Three, to inform the regulatory path and probability of a potential future approval. Now, in general, there are two broad regulatory frameworks. Under an accelerated framework, a particular single frataxin biomarker measurement is chosen as a primary endpoint, which would be based on potential future regulatory alignment.
Our goal with RESTORE-FA is to take the data from, you know, four measures across blood and muscle and mRNA and protein and zero in on a single biomarker as the potential primary surrogate reasonably likely to predict clinical benefit. Further, since observing clinical benefit would be expected under either framework eventually, it would be helpful to understand possible clinical endpoints that could be used to support a potential accelerated path and provide the basis for, you know, eventual full approval. The pathogenic cascade is shown here with the disease starting with an intronic mutation in the frataxin gene in the DNA. Now, because the pre-mRNA made from the mutant gene is different, but the spliced mRNA is identical to the wild-type mRNA, just lower in quantity, our assay is specific to the spliced wild-type mRNA.
Once the spliced mRNA is made, the rest of the cascade is intact in patients with FA. Patients make protein normally, lower in quantity, and both mRNA and protein are measured in the clinical trial. We've reported in the past that the protein made in cellular systems by treating with an FA GeneTAC molecule is functional as measured by increases in downstream effects like cis-aconitate levels, and that's in the science paper, and by increasing mitochondrial function as measured by cellular respiration and oxygen consumption by the cells. This was reported by us at a scientific meeting. As shown in this cascade, clinical effects would be downstream of the cellular effects, and they are being assessed in the clinical trial. An area to spend a moment on is our choice of various measures of frataxin as a biomarker.
The first point to address is, you know, why we selected whole blood and muscle to measure frataxin response. Well, endogenous whole blood protein was chosen because it is the tissue and biomolecular analyte that is at the center of the natural history data, which has been generated to establish frataxin as a reasonably likely surrogate for predicting clinical effects in the literature, and therefore is the most robust biomarker from a future regulatory alignment point of view. There is some data using whole blood RNA, and unfortunately, very little information about muscle RNA or protein in the literature. Eventually, when a single analyte is chosen, we believe for purposes of regulatory alignment, it would potentially need to bridge to blood protein to directly reference the natural history studies.
The muscle biomarkers were chosen partly because we had the assay from our previous studies, and it is another affected tissue. The second question is: Do we know how these different assays perform with regard to longitudinal variability and assay variability? In other words, if one were to measure the same analyte in the same tissue at two different time points, how do these assays perform? As we had mentioned previously, we've been running studies in the background with the biomarker assays in untreated patients and healthy individuals to assess both assay performance and intra-patient variability. In general, these assays perform acceptably, although blood assays are tighter than the muscle biopsy-based assays.
As far as how to think about evaluating frataxin responses, for reasons noted both in the footnote and the cited paper, it's noted there's no normalized standards in the FA field, and because of things like assay variability and other such factors, change relative to baseline is considered the more robust readout in interventional trials rather than absolute frataxin thresholds. You can see that in the quote below. We plan to report data in the second half based on change from baseline. Now, a third question we get on the biomarkers is, well, which of these assays can be best used to determine whether the drug effect gets into a carrier range?
To answer that question, we have compared levels by each of these assays to find the best one to answer that question, and the blood mRNA assay has the least observed overlap between patient and carrier levels, making that assay, in our opinion, best suited to make such a determination. Well, how much frataxin do we believe is enough? No one really knows the definitive answer to this question yet because no one has increased endogenous frataxin production. The answer will ultimately come from correlations between therapeutic clinical effects and frataxin levels. The natural history studies suggest that differences in frataxin levels between patients correlate as a continuous variable with all major clinical outcomes like age of onset, when is loss of ambulation, disease severity, disease progression.
Further, based on commentary from other sponsors like Lexeo, it appears that they have alignment on the accelerated development pathway with frataxin expression as a co-primary endpoint to be evaluated for any increase from baseline rather than a numeric threshold. For the biomarker readouts, there are three central questions that we are attempting to answer with the RESTORE-FA data. Does DT-216 increase frataxin mRNA using either tissue? Does 216 increase frataxin protein using blood or muscle? Does it have activity in both blood and muscle using either mRNA or protein? The biomarker data scorecard is therefore on the right. The data readout will inform whether DT-216 checks zero, one, two, or all three criteria.
It's not expected in the study at this stage to observe any clinical benefit, any clinical trends, if observed, could be useful for designing future clinical studies. Ultimately, correlations of these clinical measures with frataxin levels will have to be used to understand how much frataxin increases are indeed therapeutic. To that end, this is a summary of the clinical observations that have been seen with mFARS, which is a clinician administered tool used to measure neurologic dysfunction and disease progression in FA. mFARS was used by omaveloxolone in their pivotal study, which is called the MOXIe study, as a primary endpoint. An approximately 2.4 point group difference between treated and placebo at 48 weeks was observed. This reflects a change from baseline of 1.56 points against a worsening placebo, which worsened by 0.85 points over 48 weeks.
The 1.5 point or 1.6 point change from baseline was observed at week four and week 12, but the placebo had improved by approximately 1 point at those time points. Therefore, over 48 weeks, the treated arm maintained its change from baseline against a worsening placebo group since this is a progressive disease. To our knowledge, thus far, Lexeo reports a 2-point improvement change from baseline with an N of 16 at 6 months, and Larimar has reported 2.25 point improvement over baseline with an N of 8 at one year. The approved drug uses upright stability score, a component of mFARS, as a primary endpoint in the BRAVE study. USS is considered the most objective, least variable component of mFARS.
Lastly, fatigue is an important complaint for patients living with FA, and we're using a validated PRO scale called the PROMIS Fatigue Scale, which is disease agnostic and has been used for various regulatory submissions for other drugs. A 3-point improvement is cited in the publication below as an MIC or minimal important change. Well, this completes our FA update. We look forward to the results of the RESTORE-FA study in the second half of this year.