This is because of a shorter alpha phase and the elimination half-life between the prior and new drug products are very similar. This profile has been achieved by using a proprietary and novel excipient in the formulation. DT-216P2 also has a sustained exposure profile when administered by subcutaneous route of administration as shown on the right slide. This profile has a blunted CMAX and a sustained exposure with low peak to trough level fluctuations. We have flexibility in both root of administration as well as frequency of dosing as seen here with both a daily or weekly subcutaneous injection in non-human primates. In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure, and this is typical of a small molecule drug.
The new drug product also shows that the tissue levels as measured by muscle biopsy in non-human primates is in line with plasma exposures, providing comfort that the extended profile seen in plasma will provide the desired extended profile in tissues. Repeat dose studies done in non GLP assessments have also been encouraging and the program will be proceeding to GLP studies, which are planned to be completed by the end of this year to support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies, our plan is now to conduct a Phase 1 clinical trial in healthy volunteers so as to confirm the pharmacokinetics and also to confirm injection site tolerability. This will also help us in choosing a dosing root and dosing frequency for longer term studies.
Subsequent trials will be in FA patients, which we plan to conduct to determine safety, tolerability, and the effect of treatment on endogenous frataxin levels. Skyclarys is now approved for the treatment of FA and its update confirms that this is a large market opportunity. Since Skyclarys does not affect frataxin levels. We believe this approval has no appreciable impact on the potential opportunity for DT-216. As we’ve discussed before, GeneTAC small molecules have several potential advantages over any other genomic medicine modalities. Now, in case you see any literature reports of possible effects of other molecules on frataxin expression, we show here that GeneTAC molecules restore frataxin in a more substantial way than anything else reported in the literature, which is not surprising given its direct and elegant mechanism of action.
Fuchs Endothelial Corneal Dystrophy, or FECD is a degenerative disease of the cornea that’s been known for over a hundred years. The literature widely cites that this disease affects 4% of all adult Americans over the age of 40. Only in the last decade though, has it been shown that approximately 70% to 80% of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the TCF4 gene. Based on the current census, this works out to approximately 4.6 million to 5.3 million U.S. FECD patients. There are no approved disease modifying prescription drugs for FECD, and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea. Eventually, a small fraction of patients gets a corneal transplant surgery, which there are about 18,000 to 30,000 corneal transplant surgeries done in the United States annually, and that’s a very small fraction and represented by the red figure.
Most patients unfortunately quietly suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage Fuchs. The analogy is sometimes that of a foggy and rainy windshield resulting in loss of low contrast, visual acuity glare and contrast sensitivity. And we have heard from a number of clinicians who see these patients that if there was anything that slowed progression and was well tolerated, they would treat everyone, even patients who were presymptomatic. FECD is caused by dysfunction in the cells of the endothelial, monolayer of the cornea, and these cells have a role in maintaining a dehydrated stroma and keep the cornea free of extracellular matrix deposits.
These cells are slowly lost over time due to the disease, and they’re sick because of the TCF4 mutation, which is the CTG repeat expansion in the non-coding region of the gene, this inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this? By helping restore cellular health to the endothelial layer and this cell dysfunction arises from this single inherited mutant allele. The polymerase reads the mutant allele and makes an RNA containing these repeats. The RNA folds over on itself, creates tangles, and you can see them. You can stain for them. These tangles sequester MBNL splice proteins and cause mis-splicing of a number of downstream genes, which then drive cellular dysfunction. We have designed GeneTAC to bind and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic TCF4 mutant RNA.
This slide shows the effectiveness of the GeneTAC molecule. Recall I said that you could stain for these mutant foci. They’re shown in the above panel in the middle section as dots that light up with a fluorescently labeled probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who’ve undergone surgery. On the lower panel, we observed that these foci largely go away when these patient corneal cells are treated with DT-168. The compound has — potency as shown in the dose response curve on the right. This slide shows the results of assay for wild type TCF4 transcripts from patient cells as shown here. Drug treatment has no effect on the wild type TCF4 expression. This is an allele selective inhibition, which is highly desirable.
This slide looks at mis-splicing that occurs in a variety of downstream genes at baseline and light green, and with drug treatment as mutant TCF4 expression is dialed down and sequestered splicing proteins are released, downstream normal splicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desired product profile, we have also been able to formulate this to be suitably delivered as an eye drop. All the required nonclinical safety studies have been conducted and reviewed by the FDA resulting in an IND that’s been cleared. We plan to initiate Phase 1 development for DT-168 in 2024. We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease.
