PTC Therapeutics, Inc. (NASDAQ:PTCT) continues to make significant progress in its pipeline. This is especially true when you consider that it has already been able to report positive interim results from its phase 2 PIVOT-HD study, which used PTC518 for the treatment of patients with Huntington’s Disease [HD]. The last time I wrote about this article in a Seeking Alpha article entitled “PTC Therapeutics: Multiple Regulatory Submissions Along With Data Cuts,” data for PTC518 was not released. Not only has this data now been released, but it was shown that the drug was able to reduce mHTT protein in the blood and cerebral spinal fluid [CSF] in a dose-dependent manner.
There were other positives that were released with this program as well, which I will be going over below. Another program I didn’t go over last time around, which I want to discuss this time, would be the New Drug Application [NDA] submission of sepiapterin for the treatment of patients with PKU or phenylketonuria. This submission was achieved back in July 2024, but I believe that shareholder value can be further built upon with other regulatory submissions planned for other territories in 2024. With positive interim HD data released from a mid-stage study, plus several other regulatory advancements, I believe that investors could benefit from any potential gains made.
PTC518 Interim Data Were Highly Encouraging To Move Forward With
As I noted above, PTC Therapeutics was able to release interim data from its phase 2 PIVOT-HD study, which used its small molecule drug PTC518 for the treatment of patients with Huntington’s Disease. Before going over this mid-stage study, plus any catalysts to come out of this program, it is first important to go over what this disorder is and what the possible market opportunity might be for it.
Huntington’s Disease is a type of rare neurological disorder of the central nervous system [CNS], whereby a defective gene produces a mutated Huntingtin [mHTT] protein. Why is this bad? That’s because this mutated protein can cause neuron damage or death. Where does PTC581 fit into this equation? It is responsible for reducing the production of it. While there are some therapies that help treat this neurological disorder, there are no approved drugs that target the underlying cause of it. The global Huntington’s Disease treatment market is expected to reach $3.06 billion by 2033. This is a considerable market opportunity and honestly, the hope here is to be able to offer these patients a disease-modifying therapy.
To see if its splicing developed small molecule PTC518 would be capable of being able to help patients with HD, it is running the phase 2 PIVOT-HD study. This particular study is expected to recruit up to a total of 252 patients who were randomized to receive either one of two doses of the drug [5 mg and 10 mg of PTC518] or a placebo over an 18-month period. However, the 18-month portion of this trial would only look at the safety of the drug. Whereas, biomarkers and other efficacy data were evaluated over a 12-month period. Speaking of which, this drug did very well in a 1-year period regarding reducing mHTT protein in the blood and the CSF. For instance, at month 12 the mHTT was reduced in a dose-dependent manner as follows:
- Dose-dependent lowering of mHTT in the blood of 22% from baseline using 5 mg of PTC518.
- Dose-dependent lowering of mHTT in the blood of 43% from baseline using 10 mg of PTC518.
- Dose-dependent lowering of mHTT in CSF of 21% from baseline using 5 mg of PTC518.
- Dose-dependent lowering of MHTT in CSF of 43% from baseline using 10 mg of PTC518.
The lowering of the mutant Huntingtin protein in both the blood and CSF is good, but ultimately does it improve cognition and reduce symptoms for these patients? This remains to be seen, but there was something else revealed in the press release, which might indicate that this drug might actually be able to help these patients. Beyond the biomarkers that were shown with this interim analysis.
In particular, it was noted that the drug was able to do much better in slowing the progression of Total Motor Score [TMS] for these HD patients. Consider that patients who took 5 mg and 10 mg of PTC518 were able to achieve only 2 points and 1.3 points of worsening, respectively. While those given placebo saw 4.9 points of worsening. There is still some work to be done here, but it is good to see that over a 12-month period that this company was able to achieve this. Another positive development that came about for this program is that the FDA lifted the partial clinical hold because of this positive interim PIVOT-HD data.
NDA Of Sepiapterin Creates Another Positive Milestone To Look Forward To
This time around, I wanted to go over another clinical candidate in PTC Therapeutics’ pipeline, which is sepiapterin. This particular drug is being developed to treat patients with phenylketonuria [PKU]. The program is far advanced compared to the HD program noted above, that’s because not only has a phase 3 study been completed successfully, but in addition, an NDA of sepiapterin was submitted to the FDA in July 2024. Before going over the phase 3 study itself, plus any other catalysts to come out of this program, I believe that it is important to go over what this disorder is and what the possible market opportunity could be.
Phenylketonuria is a rare metabolic disorder whereby a defective PAH gene, responsible for producing the enzyme phenylalanine hydroxylase, is unable to remove or break down the amino acid phenylalanine in the body. With this enzyme not broken down, then it leads to a buildup of it in the patient’s body. In turn, this causes numerous problems for a person, such as the following:
- Severe disabilities.
- Loss of memory.
- Behavioral problems.
- Emotional issues.
- Seizures.
- Intellectual disability.
Not only that, but there is something else to consider here, which is that there are plenty of foods that have the amino acid phenylalanine [Phe]. The foods that have this amino acid are eggs, nuts, milk, and meat. The phenylketonuria treatment market is expected to hit $2.6 billion by 2033. As you can see, this is another large market opportunity for the company to go after.
To see if sepiapterin would be able to help these patients with PKU, it ran the phase 3 APHENITY trial. This particular late-stage study recruited a total of 156 children and adults with PKU and were randomized to receive either of the following treatments:
Remember above, where I noted that these patients have a major problem with blood phenylalanine levels? Well, the primary endpoint deployed was the reduction of phenylalanine levels over a 6-week period of the drug compared to the placebo. First and foremost, it is important to note that both PKU and classical PKU patients achieved a huge percentage reduction of Phe. The percentages achieved were as follows:
- Phe reduction of 63% for all PKU patients.
- Phe reduction of 69% for a subset of classical PKU patients.
Not only were these Phe reductions achieved, but they were done so in a highly statistically significant manner, with a p-value of p<0.0001. Besides the fact that the NDA of sepiapterin is already being submitted to the FDA, there are a few other milestones expected later in 2024. It is expected that regulatory submissions of this drug, for the treatment of these PKU patients, will be submitted to Japan and Brazil at that time.
Financials
According to the 10-Q SEC Filing, PTC Therapeutics had cash, cash equivalents, and marketable securities of $1.09 billion as of June 30th, 2024. The reason for the cash on hand is that the company amended its agreement with Royalty Pharma and exercised one of its put options in exchange for $250 million in cash, less royalties to be received. The company is likely going to need to raise additional cash in the coming months. What makes me say this? It is because it states in its 10-Q SEC Filing that it believes it has enough cash on hand to fund its operations, or cash runway, for at least the next 12 months.
Risks To Business
There are several risks that investors should be aware of before investing in PTC Therapeutics. The first risk to consider would be in terms of the positive interim results from the phase 2 PIVOT-HD study, using PTC518 for the treatment of patients with Huntington’s Disease. Even though there was a dose-dependent lowering of the mutant Huntingtin [mHTT] protein in both the blood and CSF of these patients at the interim time point, that doesn’t mean that final data will be achieved similarly. Plus, it is also likely that the company is going to seek to move this program toward the next stage of clinical testing. Thus, there is no assurance that a larger late-stage study will meet the eventual primary endpoint with statistical significance.
The second risk to consider would be in terms of the NDA of sepiapterin that was submitted to the FDA for the treatment of patients with PKU. The risk is that even though the regulatory application of this drug for the treatment was submitted does not mean that the agency will accept it in its present form. Even if the NDA is accepted for review, there is no assurance that the FDA will approve sepiapterin for these patients with PKU.
The third risk to consider would be in terms of the upcoming topline data to be released for utreloxastat. That’s because this drug is being developed for the treatment of patients with amyotrophic lateral sclerosis [ALS] in the phase 2 CardinALS trial. Top-line data from this particular mid-stage study is expected to be released in Q4 of 2024. There is no assurance that the primary endpoint of change from baseline in ALS Functional Rating Scale-Revised [ALSFRS-R] score at Week 24 will be met with statistical significance.
The fourth and final risk to consider would be in terms of the Biologics License Application [BLA] of PTC-AADC for AADC deficiency that was accepted by the FDA with Priority Review, with a PDUFA date of November 13th, 2024. The risk is that there is no assurance that the FDA will approve this drug for the treatment of this patient population upon completion of the review.
Conclusion
PTC Therapeutics has several milestones for investors to look forward to in the coming year. I already went over some of them above, but there are a few other programs to keep an eye on. For instance, PTC resubmitted its NDA of Translarna to the FDA for the treatment of nonsense mutation Duchenne Muscular Dystrophy [nmDMD] in July 2024. It remains to be seen if the U.S. agency accepts the resubmission for this program. Another milestone to keep an eye on would be the expected NDA submission of another drug in its pipeline, known as Vatiquinone for the treatment of patients with Friedreich’s Ataxia [FA]. Such a regulatory submission is expected to happen in late 2024 and this could be another catalyst that might have a significant impact on the stock price.
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