Nemes Laszlo/iStock via Getty Images
Nemes Laszlo/iStock via Getty Images
REGENXBIO Inc. (NASDAQ:RGNX) has made remarkable progress in being able to advance its pipeline with various types of gene therapies. The last time I wrote about this article it was in a Seeking Alpha article entitled "Regenxbio: Biotech To Watch With 2 Possible Accelerated Approval Pathways". Since then, I'm happy to report that it was able to achieve two important milestones. The first of which is that it reported 3-month data from the phase 1/2 study using RGX-202 for the treatment of patients with Duchenne Muscular Dystrophy [DMD]. That is, the higher dose level 2 of this treatment was able to help patients achieve robust microdystrophin expression. In addition, there was the release of the primary endpoint being met in the ongoing phase 1/2/3 CAMPSITE study, using RGX-121 to treat patients with MPS II. It was noted that the primary endpoint in reduction of CSF biomarker of MPS II disease was met with statistical significance. Such statistical significance was achieved with a p-value of 0.00016. Both of these reasons have led me to increase the rating from buy to strong buy. That is because the odds of reaching the finish line, with respect to regulatory approvals, have increased significantly. The whole basis for the company being able to achieve such results is because of its NAV Technology Platform, which is building upon next-generation AAV vectors to enhance efficacy, compared to prior generation types. The thing is that dose escalation presses on and leads to one minor catalyst, which is a pivotal dose determination assessment in mid-2024.
If that isn't enough, it is also expected to report additional functional data and initiate a pivotal study for RGX-202 in the 2nd half of 2024. Lastly, there is a chance for an Accelerated Approval pathway with the FDA as well, because it could be feasible that microdystrophin expression could be used as a surrogate biomarker to support a Biologics Licensing Application [BLA] filing as well. The point here with this biotech is that its technology has not only established proof-of-concept for its next-generation NAV Technology platform with RGX-202, but it has also done so with RGX-121 for the treatment of patients with MPS II and ABBV-RGX-314 for the treatment of patients with wet age-related macular degeneration [Wet-AMD]. Speaking of RGX-121 for MPS II, it is believed that it is on track to file a BLA filing for this program in 2024. This sets up another major catalyst for investors to keep an eye on.
As noted above, RGX-202 is being advanced in the phase 1/2 AFFINITY study for the treatment of patients with Duchenne Muscular Dystrophy. The ongoing trial is recruiting children ages 4 to 11 with this disorder. The thing is that in order to advance this program, REGENXBIO has deployed the AAV8 vector as part of its NAV Technology platform. In essence, what is known as the NAV AAV8 vector. Why this specific vector? Well, that's because this vector has been specifically designed to be able to deliver transgenes to skeletal and heart muscles. It is already being deployed in other trials and has a well-established muscle-specific promoter [Spc5-12]. The most notable about this vector, which I believe might set itself apart from other gene therapy vectors, would be that it is incorporated as part of RGX-202 to deliver functional elements of the C-terminal [CT] domain found in naturally occurring dystrophin. Whether this specific function results in the ability to improve upon efficacy over other gene therapies remains to be seen in clinical testing, but an important item to watch for sure. Thus far it has been shown in one patient who was given dose level 2 of RGX-202, which was a single infusion of 2x10^14 GC/kg body weight.
Duchenne Muscular Dystrophy [DMD] is a disorder characterized as an inherited disorder of muscle weakness, which is primarily seen in boys. The Duchenne Muscular Dystrophy Treatment Market size is estimated to reach $4.32 billion by 2029. How can a one-time gene therapy infusion like RGX-202 help this patient population? Well, that's because DMD is caused by a mutation of the dystrophin gene. In turn, this causes muscles to become weak due to the loss of fiber connections. What RGX-202 might be able to do is to deliver microdystrophin with function C-terminal domain. The hope is that this reverses the course of muscle fiber loss and allows patients to produce proper dystrophin to avoid disease. REGENXBIO believes that its next-generation NAV AAV8 vector can achieve greater efficacy over prior-generation gene therapy vectors. It is on the right track so far, where one 12-year old patient who took dose level 2 of RGX-202 had robust microdystrophin expression with 75.7% of control. Patients in the prior dose of this gene therapy, dose level 1 [1×10^14 GC/kg body weight] also did well in terms of % control of microdystrophin, with each patient achieving the following:
Even though early in nature, dose level 2 data is encouraging. Not only that, but there is another factor at play to consider here and that is this the positive interim data obtained thus far was with only two dose levels. This program is not just going to end with only these two doses. What makes me say that? For starters, it's all about the safety data that was released with a cut-off date of February 28th, 2024. The bottom line is that the 5 DMD patients who were given both dose levels of RGX-202 had no drug-related serious adverse events [SAEs]. Thus, if REGENXBIO wants to escalate to higher dosing, then it may do so. The second reason is because of what is yet to come. A pivotal dose determination for this DMD treatment program is expected to happen in mid-2024. Investors won't have to wait long to see if this company can improve upon efficacy for this patient population either because it is expected that functional and strength data is going to be released in the 2nd half of 2024. This is also when the company intends to initiate a pivotal study for this RGX-202 program as well. The last item to mention about this gene therapy candidate is on the potential for an Accelerated Approval pathway from the FDA. The plan for this biotech is to use microdystrophin expression as a surrogate endpoint that may support a Biologics License Application [BLA] of RGX-202 for the treatment of this patient population. This is not guaranteed to happen, but as I will describe below in the "Risks To Business" subsection, another competitor developing a gene therapy of their own, has already received an Accelerated Approval pathway from the FDA on the basis of only achieving functional microdystrophin as a surrogate endpoint.
According to the 10-K SEC Filing, REGENXBIO had cash, cash equivalents and marketable securities of $314 million as of December 31st, 2023. It believed that it would have enough cash on hand to fund its operations into the 2nd half of 2025. However, this projection of cash on hand, didn't include what it could possibly obtain through its AbbVie Inc. (ABBV) collaboration agreement. Despite this projection of cash, it still decided that it needed to raise funds. Thus, it enacted an upsized public offering of common stock and pre-funded warrants. That is, an offering to sell 4.56 million shares of its common stock at a price of $23 per share and 1.52 million pre-funded warrants at a price of $22.9999 per warrant. Total gross proceeds from this offering, before deducting expenses, are expected to be approximately $140 million. This offering is expected to close on March 11th, 2024 and this would be a significant amount of cash moving forward.
The first risk to consider would be with respect to competitors in the DMD space, with the primary one being Sarepta Therapeutics, Inc. (SRPT). That's because it was able to receive Accelerated Approval of Elevidys for the treatment of patients with ambulatory DMD between the ages of 4 to 5 with a confirmed mutation of the DMD gene. This company is attempting to expand the label of its gene therapy for all ambulatory patients with a confirmed mutation of the DMD gene. Not only that, but to move from an Accelerated Approval to Full Approval of Elevidys. The FDA has granted a Priority Review assessment of this drug for the treatment of this patient population with a review goal date of June 21st, 2024. There is no plan at the moment for an advisory committee with respect to this review. Should the FDA grant both of these items, then Sarepta would entrench itself further as the leader to beat in the DMD treatment space. Especially, since Elevidys is a gene therapy treatment option being offered to these patients.
The second risk to consider would be in terms of the advancement of RGX-202 for the treatment of patients with DMD. Even though dose level 2 was shown to improve microdystrophin in one 12-year old patient, there is no assurance that it will also do so in other patients to be recruited into this study. There is no guarantee that functional and strength data to be released in the 2nd half of 2024 will turn out to be positive, not that higher dosing of RGX-202 will result in increased microdystrophin expression. The goal is to use microdystrophin expression as a surrogate biomarker for Accelerated Approval of this gene therapy in DMD. However, there is no way of knowing as of now whether or not the FDA will allow for such a quicker pathway to U.S. marketing approval.
The third risk to consider would be in terms of the advancement of ABBV-RGX-314, which is being advanced with AbbVie for the treatment of patients with Wet-AMD. The use of this gene therapy for the treatment of this patient population is currently being explored in two pivotal phase 3 studies, known as ATMOSPHERE and ASCENT. Should these studies go well, then REGENXBIO intends to file regulatory submissions of ABBV-RGX-314 to the FDA and European Medicines Agency [EMA] in late 2025 and 1st half of 2026 respectively. There is no guarantee that the primary endpoint will be met in either of these pivotal late-stage studies nor that either regulator will give marketing approval for ABBV-RGX-314.
The fourth and final risk to consider would be with respect to the advancement of RGX-121 for the treatment of patients with MPS II. The phase 2/3 CAMPSIITE trial achieved the primary endpoint and thus REGENXBIO is seeking an Accelerated Approval pathway for this program in 2024. Should the FDA approve RGX-121 for this patient population for an Accelerated Approval pathway, then the company would be eligible for a Priority Review Voucher in 2025. Despite the primary endpoint being met in the pivotal CAMPSIITE study, there is no assurance that the FDA will allow for such an Accelerated Approval pathway BLA filing, nor that this gene therapy will ultimately be approved to treat this specific patient population.
I believe that REGENXBIO is well-equipped to move the treatment paradigm forward with respect to developing substantial next-generation AAV capsids for gene therapies. It is going to accomplish this using its NAV Technology platform, which has already been able to establish proof-of-concept across several indications already. I primarily went over the recent positive interim analysis that was achieved with RGX-202 for the treatment of patients with Duchenne Muscular Dystrophy [DMD] in the ongoing phase 1/2 AFFINITY study. However, the company is already in the process of gearing up to possibly file a BLA of RGX-121 for the treatment of patients with MPS II in 2024. In addition, additional filings for ABBV-RGX-314 for the treatment of patients with Wet-AMD in the coming years.
The bottom line is that the NAV Technology platform is a very proven product for advancement. Why is that? This is because it has already been deployed in Zolgensma, which is a treatment for patients with spinal muscular atrophy [SMA]. This gene therapy from Novartis AG (NVS) has allowed it to report Q4 2023 and full-year 2023 global sales of $286 million and $1.21 billion respectively. Novartis, Rocket Pharmaceuticals, Inc. (RCKT), Ultragenyx Pharmaceutical Inc. (RARE), and Eli Lilly and Company (LLY) all have several gene therapy candidates that use the NAV Technology in phase 2 testing for neurodegenerative diseases. Consider that REGENXBIO has many AAV capsids like AAV7, AAV8, AAV9, AAVrh10, and over 100 other novel AAV vectors that use this technology platform. Thus, my belief that this is one biotech that I believe is a long-term buy because of the expansion opportunities generated because of it.
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