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Regulus Therapeutics Inc. (NASDAQ:RGLS) is advancing the use of its drug RGLS8429 for the treatment of patients with autosomal dominant polycystic kidney disease [ADPKD] in an ongoing phase 1b study. It recently reported positive results from cohort 2 of this study using this drug to treat this patient population.
Why I believe that investors might benefit from looking into this name because it is gearing up to report results from cohort 3 of this phase 1b study in mid-2024. This data is going to include patients in cohort 3 who are taking 3 mg/kg of RGLS8429. Not only that, but it has already made plans to increase enrollment in cohort 4 with additional patients and explore a fixed dose that might do better to help these patients with ADPKD.
This biotech had a major hiccup in the past in advancing a drug targeting this genetic kidney disorder, but has been able to learn from it. It has gone on to develop RGLS8429 as a next-generation oligonucleotide to treat this specific patient population. It remains to be seen what happens with the upcoming cohorts, but thus far it has been able to make progress. Lastly, should things pan out in being able to use this drug to treat this specific patient population, it may have a chance for Accelerated Approval. This is because it met with the FDA, and it was noted that a single phase 2 study would be sufficient for it to file for Accelerated Approval of RGLS8429. With continued success in advancing an ADPKD drug in clinical testing, plus a mid-2024 catalyst rapidly approaching, I believe that this might be a good biotech to look into.
Coming Back From A Setback Is Not An Easy Task
As I noted above, Regulus Therapeutics is currently exploring the use of RGLS8429 as a next-generation oligonucleotide for the treatment of patients with autosomal polycystic kidney disease [ADPKD]. It is being explored in the ongoing phase 1b study, deploying several cohorts to see if this drug is ultimately effective in being able to treat patients with this genetic kidney disorder.
A little backstory is that it was developing another oligonucleotide before this one known as RGLS4326 for the treatment of this patient population. This first-generation candidate did okay, but the cause for concern was that it didn’t have a huge impact on PKD1 or PKD2 genes for continued advancement. This would be one reason enough to jump ship to the other next-generation oligonucleotide candidate.
However, there was another situation that ensued as well. The FDA told Regulus that going forward it would have to shift to a lower dose of it. This would have been bad because there would be no room for improvement with continued advancement. Management made a bold move to the new candidate, but looking back at it now, I believe it was the right move. If this setback is the case, then what is different this time around? Well, at the time it decided to shelve the program it stopped at cohort 2 noting off-target central nervous system [CNS] effects, plus the guidance to move to lower dosing. Not only was it able to successfully complete its second cohort for this phase 1b study using RGLS8429 for the treatment of patients with ADPKD, but it was able to add on two additional cohorts going forward [cohort 3 & cohort 4].
Autosomal dominant polycystic kidney disease [ADPKD] is a genetic kidney disorder where mutation of the PKD1 and PKD2 genes causes the organ to develop small fluid-filled sacs [cysts] to form. In addition, these patients also experience an enlargement of their kidneys as well, along with other extrarenal organ involvement. Mutations of both of these genes cause an increase in the oncogene c-MYc, which triggers other mutated genes to ensue. Other genes triggered by this oncogene are:
- PPAR-a.
- PKDKk.
- PPAR-g.
- MTOR.
All of these genetic factors cause the proliferation and formation of these cysts in the kidney. This characteristic, plus the enlargement of the organ that happens, causes it to not work as well as it should. What was RGLS8429 designed to do for these ADPKD patients? It was designed to inhibit mIR-17 in hopes of providing the kidneys with functioning PKD1 and PDK2 genes necessary to reduce cyst formation. The Phase 1b MAD study is a double-blind randomized placebo-controlled trial, which is recruiting these patients with ADPKD.
One quick thing to note is that 85% of patients with this disorder have a mutation of the PKD1 gene and have far more disease severity than its counterpart gene, PKD2. Both of these genes are also responsible for the formation of polycystin proteins, polycystins 1 and 2 [PC1 and PC2]. An increase in these proteins correlates with an improvement in height-adjusted total kidney volume and estimated glomerular filtration rate [eGFR]. This is precisely what was observed with the released data from cohort 2, in that the 2 mg/kg dose of RGLS8429 resulted in greater improvements of the PC1 and PC2 proteins compared to that observed with those who were given 1 mg/kg of drug or placebo instead. Matter of fact, 3 of the patients who had the highest increase for both of these proteins had seen the best height-adjusted total kidney volume [>4% improvement].
With all of these positive outcomes on hand, it has decided to increase enrollment of cohort 4 to 30 patients. What can investors expect next from this program? Well, this is where a catalyst opportunity comes into play, in that Regulus will release results from cohort 3 of the phase 1b study using 3 mg/kg of RGLS8429 for the treatment of patients with ADPKD in mid-2024.
The importance of this is that it is quite possible that the implementation of this increased dosing could cause an even greater improvement response in terms of reducing cyst formation and kidney volume [reducing kidney expansion]. It is even taking it one step further by already exploring cohort 4. This particular cohort for this trial is going to deploy a fixed dose of 300 mg of RGLS8429. The hope here is that such high drug exposure will inform this biotech on what to do going forward, plus again look to see if it can greatly reduce cyst formation.
I believe another important consideration about this program, should it continue to achieve success in the clinic, would be the highly productive outcome it had with the FDA in a Type D meeting. Why is that? That’s because it won’t have to go all the way to test a phase 3 study of this drug for the treatment of this ADPKD patient population. The FDA stated that a single phase 2 study, barring a positive outcome, would be enough to file for FDA Accelerated Approval of RGLS8429.
Financials
According to the 10-K SEC Filing, Regulus Therapeutics had cash and cash equivalents of $23.8 million as of December 31st, 2023. This is a low amount of cash on hand, but with all the positive data from the phase 1b study I highlighted above using RGLS8429, it was able to close an oversubscribed $100 million private placement agreement on March 12th, 2024.
With the $23.8 million it had, plus this private placement agreement being done, it has a cash runway into the 1st half of 2026. It has a cash burn of about $8.3 million per quarter.
For all of these factors stated, I believe that Regulus Therapeutics Inc. should be in good shape to reach several milestones over the course of the next few years.
Risks To Business
There are several risks that investors should be aware of before investing in Regulus Therapeutics. The first risk to consider would be regarding the advancement of RGLS8429 in the ongoing phase 1b study treating patients with ADPKD. That’s because it is currently gearing up to report results from cohort 3 of this early-stage study. Despite having a successful outcome reported from cohort 2, there is no assurance that a higher dose of 3 mg/kg of the drug is going to have an increased effect on reducing cyst formation and kidney volume.
A second risk to consider would be the Type D meeting it had with the FDA so that it could discuss a possible Accelerated Approval pathway of RGLS8429 for ADPKD. It was a productive meeting, where it was stated that a single phase 2 study would be enough for it to file for such an FDA Accelerated Approval filing of it.
The problem is that in order for this to happen, it has to be able to show that its drug can beat a placebo in terms of total kidney volume [TKV] as a primary endpoint. If this primary endpoint is not met with statistical significance in favor of RGLS8429, then it will not be able to file an Accelerated Approval for it. Not only that, but there is another major risk to consider relating to this possible marketing approval.
Even if this biotech gets through all the hoops it needs to receive initial marketing approval, it still has to show the FDA that its drug can succeed in phase 3 clinical testing. Thus, a post-marketing requirement would be the completion of a phase 3 study showing that RGLS8429 can achieve statistical significance compared to placebo based on another primary endpoint. This primary endpoint, for this late-stage study, is going to consist of an improvement of the estimated glomerular filtration rate [eGFR]. A decline in eGFR is associated with kidney failure; thus, if it can show that its drug improves this measure, then it will be enough to satisfy the FDA to keep its drug on the market.
The third and final risk to consider would be with the ongoing cohort 4 of the phase 1b study, using RGLS8429 for the treatment of patients with ADPKD. The goal is to see if having one fixed dose of 300 mg of this drug is going to be enough to be able to establish maximum drug exposure to treat these patients. A total of 30 patients were deployed in this study to observe such an effect. There is no assurance that establishing such a fixed dose will be enough to improve the odds of clinical success in moving the RGLS8429 program forward.
Conclusion
Regulus Therapeutics Inc. did have a setback for several years based on its first-generation oligonucleotide RGLS4326 for the treatment of patients with ADPKD. It saw a problem with dosing duration, the need to implement lower dosing going forward, and off-target CNS effects as a result of it being used as a treatment option. Consider that although management did have another candidate already in pre-clinical testing, it decided to gravitate to this next-generation one. Again, a bold move, but it seems to have paid off thus far.
Regulus Therapeutics Inc. has been able to do well in cohort 2 this time around with RGLS8429 in a phase 1b study compared to the prior generation drug which was ultimately shelved. The reason why I believe that there might be value here is because it is expected that it will release updated results from this study in the coming months. Another round of positive data would signify that it may have overcome the problems it had in the past with its first-generation oligonucleotide.
