Dianthus Therapeutics, Inc. (NASDAQ:DNTH) is advancing its potential best-in-class complement inhibitor drug DNTH103 for a wide variety of autoimmune disorders. In particular, it is looking at advancing the targeting of the classical C1s component observed in these disorders. However, doing so with the advantage of selectivity, which could ultimately yield several competitive advantages compared to other complement inhibitors approved or in clinical development. The lead program from the company is the evaluation of DNTH103 for the treatment of patients with Generalized Myasthenia Gravis [gMG] in the ongoing phase 2 MaGic trial.
This trial is expected to have a topline data readout in the 2nd half of 2025, where it will be fully shown whether this drug can help these patients. What is encouraging is that data released from a phase 1 healthy volunteer study, using this drug to treat gMG patients, showed that active complement inhibition was possible in a dose-dependent manner. Along with the fact that its YTE half-life technology incorporated into it was proven to extend drug activity for an extended period of time. The whole thing about this biotech is that DNTH103 has the potential to become a best-in-class C1 complement inhibitor in a few other disorders like multifocal motor neuropathy [MMN] and chronic inflammatory demyelinating polyneuropathy [CIDP].
Regarding the MMN program, it is already underway and topline data from the ongoing phase 2 study is expected in the 2nd half of 2026. A closer near-term catalyst to consider would be the initiation of a phase 2 study using DNTH103 for the treatment of patients with CIDP, which is expected in the 2nd half of 2024. The promise with this biotech is to effectively target autoimmune disorders upstream, foregoing the problems of complement inhibitors that target downstream instead leading to bacterial pathogens and other safety problems seen in the lectin and active pathways.
DNTH103 For The Treatment Of Patients With Generalized Myasthenia Gravis
The first and most advanced program in Dianthus Therapeutics’ pipeline would be the development of its lead candidate DNTH103. This particular long-acting monoclonal antibody is being explored in the ongoing phase 2 MaGic trial. Before going over this mid-stage study, plus any catalysts to come out of this program, it is first important to go over what myasthenia gravis is and what the possible market opportunity might be for it.
Myasthenia Gravis [MG] is a type of chronic autoimmune disorder where the communication or function between the nerves and muscles are affected. What happens is that the receptors of the muscles are impacted because of it, which in turn blocks a chemical that is needed to generate voluntary muscle movement. The chemical being acetylcholine, which is responsible for muscle contraction. Some symptoms of patients with this autoimmune disorder are as follows:
- Visual problems.
- Muscle function issues.
- Fatigue.
- Trouble swallowing.
- Weakness of the limbs.
The global myasthenia gravis treatment market size is estimated to reach $2.2 billion by 2028. This is a pretty large market opportunity, even if you only consider the fact that it is targeting the generalized population. What does this term “generalized” refer to? Well, there are two common types of these patients with gMG, which are:
- Generalized — affecting most muscles limbs.
- Ocular — impacting eye movement.
Even if only targeting the generalized market segment, it is still a solid opportunity for Dianthus. This is because it is said that up to 85% of patients diagnosed with Myasthenia Gravis have generalized myasthenia gravis [gMG].
To see if its C1 selective complement inhibitor is capable of being able to treat these patients with gMG, it had initiated its phase 2 MaGic study, which I noted directly above. This particular trial is expected to recruit up to 60 patients with gMG who are to be randomized to receive one of the following doses as follows:
- Low-dose DNTH103 given Q2W [Once every 2 weeks subcutaneously].
- high-dose DNTH103 given Q2W.
- Placebo comparator given Q2W.
The primary endpoint being deployed first and foremost would be the incidence and severity of treatment emergent adverse events [TAEs]. There are several secondary endpoints being deployed as well, such as Quality of life [QoL] improvements and also how well patients improve in terms of daily living. Speaking of which, one efficacy measure typically used for these patients is known as “change from baseline in Myasthenia Gravis Activities of Daily Living or MG-ADL scale score”. This endpoint is to be evaluated from Day 1 to Week 13 to see if DNTH103 can beat out its placebo counterpart regarding this measure over this period of time. It is an 8-item score, where each item is evaluated between “0” to “3”. The total score possible would be 24 points, and this would be bad. Why is that? That’s because the higher the score is, the greater of disease severity that is implicated. Thus, a drug that works should help patients achieve a lower overall score when given the drug compared to placebo. Initial top-line results from the phase 2 MaGic trial, using DNTH103 for the treatment of patients with gMG, are expected in the 2nd half of 2025.
It remains to be seen whether the top-line data to be released by then is ideal, but there was some data released from a phase 1 healthy volunteer study. The promise of this data is that the C1 complement inhibitor was able to show a dose-dependent response in these healthy volunteer patients. Such an outcome was assessed using two assays known as CH50 inhibition and Wieslab. Further confirmation between DNTH103 and placebo will be evaluated. However, this was a good outcome for the presence of competitive advantages being established over existing C5 inhibitors approved to treat patients with Myasthenia Gravis [MG] and other autoimmune disorders affected by complement pathway. How so? Well, this C1 inhibition was achieved with patients only needing to receive one dose of DNTH103 once every 2 weeks [Q2W].
This is important because it would offer a more convenient dosing option for patients. Especially, when you consider that this might end up being the first of its kind self-administered subcutaneous option for these patients that can be given Q2W. This is possible thanks to the YTE half-life extension technology incorporated into the drug, which gives it this capability. Another item that helps it to have a prolonged effect, with little drug being necessary, would be the ability to bind to active C1s and not inactive C1s. Speaking of which, C1s inhibition leaves the lectin and alternative pathways alone.
The significance of this is complement inhibition similar to that of C5 complement inhibitors approved or in clinical development, but at the same time not having an increased serious risk of bacterial disorders. This is another competitive advantage that may come to light after the phase 2 study is completed.
Consider that one drug from AstraZeneca PLC (AZN) known as Ultomiris [ravulizumab-cwvz] had been approved to treat adults with gMG who are acetylcholine receptor [ACHR] antibody positive. The point I’m making here is that this and other C5 inhibitors, with downstream lectin/active pathway inhibition, leads to FDA boxed label warnings of risk for serious bacterial infections. Other drugs that target the lectin pathway area are Soliris and Zylbrisq [Zilucoplan] from UCB. Zylbrisq is the first C5 inhibitor of its kind to be given as a self-administered treatment option for patients with MG. The problem is that this drug still has the issue of having an increased risk of serious bacterial infection. Plus, it has to be taken every day subcutaneously. On the other hand, DNTH103 avoids targeting the lectin [C5 inhibition seen here] and alternative pathways [c3a, c35a and other pathways seen here].
Having said that, a competitive advantage would be patients not having any risk of serious infections when receiving treatment. This would avoid a boxed label warning from the FDA as well. Not only that, but patients could self-administer it once every 2 weeks instead of needing daily injections.
Financials
According to the 10-Q SEC Filing, Dianthus Therapeutics had cash, cash equivalents and short-term investments of $377 million as of March 31st of 2024. The reason for the cash on hand is because of a PIPE financing transaction that was completed back in January 2024. This was where it was able to generate net proceeds of about $230 million from it before deducting fees and expenses.
The thing is that this biotech has plenty of cash runway to reach several of the milestones anticipated in the pipeline. The expectation is that it has enough cash runway to fund its operations into the 2nd half of 2027. Its cash burn per quarter is $18.7 million.
Risks To Business
There are several risks that investors should be aware of before investing in Dianthus Therapeutics. The first risk to consider would be regarding the development of DNTH103 for the treatment of patients with generalized myasthenia gravis [gMG] in the ongoing phase 2 MaGic trial. Top-line data from this mid-stage study is expected to be released in the latter part of 2025. There is no guarantee that the results will be positive, nor that the drug will be safe/tolerable for these gMG patients to take. Nor, that the drug will do well enough in the efficacy measures of MG-ADL, Quantitative Myasthenia Gravis [QMG] scale score, or others to warrant further development of this drug into late-stage testing.
A second risk to consider would be regarding possible competitors in the complement inhibition autoimmune disorder treatment space. As I noted above, there are several C5 inhibitors that have been approved to treat gMG and other disorder types. The goal for the company is to effectively target the classical C1s pathway to avoid bacterial infections with C5 inhibitors and be able to allow for other competitive advantages like convenient dosing. There is no guarantee that the final trial results will not show any TRAEs or other safety issues. Nor, that the drug will prove to effectively be equivalent or superior to other complement inhibitors. What the biotech does have going for itself though is that there are no biologics approved by the FDA to treat patients with MMN and CIDP. These two neuromuscular autoimmune disorders are huge unmet medical needs.
The third and final risk to consider would be regarding C1s classical pathway inhibition for autoimmune disorders. While a phase 1 healthy volunteer study proved dose-dependent classical pathway inhibition with CH50 inhibition and Wieslab assays, there is no assurance that this will translate into the other autoimmune disorders being targeted effectively. In addition, this pathway inhibition carries both validation and risk at the same time. Why is that? That’s because Sanofi (SNY) is advancing its C1s inhibitor drug riliprubart for the treatment of patients with chronic inflammatory demyelinating polyneuropathy [CIDP]. It posted positive 1-year results from its phase 2 study using this drug to treat this patient population. Not only that, but it is already in the process of running two phase 3 studies for this specific program.
The risk here is that this could potentially become a future competitor in relation to C1s classical pathway inhibition for autoimmune disorders. In addition, there is no assurance that DNTH103 will achieve a superior safety and/or efficacy profile compared to that of riliprubart or other drugs that have a similar mechanism of action.
Conclusion
Dianthus Therapeutics has positioned itself well in the development of its complement inhibitor drug for the treatment of patients with autoimmune disorders. It is taking the approach of targeting the classical C1s pathway which is upstream for these disorders, rather than C5 inhibitors which target downstream instead. Again, where it may fall into competition would be regarding what I described above, which is that Sanofi had made significant progress using its own C1s inhibitor riliprubart for CIDP. However, this is why it will be important to track the data to be released in the 2nd half of 2025 from the phase 2 MaGic study from Dianthus, which is targeting patients with gMG. Such data will prove whether DNTH103 can match or beat future competition in the autoimmune disorder space. Especially, relating to C1s inhibitors being developed by other companies.
Success from this mid-stage study, would mean the ability to target a massive chunk of the global myasthenia gravis treatment market size, which is estimated to reach $2.2 billion by 2028. From there, it may or may not be able to expand towards regulatory approvals for other indications such as CIDP and/or multifocal motor neuropathy [MMN]. With the release of gMG treatment data from a phase 2 study in the 2nd half of 2025, plus the targeting of the C1s classical pathway [active targeting components only & not inactive forms] for autoimmune disorders, I believe that investors could benefit with any potential gains made.
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