MSCLF: AAK1 Disclosed as Drug Target for DMD Program…
OTC:MSCLF
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Business Update
AAK1 Disclosed as Drug Target for DMD Program
On November 14, 2023, Satellos Biosciences Inc. (OTC:MSCLF) announced that AAK1 is the drug target for the company’s Duchenne muscular dystrophy (DMD) program, that SAT-3247 has been nominated as the lead drug candidate, and that IND-enabling studies and GMP manufacturing are ongoing. Preclinical results showed that SAT-3247 matched the results of SAT-3153 (the former lead development candidate) in terms of affecting muscle stem cell polarity, enhancing muscle regeneration, and improving muscle force in a mouse model of DMD. However, SAT-3247 also showed improved oral bioavailability, target specificity, and tissue distribution when compared to SAT-3153.
Adapter Associated Kinase 1 (AAK1) belongs to the Numb-associated kinase (NAK) family of Ser/Thr protein kinases (Sorenson et al., 2008). It is implicated in a number of biological signaling pathways. Satellos is targeting it due to its role in the Notch signaling pathway, which plays an important role in satellite cell division and muscle cell regeneration (Bjornson et al., 2012). In the mdx mouse model, which serves as a mouse model of DMD, satellite cells show defective self-renewal that is associated with attenuated Notch signaling (Jiang et al., 2014). In addition, the Notch signaling pathway has been implicated in the restoration of asymmetric muscle stem cell division.
Previous preclinical results presented by Satellos showed that SAT-3153 increases the percentage of asymmetric cell divisions in vitro, restores asymmetric cell division in vivo, and increases muscle force. We believe similar results were seen for SAT-3247. For a full analysis of the preclinical data the company has presented thus far for targeting AAK1, please see our previous reports (here and here).
Satellos is currently conducting IND-enabling studies and GMP manufacturing of SAT-3247 and we continue to expect an IND filing in mid-2024 with a Phase 1 clinical trial in healthy volunteers initiating shortly thereafter. The Phase 1 safety studies in healthy volunteers should be completed before the end of 2024 at which time the company intends to advance into clinical trials with Duchenne patients.
AAK1 Targeted for Other Indications
AAK1 is currently the target of other developmental therapeutic programs. Lexicon Pharmaceuticals is developing LX9211, an AAK1 inhibitor that penetrates the central nervous system (CNS) and is being developed for the treatment of diabetic peripheral neuropathic pain. The drug has been evaluated in the following studies:
• A Phase 1 randomized, double blind, placebo controlled, single-dose ascending and multiple-dose ascending study of LX9211 in healthy participants found that the drug had a good safety profile with no deaths or serious adverse events reported (Bundrant et al., 2021). The single-ascending dose study evaluated doses of LL9211 of 5 – 300 mg. For the multiple-ascending dose portion of the study, patients were treated with a loading dose on Day 1 and a maintenance dose on Days 2-14. The treatment groups were 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. All treatment-emergent adverse events (TEAEs) were mild, with the exception of moderate nausea and vomiting in one participant in the highest dose group (300 mg) and all TEAEs were considered recovered or resolved except for blurred vision in one participant in the 300 mg cohort that was ongoing at the last visit. The most common TEAEs were headache, dizziness, constipation, and nausea.
• Lexicon also evaluated LX9211 in a Phase 2 randomized, double blind, placebo controlled study for the treatment of diabetic peripheral neuropathy (Busui et al., 2023). A total of 319 adults were enrolled in the trial and randomized to placebo, LX9211 100/10 mg (100 mg Day 1, 10 mg/day thereafter), or LX9211 200/20 mg (200 mg Day 1, 20 mg/day thereafter). The results of the study showed that at Week 6, LX9211 was associated with significant improvement in the Neuropathic Pain Symptom Inventory total score. No treatment-related serious adverse events (SAEs) were reported and the drug did not affect key cardiometabolic parameters (body weight, blood pressure, glucose control, cholesterol levels).
We highlight the above studies for LX9211 as evidence that targeting AAK1 can be done safely, as evidenced by the good tolerability profile and lack of serious adverse events in a large number of trial participants. However, we don’t believe that LX9211 is a compound that could be repurposed as a therapy for DMD, based upon the fact that the drug was optimized to penetrate the CNS for purposes of treating neuropathic pain. Satellos has optimized its compounds to penetrate muscle and limit its exposure to the CNS, thus optimizing it for treating degenerative muscle disorders.
Leadership Team Expansion
In the past few months, Satellos has made multiple additions to the company’s leadership team, including:
• Michael Cross, PhD, MBA has been appointed Chief Business Officer. Dr. Cross has more than 25 years of biotech and life science experience, particularly in the areas of financing and licensing transactions, leadership in operations, clinical product development, and corporate strategy.
• Elizabeth Williams, CPA CA has been appointed Chief Financial Officer (CFO) and William Whitehead, CPA, CMA, who served as CFO for two years, has moved to Head of Corporate Strategy. Ms. Williams has nearly 20 years of experience in biotech, working with publicly traded companies in both Canada and the U.S.
• Ms. Courtney Wells has been appointed Senior Vice President of Clinical Development Operations. Ms. Wells has more than 20 years of experience in clinical development for large pharmaceutical companies and biotech companies, including in orphan diseases and DMD.
Financial Update
On November 22, 2023, Satellos announced financial results for the third quarter of 2023. Net loss for the third quarter of 2023 was CAD$3.6 million compared to a net loss of CAD$1.9 million for the third quarter of 2022. The increase in net loss was primarily due to increased spending on R&D spending and increased personnel, recruitment, travel, and professional fees. R&D expenses for the third quarter of 2023 were $2.7 million compared to $0.9 million for the third quarter of 2022. The increase was due to increased pre-IND-enabling expenses, salaries, management fees, and stock-based compensation. G&A expenses for the third quarter of 2023 were CAD$1.8 million compared to CAD$0.9 million for the third quarter of 2022. The increase was primarily due to increased salaries, management fees, and stock-based compensation.
As of September 30, 2023, Satellos had approximately CAD$44.3 million in cash and cash equivalents. This was due in part to the equity offering in May 2023 that raised gross proceeds of $55 million. As of November 21, 2023, Satellos had approximately 112.8 million shares outstanding and, when factoring in stock options and warrants, a fully diluted share count of approximately 178.4 million.
Conclusion
Now that Satellos has selected the lead compound to move into IND-enabling studies, we anticipate incremental updates as the company moves closer to an IND filing and a Phase 1 study in mid-2024. Knowing that the target for the DMD program is AAK1, a protein that is currently being targeted by Lexicon Pharmaceuticals for the treatment of diabetic peripheral neuropathic pain, helps to de-risk Satellos’ DMD program as Lexicon has shown AAK1 can be safely targeted without the emergence of serious adverse events. Given the different distribution profiles for LX9211 vs. SAT-3247 (CNS penetrant compared to muscle penetrant) we see no overlap between the two compounds and little to no competitive risk. With no changes to our model our valuation remains at $0.70.
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