Original article by Shay Xie, "Ren Zai Yao Tu", October 17, 2024
Frontotemporal Dementia FTD(GRN) and Epidemiology
Frontotemporal dementia (FTD) is a devastating and rapidly progressive form of dementia that causes a decline in motor function and coordination. It has a rapid impact on patients, often destroying their personality within two years of diagnosis, and is a highly heritable dementia.
Genetic analysis of chromosome 17q21 led to the identification of 70 pathogenic mutations in progranulin (PGRN) that cause FTD. These mutations primarily lead to haploinsufficiency of the protein. Haploinsufficiency of the PGRN gene accounts for 25% of all cases. Patients with heterozygous loss-of-function mutations in the PGRN gene exhibit a reduction in extracellular protein levels exceeding 50% and will invariably develop frontotemporal dementia, making PGRN a causative gene for the disease. Moreover, PGRN mutations have been identified in Alzheimer's disease (AD) patients, while high levels of extracellular PGRN have been shown to be protective in models of ALS, Parkinson's disease, stroke, arthritis, and atherosclerosis.
The frequency of GRN mutations is estimated at up to 11.7% of the total FTD population and accounts for 25% of familial cases. The incidence of FTD-GRN is 3 to 15 cases per 100,000 individuals aged 45-64. There are approximately 17,400 FTD(GRN) patients and around 140,000 carriers at risk in major markets who will go on to develop FTD. With no available disease-modifying treatments, there is a clear and critical unmet need.
In many cases, FTD patients exhibit abnormal motor function and coordination, including Parkinsonian syndromes and motor neuron diseases. Symptoms typically emerge before age 60, with a life expectancy typically associated with 7-10 years after symptom onset.
Currently, no FDA-approved therapies are available for FTD. The only available treatments target the behavioral symptoms of the disease.
Key Functions and Pathogenesis of Sortilin
Sortilin (SORT1) is a type I transmembrane protein that functions as a receptor for a variety of ligands, playing important roles in multiple organs including the central nervous system, eyes, cardiovascular system, and is also associated with dyslipidemia and cancer.
Main Functions of Sortilin:
Acts as a receptor involved in signaling pathways.
Mediates the selective sorting of cargo between the cell surface, the trans-Golgi network, and the endocytic pathway.
Role of Sortilin in Diseases:
Interaction with PGRN: Sortilin is the major clearance receptor for PGRN, negatively regulating its concentration in plasma and brain by endocytosis and degradation. PGRN is a protein involved in various cellular functions, including safeguarding lysosomal function, anti-inflammatory responses, and neurotrophic stimulation. Sortilin has been identified as the most important clearance receptor for PGRN. Therefore, sortilin negatively regulates extracellular levels of PGRN in the periphery and brain. In fact, a lack of or blockade of this receptor increases plasma PGRN levels in mice and humans.
Relationship with Frontotemporal Dementia (FTD): PGRN does not require Sortilin to exert its function. Therefore, neurons lacking sortilin expression exhibit an equivalent response to PGRN-induced neuronal growth. Furthermore, in cells lacking sortilin, PGRN is successfully delivered to neuronal lysosomes, indicating the presence of alternative transport pathways. Blocking Sortilin can prevent PGRN clearance, leading to increased PGRN levels and potentially improving FTD symptoms.
Clinical Progress of FTD(GRN) Drugs
Currently, the most advanced therapies for FTD(GRN) include gene therapies directly targeting PGRN and monoclonal antibodies that inhibit SORT1.
Latozinemab, a SORT1 monoclonal antibody developed by GSK/Alector, is currently the most advanced drug. In 2022, Phase II results revealed that latozinemab restored PGRN levels in patient plasma and cerebrospinal fluid to those of age-matched healthy volunteers. Preliminary assessment data also indicated that latozinemab might slow disease progression compared to historical controls. This result has achieved clinical proof of concept, providing sufficient confidence in developing SORT1-targeting drugs. The drug was granted Breakthrough Therapy Designation by the FDA on February 8th of this year and is currently in Phase III registration trials.
Prevail Therapeutics (Eli Lilly)'s AAV gene therapy PR006 also reported interim results from its Phase 1/2 trial in Nature Medicine this year. By infusing patients with an AAV9 viral vector carrying the GRN gene, successful expression of the GRN gene in neurons was achieved. At the 6-month follow-up, 89% of patients showed CSF progranulin levels at or above the normal range, and this proportion reached 75% at 12 months.
VES001, Vesper Bio's small-molecule SORT1 inhibitor, recently published positive results from its Phase I clinical trial. The study demonstrated excellent safety, tolerability, and effective target binding, leading to increased PGRN levels in both plasma and the central nervous system. VES001 is designed to cross the blood-brain barrier and has shown promising results in normalizing PGRN levels, potentially altering the disease course. Vesper Bio plans to initiate a Phase IIa proof-of-concept study for VES001 in the fourth quarter of 2024.
Of course, Vesper Bio has also emphasized the significant advantages of VES001 as a small-molecule drug compared to Sortilin monoclonal antibodies, which need not be elaborated further.
Competition Landscape for Small-Molecule Sortilin Inhibitors
While VES001 currently leads the pack, it is not the first small-molecule Sortilin inhibitor.
Lundbeck, a leader in the CNS field, was one of the first companies to develop Sortilin monoclonal antibodies/small molecules. In 2014, they published a research article (Bioorg Med Chem Lett. 2014 Jan 1;24(1):177-80.) and filed a patent (WO2014114779A1), reporting Sortilin inhibitors based on the optimization of AF40431 (Crystallographica Section D: Biological Crystallography, 70(2), 451-460.), the first reported Sortilin inhibitor. These inhibitors, exemplified by AF38469, exhibited good activity, high selectivity, and high oral bioavailability.
The remaining patents focus on three companies: Insusense ApS, Vesper Bio, and Sortina pharma.
Insusense and Vesper
Both Insusense and Vesper were incubated by Lundbeck Foundation, the foundation behind Lundbeck, leading to significant patent overlap, hence a combined analysis. It is worth noting that both companies share the same inventors across these series of patents, essentially a handoff from one to the other.
Insusense is actually a company focused on type II diabetes and obesity. Therefore, their initial research on Sortilin inhibitors centered on treating or preventing diabetes/diabetic retinopathy, etc., but without significant progress. Perhaps compared to VEGF-A monoclonal antibodies, Sortilin-targeting drugs are not the optimal solution? Hence, we will only discuss compound modification and FTD-related data below.
WO2021186054A1
This patent is a medicinal use patent for WO2014114779A1 for treating diabetic retinopathy. Ex.8 is AF38469, with PPI inhibitory activity against Sortilin and its ligand Neurotensin (NTS) of 330 nM, and other compounds, Ex.29 and Ex.30, have better activity than Ex.8.
WO2022074119A1
This patent is a medicinal use patent for WO2014114779A1 in treating or preventing hearing loss. However, unlike the previous patent, this patent also discloses a new molecular scaffold series of compounds. The preferred embodiments are shown below. However, the evaluation system for these compounds is the HTRF assay for PGRN/SORT1. Comparing Ex.44 with Ex.8 in the NTS inhibition evaluation system, Ex.44 exhibits better inhibitory activity.
WO2022157271A1
Compound patent, clearly further optimization based on WO2021186054A1, Ex.2 showing better activity. The patent also provides a docking model of Ex.23 with Sortilin, guiding further optimization of the compounds.
WO2022223805A1
The patent is based on further modification of Ex.44 series of compounds in WO2022074119A1, with some improvement in activity. The most optimized compound, Ex.6 (NTS IC50 = 60 nM). The patent also provides a co-crystal structure of Ex.3 with hSortilin.
WO2022238565A2
While retaining the core group, further skeletal extension is made. Preferred compounds show comparable activity compared to previous patents. Preferred embodiment Ex.12 (NTS IC50 = 70 nM), and a co-crystal structure of Ex.12 with Sortilin is provided.
WO2023031440A1
The above five patents did not explicitly specify the clear indication for the Sortilin inhibitor. Unlike them, this patent clearly points out the close relationship between Sortilin and CNS diseases, and emphasizes the potential therapeutic benefits of inhibiting Sortilin for FTD(GRN), laying the foundation for the subsequent development of Sortilin inhibitors for treating FTD(GRN).
The patent retains key functional groups while simplifying the compound structure, but this has also led to a reduction in compound activity. The patent also explored the influence of compound free acid and different salt forms, proving that alkyl methanesulfonate (MsOH) may be the optimal salt form.
From the perspective of layout timeline, this patent from Insusense was likely inspired by the preliminary clinical results of latozinemab. The patent also evaluated the brain permeability of Ex.5, Ex.6, and the control compound AF38469.
In contrast, AF38469 did not show BBB penetration, while Ex.5/6 exhibited good BBB permeability, which is the foundation for a CNS drug.
WO2023161505A1
Compared to the previous patent, the main change in this patent is the introduction of a urea group. However, there is no significant improvement in activity. The patent also provides co-crystal structures of Ex.1/2 with Sortilin.
WO2024047227A1
This patent is based on modification of WO2023031440A1, resulting in a new series of compounds with Ex.3 being the most preferred embodiment. While Ex.3 did not show improved inhibitory activity, its optimization lies in its excellent drug-like properties:
Ex.3 exhibited a brain/plasma ratio of 21% in mice, indicating its good brain penetration. Ex.3 achieved a Kpuu of 0.49 in beagle dogs, further demonstrating its excellent BBB permeability. Pharmacokinetic studies have also shown that Ex.3 (MSOH salt) has excellent oral bioavailability.
Of course, the patent also constructed a rat model to investigate the in vivo efficacy of Ex.3, and the results showed that Ex.3 can increase PGRN in the microdialysate of the hippocampus in adult male SD rats and significantly increase PGRN levels in the plasma of adult male SD rats. These results demonstrate the outstanding potential of Ex.3 as an oral formulation to cross the BBB and treat FTD. Ex.3 is likely Vesper Bio's clinical compound VES001.
WO2024089049A1
This patent has limited examples and data, and the affinity activity is generally low.
WO2024184469A1/WO2024184468A1/WO2024184471A1
There is not much to describe about these few patents, but the compound modification also shows the shadow of Ex.3 in WO2024047227A1, further confirming the possibility that Ex.3 is VES001. Therefore, only representative structures are listed for each patent.
Sortina Pharma
Sortina is unique in that they have developed three types of Sortilin inhibitors: SORT1.1 for treating cancer, SORT2.1 for treating neurodegenerative diseases, and SORT3.1 whose target is yet to be announced.
WO2023101595A1
This patent is Sortina's only currently published patent. Unlike Lundbeck's series of patents, this patent is likely the core patent for SORT1.1, focusing on the application of Sortilin inhibitors in cancer. This is not the focus of this article, so we will only briefly discuss compound modification.
The compound design in this patent is also based on Lundbeck's series of patents. However, the biggest difference is that Sortina modified the key functional group in the compound, introducing an alkenyl group into the saturated carbon chain, resulting in a significant increase in the inhibitory activity of the compound. The positive controls RC2, RC3 in the patent are also familiar, namely Ex.44 and Ex.8 in WO2022074119A1. The preferred embodiments SI1 and SI5 show a significant improvement in activity. However, whether this series of compounds still has BBB permeability is questionable.
Merck & Co
Merck published a BMC Lett article in 2020 reporting a Sortilin inhibitor. Although they claim that the compounds are based on structure optimization after internal HTS, oddly, all the compounds in the article come from Insusense's patent WO2022074119A1.
However, the article also provides some valuable information, such as the physicochemical properties of Cpd.11/22/23, indicating their CNS permeability.
The article also provides the co-crystal structure of the C-terminal residues (10-Pro-Tyr-Ile-Leu-13) of NTS with Sortilin, indicating its importance in SORT binding. Of course, this also proves the influence of this key functional group on the activity of the compound.
Afterword
Latozinemab is currently in Phase III registration trials and is expected to complete by October 2027. If this clinical trial succeeds, it will be the first treatment for FTD(GRN), bringing relief to millions of patients suffering from this incurable disease.
Once latozinemab achieves success, it will open up vast clinical prospects for small-molecule Sortilin inhibitors with the same mechanism of action (inhibiting the Sortilin-PGRN PPI). This article simply outlines the development trajectory, highlighting its development value.
Currently, there are few players in this field, and the activity of VES001 seems to have considerable room for improvement. Those interested can consider making relevant layouts.
After all, small molecules are forever king!
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