Identification of a Novel and Efficacious Oral Proteasome Inhibitor As a Potential Clinical Development Candidate

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4808-4808
Author(s):  
Kwang-Ai Won ◽  
Byung Gyu Kim ◽  
Cheol-Kyu Jung ◽  
Eok Park ◽  
Eunbok Baek ◽  
...  
Keyword(s):  
Oral Administration ◽  
Solid Tumor ◽  
Lung Tumor ◽  
Life Sciences ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Clinical Development ◽  
Tumor Xenograft ◽  
Orally Bioavailable ◽  
New Generation

Abstract The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors call for a new generation of drugs. LC53-0110 and its analogues were identified as novel, reversible, selective, potent, and orally bioavailable proteasome inhibitors which have physicochemical profiles that are distinct from bortezomib, carfilzomib or ixazomib. As compared to those inhibitors, LC53-0110 is far more selective for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome, with an IC50 value of less than 10 nM over the trypsin-like site and the caspase-like site. LC53-0110 treatment showed accumulation of ubiquitinated proteins and inhibited cell viability with a low nM range potency in various hematologic and solid tumor cell lines including multiple myeloma (MM), lymphoma, colon tumor, breast tumor, and lung tumor. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM and solid tumor xenograft models. The robust pharmacodynamic responses in tumor translated to the efficacy studies. In the RPMI8226 (MM) efficacy model, oral administration twice a week at 50 mg/kg inhibited tumor growth 68% by three weeks. In the MM.1S (MM) efficacy model, oral administration twice a week at 100 mg/kg completely abolished measurable tumor mass by one week and prevented any tumor re-growth during the three-week study period. In the initial studies, LC53-0110 also showed potent activity on freshly isolated CD138+ cells from MM patients (pts) who are resistant/refractory (r/r) to current FDA-approved drug treatment. Further studies, including comparison of the naïve pts vs. thalidomide r/r pts and bortezomib r/r pts as well as their potential clinical implications will be discussed. Disclosures Won: LG Life Sciences: Employment. Kim:LG Life Sciences: Employment. Jung:LG Life Sciences: Employment. Park:LG Life Sciences: Employment. Baek:LG Life Sciences: Employment. Park:LG Life Sciences: Employment. Kang:LG Life Sciences: Employment. Kim:LG Life Sciences: Employment. Jung:LG Life Sciences: Employment.

Phase 1 Clinical Trial of the Novel Structure Proteasome Inhibitor NPI-0052.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2693-2693 ◽  
Author(s):  
Andrew Spencer ◽  
Michael Millward ◽  
Paul Mainwaring ◽  
Simon Harrison ◽  
Laurence Catley ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Mononuclear Cells ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Pharmacokinetic Data ◽  
Employment Equity ◽  
Cognitive Changes ◽  
Equity Ownership

Abstract Abstract 2693 Poster Board II-669 Background: NPI-0052 is a proteasome inhibitor with a novel bicyclic structure (other proteasome inhibitors in clinical use are peptide based). Preclinical studies indicate rapid, broad and prolonged inhibition of all 3 catalytic sites of the proteasome, and subsequently unique proteasome inhibition, signal transduction, toxicology and efficacy profiles. Taken together these suggest the potential for improvements in therapeutic ratio and activity in hematologic and solid tumor malignancies. Materials and Methods: Patients with solid tumor, lymphoma, leukemia or myeloma diagnoses without standard treatment options have been treated with IV NPI-0052 on one of two arms (weekly or twice weekly) in this 3+3 design dose escalation study. This is followed by 10 patient Recommended Phase 2 dose Cohorts of patients with lymphomas, CLL and myeloma respectively. Proteasome inhibition (pharmacodynamics) and pharmacokinetics are also assayed in whole blood, and proteasome inhibition in peripheral blood mononuclear cells (PBMC). Results: 44 patients have been treated with NPI-0052 at doses ranging from 0.075 mg/m2 to 0.9 mg/m2. Common adverse events include fatigue, parosmia/dysgeusia, transient peri-infusion site pain, lymphopenia, headaches, dizziness / unsteady gait, closed-eye visuals, cognitive changes. Incidence and grade of these events correlate with dose, being quite tolerable at the MTD of 0.7 mg/m2 on the weekly dosing arm. An MTD has not yet been determined for the twice weekly dosing arm. Pharmacokinetic data has demonstrated a rapid elimination half-life (<20 minutes) and relatively large volume of distribution. Assessment of proteasome inhibition has demonstrated increasing inhibition of chymotrypsin-like activity of up to 88% Day 1 and 100% Day 15. Inhibition of caspase-like and trypsin-like activity of up to 52% and 71% respectively has also been seen. Inhibition remains between doses in whole blood (principally RBC), but recovers between doses in PBMC. Clinical benefit, including stable disease, regression or response, was reported in patients with mantle cell lymphoma, myeloma, Hodgkin's lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range, while producing a toxicity profile that is dissimilar to what is reported with other proteasome inhibitors (notably deficient in peripheral neuropathy, neutropenia and thrombocytopenia) in spite of producing equal or greater proteasome inhibition. These data indicate a broad range of potential uses, and led to additional studies in hematologic malignancies and solid tumors alone and in combination. Disclosures: Longenecker: Nereus Pharmaceuticals: Employment. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership. Lloyd:Nereus Pharmaceuticals: Employment, Equity Ownership. Neuteboom:Nereus Pharmaceuticals: Employment, Equity Ownership. Spear:Nereus Pharmaceuticals: Employment, Equity Ownership.

The Novel Proteasome Inhibitors Carfilzomib and Oprozomib Induce Milder Degenerative Effects Compared To Bortezomib When Administered Via Oral Feeding In An In Vivo Drosophila Experimental Model: A Biological Platform To Evaluate Safety/Efficacy Of Proteasome Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1930-1930
Author(s):  
Evangelos Terpos ◽  
Eleni N. Tsakiri ◽  
Efstathios Kastritis ◽  
Tina Bagratuni ◽  
Vassilis G. Gorgoulis ◽  
...  
Keyword(s):  
Oral Administration ◽  
Proteasome Inhibitor ◽  
Germ Line ◽  
Conflicts Of Interest ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Somatic Tissue ◽  
Oral Feeding ◽  
Somatic Tissues

Abstract The proteasome is involved in the degradation of both normal, short-lived ubiquitinated proteins and mutated or damaged proteins. Carfilzomib is a tetrapeptide epoxyketone–based proteasome inhibitor and oprozomib is an orally bioavailable tripeptide epoxyketone-based proteasome inhibitor. The primary target for both agents is the chymotrypsin-like β5 subunit of the constitutive proteasome and immunoproteasome. Oprozomib is 5-fold less potent than carfilzomib, but displays similar cytotoxic potential with longer exposure times due to its time-dependent proteasome inhibition. In contrast, bortezomib is a slowly reversible proteasome inhibitor with potency of proteasome inhibition similar to carfilzomib. We propose the fruit fly Drosophila melanogaster as an in vivo platform for screening and characterizing proteasome inhibitors at the whole organism level. Drosophilais well-suited to this line of investigation, due to its powerful genetics, its similarities in key metabolic and aging pathways with humans, the fact that it expresses proteasomes that structurally resemble those from mammals, and also because it comprises a soma-germ line demarcation composed of both post-mitotic and mitotic cells. Moreover, flies live for few months and thus, drug screening on large cohorts can be completed in a reasonable time. We validate our model by investigating the effects of orally administered carfilzomib and oprozomib vs. bortezomib. In isolated Drosophila proteasome in vitroassays, carfilzomib showed a pattern of inhibitory activity similar to bortezomib, whereas oprozomib was less effective. After continuous oral administration of the inhibitors (∼50 μM of carfilzomib and ∼300-400 μM of oprozomib) to young flies (by adding the inhibitor in the flies’ culture medium) a proteasome inhibitory effect in somatic tissues roughly similar to 1 μM bortezomib was induced. Similar findings were noted when we analyzed distinct somatic tissue parts (i.e., head, thorax and abdomen), indicating that orally administered proteasome inhibitors are equally distributed to different body parts. As in the case of bortezomib, the effects of the inhibitors were less pronounced in the reproductive tissues. At the molecular level, carfilzomib (as compared to bortezomib) induced a milder disruption of fly somatic tissue proteostasis, lower rates of somatic tissue oxidative stress and less intense activation of genomic antioxidant response elements that correlated with reduced intensities of proteasome genes and protein subunit upregulation. Proteasome subunit induction was found to depend on the activity of the transcription factor Nrf2, a master regulator of cellular anti-oxidant responses. Furthermore, carfilzomib promoted the induction of lysosomal enzymes (e.g. cathepsins) and autophagy-related genes but less intensively compared to bortezomib. At concentrations that induced rates of proteasome inhibition that were similar to bortezomib, there were no significant toxic effects of either carfilzomib or oprozomib to oogenesis or to embryogenesis. Compared to bortezomib, both inhibitors exerted a significantly milder impact on the neuromusculatory system (locomotor performance) of the flies. Finally, we found that sustained oral administration of either carfilzomib or oprozomib exerted significantly milder effects (as compared to bortezomib) on flies’ mortality rate, healthspan and overall longevity. Our in vivo data support that carfilzomib is significantly less toxic compared to bortezomib, including neuromusculatory toxicity. Oprozomib was also less toxic but it is worth noting that it showed reduced activity against fly proteasomes. In support, our preliminary analyses indicated that in comparison to bortezomib and carfilzomib, oprozomib was less potent when tested in human osteosarcoma cancer cell lines. The validity of our in vivo pharmacological model is exemplified by the observed similarities with the reported clinical adverse effects, while the ratio of the different doses used to achieve similar rates of proteasome inhibition in Drosophila somatic tissues (i.e. ∼1 μM bortezomib, ∼50 μM carfilzomib) is reminiscent of the doses used in the clinic (i.e. ∼1.3 mg/m2 bortezomib and ∼25-56 mg/m2 carfilzomib). We conclude that fruit flies represent a valid biological platform for evaluating the efficacy and toxicity of proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

Pharmacologic Evaluation of Orally Bioavailable Inhibitors of the 20S Proteasome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3581-3581
Author(s):  
Christopher J. Kirk ◽  
Monette A. Aujay ◽  
Mark Ho ◽  
Jing Jiang ◽  
Guy J. Laidig ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Proteasome Inhibitors ◽  
Systemic Exposure ◽  
Proteasome Inhibition ◽  
Cell Permeability ◽  
Intestinal Cell ◽  
Pharmacokinetic Analysis ◽  
20S Proteasome ◽  
Orally Bioavailable

Abstract Clinical application of proteasome inhibitors in the treatment of hematologic malignancies such as myeloma and lymphoma is restricted in part by the necessity of frequent IV administration and would be improved by oral (PO) administration. Selective inhibitors of the protease subunits of the 20S proteasome can be generated from peptidyl aldehydes, boronates, vinyl sulfones, and epoxyketones. Many of these peptide based proteasome inhibitors are cell permeant and capable of systemic proteasome inhibition upon intravenous (IV) administration to experimental animals such as mice and rats. In the cases of the peptidyl boronate bortezomib (Velcade™) and the epoxyketone PR-171, proteasome inhibition can be achieved in patients with IV administration. However, systemic exposure following PO administration of these inhibitors may be limited by several factors including gastric pH, gastric and intestinal peptidases, efflux pumps, biliary excretion and intestinal and hepatic metabolic activities. We have tested over 80 peptide epoxyketones with potent (IC50 <100 nM) in vitro inhibitory activity against the chymotrypsin-like activity of the 20S proteasome for bioavailability following PO administration in mice. Systemic exposure was monitored by measuring chymotrypsin-like inhibition in a number of tissues and an approximation of the relative bioavailability for selected compounds was measured by comparing the pharmacodynamics of IV and PO administration using a range of doses. These compounds were also tested in vitro for solubility, intestinal cell permeability, intestinal and hepatic metabolism, and sensitivity to the multidrug resistance protein 1 (MDR1) efflux pump in order to determine which properties were associated with oral bioavailability. We have found that oral bioavailability in mice is associated with increased intrinsic solubility and metabolic stability and reduced MDR1 sensitivity. Proteasome inhibition following PO administration is rapid, resulting in maximal proteasome inhibition within 15 minutes. Rapid absorption and clearance of selected compounds was also confirmed in mice and rats by pharmacokinetic analysis. Repeated oral administration was well tolerated at doses that resulted in significant (>80%) proteasome inhibition in most tissues. The anti-tumor efficacy of these orally bioavailable proteasome inhibitors are being assessed in both human tumor xenograft and mouse syngeneic models. The results from these studies will enable further pre-clinical development of potent, orally bioavailable proteasome inhibitors for the treatment of malignant diseases.

Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3582-3582
Author(s):  
A. R. Townsend ◽  
M. Millward ◽  
T. Price ◽  
P. Mainwaring ◽  
A. Spencer ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Hematologic Malignancies ◽  
Volume Of Distribution ◽  
Preclinical Research ◽  
Eyes Closed ◽  
Advanced Malignancies

3582 Background: The novel structure (non-peptide based) of NPI-0052 (NPI) appears to lead to unique proteasome inhibition (PI), toxicology and signal transduction profiles. Preclinical research suggests improvements in therapeutic ratio and activity in hematologic and solid tumor models, leading to clinical trials in patients with myeloma, lymphomas, leukemias, and solid tumors. Methods: Patients with solid tumor, lymphoma or leukemia diagnoses without standard treatment options were treated with IV NPI on Days 1, 8 and 15 of 28-day cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). Enrollment then began in 10 patient lymphoma and CLL RP2D cohorts. PI (D1 and D15) and PK (D1 and D15) were assayed. Results: 30 patients were treated at doses ranging from 0.1 mg/m2 to 0.9 mg/m2. 0.7 mg/m2 was selected as the RP2D secondary to DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait at 0.9 mg/m2. At the RP2D fatigue, parosmia/dysgeusia, transient peri-infusion site pain and lymphopenia were commonly ascribed to NPI. At the RP2D PK data showed: half-life = 31 ± 28 min; AUCtotal = 270 ± 219 ng/mL*min; Cmax = 33.4 ± 34.2 ng/mL; clearance = 7.17 ± 0.40 L/min; volume of distribution (Vz) = 223.3 ± 229.7 L. PI was assayed in blood, indicating a dose:response relationship with mean inhibition of chymotrypsin-like activity up to of 88% Day 1 and 100% Day 15, and inhibition of caspase-like and trypsin-like activity of up to 51% and 72%. PI remained between doses in whole blood (RBC), but recovered between doses in PBMC. Stable disease was induced in 31% of patients, including one each with mantle cell, Hodgkin's lymphoma, follicular lymphoma, sarcoma, prostate carcinoma, and two with melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range to an MTD, while producing a toxicity profile that is tolerable and dissimilar to bortezomib in spite of reaching higher PI levels. These data indicate potential for a greater range of uses than other proteasome inhibitors and lead to additional studies being initiated in hematologic malignancies and solid tumors alone and in combination. [Table: see text]

Preclinical Pharmacology and in Vitro Characterization of PR-047, An Oral Inhibitor of the 20S Proteasome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3671-3671
Author(s):  
Tony Muchamuel ◽  
Monette Aujay ◽  
Mark K Bennett ◽  
Maya Dajee ◽  
Susan Demo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oral Administration ◽  
Tumor Cell ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Preclinical Pharmacology ◽  
Orally Bioavailable ◽  
Anti Tumor Activity ◽  
Dose Dependent

Abstract The clinical utility of proteasome inhibitors as treatment for multiple myeloma and non-Hodgkin’s lymphoma (NHL) has been validated with two parenterally administered agents: bortezomib, a dipeptide boronate that was approved by the FDA in 2003; and carfilzomib, a tetrapeptide epoxyketone that has shown promising activity in Phase 1 clinical trials. The clinical development of an orally bioavailable proteasome inhibitor would offer improvement in both dosing flexibility and patience convenience over intravenous (IV) administration. Furthermore, oral administration will allow a practical approach to investigating the affect of prolonged proteasome inhibition by repeated daily dosing in patients with advanced malignancies. Here we describe the preclinical pharmacology of PR-047, a tripeptide epoxyketone that was selected through a medicinal chemistry effort designed to find a selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome that combined the efficacy and safety of carfilzomib with the patient convenience of oral dosing. In vitro, PR-047 demonstrated potency against the proteasome CT-L activity comparable to that of carfilzomib and induced tumor cell death across multiple tumor cell types with IC50s <100 nM. In rodents and dogs, oral administration of PR-047 resulted in a prolonged dose-dependent inhibition of the proteasome in all tissues examined with the exception of brain. Proteasome inhibition following PO administration was rapid, resulting in maximal proteasome inhibition within 15 minutes. Plasma pharmacokinetics studies, also assessed in rodents and dogs, confirmed the rapid systemic exposure following oral administration. Absolute bioavailability, as measured by plasma levels of PR-047, was dose dependent and was >20% across all species tested. Doses of PR-047 that resulted in significant (>80%) proteasome inhibition in most tissues were 4–10 fold below the maximum tolerated dose (MTD) and were well tolerated when administered for five consecutive days. These data suggest that repeat daily dosing of PR-047 may be feasible. Single or repeated administrations of PR-047 did not affect kidney or liver function as measured by clinical chemistry. When assessed for anti-tumor activity, PR-047 induced consistent anti-tumor responses in human tumor xenograft models including multiple myeloma (MM1.S), NHL (RL) and solid tumors (HT-29, A549). The anti-tumor activity of PR-047 was equivalent or better than that of carfilzomib and was observed at well tolerated doses. Furthermore, TUNEL staining of tumor sections confirmed that the anti-tumor response was mediated in part by tumor cell apoptosis. PR-047 represents a promising orally bioavailable proteasome inhibitor with a favorable toxicologic profile. The results from these studies have facilitated further development of PR-047 in the treatment of malignant diseases.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

Enhanced antitumor activity of irofulven in combination with irinotecan in pediatric solid tumor xenograft models

2004 ◽  
Vol 55 (5) ◽  
pp. 411-419 ◽  
Author(s):  
Michael H. Woo ◽  
Jennifer K. Peterson ◽  
Catherine Billups ◽  
Hua Liang ◽  
Mary-Ann Bjornsti ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumor ◽  
Tumor Xenograft ◽  
Pediatric Solid Tumor ◽  
Xenograft Models

Discovery of SB-705498: A potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development

2006 ◽  
Vol 16 (12) ◽  
pp. 3287-3291 ◽  
Author(s):  
Harshad K. Rami ◽  
Mervyn Thompson ◽  
Geoffrey Stemp ◽  
Steve Fell ◽  
Jeffrey C. Jerman ◽  
...  
Keyword(s):  
Clinical Development ◽  
Orally Bioavailable ◽  
Trpv1 Antagonist

scholarly journals PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 434
Author(s):  
Nikolay Kuzmich ◽  
Elena Andresyuk ◽  
Yuri Porozov ◽  
Vadim Tarasov ◽  
Mikhail Samsonov ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Side Effects ◽  
Mechanisms Of Action ◽  
Lipid Lowering ◽  
Low Molecular Weight ◽  
Pcsk9 Inhibitors ◽  
Ldl Receptors ◽  
Orally Bioavailable ◽  
New Generation ◽  
Membrane Cell

PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.

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