TGF-𝛃; Transforming Growth Factor-beta, MAPK; Mitogen-Activated Protein Kinase, ACTA2; Alpha Smooth Muscle Actin, COL1A1; Collagen Type I Alpha 1 Chain.
Pamrevlumab
A recombinant antibody called pamrevlumab has the capability to recognize the connective tissue growth factor (CTGF), binds to it, and therefore stops it from cytokines binding, thus avoiding following inflammatory signaling [33]. The CTGF is released by multiple types of cells like fibroblasts, myofibroblasts, and endothelial cells and it’s a glycoprotein . It is thought CTGF has interactions with different regulators, like TGF- β, VEGF, and integrin receptors. This way, CTGF regulates the response of cells to the environment, such as secretions, sorting, production of ECM, motility of cells, and adhesion. These biological processes have been linked to cancer formation and abnormal tissue healing, including fibrosis [34]. PRAISE trial (a phase 2 trial) showed in 2019 that pamrevlumab taken intravenously decreases the decline in FVC successfully by 70% in approximation in patients with IPF in comparison with those receiving placebo[34]. Interestingly, the benefits from the treatment were seen, unlike any other trials, in spite of whether the change in FVC was expressed as an alteration in percentage predicted values, volume change, or in a categorical analysis of free-of-progress survival as the majority component[35]. The impact of treatment was noticeable with equal treatment effects in radiological and symptomatic parameters, which was not found in other studies, yet the results should be treated cautiously until an appropriately powered phase 3 investigation is done [34]. This study’s findings are perhaps on the top of phase 2 trials results, and whether pamrevlumab’s therapeutic advantages might be enhanced with the administration of antifibrotic medications is now under studies[35,36].
Pentraxin-2
The naturally occurring protein called pentraxin-2 has a recombinant form, named recombinant human pentraxin-2 (rhPTX-2; aka PRM-151). This drug is being investigated for its potential to be a probable option in IPF treatment. A phase II trial, which was a double-blind randomized, placebo-controlled PRM-151-202 portion research that tested rhPTX-2 in patients with IPF (NCT02550873), has shown results that are now published [37]. When compared to placebo, rhPTX-2 considerably slowed the decrease in FVC and stabilized 6-min walk distance (6MWD) after receiving the drug, according to the placebo-controlled study of PRM-151-202 [37]. For those patients receiving either PFD or NDB with it, as well as individuals receiving rhPTX-2 monotherapy, efficacy patterns of rhPTX-2 were seen [37]. This Phase II study’s observation of rhPTX-2’s impact on 6MWD was novel because this is the first time a clinical trial for IPF uses a 6MWD to demonstrate the stability of functional status of patients[37, 38].
In the group taking the medication, a decrease in the drop in the mean percent predicted FVC and 6MWD in meters was shown, and this was maintained for up to 52 weeks[37,39]. When patients started taking Pentraxin-2 during the extension phase of the study, the percent of their FVC decline was enhanced from 8.7% a year to 0.9% a year and their 6MWD leveled up from 54.9 meters a year to 3.5 meters a year. However, the long-term consequences of IPF were still consistent with the results, occurring in about 28% of patients [39]. These results will be explored more in a 52 week Phase III research of rhPTX-2 (STARSCAPE), a long term OLDE study will also follow the phase III trial, in order to evaluate the clinical importance. If the results of the Phase III study are consistent with the results of Phase II trial, rhPTX-2 could be very promising as an adjunctive option to current antifibrotic drugs to delay IPF progression as well as an efficient monotherapy option in patients who are unable to tolerate the available choices [39].
BI 1015550
One of the drugs that are now being investigated is the inhibitor of phosphodiesterase 4 group, BI 101550. Phosphodiesterase 4, or PDE4, is described by proteins which play crucial roles in the cells of a human being. Drugs that suppress PDE4 activity have been demonstrated in prior research to reduce inflammation and scarring.[40] Inhibition of PDE4 leads to the inhibition of fibroblast action, further preventing the transformation of fibroblast to myofibroblast. PDE4 group has many functions, inhibiting all of its functions could be problematic as it may cause side effects. This drug primarily works on PDE4B, and it is anticipated by researchers that this will decrease the likelihood of side effects. A phase II double-blinded, randomized study was done and the drug BI 1015550 was examined for having the potential to become an option in managing IPF. The study compared the placebo with BI 1015550 [40]. In total, 147 IPF patients from 22 different countries participated in the trial. The findings demonstrated that BI 1015550 protected IPF patients’ lungs function from deteriorating. With BI 1015550 or placebo, no difference was seen in patients with medical conditions the study physician classified as severe. However, diarrhea affected more persons who received BI 1015550 treatment. Thirteen patients receiving BI 1015550 had to stop their treatment because of health problems; none of the patients receiving a placebo had to stop their treatment because of health problems [40].
Ziritaxestat
Lysophosphatidic acid (LPA) is hypothesized to at least in part mediate the abnormal wound healing responses that lead to fibrosis that is seen with IPF. IPF patients have higher levels of LPA and the enzyme responsible for its formation, autotaxin (ATX), demonstrating their involvement in the etiology of the disease and suggesting possible targets for novel therapeutics [41].
A phase IIa research was done involving 23 IPF patients. Ziritaxestat, which is a small-sized molecule of selective autotaxin inhibitor [42,43], demonstrated promising outcomes [44]. When compared to placebo at week 12, those on ziritaxestat showed a reduced change in FVC. Ziritaxestat here was well tolerated. Ziritaxestat also decreased plasma LPA concentration, showing a maximal decline from baseline of almost 90%, indicating target reach [44]. Phase 3 of two randomized clinical studies, ISABELA 1 and 2, with identical designs, had been done to further assess the effectiveness and safety of ziritaxestat in IPF. In this trial, in patients getting treatment with PFD or NDB or in those not receiving the PFD/NDB treatment, ziritaxestat did not prove to have a better clinical outcome compared to placebo [45]. That’s part of the reason why the ISABELAs failed, which needs to be looked into more. This could be looked into by continuing research on other autotaxin inhibitors, such as BBT-87723, or LPA receptor antagonists, such as BMS-98627824, which have different pharmacological properties from those in ziritaxestat. It should be noted that the LPA receptor antagonist (BMS-986020) was halted because of the resultant hepatobiliary toxicity, but it was later determined that this was unrelated to LPA antagonism [46, 47] in fact, no such safety concerns were detected in the ISABELAs.
PBI-4050
PBI-4050, which is an orally active low molecular weight chemical considered first-in-class, is being tested in trials for the treatment of disorders of fibrosis including IPF. It is the sodium salt of 3-pentylbenzeneacetic acid. It is an artificial form of a medium-chain fatty acid that binds to the G-protein coupled receptors GPR40 and GPR84 with agonist and antagonist affinities, respectively. By regulating fibroblasts/myofibroblasts, macrophages, and epithelial cells, it can reduce or reverse fibrosis [48]. By interacting with GPR40 and GPR84, PBI-4050 stops the progression of fibrosis by regulating a number of anti-fibrotic pathways through this interaction connected to the emergence of IPF [48]. The absence of the expression of alpha-smooth muscle actin in fibroblasts and the concomitant increase of ECM deposition and fibrosis are an evidence that the drug prevents the differentiation of fibroblasts into myofibroblasts. Monocyte chemoattractant protein-1, IL 8 and 6 which have the major role in inflammatory processes in addition to CTGF which has a major role in developing IPF all had been decreased by PBI-4050 [48]. PBI-4050 also dramatically reduces fibrosis in bleomycin-induced lung fibrosis in a murine model as well as models in the heart, liver, lung, kidney, pancreas, and skin [48]. The drug caused a 47% reduction in lung tissue disruption, fibrosis, as well as alveolar wall thickness [48]. According to these findings, PBI-4050 may have clinical benefits for fibrotic disorders like IPF. A phase II single-arm open-label research (NCT02538536) was carried out for 12 weeks at six sites across Canada in people with IPF [49]. The main goal of this study was to assess PBI-4050’s safety and tolerability in this patient population. The findings of this trial demonstrated that there were no safety concerns following 12 weeks of management in patients with primarily mild to moderate IPF, whether used as monotherapy or combined with nintedanib or pirfenidone. PBI-4050’s PK profiles were identical when used alone and in conjunction with nintedanib, but they were altered when combined with pirfenidone, pointing to a potential interaction between drugs. FVC outcomes for PBI-4050 by itself and when combined with nintedanib were promising [49].
Bexotegrast
Or PLN 74809, an oral small molecule had been confirmed in vivo to have antifibrotic by inhibiting dual αvβ6/αvβ1 integrin (important mediators of activation of TGF-β in fibrosis), this results in the partial inhibition of the TGF-β signaling pathway. By this mechanism of action, Bexotegrast can be used for the reduction of systemic side effects and toxicities produced by the full TGF-β signaling pathway inhibition in the treatment of IPF, as well as inhibiting the expression of mRNA collagen [50]. A phase IIa, open, four-part, double-blind, randomized, placebo-controlled study known as INTEGRIS-IPF is now investigating the safety, tolerability, and pharmacokinetics of PLN 74809. Good efficacy, safety, and tolerance were shown by PLN 74809. For all patients receiving PLN-74809, the average decrease in FVC was 15.1 mL in contrast to 74.1 mL for individuals receiving the placebo. With larger doses of the medication, the FVC decline was improving, and in line with the encouraging outcomes seen thus far for larger doses, Pliant has disclosed a trial extension that assesses the effectiveness of 320 mg of PLN-74809 administered daily for six months to persons with IPF. Early in 2023, preliminary trial results ought to be made public [51].
BMS-986020
In a phase II study, the first generation drug, BMS-986020, which is an oral LPA1 antagonist, showed mechanism proof in patients with IPF [52]. In general, BMS-986020 decreased FVC decline during the course of 26 weeks when compared to placebo, with substantial changes occurring after 600 mg twice daily (BID) treatment. BMS-986278 which is the second generation of LPA1 antagonist, is being developed to treat people with IPF. In contrast to BMS-986020, in vitro research demonstrates that BMS-986278 shows no inhibitory effect on the transporters of liver efflux, specifically the multidrug resistance 3 (MDR3) and the bile salt export protein (BSEP). Additionally, in vivo testing and phase 1 studies have not revealed any signs of direct hepatobiliary toxicity.[53,54] This phase II trial’s aim is to assess BMS-986278 in IPF patients or IPF-ILD patients given that the antagonism of LPA1 was proven to be helpful in IPF patients.
TD 139
The expression of galectin (Gal)-3, a key regulator of lung fibrosis, is raised in the lavage fluid and serum of the bronchi and alveoli of IPF patients, and this expression is further elevated during acute phases.[55, 56] In mouse models of pulmonary fibrosis, TD139, a Gal-3 inhibitor with a strong affinity for the carbohydrate recognition domain of Gal-3, has demonstrated effectiveness [55, 56]. The key to TD139’s antifibrotic potential is the inhibition of recruitment and growth of Gal-3-secreting macrophages, which promote local myofibroblast activation, [57, 58]. Preclinical studies have demonstrated that TD139 is effective on all of the major IPF cell types, including fibroblast activation,Gal-3/Macrophage phenotype expression, a reduction in the activity of important profibrotic growth factors on myofibroblasts, and epithelial-mesenchymal transition inhibition[55,56,58]. A phase 1/2a, multicenter, randomized trial conducted in the UK assessed the effectiveness of TD 139. With the exception of TD139 being less preserved in the lungs of patients with IPF, the pharmacokinetic characteristics were basically similar between the healthy and IPF participants. Additionally, TD139 was found to have good tolerance by both healthy people and IPF patients, with the most common side effects being disturbance of taste (36.1%) and cough (11.1%). No significant changes on clinical terms were found in electrocardiographs, nor any hematological, biochemical markers, or clinical findings [59].
Dasatinib (D) and Quercetin (Q)
Animal models have been used to carry out cellular senescence targeted senotherapeutic medications, and they have shown better and functional status [60,61]. Senescent cell anti-apoptotic pathways or SCAPs are inhibited by senolytics, which kill senescent cells in a targeted manner. Dasatinib with quercetin (D & Q), when combined synergistically, were the first medicines regarded as senolytics discovered in 2015 under the direction of Zhu et al [62]. Dasatinib is originally a chemotherapeutic medication for the management of chronic myeloid leukemia that shows resistance to imatinib, another tyrosine kinase inhibitor. It inhibits numerous tyrosine kinases with broad targeting of Src kinases in its action. Quercetin on the other hand, is a non-synthetic and non-specific kinase inhibitor that works on PI3K/AKT pathways, in addition to BCL-2, insulin/IGF-1, and HIF-1 SCAPs components. It also show a senolytic action, presumably as a result of the inhibition of many SCAP genes (like PI3K and other kinases), and it targets a number of SCAPs pathways.[62,63,64] When taken together, D + Q are complementary and result in greater senolysis. They also reduce the burden of senescent cells and human tissue SASP after two days of administration.[62,65] In order to make it easier to organize larger efficacy trials, an affirmative randomized, placebo-controlled study of D+Q in IPF patients was conducted to assess the efficacy and ability to tolerate of D + Q compared to placebo. The prescribed drug dosage schedule (108/108 doses) and the intended assessments (60/60) were completed by all participants. No significant side effects connected to D + Q were addressed, despite the fact that the placebo contained fewer total mild AEs. The majority of AEs with D + Q treatment are typical in patients with IPF or expected D AEs. Anxiety and sleep problems were overrepresented in the D + Q treatment. Before and after intermittent D + Q, fragility, pulmonary function, and physical function were examined; although underpowered to detect differences, these variables do not seem to be significantly different across groups. It is possible and typically well tolerated to provide D + Q intermittently to people with IPF. To establish the safety and effectiveness of D + Q in IPF patients, additional research, like a bigger RCT, is required.