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.