Idiopathic Pulmonary Fibrosis (IPF)


Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD). IPF is characterized by symptoms of chronic cough, exertional dyspnea, “velcro” crackles on lung auscultation, and “finger clubbing” involving swelling of the distal phalanx.1 The clinical course of IPF is variable but prognosis is generally poor with a median survival of 3-4 years after diagnosis.2 Currently, only two drugs have been FDA approved for the treatment of IPF to date, pirfenidone and nintedanib.2 Both are antifibrotic drugs that have been shown to slow the decline in forced vital capacity (FVC) in patients with some evidence that they may reduce the risk of acute exacerbations as well.2 While these drugs have been able to modestly slow the disease course, there is still a need for treatment that can halt or reverse disease progression. Several experimental therapies are still being investigated.

AD-214

AD-214 is an investigational treatment being developed by AdAlta. AD-214 is an i-body, a human antibody engineered with two loops to mimic the antibodies of sharks.3 The loops help the i-bodies interact and bind to their target, the C-X-C chemokine receptor type 4 (CXCR4).4 AD-214 is a redesign of a previous i-body molecule, AD-114, combined with an Fc Fragment which binds to cells expressing Fc receptors in order to extend the half-life of the molecule.4 The i-body portion of the molecule has been shown to bind specifically to IPF tissue and have anti-fibrotic and anti-inflammatory effects in preclinical models.5 AD-214 is currently being investigated in a Phase 1 clinical trial (NCT04415671) in healthy volunteers. The trial was initially going to be divided into three parts with the first part being in healthy volunteers with parts two and three being in ILD patients. The trial was updated to include only healthy volunteers in a single ascending dose portion (SAD) and a multiple ascending dose (MAD) portion, both with placebo comparators. The study is estimated to conclude in July 2022.

BBT-877

Bridge Biotherapeutics is developing an IPF treatment, BBT-877, that targets a novel protein called autotaxin (ATX). ATX is an extracellular enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid which has been suggested to play a role in the progression of IPF.6 BBT-877 has been shown to inhibit ATX in preclinical testing. A Phase 1 clinical trial showed that BBT-877 was well-tolerated and reduced plasma LPA levels.7 Bridge Biotherapeutics had been in a licensing deal with Boehringer Ingelheim to develop BBT-877 but that deal was canceled in November 2020 after potential toxicity concerns.8 The future of BBT-877 is uncertain as to whether Bridge Biotherapeutics will continue development or not.8

BI 1015550

BI 1015550 is an antifibrotic agent being developed by Boehringer Ingelheim.9 The treatment is an oral phosphodiesterase 4 (PDE4) inhibitor9 and has already completed a Phase 1 clinical trial (NCT03422068) in 15 IPF patients who were randomized to receive either BI 1015550 or a placebo for up to 35 days. Results of the study have not been reported but must have been sufficient as BI 1015550 is now being investigated in a Phase 2 clinical trial (NCT04419506). The trial is currently recruiting up to 150 IPF patients to receive the therapy or placebo for 12 weeks and is estimated to conclude in October 2021.

BLD-0409

Another ATX inhibitor in development is BLD-0409 from Blade Therapeutics.10 BLD-0409 has already completed an initial Phase 1 trial (NCT04146805) in 80 healthy volunteers. Blade Therapeutics is now recruiting healthy volunteers for Phase 1b trials to investigate differences between tablet and oral solution forms of the drug (NCT04814472) and drug-drug interactions (NCT04814498). Blade Therapeutics also plans a Phase 1b trial to investigate drug-drug interactions with IPF standard of care therapies as well as a Phase 2 trial in IPF patients.11

BMS-986020, BMS-986234, and BMS-986278

Bristol-Myers Squibb is developing a lysophosphatidic acid receptor 1 (LPA1) antagonist for the treatment of IPF. LPA1 has been implicated in the recruitment of fibroblasts, increased vascular permeability, and dysfunction of endothelial cells in animal models of IPF.12 Bristol-Myers Squibb first tested BMS-986020 in a randomized, double-blind, placebo-controlled phase 2 trial (NCT01766817). The trial showed that BMS-986020 significantly reduced the decline in FVC compared to patients receiving placebo.12 The study was terminated early, however, as three cases of cholecystitis were found in patients receiving BMS-986020.6

Bristol Myers Squibb is now investigating a new LPA1 antagonist, called BMS-986234, which has not shown the same effects on bile homeostasis in animal models that were caused by BMS-986020.13,14 BMS-986234 is still in preclinical testing.

Another LPA1 antagonist, BMS-986278 is also being investigated for pulmonary fibrosis. BMS-986278 has already successfully completed preclinical15 as well as Phase 1 SAD and MAD trials.16 The treatment is now being investigated in a Phase 2 clinical trial (NCT04308681) in up to 360 patients with IPF or progressive fibrotic interstitial lung disease (PF-ILD). The study is estimated to conclude in December 2023.

CC-90001

CC-90001 is a c-Jun N-terminal kinase (JNK) inhibitor that was originally being developed by Celgene (a subsidiary of Bristol-Myers Squibb). CC-90001 has a JNK1 bias, which may play a larger role in fibrosis than JNK2.17 A Phase 1b trial of CC-90001 in 16 pulmonary fibrosis patients (15 of which had IPF) showed a mean increase in FVC of 168 ml after 12 weeks of treatment.18 CC-90001 is now being investigated in a randomized, double-blind, placebo-controlled, Phase 2 clinical trial (NCT03142191) that is recruiting up to 210 with IPF. Patients will be randomized to receive one of two doses of CC-90001 or a placebo for 24 weeks followed by an 80-week active extension. The trial is expected to conclude in February 2024.

C21 (VP01)

C21 (VP01) is an oral, small molecule angiotensin II type 2 receptor (AT2R) agonist being developed by Vicore Pharma for the treatment of IPF, systemic sclerosis, and COVID-19.19 Preclinical trials of C21 showed beneficial effects on fibrosis and pulmonary hypertension.20 Based on the preclinical success, Vicore Pharma is now investigating C21 in an open-label Phase 2 clinical trial (NCT04533022) in up to 30 IPF patients. Patients will receive C21 twice a day for up to 36 weeks while the frequency and nature of adverse events are monitored. The trial is estimated to conclude in December 2022.

Epigallocatechin-3-gallate (EGCG)

Epigallocatechin-3-gallate (EGCG), is a polyphenol contained in green tea that has been investigated as a treatment in IPF patients. EGCG has been shown to be an inhibitor of lysyl oxidase-like 2 (LOXL2) and transforming growth factor-beta (TGF-β) receptors 1 and 2 (TGF-βR1/2) kinase.21 It has also been investigated in a small study of IPF patients and shown that 600 mg oral capsules of EGCG given daily for 14 days reduced several histological and serum biomarkers of fibrosis to normal levels.21 The trial was small and only had 20 patients so further investigation is needed. EGCG is being investigated by researchers at the University of California, San Francisco through an early Phase 1 trial (NCT03928847) in healthy volunteers and IPF patients.

GB0139

An inhaled therapy called GB0139 (formerly TD139) developed by Galecto Biotech is also currently being investigated in clinical trials for IPF patients. The drug is a small molecular inhibitor of galectin-3, a pro-fibrotic β-galactoside-binding lectin believed to play a role in IPF progression.22 GB0139 is being tested in a double-blind, placebo-controlled Phase 2 trial (NCT03832946) of up to 500 IPF patients who will receive the inhaled therapy daily for over 52 weeks. The trial is expected to conclude in December 2022.

INOpulse

Bellerophon Therapeutics is developing a device called the INOpulse for the treatment of pulmonary hypertension (PH) in patients with ILD, including IPF. The INOpulse device delivers inhaled nitric oxide to patients in an effort to dilate the blood vessels in the healthy portions of lung tissue and increase gas exchange. The product showed positive topline results of decreased pulmonary arterial pressure and vascular resistance from their Phase 2 clinical trial (NCT03727451) and improvements in levels of activity in Phase 2 of their REBUILD study (NCT03267108).23 Bellerophon continues to recruit patients for the Phase 3 portion of the REBUILD study where patients with pulmonary fibrosis on supplemental oxygen will be randomized to receive pulsed inhaled nitric oxide or a placebo for 4 months followed by an open-label extension. The trial is expected to conclude in October 2022.  

LTI-103

Lung Therapeutics is developing a new IPF therapy, LTI-103, containing a 7 amino acid portion of the scaffolding domain of caveolin 1 (Cav1).24 Cav1 is believed to be involved in regulating wound healing and the protein is usually absent in many fibrotic diseases.24 Preclinical testing showed that LTI-103 reduced extracellular protein levels and increased epithelial cell survival.24 LTI-103 is being investigated as an inhaled therapy in a Phase 1 trial (NCT04233814) in healthy subjects. The trial is currently suspended pending clinical laboratory analyses, however. The trial was scheduled to conclude in December 2021.

Lung Spheroid Cells

Research is ongoing into the use of lung progenitor and supporting cell lines cultured to form spheroids called lung spheroid cells (LSCs). The research into LSCs is being done by researchers at North Carolina State University and a startup company called BreStem Therapeutics. Preclinical testing showed that the use of LSCs25 or their secretome or exosomes were safe and effective in the treatment of murine fibrosis models.26 Two different models of LSCs are being developed,27 autologous (BRS101) and allogeneic (BRS102), with the autologous LSCs currently being investigated in Phase 1 clinical trial (NCT04262167) in up to 24 IPF patients. During the trial, autologous LSCs will be grown from trans-bronchial pulmonary biopsy specimens for each patient. Patients will be divided into 2 groups with the first 6 being randomized 2:1 to receive intravenous (IV) infusions of either 100 million LSCs or placebo. The second group of 18 patients randomized 2:1 to receive 200 million LSCS or placebo. All patients will be followed for up to 24 months after infusion. The trial is estimated to conclude in October 2024. BreStem is also investigating inhalable LSC factors (BRS201) and exosomes (BRS202).

MN-001

MN-001 (tipelukast) is an antifibrotic and anti-inflammatory, oral small molecule being developed by MediciNova for fibrotic diseases including nonalcoholic steatohepatitis and IPF.28 In preclinical trials, MN-001 showed antagonistic properties against the leukotriene receptor, as well as inhibitory effects on phosphodiesterases and 5-lipoxygenase which are believed to play a role in fibrosis.28 MN-001 is currently being investigated in a Phase 2 clinical trial (NCT02503657) in up to 15 patients with IPF who will be randomized 2:1 to receive MN-001 or placebo twice daily for 6 months followed by a 6-month open-label extension. The study is no longer recruiting and is expected to conclude in December 2021.

ND-L02-s0201

Nitto Biopharma is developing ND-L02-s0201, a small interfering RNA (siRNA) encapsulated in a lipid nanoparticle, which inhibits the expression of heat shock protein 47 (HSP47).29 HSP47 is a collagen-specific molecular chaperone that may play a role in excessive collagen accumulation in fibrotic diseases.29 Preclinical trials in rats have shown that ND-L02-s0201 was able to reverse pulmonary fibrosis.29 Based on promising preclinical results, ND-L02-s0201 is currently being investigated in an international Phase 2 trial, called JUNIPER (NCT03538301), in up to 120 IPF patients. Patients in the trial will receive intravenous ND-L02-s0201 at one of two dose levels or a placebo every 2 weeks for 24 weeks. The trial is expected to conclude in September 2021. 

NIP292

NIP292 is a small molecule, developed by CR Pharma, believed to function through multiple mechanisms including anti-inflammation, anti-fibrosis, blood vessel expansion, and vascular endothelial repair.30 NIP292 is currently being investigated in a Phase 1 clinical trial (NCT04720443) in up to 72 healthy volunteers who will receive either SAD or MAD doses to establish its safety and tolerability following an overnight fast. The trial is estimated to conclude in December 2021.

NP-120 (Ifenprodil)

Algernon Therapeutics is investigating the repurposing of a small molecule for the treatment of IPF. NP-120 (ifenprodil) was originally developed by Sanofi to treat peripheral circulatory disorders in the 1990s.31 The drug is an N-methyl-d-aspartate (NMDA) receptor glutamate antagonist which also acts as an agonist to the sigma-1 receptor.31 The exact mechanism of action in IPF is still being investigated. Animal studies showed that NP-120 was able to reduce fibrosis by 56% and reduce cough frequency by 42% and delay cough onset compared to controls. Since NP-120 already had undergone extensive safety testing.32 Algernon was able to immediately move into an open-label Phase 2 trial (NCT04318704) in up to 20 IPF patients. Patients will receive 20 mg of NP-120 three times a day for 12 weeks. The study is estimated to conclude September 2021.

ORIN1001

ORIN1001 is an oral compound primarily being developed by Orinove for advanced solid tumors and relapsed refractory metastatic breast cancer.33 The treatment is also being investigated for use in IPF patients.33 A double-blind, placebo-controlled Phase 1 trial (NCT04643769) in IPF patients is currently recruiting. Patients will be divided into three dose cohorts (25 mg, 50 mg, or 100 mg). A total of 8 patients will be assigned to each cohort with 5 being randomized to active treatment while 3 will receive placebo for 28 days. The study is estimated to conclude in March 2022.

Pamrevlumab

FibroGen is developing a fully-human monoclonal antibody, called pamrevlumab, that inhibits connective tissue growth factor (CTGF).34 CTGF has been shown to be involved in the process of fibrosis.34 Pamrevlumab appeared to slow disease progression and was well-tolerated in a Phase 2 clinical trial, called PRAISE (NCT01890265), in 103 IPF patients (50 receiving pamrevlumab and 53 receiving placebo).34 Two Phase 3 clinical trials, Zephyrus (NCT03955146) and Zephyrus II (NCT04419558), will each investigate the efficacy of 30 mg/kg IV infusions of Pamrevlumab every 3 weeks compared to a placebo. The studies will continue for 48 weeks followed by an optional, open-label extension period. The Zephyrus trial is limited to patients who are not currently or have a history of intolerance for an approved IPF treatment while the Zephyrus II trial is exclusive to patients who had been previously treated but discontinued for various reasons. The Zephyrus trial is estimated to conclude in January 2023 with the Zephyrus II trial concluding in May 2023. Pamrevlumab is also being investigated in Phase 3 studies of locally advanced unresectable pancreatic cancer (LAPC) and Duchenne muscular dystrophy (DMD).35

PLN-74809

PLN-74809 is an oral, small molecule being developed by Pliant Therapeutics. PLN-74809 is an inhibitor of integrins αVβ6 and αVβ1, two factors which activate TGF-β and lead to increased collagen production and fibrosis.36 The treatment has already demonstrated antifibrotic activity in preclinical testing and reduced TGF-β activity in healthy participants.37 A 3-part, Phase 2 clinical trial, called INTEGRIS-IPF (NCT04396756), is currently underway to investigate PLN-74809 in an estimated 84 IPF patients. Part A of the trial involves patients receiving one of two dose levels of PLN-74809 or a placebo for 4 weeks. Part B involves patients receiving the second dose level of PLN-74809 or a placebo for 12 weeks. Part C involves up to 2 additional dose levels compared against placebo for 12 weeks. A PLN-74809 dose response was observed across all single doses from 60 mg to 320 mg in the ongoing Phase 2a trial. No serious adverse events were reported across all doses. The trial is estimated to conclude in January 2022.

rhPTX-2 (PRM-151)

Recombinant human pentraxin-2 (rhPTX-2), previously PRM-151, was originally being developed by Promedior but is now being advanced by Roche after they acquired Promedior. Pentraxin-2 is an inhibitor of monocyte differentiation into profibrotic macrophages as well as TGF-β.38 Results of a Phase 2 clinical trial (NCT02550873) and subsequent open-label extension showed that rhPTX-2 slowed decline of FVC and 6-minute walk distance (6MWD) compared to placebo.38,39 Roche is currently recruiting up to 658 IPF patients to take part in a Phase 3 clinical trial, called STARSCAPE40 (NCT04552899), to receive multiple IV infusions of rhPTX-2 or placebo for 48 weeks. Patients completing this trial or who completed the Phase 2 trial will be eligible for a separate Phase 3 open-label study (NCT04594707) that has not opened enrollment yet. The STARSCAPE trial is scheduled to conclude in April 2023 with the open-label Phase 3 study concluding in December 2028.

RXC006 and RXC007

Redx Pharma is developing two small molecule inhibitors for the treatment of fibrosing diseases including IPF. The first, RXC006, targets the porcupine (PORCN) enzyme, a membrane-bound O-acyltransferase that is a key component in the Wnt signaling pathway.41 Abnormal Wnt signaling is present in fibrogenesis and preclinical studies showed that RXC006 had anti-fibrotic effects against kidney, liver, and lung fibrosis.41 In August 2020, RXC006 was licensed to AstraZeneca to further its development into clinical trials.42 Redx is still developing RXC007, a highly-selective rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor.43 The ROCK pathway is believed to play a role in the development of IPF due to oxidative stress.44 Based on preclinical results, RXC007 is now being studied in a Phase 1 clinical trial (NCT04931147) in healthy volunteers. The study will be divided into three parts with volunteers in Part A receiving single doses, those in Part B will receive daily doses for 14 days, and Part C will be determined based on the results of Parts A and B. The trial is estimated to conclude in December 2021.

Saracatinib

Researchers at National Jewish Health, the Icahn School of Medicine at Mount Sinai, and Yale School of Medicine are investigating saracatinib for treatment of IPF.43 Saracatinib was originally developed as an anti-cancer treatment by AstraZeneca but is being tested in IPF due to overlap in relevant signaling pathways.45 Saracatinib is currently being investigated in a Phase 1b/2a clinical trial, called STOP-IPF (NCT04598919), in patients with IPF. A total of 100 patients will be randomized 1:1 to receive either 125 mg of oral saracatinib or placebo daily for 24 weeks. The study is estimated to conclude in December 2022.

Setanaxib (GKT137831/GKT831)

Setanaxib (previously known as GKT137831 or GKT831) is a NOX1/4 inhibitor being developed by Genkyotex for the treatment of fibrotic diseases.46 Through a US National Institutes of Health (NIH) grant, setanaxib is currently being investigated for the treatment of IPF at the University of Alabama at Birmingham in a Phase 2 clinical trial (NCT03865927). During the trial, 60 IPF patients will be randomized 1:1 to receive either 400 mg of setanaxib or a placebo twice a day for 24 weeks. Changes in biomarkers, FVC, 6MWD, and adverse events will be monitored during the study. The study is estimated to conclude in July 2024.

Treprostinil (Tyvaso)

Inhaled treprostinil (brand name Tyvaso) is currently approved to treat pulmonary hypertension (PH) in ILD patients including IPF and is also being investigated for its antifibrotic activity in IPF patients.47 The US Food and Drug Administration (FDA) approval for treatment of PH was based on data from the Phase 2/3 INCREASE study (NCT02630316).48,49 Based on data from the INCREASE study which showed impacts of treprostinil on FVC and reduced exacerbations of lung disease,48 inhaled treprostinil is now being studied as a treatment for IPF in a Phase 3 clinical trial called TETON (NCT04708782).45 The trial will recruit 396 IPF patients who will be randomized 1:1 to receive either inhaled treprostinil or a placebo for 52 weeks. Participants will start with 3 breaths administered 4 times per day and will titrate up to 12 breaths 4 times per day as tolerated. Patients will be monitored for changes in FVC, time to clinical worsening, time to acute exacerbation, overall survival, and change in King’s Brief Interstitial Lung Disease questionnaire.47 The trial is estimated to conclude in June 2024.

TRK-250 (BNC-1021)

TRK-250 (also known as BNC-1021) is a novel siRNA-based oligonucleotide being developed by Toray Industries and Bonac Corporation for the treatment of IPF. TRK-250 targets TGF-β1 and has been shown to significantly reduce its expression in preclinical models.50 TRK-250 is currently being investigated in a Phase 1 clinical trial (NCT03727802) recruiting up to 34 IPF patients. Patients will receive either TRK-250 or a placebo for 4 weeks to investigate the safety, tolerability, and pharmacokinetics of the treatment. The trial is estimated to conclude in April 2022.

VAY736 (Ianalumab)

Novartis is currently investigating VAY736 (ianalumab) for treatment in IPF as well as several other disorders including hematological malignancy and systemic lupus erythematosus. VAY736 is a monoclonal antibody that depletes B-cells and blocks B-cell activating factor receptors.9 It recently concluded testing in a Phase 2 clinical trial (NCT03287414) in 30 IPF patients who were randomized 1:1 to receive subcutaneous injections of VAY736  or a placebo every 4 weeks for 48 weeks. The trial was initially intended to recruit 84 participants. The reason for completing without reaching the desired recruitment has not been released. The trial concluded in May 2021 but results have not been announced as of early July.

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Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.

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