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Idiopathic pulmonary fibrosis (IPF) is a rare condition where the lungs become scarred, making it hard to breathe. The cause of the disease is unknown, which is why it is called ‘idiopathic.’ So far, U.S. regulators have only approved two drugs for the treatment of idiopathic pulmonary fibrosis and patients have unmet needs. There is a lot of research going on in the field at present, in the hope that more therapies reach patients sooner.
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Refoxy Pharma bags $9.58 million to develop preclinical idiopathic pulmonary fibrosis drug candidate
One promising candidate is Refoxy Pharma’s FOXO3 therapy. The Cologne-based biotech made the news this morning after it secured €9.1 million ($9.58 million) in a financing round led by Boehringer Ingelheim Venture Fund.
It will use the funds to accelerate the preclinical development of its IPF candidate RP-01, which is designed to target FOXO3, a “pivotal master regulator of healthy aging,” according to Victor Bustos, chief executive officer (CEO) and co-founder of Refoxy Pharma.
“Our efforts have been centered on identifying pharmacological activators of FOXO3 using our proprietary platform, F.act Finder (FOXO Activator Finder). This platform integrates cellular, biochemical, and bioinformatics-based assays to pinpoint candidates with the potential to modulate FOXO3 activity,” said Bustos.
FoxO3 is a key player in fibrogenesis, according to a report published by the National Institutes of Health. Fibrogenesis is a mechanism that aids wound healing and repair. However, prolonged injury causes can result in the disruption of normal processes and lead to fibrosis – the scarring of tissues. The two drugs cleared by the U.S. Food and Drug Administration (FDA) are the kinase inhibitor nintedanib and synthetic pyridone drug pirfenidone but neither can reverse or halt disease progression, explained Bustos.
“Most traditional drug development focuses on identifying and counteracting specific molecular pathways that are dysregulated in disease,” said Bustos. “These therapies are also associated with high discontinuation rates due to their impact on patients’ quality of life, often caused by challenging side effects. There is a critical need for therapies that not only improve clinical outcomes but also enhance the overall patient experience.”
Rather than opposing single specific pathways, Refoxy’s anti-fibrotic candidate targets this master switch of tissue repair FOXO3. Bustos added: “While it is still early in development, our data suggest we are on the right track, and underscores a potentially novel angle to tackle IPF.”
Boehringer to submit NDA for nerandomilast for IPF
While RP-01 is expected to hit the clinic in 2027, there are quite a few drugs in the clinic at the moment, like German pharma giant Boehringer Ingelheim’s nerandomilast. It is an oral inhibitor of phosphodiesterase 4B (PDE4B), a protein that regulates cellular signaling pathways. The drug hit the primary endpoint in a phase 3 trial in September, which measured the absolute change from baseline in Forced Vital Capacity (FVC) at week 52 versus placebo. FVC assesses lung function and measures the maximum amount of air a person can let out after inhaling deeply.
Now, Boehringer plans to submit a new drug application (NDA) with the FDA as well as other health regulators worldwide. If approved, it will compete with Boehringer’s other IPF drug nintedanib, sold under the brand name Ofev, and Roche’s Esbriet (pirfenidone).
This actually comes after several failed clinical attempts to beat Ofev and Esbriet. These include California-based FibroGen’s anti-CTGF antibody pamrevlumab, Belgian biotech Galapagos and Gilead’s autotaxin inhibitor ziritaxestat, and Massachusetts-based Galecto’s galectin-3 inhibitor GB0139, which were all in late-stage trials before the studies were canned. More recently, Novartis and Amgen dumped their mid-stage programs of the SMURF1 inhibitor LTP001 and LPAR1 inhibitor fipaxalparant, respectively.
Insilico’s ISM001-055 and Endeavor’s ENV-101 show signs of disease improvement
Still, many biotechs continue to chase therapeutic stardom. Only recently, Insilico Medicine announced that it would push ahead with its IPF drug ISM001-055 after a successful run with phase 2a studies. The drug, which blocks the anti-fibrotic target TNIK, was discovered with the help of artificial intelligence (AI). The study – conducted in China and enrolled 71 patients – revealed a dose-dependent improvement in an efficacy endpoint that measured FVC after 12 weeks of treatment, according to a report by Fierce Biotech.
Also in the clinic is the hedgehog inhibitor ENV-101. Hedgehog is a signaling pathway that is involved in the development of embryos in animals and in maintaining tissue health. California-based Endeavor BioMedicines ENV-101 showed signs of improving lung function with a 1.9% mean improvement in FVC from baseline compared to a 1.3% decline in FVC in the placebo group. The drug was also found to reverse key measures of lung disease such as quantitative lung fibrosis (QLF) and quantitative interstitial lung disease (QILD). The biotech’s $132.5 million series C round completed in May will provide the runway for further development of ENV-101.
Idiopathic pulmonary fibrosis: Vicore’s buloxibutid and BMS’ BMS-986278 chart wins
This year, Swedish biotech Vicore’s buloxibutid has also raised the stakes for a new idiopathic pulmonary fibrosis drug to enter the market. Buloxibutid works by targeting the renin-angiotensin system, which plays a role in the progression of IPF. A phase 2a trial hit both primary and secondary endpoints based on an increase in FVC. Following this, Vicore bagged SEK 782 million ($71.20 million) to advance buloxibutid in October. The IPF drug’s licensing rights in Japan now belong to Kyoto-based Nippon Shinyaku after it struck a $10 million deal with Vicore that is worth up to $275 million in milestones.
Meanwhile, pharma giant Bristol Myers Squibb is moving its LPA1 antagonist candidate along. High levels of LPA and the activation of LPA1 have been linked to the pathogenesis of IPF and progressive pulmonary fibrosis. In a phase 2 study last year, when 60 mg of BMS-986278 was given to patients twice-daily, it reduced the rate of decline in FVC by 69% compared to placebo over 26 weeks. After these encouraging results came to light, the therapy was granted FDA Breakthrough Therapy Designation, making it the first of its kind to be given this status. A phase 3 study is ongoing.
Pliant’s dual inhibitor bexotegrast mitigates chronic cough in IPF
Most anti-fibrotics in the clinic are inhibitor drugs that aim to block the function of proteins that are implicated in the manifestation of IPF. Bexotegrast is Pliant Therapeutics’ inhibitor drug that targets the proteins αvβ6 and αvβ1. These integrin proteins are expressed at very low levels in normal healthy cells but are upregulated in pulmonary tissues of people with IPF. Both these proteins activate TGF-β, which increases collagen production responsible for the hardening and scarring of tissues in IPF. So, by targeting this site, it could halt the progression of the disease.
In May, positive topline phase 2a trial results were put out. Bexotegrast was found to decrease total lung collagen, according to a PET scan, compared to an increase in the placebo group, after 12 weeks of treatment. Moreover, the drug managed to alleviate symptoms of chronic cough in patients. The drug has been awarded Orphan Drug Designation from the FDA and the European Medicines Agency (EMA) as well as Fast Track Designation from the FDA.
IPOs and partnerships: funds pumped into idiopathic pulmonary fibrosis therapeutic field
Meanwhile, a lot of money is being poured into the research and development (R&D) space to broaden therapeutic options for people with IPF. Most recently, California-based antibody maker Surrozen joined forces with TCGFB – owned by venture capital The Column Group – to discover antibodies that target TGF-β to address IPF. The $6 million deal will make use of Surrozen’s tissue repair and regeneration expertise to develop these drugs.
“Idiopathic pulmonary fibrosis is a devastating disease, and we look forward to working with TCGFB to discover antibodies targeting TGF-β as a potential novel, first-in-class therapeutic approach to address the underlying pathology,” said Craig Parker, president and CEO of Surrozen, in a press release.
Meanwhile, Arda Therapeutics wants to see if antibody-drug conjugates that are typically used to treat cancer could cure IPF and other fibrotic diseases. Last month, it cashed in $43 million from pharma giant Lilly and other investors to pursue these potential IPF treatments.
“Arda is taking the ‘oncology toolbox’ outside of oncology,” said Vineeta Agarwala, general partner at investment firm Andreessen Horowitz.
By focusing on the cells at the core of disease, the California-based biotech seeks to develop therapies that can hopefully change patient outcomes, expressed Adam Freund, founder and CEO of Arda Therapeutics.
“With drug approval rates declining and efficacy improvements stalling, Arda’s strategy to target cells – not pathways – offers a transformative shift in how chronic diseases are treated,” said Freund.
This year has also been big for small molecules-focused Contineum Therapeutics, which made its initial public offering (IPO) back in April. Like BMS’ BMS-986278, Contineum’s candidate is also a LPA1R antagonist, which will soon enter a phase 1b study. The funds worth $108 million will fuel R&D plans for the next few years.
As IPF affects 3 million people worldwide, having more treatment approaches beyond nintedanib and pirfenidone that can neither reverse nor halt disease progression, is important. Despite trial failures, biopharmas continue to develop different types of drugs with multiple targets to address the unmet needs of patients.
Treatments related to idiopathic pulmonary fibrosis
- AAV2/9-Mediated Gene Therapy for SPLIS Treatment – University of California, San Francisco
- Treatment and Diagnosis of Idiopathic Pulmonary Fibrosis – Saarland University
- Therapeutic Inhibition of the WT1-MYCN-PLK1 Axis for Treatment of Idiopathic Pulmonary Fibrosis (IPF) – Cincinnati Children’s Hospital Medical Center
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