Pushing boundaries in idiopathic pulmonary fibrosis clinical research

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-limiting lung disease characterised by scarring (fibrosis) of the lung tissue which primarily affects older adults. The exact cause of the disease is unknown, however, certain risk factors, such as a history of smoking, and genetic predisposition, may increase the likelihood of developing the disease.

In this blog, we explore the evolving landscape of IPF research and suggest ways that early-stage biopharmaceutical teams can address the emerging challenges to chart a new roadmap to success.

While there is no cure for IPF, two antifibrotic medications (pirfenidone and nintedanib) have been approved for use in some regions and have shown efficacy in slowing the decline in lung function. However, patients and clinicians are seeking new treatments that offer improved tolerability, efficacy, and symptom management.

The opportunity is vast, but changes in the IPF landscape present new and significant challenges that companies must navigate with different strategies compared to “what has been done before”. These include:

expanding treatment options
shift towards combination and personalised treatment paradigm
pressure to expedite early-stage development
opposition to placebo-controlled designs
intensifying competition for trial participants and investigators

The changing IPF landscape

The IPF market is expected to grow from a $4bn valuation in 2021 to $6.2bn by 2030.
Global prevalence is expected to rise from 1.02m to 1.5m in this same timeframe.¹ Until 2022 pirfenidone and nintedanib dominated the marketplace. However, the pirfenidone patent exclusivity ended in 2021 broadening access. Multiple molecules are in late-stage clinical trials and by 2026, read outs from 6 late-stage trials are anticipated. This represents a dramatic shift in the disease treatment landscape.²

The high unmet medical need and pathophysiology of IPF are fuelling this wave of early-stage drug development. At all stages of the development lifecycle these newer candidates will encounter emerging challenges. Early-stage biopharmaceutical companies in this “new wave” will need to leverage different clinical development approaches from those that preceded them.³

Optimising pre-clinical phase

One of the early challenges IPF treatment researchers face is the need for robust, translatable in-vitro models. Despite encouraging results from numerous proof-of-concept animal studies, results obtained during clinical development over the past decade have been broadly disappointing.⁴

Currently available animal models have limitations, and none of them can fully recapitulate IPF’s pathology. The most current recommendations of the American Thoracic Society (ATS) identify the bleomycin mouse model for assessing antifibrotic investigational products. Multiple administrations to the bleomycin mouse model remain the most cost-effective and widely used model. Nintedanib is typically used as the positive reference control. Current best practices suggest inclusion of both genders in in-vivo experiments and the use of older mice.^{5, 6}

Efforts continue to develop more translatable models of IPF,⁷ such as models that aim to release specific cytokines and the novel “humanised mouse model” with patient cells in modified mice.⁸ However, these models are still in development and not being widely used.

To address this challenge, investigators should factor in a longer-lead time for developing niche models with highly specific targets. Anticipate an expanding treatment landscape, with robust in-vitro testing to increase confidence in the target and ensure selected in-vivo models characterise it well. A second positive control (alongside nintedanib) can be used to assess head-to-head efficacy if new drugs with a similar mechanism come to market.

Developing a strong regulatory strategy

Obtaining an early orphan drug designation (ODD) offers drug developers benefits including a positive impact on company stock price (an average increase of 3.6%), and attracting stakeholders including investors, investigators and patient advocacy organisations.⁹ Because of the high unmet medical needs of IPF, regulators no longer require sponsors to conduct two phase 3 studies. However, there are potential changes to orphan drug exclusivity on the horizon. The European Medicines Agency (EMA) released new guidance for sponsors on orphan medicinal product designation in March 2024. In an everchanging regulatory environment, sponsors must determine their regulatory strategies to optimise their route to commercialisation.

In order to capitalise on the advantages of ODD in the US and EU sponsors should apply early for designation, ideally as soon as supporting data is available. Success depends on a proactive, agile strategy which can be adapted to different regulatory requirements in all key markets.

Another challenge in IPF treatment research is demonstrating “significant benefit” for marketing in the EU. Orphan drugs are required to demonstrate clinically relevant advantages over all other available treatment options. To de-risk development, early-stage biopharmaceutical companies must pragmatically assess their assets’ benefit profiles against soon-to-be available treatment options. The European Medicines Agency’s (EMA) protocol assistance mechanism can offer guidance on clinical study design and the data that is required to meet the significant benefit criteria.

Effective collaboration with patient advocate organisations

Patient advocacy organisations (PAOs) are important drivers and enablers of research with strong connections to key opinion leaders (KOLs). In Europe, 16 countries have IPF-specific PAOs as well as the EU region organisation the European Pulmonary Fibrosis Federation (EU-PFF). Worldwide, the PF Foundation (USA) and other countries including Turkey and Australia have PAOs. Collaborating with PAOs can provide drug development organisations with greater insight into patients’ unmet medical needs. They can provide valuable input on potential barriers to patient recruitment and study enrolment. Many PAOs organise conferences and attending these events provide opportunities to network with KOLs, investigators and PAO leaders. While PAOs will often share insights with companies developing treatments for IPF without costs, consider covering the expenses associated with convening patient focus groups or advisory boards.

Engaging with IPF PAOs at the earliest stage is both advisable and best practice. Effective collaboration in study design and planning will position sponsors well for further collaboration. This can provide opportunities to educate patients, raise awareness about a trial and enable strategic collaboration with key PAOs in pre-launch and commercialisation.

Leverage novel protocol designs

Increasing competition, ethical barriers to placebo control and pressure to demonstrate clinical benefit in advance of 52 weeks require IPF focused sponsors to develop innovative study designs. Master protocol trials including umbrella, basket and platform designs offer advantages over stand alone trials in IPF research. In particular, umbrella and basket designs may help sponsors to navigate challenges of evidence-generation imposed by background therapy. This can position their assets favourably for a future combination therapy paradigm. Combining a Bayesian analytical framework with master protocols, or in stand-alone trial designs, provides many opportunities to leverage historical and accruing data. This affords a decision-theoretic framework for sponsors. Bayesian trials are increasingly common, and particularly well suited to rare disease indications, such as IPF, where nominal statistical significance may be difficult to achieve.¹⁰

Early and consistent engagement with regulatory bodies is essential during early planning to align study design features, expected trial performance and overall goals. Planning upfront for the full clinical programme, rather than a single trial, will reduce the likelihood of an uninformative programme and avoid delays and gaps in key data. Sponsors interested in master protocols should plan early for discussions on governance, execution and other complexities unique to these designs. Key decision-making stakeholders should trust in evidence-based criteria and commit to avoid “copy-paste” trial designs.

Optimise trials & clinical development planning

Participation in clinical trials should not add burdens to patients already coping with a life-limiting condition. For IPF patients, in-person site visits can be challenging due to potential exposure to respiratory viruses, physical impacts and logistical challenges. Long distance travel may be a deterrent to participation. Designing studies that reduce the need for in-person visits and instead use remote monitoring such as telephone or video appointments will align with patient preferences and standard of care practices. Carry out assessments in the patients’ homes with nurse visits where possible.

Sponsors should also reduce the financial and logistical burdens by offering participants a range of supports. These could include concierge support for travel arrangements, organising private transfers rather than public transport and providing reimbursement or prepaid cards for expenses. Consideration should also be given to providing the same supports to accompanying caregivers. Engagement with PAOs will be helpful in anticipating these needs during trial design. Creating patient-centric clinical trials is key to avoid recruitment and retention failures which could lead to delays in development and data collection. Evidence supports that patient-centric clinical trials recruit faster.¹¹

The number of early-stage IPF clinical trials on the horizon exceeds investigator capacity and the available patient pool. IPF centres of excellence treat larger volumes of patients and the proliferation of clinical research trials for new therapies may further strain their capacity. Therefore, designing IPF studies that minimise the requirement for in-person visits will be compelling to investigators. Other ways to reduce the burden on investigators and sites include providing resources, research grants and additional funding if sites are understaffed. Streamline feasibility by conducting site recruitment questionnaires over the phone, or for historically well performing sites, proceed to site qualification visits. Provide robust site and patient-facing study informational materials. Leverage digital solutions such as study platforms that help streamline site operations by deploying training, visit-by-visit guides and FAQs in real time.

Conclusion

The landscape of IPF treatment is poised for significant transformation in the coming years. While the IPF market has long been dominated by two approved antifibrotic therapies, multiple promising candidates in late-stage clinical trials and many early-stage candidates are on the horizon. Early-stage biopharmaceutical companies pursuing the vast opportunities in the shifting landscape of IPF will encounter new challenges. Navigating these challenges demands new thinking. Biopharmaceutical teams must be prepared to undertake nuanced risk-assessment and agile strategic planning informed by deep expertise at every stage of the drug development process.

Learn more in our whitepaper, ‘Pushing boundaries in idiopathic pulmonary fibrosis clinical research’.

¹ Datamonitor Healthcare (Pharma Intelligence) Idiopathic Pulmonary Fibrosis (IPF) Market Spotlight report published February 2024

² Ibid.

³ White ES, Thomas M, Stowasser S, Tetzlaff K. Challenges for Clinical Drug Development in Pulmonary Fibrosis. Frontiers in Pharmacology. 2022 Jan 31;13. doi: 10.3389/fphar.2022.823085

⁴ Myllärniemi M, Kaarteenaho R. Pharmacological treatment of idiopathic pulmonary fibrosis - preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine. Eur Clin Respir J. 2015 Feb 10;2. doi: 10.3402/ecrj.v2.26385

⁵ Barbayianni I, Ninou I, Tzouvelekis A, Aidinis V. Bleomycin Revisited: A Direct Comparison of the Intratracheal MicroSpraying and the Oropharyngeal Aspiration Routes of Bleomycin Administration in Mice. Front Med (Lausanne). 2018 Sep 24;5:269. doi: 10.3389/fmed.2018.00269

⁶ Redente, E. F., Black, B. P., Backos, D. S., Bahadur, A. N., Humphries, S. M., Lynch, D. A., et al. (2021). Persistent, Progressive Pulmonary Fibrosis and Epithelial Remodeling in Mice. Am. J. Respir. Cell Mol. Biol. 64, 669–676. doi:10.1165/ rcmb.2020-0542ma

⁷ White ES, Thomas M, Stowasser S, Tetzlaff K. Challenges for Clinical Drug Development in Pulmonary Fibrosis. Frontiers in Pharmacology. 2022 Jan 31;13. doi: 10.3389/fphar.2022.823085

⁸ Jaeger B, Schupp JC, Plappert L. et al. Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis. bioRxiv 2020 Sep 04;283408. doi:10.1101/2020.09.04.283408

⁹ Miller KL. Do investors value the FDA orphan drug designation? Orphanet Journal of Rare Diseases. 2017;12(1):114. doi:10.1186/ s13023-017-0665-6

¹⁰ Kidwell KM, Roychoudhury S, Wendelberger B, et. al. Application of Bayesian methods to accelerate rare disease drug development: scopes and hurdles. Orphanet J Rare Dis. 2022 May 7;17(1):186. doi: 10.1186/s13023-022-02342-5

¹¹ The Economist Intelligence Unit. Accessed Aug 2023. Patient-Centric Trials. https://druginnovation.eiu.com/patient-centric-trials/