THERAPEUTIC FOCUS - 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. IPF, which accounts for 20%-50% of all cases of in­terstitial lung disease (ILD), primarily affects older adults (>50 years).¹ The exact cause of IPF is unknown; however, certain risk factors such as a history of smoking and genetic predisposition may increase the likelihood of developing IPF.

Globally, the IPF market was valued at approximately $4B in 2021 and is anticipated to grow to $6.2B by 2030, while prevalence is expected to rise from 1.02M to 1.5M in this time­frame. Presently, only two approved treatments (pirfenidone and nintedanib) have shown efficacy in slowing decline in lung func­tion; however, enormous unmet medical needs remain. Patients and clinicians highlight the urgent need for treatment options that offer a better tolerability profile, address the burden of symptoms such as cough and fatigue, improve quality of life, and may ulti­mately halt or reverse fibrosis.

The past decade has seen a highly dynamic drug IPF devel­opment landscape targeting fibrogenesis and fibroproliferation. However, numerous assets showing promise in preclinical models failed to translate into clinical efficacy. Disappointingly, the efforts of the past decade have failed to deliver new options that ad­vance standard of care.²

Currently, a new wave of early stage development is under­way while the IPF landscape is shifting rapidly. With more than 170 early stage IPF clinical programs, IPF is one of the most dy­namic rare diseases spaces for development.³ The following ex­plores the changing landscape of IPF and how biopharmaceutical companies developing novel treatments can effectively navigate the emerging challenges in a rapidly evolving IPF landscape.

HOW THE IPF LANDSCAPE IS EVOLVING

Shift Away From Forced Vital Capacity (FVC) Decline as a Primary Endpoint
FVC has been the cornerstone of assessing progression in fi­brosis in IPF, but the limitations of decline in FVC as a primary endpoint have long been challenged. Patients point to a discon­nect between FVC measures and their perceived quality of life. Clinicians highlight that inherent variability in spirometry deriva­tives like FVC can confound treatment effect – a key limitation of FVC as a primary endpoint. Furthermore, evidence to support the superiority of either periodic or continual FVC measurement in tracking progression is lacking.

Despite calls for rethinking endpoints, regulators have been reluctant to depart from FVC. However, this is changing. The FDA has recently signalled openness to new endpoints, most notably in green-lighting Bellerophon’s use of a novel digital endpoint.⁴

In 2023, a cross-stakeholder collaboration comprising pa­tients and clinicians, the NIH and FDA issued a consensus on the need to replace FVC as the primary endpoint with composite end­points. These composite endpoints may include FVC as a com­ponent, but also focus on “feels, functions, survives” measures that FVC cannot capture alone.⁵ A consensus was also estab­lished on the need for endpoints that mirror the lived experiences of IPF patients, and the inclusion of patient reported outcomes (PROs) as components of primary composite endpoints.

Emerging Biomarkers
The lack of validated prognostic and therapeutic biomarkers in IPF have posed a key barrier to progress. Currently, there are no reliable means of predicting the rate of progression a patient will experience.⁶ This precludes effective stratification in studies and poses significant burden to patients facing a life-limiting diagnosis. Efforts to identify biomarkers un­dertaken in the past decade have met with limited success.⁷

In 2020, the Pulmonary Fibrosis Foundation (PFF) led the establishment of the Prognostic Lung Fibrosis Consortium (PROLIFIC) to drive progress. PROLIFIC identified and prioritized biomarkers showing promise in predicting disease progress and treatment effectiveness. The PROLIFIC biomarker panel, includes 12 blood biomarkers, including markers of epithelial damage and fibrosis, is increas­ingly common practice in early-stage IPF trial protocols.

In 2023, BRAINOMIX announced the development of the weighted reticulovas­cular score (WRVS), a novel, AI-enabled, digital biomarker implemented through its e-Lung platform. The WRVS incorporates reticular opacities and vascular structures of the lung. In an analysis of AstraZeneca’s tralokinumab Phase 2 trial, the e-Lung WRVS tool outperformed standard meas­ure for identifying patients at risk of de­cline from a single baseline CT scan.⁸ In late 2023, BRAINOMIX announced e-Lung WRVS has been incorporated in the NIHR funded TIPAL study and will be running a stub-study to validate this novel imaging biomarker.⁹

While neither of these are widely in­tegrated into clinical practice at present, as biomarker research advances, both bench and bedside may soon benefit from better patient stratification.

Unprecedented Early Stage IPF Pipeline
Presently, there are more than 170 active IPF clinical programs, an unprece­dented number, making IPF one of the most dynamic rare disease development spaces. The vast majority are early stage programs needing to establish proof of concept.¹⁰ When considering that most early stage studies must take place in cen­ters of excellence for stringent safety mon­itoring, the volume of IPF pipeline exceeds capacity and stands to place enormous pressure on sites. Patients and investiga­tors alike want to see the most promising investigational drugs prioritized and to speed up early stage development.

As a result, there is significant pres­sure on biopharmaceutical companies to design IPF studies that demonstrate clinical benefit well in advance of 52 weeks while limiting their patient population and with­out the use of true placebo.^11,12 Most early phase studies must permit the use of stan­dard of care therapy for IPF in order to ob­tain buy-in from both investigators and patients. These new constraints require today’s early stage companies to look to innovative designs, rather than what was previously done.

At a broader level, the REMAP-ILD Consortium is an international initiative that also aims to address the challenges imposed by a vast early stage IPF pipeline. This is an ambitious, investigator-led ini­tiative that aims to establish the first ever international platform trial in ILD (REMAP-ILD). It is led by Professor Gisli Jenkins, Im­perial College London and an international team of ILD experts.¹³ The REMAP-ILD Consortium numbers over 100 investigators in more than 20 countries across all regions (UK, US, Germany, France, Japan, Brazil among others).

This trial would be embedded directly into the clinical care pathway and would assess multiple interventions within various therapeutic domains and patient strata si­multaneously. If realized, a key ambition of the REMAP-ILD trial is to accelerate proof-of-concept for early stage drug can­didates, by assessing them under a single master protocol, rather than each sponsor conducting their own early stage studies.

The conceptual design for REMAP-ILD was published in October 2023.^14,15 As of January 2024, a proposed trial design has been submitted to NIHCR (UK), and sub­missions are underway in Switzerland and Brazil and broad stakeholder engage­ment, including with the biopharmaceuti­cal industry, is underway.

Shift Toward Combination & Personal­ized Treatment Paradigm
Globally, access to treatment is ex­panding. The expiry of pirfenidone patent exclusivity in 2021 broadened access. While the next 3-5 years will also see mul­tiple pivotal trial read-outs, which if suc­cessful, are considered to have high likelihood of approval.¹⁶ These may shift standard of care and speed the paradigm shift to personalized and combination therapies.

Although to date standard of care treatment for IPF has relied on single-drug treatment with one of two approved antifi­brotics, combination therapy on multiple disease targets/pathways and personal­ized treatment approaches are widely con­sidered to be the future paradigm for IPF and other ILDs.

NEW ROADMAP FOR SUCCESS IN IPF DRUG DEVELOPMENT

Early stage biopharmaceutical com­panies must leverage novel clinical devel­opment approaches to navigate the rapidly evolving IPF landscape, which is vastly different than the days of IPF re­search prior to antifibrotic drug approval and widespread use.

At the earliest stages, strong up-front due diligence with this increased complex­ity in mind is imperative for companies as­sessing potential entry into IPF. Anticipating a combination therapy landscape with a strong asset positioning strategy from the earliest stages should drive proactive reg­ulatory and clinical strategy development.

Efficiently de-risking translation from preclinical phase can be accomplished by ensuring robust in-vitro testing to increase confidence in the target and ensuring se­lected in-vivo models characterize it well. Including a second positive control may be necessary in light of today’s pivotal trials’ read-outs.

Companies will need to approach IPF clinical program development with novel strategies. Nowhere is this more pressing than in protocol development. Leveraging novel protocol designs, such as umbrella and basket trials, and looking to a Bayesian analytic framework can address challenges of evidence generation im­posed by background therapy. Using novel protocol designs could position a product favorably for a combination therapy par­adigm. These approaches can also reduce sample size, support adaptive trials, and potentially identify optimal doses more ef­ficiently. Endpoint strategy should be de­veloped in alignment with the shift away from decline in FVC in favor of composite endpoints that reflect how a patient “feels, functions, survives.” Sponsors should re­main poised to respond to advances in biomarker development and consider that the REMAP-ILD platform trial may form part of the future landscape of IPF clinical practice and drug development.

Intense competition for patients and sites requires that minimization of burdens on patients and study sites guide study conduct planning. Where possible, site vis­its and assessments should be streamlined to the greatest possible extent, through use of hybrid trial designs that enable some assessments to be carried out in the pa­tient’s home. Sponsors should monitor evolving evidence on at-home versus in-clinic pulmonary function tests (PFTs) and advancements in technology for future op­portunities to incorporate at-home assess­ments.

For required site visits, sponsors should anticipate providing participants and their caregivers robust travel support, to mitigate physical burdens and financial impacts, which can deter participation. Identifying the participation support serv­ices that will best mitigate risks of recruit­ment and retention failure and the associated budget impact to a clinical pro­gram is sometimes overlooked in early stage planning. Sponsors should also anticipate offering competitive investigator honoraria and explore capacity building strategies such as providing embedded staff support to mitigate site burden.

Strong cross-stakeholder collaboration is key to successfully navigating a clinical program through the evolving IPF landscape. Companies should seek to engage with, and strategically collaborate with key IPF patient advocacy or­ganizations (PAOs) from the earliest possible stages, ideally from translational phase. IPF PAOs are highly sophisticated, exceptionally well-networked with key opinion leaders (KOLs) and are a key driver of research. They have signif­icant experience working with biopharmaceutical companies, especially when it comes to confronting design and implementation challenges in their clinical programs. Leveraging strong strategic guidance from PAOs, KOLs, regulatory, and clinical development experts from the earliest stages will ensure companies are well-positioned to meet challenges and opportunities as they emerge.

SUMMARY

IPF drug development is poised for significant transformation in the com­ing years. Early-stage biopharmaceutical companies pursuing the vast oppor­tunities in this shifting landscape will encounter new challenges compared to those that came before. Navigating these will require departure from the “beaten path” and agile strategic planning informed by deep expertise at every stage of the drug development process.

REFERENCES

1. Castriotta RJ, et al. (2010) Workshop on idiopathic pulmonary fibrosis in older adults. Chest, 138(3), pp693-703.
2. Figure 1 Opensource illustration from Hadjicharalambous MR, Lindsay MA. (2020) Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs. International Journal of Molecular Sciences. 21(2):524. https://doi.org/10.3390/ijms21020524.
3. Citeline 2024.
4. Change in moderate to vigorous physical activity (MVPA) as measured by actigraphy.
5. Raghu, G., et al. (2024) Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on ‘Feels, Functions, Sur­vives’. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency. Am J Respir Crit Care Med, 209(6):647-669.
6. Stainer A., et al. (2021) Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions. Int J Mol Sci. 22(12):6255. doi: 10.3390/ijms22126255.
7. Ibid.
8. Data from Brainomix’s Collaboration with AstraZeneca Shows its AI-Powered e-Lung Better Identifies Lung Fibrosis Patients at Risk of De­cline. PR Newswire, 27 March 2024. Accessed 1 May 2024.https://www.prnewswire.co.uk/news-releases/data-from-brainomixs-collab­oration-with-astrazeneca-shows-its-ai-powered-e-lung-better-identifies-lung-fibrosis-patients-at-risk-of-decline-302100025.html .
9. An NIHR funded multi-centre study of lansoprazole in IPF patients in the UK.
10. Market Spotlight: Idiopathic pulmonary fibrosis (IPF) (2024) Datamonitor Healthcare.
11. Despite challenges, this has been achieved as little as 12 weeks.
12. True placebo control is no longer current practice in IPF clinical trials due to ethical and pragmatic considerations.
13. While few such platform trials exist outside of oncology, two recent examples in ILD are the REMAP-CAP trial (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) and the Scleroderma Research Foundation’s CONQUEST trial, the primary objective of which is to accelerate the evaluation of the treatments for SSc-ILD (ILD secondary to scleroderma). The CONQUEST trial began recruiting patients in April 2024 and will run in more than 130 centers in more than 22 countries.
14. Kulkarni, T. et al. (2023) A Randomized, Embedded, Multifactorial Adaptive Platform trial for ILD (REMAP-ILD): The conceptual design. European Respiratory Journal, 62: OA2588; DOI: https://doi.org/10.1183/13993003.congress-2023.OA2588.
15. REMAP-ILD trial conceptual design includes FVC (measured every 3 months) as a key primary endpoint measure. The conceptual design was published just 6 months prior to the publication of a consensus statement on replacing FVC as a primary endpoint in IPF studies, illustrating the rapid rate of change in the IPF landscape.
16. Market Spotlight: Idiopathic pulmonary fibrosis (IPF) (2024) Datamonitor Healthcare.

Laura Iliescu is Director, Patient Advocacy at ICON Biotech with 20 years of experience in development and commercialization of therapies and patient-centred healthcare services. She has held strategic development roles in leading pharmaceutical, biotechnology, CRO, and clinical homecare organizations throughout every phase of the product life cycle from preclinical to beyond patent expiry. She has deep experience in rare, metabolic, and neuromuscular indications among others. Within ICON’s Center for Rare Diseases, she advises clinical-stage rare disease-focused companies on patient-centred clinical strategy to optimize both study efficiency and the experience of patients and caregivers. She earned her Master’s Degree in Human Factors and Ergonomics from the University of Nottingham, UK.

Dr. Justin Herman is Medical Director, Medical Affairs and Scientific Affairs at ICON Biotech. He is board certified in pulmonary medicine, critical care medicine, and internal medicine and has over 10 years of clinical experience in both academic and community healthcare settings. He provides therapeutic expertise for drug development and medical monitoring for all phases of clinical trials within respiratory, critical care, and rare disease indications, among others. He earned his Medical Degree from Jefferson Medical College, Philadelphia, PA, and his Bachelor’s Degree in the Biological Basis of Behavior from the University of Pennsylvania, Philadelphia, PA.