Pitfalls with Oral Drug Administration in IPF

In the first 3 parts of our blog series on targeted delivery in  idiopathic pulmonary fibrosis (IPF), we focused on the potential of inhaled delivery and other targeting strategies to deliver efficacy uplifts for agents as an add-on to the standard of care, while minimising the likelihood of additive side effects. In this fourth installment, we highlight the need for such approaches, illustrated by examples in which oral delivery has resulted in significant limitations.

As mentioned previously, in future treatment of IPF, new approaches will need to be compatible, add-on therapy, with the current standards of care (SoC). Given the significant side effects already associated with both oral pirfenidone and nintedanib, add-on of new mechanisms via the oral route is highly likely to lead to additive side effects. As we have discussed, inhalation, and other targeting strategies, by virtue of reduced GI and systemic exposure, may represent a means to enable the add-on potential for a number of new approaches.

In Part 4 of our blog we illustrate that the challenge with add-on via the oral route is not just a theoretical concern but can lead to real issues for development programmes with two recent examples:

  • In 2017, Prometic (now Liminal BioSciences) completed a PhII study with PBI-4050 (fezagepras), which modifies fibrosis through interaction with GPR40 and GPR84. The 12-week open-label study explored the safety, efficacy, and pharmacokinetics (PK) of daily oral doses of 800 mg PBI-4050 alone and in combination with nintedanib or pirfenidone in patients with predominantly mild or moderate IPF. While lung function decline appeared to be stabilised in patients receiving PBI-4050 alone or in combination with nintedanib, this was not the case with the combination of PBI-4050 and pirfenidone. The PK analysis showed that, in combination with pirfenidone, plasma levels of PBI-4050 were reduced compared to the other two treatment groups. As a result of this drug-drug interaction (DDI) the FDA approved a PhIII design that would explore the effect of PBI-4050 alone or added-on to nintedanib, but not added on to pirfenidone. Although originally proposed to start in 2018, the PhIII study has not yet been initiated. Instead, further dose-ranging (up to 2400 mg/day) of PBI-4050 is being explored in a PhI study in healthy subjects.
  •  In November 2020, Galapagos announced positive top-line results from the PINTA PhII trial investigating the effect of a 100 mg once-daily oral dose of the GPR84 antagonist, GLPG1205. Patients received GLPG1205 or placebo for 26 weeks and could remain on their SoC as background therapy, i.e. nintedanib, pirfenidone or neither. At week 26, there was a trend for a reduced decline in lung function in patients receiving GLPG1205 versus placebo on top of SoC. This trend was consistent across the three treatment strata. From a safety perspective, no relevant signals were observed for GLPG1205 alone and on top of pirfenidone. The most frequently reported adverse events on GLPG1205 alone were gastrointestinal disorders, especially nausea. In the treatment arm of GLPG1205 on top of nintedanib, a higher rate of early discontinuations and more treatment-emergent adverse events were observed.

These are just 2 examples of the complexities that can emerge with oral add-on therapy in IPF, from both efficacy and safety perspectives.

Pursuing only oral therapies to bring increased benefit to IPF patients may mean that these benefits can never be fully realised due to side effect limitations or DDIs that compromise dosing flexibility. The likelihood of ultimate success will be increased by considering alternative strategies, including inhaled delivery and other means of targeting the diseased lung. With the discontinuation of the oral autotaxin inhibitor, GLPG1690, the now front-running novel anti-fibrotic agents in development for IPF are recombinant human pentraxin-2 (PRM-151) and the connective tissue growth factor antibody, pamrevlumab. Interestingly, both agents require intravenous administration, bringing additional practical challenges, particularly in the COVID-19 era. The optimal approach will be dependent on the target and properties of the therapeutic entity, and we have to be mindful that new complexities can arise. For example, during compilation of this blog, Galecto announced a significant redesign of the GALECTIC-1 study with the inhaled galectin-3 inhibitor GB01394. This was in response to recommendations from the Drug Safety Monitoring Board following observation of an imbalance in serious adverse experiences across the study groups. The causative factors are not yet clear. The study will now continue with recruitment limited to patients who are not on SoC, randomized to receive GB0139 3 mg or placebo.

Please get in touch with us to discuss how your project can benefit from targeted strategies (route of delivery- and pharmacology-based), or other strategies to build drugs that are fit for the real world. 

You can read our other blogs from the series here:

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