Inhalation: the potential for faster onset and fewer side-effects

Asthma is routinely treated using small molecule drugs administered via a metered dose inhaler. Whether the inhaler contains a preventer drug such as a corticosteroid, or a bronchodilator designed to treat acute exacerbations, such as the beta-2 receptor agonist salbutamol, it is a real advantage that the drug goes straight to the tissue where it’s needed – the lungs.

These devices are also an ideal way to improve outcomes by combining more than one medicine in a single dose, a strategy that greatly increases patient convenience and compliance. It is even possible to delivery three actives at the same time, via products such as GSK’s Trelegy, which combines the corticosteroid fluticasone with the long-acting beta-agonist vilanterol and umeclidinium, a long-acting muscarinic antagonist.

Metered dose inhalers are not the only devices routinely used to deliver drugs directly to the lungs, however. Nebulisers, in particular, have advantages in certain circumstances. While they’re not as convenient to pop in a pocket or bag as a metered dose inhaler, they can be extremely useful for patients who find it difficult to operate an inhaler correctly, such as paediatric and geriatric patients.

Inhalation is already used as a route of drug delivery in other diseases of the lung, too. Chronic obstructive pulmonary disorder, or COPD, is becoming far more common and, like asthma, a fast-acting inhaler is extremely beneficial in getting treatments to work as quickly as possible. Many of the drugs used to treat it are the same as those prescribed for asthma.

A very different lung disease where a treatment is already given via inhalation is cystic fibrosis. Chiesi’s Bronchitol is an inhaled formulation of mannitol in a dry powder inhaler, and helps patients to clear mucus from their lungs.

Then there’s pulmonary arterial hypertension, where Janssen’s Ventavis, the synthetic prostacyclin analogue ilaprost, is delivered to the lungs via a mesh nebuliser. In combination with a modern nebulising device, this formulation has proved extremely useful in reducing the treatment burden on these seriously ill patients.

Away from asthma small molecules

Yet there are many other, non-lung, diseases where one might imagine that inhaled delivery could be beneficial. The rapid onset of action that results can be a real advantage. But, importantly, a drug given in this way does not undergo the first pass of the liver, so it might avoid the problems this can cause if, for example, unwanted metabolites are formed.

While small molecule drugs are familiar in inhaled delivery devices, they are not the only type of drug that are used to treat lung diseases. In severe cases of asthma, monoclonal antibodies are routinely used: five are already approved in Europe and the US. Four of these – Dupixent (dupilimab, Sanofi/Regeneron), Fasenra (benralizumab, AstraZeneca), Nucala (mepolizumab, GSK) and Xolair (omalizumab, Genentech/Novartis) – are administered via an injection, either by a medical professional or by the patient at home using a prefilled syringe. The fifth, Cinqaero/Cinqair (reslizumab, Teva) has to be given intravenously.

These are undoubtedly effective methods for treating severe asthma, but might it be possible to deliver an antibody drug via inhalation instead? And there are other lung conditions that could also benefit if this were the case. Various antibodies were approved during the Covid-19 pandemic for those with severe cases of the disease. And Synagis (palivizumab, Arexis/Sobi) can be used to prevent severe lung disease caused by RSV in children who are particularly vulnerable, such as the premature and those with certain other lung or heart problems. One might imagine that antibody drugs for these diseases might be better delivered directly to the lungs.

The prospect of inhaled biologics

Formulating a small molecule drug so that it is suitable for a dry powder inhaler is already a challenge: the particles need to be consistent in size, and below 5µm in diameter if they are to reach the deep lung, where they will be absorbed by the lung tissue. But the challenges are – unsurprisingly – even greater for an antibody.

Yet it is not impossible to create stable dry powders of antibodies using spray drying technology. First, the antibody and any excipients are combined in a buffer solution. The solution is then passed through an atomiser, forming small droplets that are sprayed into a drying chamber. In the chamber, droplets encounter a heated gas that causes the droplets to dry quickly. With carefully-tuned parameters, including spray rate and temperature, particles can be created that have that ideal diameter of 1–5µm for pulmonary delivery.

Biologics such as monoclonal antibodies require careful handling to avoid stress damage from dehydration, heat and shear. But as long as this is taken into account when designing a spray drying process, it is not an insurmountable problem for many actives. Indeed, evaporative cooling occurs within the droplets as they are sprayed into the drying chamber, and that will reduce the impact of the high temperatures within it. A further technique that can help is to include some form of protective excipient within the formulation which will help stabilise the protein as it dries. Trehalose, a naturally occurring sugar that is commonly used to stabilise proteins in liquid formulations, is particularly appropriate here.

While no monoclonal antibody drugs have yet been commercialised in inhaled form, there is some precedent that suggests it is not unfeasible. A couple of antibody fragments, both stabilised using trehalose, have already been through Phase 1 clinical trials for asthma – eclerimab from Novartis, and abrezekimab from UCB in collaboration with Vectura. The Novartis fragment has advanced into Phase 2 in both COPD and uncontrolled asthma.

Further precedent comes in the form of two inhaled insulins, Exubera from Pfizer and Afrezza from Mannkind. The fact that the US FDA granted them regulatory approval (Exubera in 2006 and Afrezza in 2014) clearly shows that its scientific experts are not averse to the concept of delivering a protein drug via inhalation. This bodes well for inhaled antibodies.

Inhaled biologics in cancer?

The driver behind the development of the inhaled insulins was to remove the need for injections, rather than to deliver the drug to the tissue where it is needed. However, there is a whole range of lung diseases that might benefit from direct pulmonary delivery of biotherapeutic actives.

One such disease is lung cancer. Many of the drugs now routinely given to treat cancers are protein-based, including monoclonal antibodies and fusion proteins. Here at Lonza, we carried out a case study using an inhaled version of bevacizumab, a vascular endothelial growth factor inhibitor that is already on the market for a range of cancers, including non-small cell lung cancer. It is given alongside chemotherapy as an intravenous infusion in three-week cycles, but one of its major side-effects is that it can cause uncontrolled bleeding.

If the drug were delivered straight to the lungs rather than systemically, then it might be possible to significantly reduce the dose required and, therefore, also minimize the impact of serious side-effects, with significantly lower exposure of healthy cells to the antibody. It could even improve compliance with treatment regimens, if patients were able to be treated at home rather than in hospital.

Our work on bevacizumab highlighted the importance of ensuring the protein drug retains its activity when formulated as a powder, and that the powder has the appropriate aerosol properties for direct delivery to the lung. Room temperature stability is also desirable, as this would avoid the need for cold chain distribution and storage. Excipients play an important role here. As well as trehalose as a stabiliser, the amino acid L-leucine can be incorporated to improve the dispersibility of the powder.

In our studies on bevacizumab, we included both these excipients in the powder, and found that a powder that was, by weight, 40% antibody, 40% trehalose and 20% leucine. The protein remained intact after spray drying, and with a median diameter of 2.2µm, the particles were ideal for deep lung delivery. And, other than a small increase in water content, it was stable on storage at both 5°C and 25°C for a year. In vivo lab tests in rats indicated that a dose size 10% of the injected dose was equally effective.

We also created fixed-dose combinations of bevacizumab with either a platinum-based chemotherapy or the EGFR inhibitor erlotinib. Despite the significant manufacturing challenges this posed, spray drying once again was the key. This time, because of the poor aqueous solubility of the other drugs, the answer lay in a simul-spray process. Two separate solutions – an aqueous one and another in a suitable organic solvent – were atomized through individual nozzles into the drying chamber simultaneously, and the two different powders that were created formed an intimate mixture. Again, activity was retained, and with the median size of the particles in the range 1.8–2.9µm and the powder having good aerosol properties, it was once more ideal for pulmonary delivery.

While no antibody drugs have yet to gain regulatory approval in dry powder inhaler form, the prospects for future success appear promising. With combinations of drugs already routinely delivered together via inhalation, the idea of biologics being delivered alongside other components of combined therapy in a single dry powder inhaler are not at all far-fetched. And the benefits for patients in terms of reducing treatment burden, minimising side-effects and increasing compliance would be significant.

Author

Kimberly Shepard, Ph.D.

Principal Engineer, R&D

Lonza Small Molecules

 

Kim Shepard is a Principal Engineer in the Research group at Lonza’s site in Bend, Oregon, USA, where she has worked since 2015. She leads projects focused on developing new technologies for bioavailability enhancement and pulmonary delivery. Kim’s areas of expertise include the formulation and manufacturing of spray-dried dispersions for inhalation and oral delivery, as well as the physics of polymers and amorphous materials. Kim received her Bachelor and and Master’s degrees in Chemical Engineering from Stevens Institute of Technology and her Ph.D. in Chemical Engineering from Princeton University.