Exploring Innovative Means for Biologics Delivery

Despite their track record of demonstrating significant therapeutic efficacy, biologics still face daunting challenges in their drug delivery. Biologics such as monoclonal antibodies (mAbs) and some vaccines are largely administered via injection or by infusion. These methods can often be a barrier to patient compliance. Less invasive forms of biologic drug delivery are in development, particularly oral administration and inhalation routes.

The current rapid rate of new drug target discoveries, coupled with increasingly effective engineering processes and a growing knowledge and understanding of how biologics are processed in the body have resulted in a higher number of biologics in clinical development and approved for the market. However, to date, formulations of biologics have mostly been designed for the parenteral route of administration. Because of this design, many biologics have short plasma half-lives which require frequent administration. The need to use needles on a frequent basis leads to sometimes painful administration and ultimately poor patient compliance (1).

Addressing the challenges

Frank Tagliaferri, PhD, chief scientific officer at Pace Life Sciences, emphasizes that biologics are typically larger molecules with more structural requirements as opposed to small-molecule therapeutics. The latter has long dominated the traditional oral route of delivery. Biologics also encounter more structural sensitivities that need to be overcome, Tagliaferri says.

“These limitations often result in poor bioavailability for a variety of reasons, including degradation while in the alimentary tract, inability to overcome intestinal cell or mucosal barriers, and first-pass metabolism, which is avoided with the traditional injection routes,” Tagliaferri explains. He further adds that, “While there may be beneficial solutions to these hurdles individually, it is a significant challenge to overcome all of them with what will generally be a higher-cost biologic drug where extremely low bioavailability is not always economically feasible.”

Today, alternative biologics drug delivery methods that have shown promise include inhaled biologics and oral solid biologics. Past-case scenarios include inhaled insulins. As Tagliaferri notes, “the utility of inhaled biologics showed some promise during the development of both the Pfizer and Mankind inhaled insulin products, where numerous technical hurdles for lung delivery were overcome. But the lack of a commercial success to date demonstrates that issues such as ergonomics, patient-to-patient variability, and high cost of goods all contribute to public acceptance and the ultimate success of an alternate route” (2,3).

Oral solid biologics, on the other hand, possess different, but just as significant, challenges compared to inhaled biologics, Tagliaferri says. Yet, there appears to have been more significant progress in oral solid biologics, he avers. “The small-molecule development history has provided several delivery enhancements to oral delivery that have been successfully applied to a limited number of biologics. These include techniques such as enteric coating of capsules, additives to control release and residence time in the gut, [and] physical formulation techniques such as spray drying or lyophilization designed to help stabilize the molecules,” Tagliaferri explains. “When we combine these techniques with advancements in the use of additives to protect molecules or enhance delivery such as polymers, penetration enhancers, chelating agents, etc., there has been success as demonstrated in the delivery of some metabolic enzymes to the gut using spray dried proteins and enterically coated capsules.”

Tagliaferri also observes that there does not seem to be a universal “needle-fee” path for all biologics. Rather, depending on the molecule, dose, and intended site of action, current alternative options such as inhaled, nasal, transdermal, buccal, oral, etc., would all have some utility in the market. “Due to its convenience, compliance, and overall acceptance, however, the oral route will continue to be aggressively pursued and—with emphasis on future particle engineering or novel excipient advancements—may eventually be achieved,” he says.

Where are we now?

At a 2022 Oxford Global conference on formulation and delivery (4), speakers discussed how the field of inhaled biologics had reached an interesting phase of development. Speakers noted how scientists are currently working on optimizing the process by focusing on methods that reduce the necessary dose needed to be effective and delivering the biologic to the site of action. They point to one example in which researchers are working toward more specific delivery to target organs in the body, such as cancer cells in the lungs, rather than the conventional treatment which targets the whole body via injection. However, developing an inhaled biologics formulation for this case scenario, and others, requires overcoming the issues inherent with creating stable and safe formulations for biologics (4).

Much work is currently going into developing biologics formulations that can be inhaled to deliver therapy locally to the lungs for treating respiratory diseases, according to speakers at the 2022 conference. The work has led to innovations that include antisense oligonucleotides, messenger RNA (mRNA), and lipid nanoparticles (LNPs), the speakers noted (4). The speakers also noted that the recent interest in developing inhaled and nasal biologics was partly spurred by the urgency seen during the development of COVID-19 vaccines and treatments for other viral pathogens (4).

Meanwhile, more progress was made on oral vaccines with the completion in 2023 of a Phase I clinical trial for an oral vaccine platform known as QYNDR, which is a self-administered drinkable vaccine, reportedly the first of its kind, according to US Specialty Formulations, a manufacturer of sterile injectable, topical, and specialty pharmaceuticals (5).

QYNDR, a next-generation protein-based oral vaccine (mucosal vaccine), was developed as a means to addresses challenges seen with current COVID-19 vaccines. In the results from the Phase I clinical trial, the vaccine demonstrated longevity and cross-variant protection from multiple COVID-19 strains. The study may have also possibly identified a correlation of protection against the virus and other strains, which the company will be further investigating in a Phase II clinical trial (5).

“The [P]hase I clinical data showed strong evidence that this oral platform and vaccine is a revolutionary industry disruptor and will become the preferred method of vaccination in the future,” said Kyle Flanigan, CEO of USSF, in a press release issued at the time that the Phase I trial was completed. “As we proceed into Phase II and III, we are confident this next-generation vaccine will be more effective than other mucosal vaccines in current development and testing” (5).

Other drug delivery routes to consider

Meanwhile research is also being done that considers other alternative routes to biologics administration besides the inhaled route or oral route, or the conventional parenteral route.

“While purely topical biologics will likely have limited utility due to the significant barrier posed by the skin, there has been significant work in the transdermal delivery of biologics, particularly around insulin,” says Tagliaferri. “Physical skin perturbation techniques ranging from microneedles, microporation, sonophoresis, iontophoresis, and even jet injection have all shown some utility for delivering primarily smaller proteins or peptides, and especially vaccines where dose requirements are frequently very low.”

However, the challenges to a topical route of administration again revolves around getting the biologic through the stratum corneum barrier of the skin and into microcirculation, while remaining intact, Tagliaferri explains. “Since a number of these transdermal techniques require time to realize the sufficient diffusion through the skin, the stability of the payload is a factor along with accessing sufficient surface area to allow diffusion of the required dose,” he says.

Market potential and future growth

Market potential for alternative drug delivery routes for biologics is substantial. For the inhalation contract development and manufacturing organization (CDMO) market, the market size has seen strong growth in recent years and is expected to see a compound annual growth rate (CAGR) of 7.1% year-over-year, increasing from $1.94 billion in 2023 to $2.08 billion in 2024 (6). This growth is attributed to a rising prevalence of respiratory disorders as well as growing demand for personalized medicine, both of which are expected to lead to an increase in outsourcing by pharmaceutical companies and growth of the biopharmaceutical industry (6).

Further growth in the inhalation CDMO market size is expected in the next few years, growing at 6.8% CAGR to $2.7 billion in 2028. This forecasted growth is attributed to several factors, such as a focus on precision medicine and targeted therapies, an expected rapid expansion of biopharmaceutical inhalation therapies, increasing emphasis on patient-centric solutions, global market expansion, and opportunities that are expected to emerge in new markets (6).

Meanwhile, future market potential for biologics in general is on a strong trajectory, while the possible potential for inhaled biologic formulations for a market such as asthma, for example, is ripe. For one, regulatory bodies are hastening the approval of biologics, especially for respiratory disorders, and secondly, many conventional biologics that have been approved to treat asthma have a favorable profile because they offer specific and precise treatment of asthma symptoms. Finally, rising awareness among healthcare providers of these favorable profiles for asthma treatment using (conventional) biologics is driving healthcare providers to increasingly include a biologics treatment in their asthma healthcare regimen for patients (7).

The global asthma biologics market was estimated at $6.5 billion in 2022. Growth of the market is projected to increase at a CAGR of 12.5% from 2023 to 2031 and is expected to reach more than $19.2 billion by the end of 2031 (7).

Biologics are particularly used to treat severe cases of asthma that are otherwise difficult to treat with conventional inhaled medicines. Asthma-treating biologics assist in enhancing lung function, which lessens the dependence on oral corticosteroids while reducing the severity of asthma symptoms. Biologics that have been approved for treating asthma typically focus on several processes related to the disease, including inflammation, allergic reaction, and airway remodeling (7).

These biologics target pathways that lead to lung inflammation, which minimizes asthma attacks, alleviates symptoms, and reduces dependency on steroids. However, asthma-related biologics are routinely administered via injection or by infusion in hospitals; although, some biologics can be self-injected by the patient at home. FDA-approved biologics for treating asthma include omalizumab (anti-immunoglobulin E treatment), mepolizumab (anti-interleukin-5 [IL-5]), resiluzumab (anti-IL-5), benralizumab (anti-IL-5 receptor), dupilumab (anti-IL-4-13 receptor), and tezepelumab (7).

The reality of an inhaled biologic product hitting the market is still far off, however. Tagliaferri emphasizes that the effective development of an inhaled or even oral biologic (particularly a monoclonal antibody [mAb]) still seems a way off; however, he states, “Based on current clinical trials, we are likely to see self-administered inhaled or nebulized mRNA/LNP biological products, particularly for lung-related conditions in the near future.”

Tagliaferri adds that many of the more successful mAb therapies currently on the market may likely continue to transition to a more patient-friendly, self-administered subcutaneous administration format when applicable. He points out, however, that current technologies still seem insufficient to overcome the dose and stability challenges.

References

1. Skalko-Basnet, N. Biologics: The Role of Delivery Systems in Improved Therapy. Biologics 2014, 8, 107–114. DOI: 10.2147/BTT.S38387
2. Pfizer. Pfizer Reports Third-Quarter 2007 Results; Reconfirms 2007 and 2008 Revenue and Adjusted Diluted EPS(1) Guidance. Press Release, Oct. 17, 2007.
3. Pfizer. MannKind and Pfizer Announce Collaboration for Certain Exubera Patients to Transition to MannKind’s Inhaled Insulin Therapy. Press Release, Sept. 15, 2008.
4. Cohen, T., Ed. Inhaled Biologics: Where Are We Now? oxfordglobal.com, April 13, 2023.
5. US Specialty Formulations. US Specialty Formulations Completes Phase I of Clinical Trials for the Qyndr Vaccine. Press Release, Sept. 7, 2023.
6. Research and Markets. Inhalation CDMO Global Market Report 2024. Market Research Report, April 2024.
7. Transparency Market Research. Asthma Biologics Market (Drug Class: Selective Immuno-suppressants, Interleukin Inhibitors, and Others; Distribution Channel: Retail Pharmacies, E-commerce, and Others)–Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 2023–2031. Market Research Report, October 2023.

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article details

BioPharm International®
Vol. 37, No. 8
September 2024
Pages: 7–9

Citation

When referring to this article, please cite it as Mirasol, F. Exploring Innovative Means for Biologics Delivery. BioPharm International 2024, 37 (8), 7–9.