Tackling 3 Challenges In Developing An Inhaled Gene Therapy
By Joan Lau, Ph.D., Spirovant
A progressive disease that limits life expectancy, cystic fibrosis (CF) currently has no cure — and its standard of care urgently needs updating. While current treatments target symptoms rather than causes, the development of novel therapeutics addressing the underlying genetic cause of the disease has the potential to reverse lung or organ damage. This is especially important for those who do not respond to or do not tolerate approved modulator therapies; of the approximately 40,000 people in the U.S. and an additional 70,000 people worldwide living with CF, roughly 10 percent do not respond to the current standard of care due to their specific genetic mutations.
As a monogenic disorder, CF is an ideal candidate for gene therapy. These therapies have tremendous potential to treat underlying genetic mutations that affect the CFTR gene, which plays a critical role in appropriate hydration of airway mucus and lung function. By delivering a new correct version of the faulty CFTR gene into a CF patient’s cells, gene therapy gives the patient the ability to make normal CFTR protein, opening the door to a new method of treating this debilitating disease.
Providing gene therapy has therefore become urgent, and the development of an effective delivery system or inhaler — which provides direct access to the most seriously affected cells lining the respiratory tract — is an additional critical need. These promising innovations bring specific challenges in both delivery and manufacturing. My company’s experience with the development of gene therapy and the challenges we faced associated with making that therapy inhalable are worth examining.
Tackling Challenge 1: Therapeutic Delivery
To develop an inhaled gene therapy, viral vector biology and chemistry must merge with drug delivery device aerosol physics. By combining our viral vector with biologic-friendly nebulizers, we have been able to better understand their interactions and maximally and precisely target airway epithelia.
For us, achieving this required bringing drug inhalation expertise in-house by hiring experts as full-time employees or consultants. And, by partnering with specialized contract research that focuses on formulation and delivery of viral vectors, we have learned how gene therapy is most efficiently and effectively delivered to the lung, making it possible to satisfy IND application requirements. In addition, supplying IND-enabling GLP pharm/tox studies with clinical-grade product has allowed for more accurate lung-deposited dose estimations and reduced comparability risks when going from nonclinical to clinical use.
Tackling Challenge 2: Efficiencies In Clinical Development And Manufacturing
This combined approach to drug development creates efficiencies and innovations that advance gene therapy and its effective delivery and also improves clinical studies. For example, by incorporating design elements in our vector, we saw improvement in CFTR transgene expression by orders of magnitude in comparison to vectors that were used in the 1990s to develop gene therapies for CF. In addition, the development of robust cellular in vitro assays using primary cells derived from human lungs that have a high predictive value for clinical efficacy gave us powerful tools to assess the potency and cell-specificity for inhaled gene therapies. These assays are an important innovation for both nonclinical and clinical development phases.
We also identified a relevant animal species, the ferret, which closely resembles human lung anatomy and disease pathology for in vivo safety, biodistribution, and pharmacology studies of inhaled gene therapies. The ferret was selected because (1) our AAV vector has demonstrated similar potency for ferret airway epithelia and (2) performing studies in CF ferrets closely recapitulates the hallmarks of CF lung disease.
Likewise, early investments in well-characterized drug–inhaler device interactions are necessary to support both clinical and nonclinical development. In particular, comprehensive studies early on enabled understanding of how stable the drug is in the device, how much drug comes out of the nebulizer, and how much of that drug enters the lung. This allowed precise translation of clinical doses from nonclinical studies.
Tackling Challenge 3: Preparing For Future Manufacturing Needs
In addition to current development work, companies must make investments that will support expansion of key program components. In our case, we built a viral vector core and end-to-end process development lab with the infrastructure capable of producing research-grade drug candidate screening preparations and larger material amounts at quantity and quality suitable for non-GLP dose range finding studies and IND-enabling GLP toxicology studies. Better production systems were enabled by leveraging a multidisciplinary team that includes process, analytical, and formulation specialists with years of viral vector manufacturing experience. This lab enables platform processes to be built with an eye on late-stage demands, allowing Spirovant to supply nonclinical and clinical studies with consistent, high-quality material early on, decreasing the need for comparability studies later during drug development. We are paying specific attention to establishing appropriate production models and employing state-of-the-art equipment (for example, a high-performance, single-use benchtop bioreactor system that accelerates development of drug candidates), which allow for accelerated development and early understanding of process parameters.
Moving Forward In The Fight Against CF
These innovations and investments are necessary to help those living with CF for whom the current standard of care is inadequate. While average life expectancy has increased from 30 to 50 years since 1990, people living with CF still face tremendous quality of life challenges. CF doesn’t just impact a person’s health; it affects their relationships and well-being by making it impossible to see loved ones because of the risk of catching a potentially life-threatening virus. As such, it often means missing out on important life events because of lengthy hospital stays.
While the jury is still out on the clinical success of inhaled gene therapies, there are many examples in animal models of diseases that highlight their enormous potential. These include models of cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, surfactant protein deficiency and primary ciliary dyskinesia demonstrating the benefit of locally delivered viral vector-based gene therapies or nanoparticles that contain RNA or DNA. While other pharmaceutical companies, such as 4D Molecular Therapeutics and Arcturus, are developing inhaled gene therapies for respiratory diseases, our use of augmenters alongside AAV to achieve the necessary potency to correct the genetic phenotype and ultimately benefit patients is unique.
We are at a pivotal moment in the treatment of respiratory diseases. Inhalers hold tremendous potential for delivery of high concentrations of gene therapy directly into the lung. Considering the promise shown in early data — and the ability of the inhaler to deliver effective gene therapy where it’s needed most — investment and innovation in this area are overdue. But most importantly, it signals hope for respiratory disease patients with unmet needs, especially those with CF, for whom the standard of care has thus far been inadequate.
About The Author:
Joan Lau, Ph.D., has more than 20 years of executive leadership experience, including as chief executive officer, chief operating officer, trustee, and non-executive director. In 2016, she co-founded Talee Bio, renamed Spirovant after its acquisition, a company focused on discovery and development of gene therapies for respiratory diseases, and currently serves as its Chief Executive Officer. In 2013, she co-founded and became partner of Militia Hill Ventures, which creates and builds innovative life science entities. She has been recognized as a Philadelphia Entrepreneur of Year by Ernst & Young and as a Woman of Distinction by the Philadelphia Business Journal.