Using its deep virology expertise and targeted genome editing technologies, Agenovir is on a mission to develop novel antiviral therapeutics, bringing hope to millions of patients who suffer from devastating, persistent viral infections. In particular, the South San Francisco start-up is using CRISPR-Cas9 technology to create topical treatments targeting immune system-weakening cytomegalovirus, cervical cancer-causing human papillomavirus and other viral infections.

Leading this charge is Agenovir’s president and CEO, Dirk Thye, M.D., who brings 20 years of drug development experience to the company. Most recently, Thye served as Chief Medical Officer of Cidara, Inc., building and managing all aspects of drug development, including the filing of several Investigational New Drug (“IND”) applications and advancement of two programs into Phase 2 clinical trials. Previously, he co-founded Cerexa and served as president for the last several years of his tenure, following the acquisition by Forest Laboratories. While at Cerexa, Thye led the development of ceftaroline (Teflaro®) from pre-IND to New Drug Application filing, FDA Advisory Committee and approval. Dr. Thye was a founder and Senior Vice President of Clinical Development for Peninsula Pharmaceuticals (acquired by Johnson & Johnson in 2005), a company that developed doripenem (Doribax®) for severe bacterial infections in hospitalized patients.

WuXi AppTec Communications, as part of a new industry series, recently spoke with Thye, about the challenges of directing precise gene sequences, Agenovir’s clinical direction and goals, as well as the future benefits and obstacles of this new ground-breaking treatment.

WuXi: What diseases are best treated with therapeutic gene editing?

Dirk Thye: The best disease targets for gene editing drug products are those that have a well-defined etiology linked to a specific genetic mutation.  Furthermore, disrupting or disabling a gene defect is technically easier than attempting to repair or replace a defective gene with an appropriately functioning copy. Agenovir leverages these advantages by focusing on disrupting or eliminating latent viral infections in humans, which cause a wide variety of serious and deadly diseases. The company’s first program is targeted at human papilloma virus (HPV), which causes 95% of all cervical cancer in women, anal dysplasia and cancer in both men and women, and is an increasingly prevalent cause of head and neck cancer. HPV represents an attractive target for gene editing as the viral reservoir is local and can be accessed with a topical therapy, thus reducing the complexity of drug delivery.  In addition, disruption or elimination of the virus eradicates the fundamental etiologic factor leading to dysplasia or cancer in these patients.

Other viral targets of interest to us are hepatitis B virus (HBV), cytomegalovirus (CMC), Epstein-Barr virus (EBV), and herpes simplex virus (HSV).  All of these disease targets share the common feature of being caused by foreign (viral) DNA within the human cell.  By disrupting or eliminating this foreign DNA, the cause of disease is eliminated.

WuXi: Can you describe the type of gene editing Agenovir is using and how the company is applying it?

Dirk Thye: Agenovir has developed a variety of CRISPR-nuclease products that specifically target viral DNA. These drug products emerged from thorough screening assays that focus on genetic specificity and potency. Our initial programs are aimed at viral disease targets for which drug delivery is less challenging.  In the case of HPV, we use topical application of our drug product within a lipid nanoparticle (LNP) to a local viral reservoir located within epithelium at the surface of the body. This anatomical location can be accessed manually by the physician and the topical application avoids the risks associated with systemic exposure.  In the case of CMV and EBV, we use an ex vivo approach, in which human cells used for a bone marrow transplant are treated prior to patient administration. In the case of HBV, we use a systemically administered LNP approach, as LNP delivery has been shown to be effective to the liver

WuXi: How does Agenovir’s approach differ from other companies in the gene editing field?

Dirk Thye: I believe the viral reservoirs we are targeting represent a technically less challenging disease area than many of the typical targets for gene editing. Our lead program in HPV is a good example of these technical advantages. First, delivery of the gene editing drug product, which is generally considered the biggest challenge in the field, is mitigated by a topical approach to a local viral reservoir at the surface of the body. Delivering to a small anatomical area that can be manually accessed provides a significant advantage.  In addition, as opposed to correcting or modifying a gene defect, we are instead specifically targeting viral DNA for destruction. This commonly leads to death of the HPV infected cell, which in our case is a desirable outcome as this could represent a cell that has the potential to cause cancer. If we were attempting to correct a gene defect, cell death would be an adverse outcome, but for our disease target it’s actually the desired goal.  This fact provides us meaningful technical advantages with respect to the safety and efficacy objectives of our development program

WuXi: What kinds of global partnerships do you have or plan to pursue?

Dirk Thye: Celgene is an investor in Agenovir today. We do not have any global partnerships to date, but we would like to partner with the right pharmaceutical company to expand our development capabilities. In addition to R&D funding, the right pharmaceutical partner can bring scientific and commercial expertise to supplement our own, especially in complex therapeutic indications and markets such as HBV. Additionally, a pharmaceutical partner may have an approved drug, development candidate or delivery technology that provides unique synergy with the CRISPR platform, and we welcome discussions with such companies.

WuXi: What manufacturing challenges do you face with commercializing gene editing products?

Dirk Thye: The major manufacturing challenges are primarily related to the nascent nature of the field.  RNA manufacturing, as well as manufacturing of the delivery technology, is less developed than in the field of small molecule drugs. The relatively low number of vendors, less experience in GMP manufacturing, limited experience in large scale manufacturing, and few clinical trial successes with manufactured drug product all represent challenges in this field.  However, there is a tremendous amount of time, money and effort allocated to these challenges by many companies in the gene editing field. The manufacturing sector is maturing very quickly, and new advances in the process are continually occurring. I’m optimistic that the manufacturing sector will progress very rapidly, with many strong companies emerging as legitimate competitors within the sector.

WuXi: How should gene editing therapies be priced?

Dirk Thye: The pricing of drugs is obviously a very controversial topic at this time. At this point in the history of gene editing technologies, it’s not clear how these will be priced.  As with other therapeutic modalities, the specific indication, risk-benefit analysis, pharmacoeconomics and cost of development will all be important factors in considering the price of an approved drug. Because gene therapy drugs are so technically complicated and require a variety of sophisticated components, in addition to an adjunctive delivery technology, the initial cost could be relatively high. The cost of manufacturing and development also represents a very large cost burden for the company.  However, the tremendous potential benefits that these products may confer upon humanity will provide a sound pharmacoeconomic justification for the costs of these new technologies. 

WuXi: What key regulatory concerns or hurdles need to be overcome with approaches using gene editing?

Dirk Thye: The regulatory pathway for gene editing products is not well established.  However, there have been some early successes and progress with respect to defining clear nonclinical requirements and expectations for clinical development. The potential for off-target mutagenicity, both acute and long term, is an important issue for extensive study for any new gene editing product.

As these biologic constructs are complex and often composed of several components, investigating the pharmacokinetics and pharmacodynamics is complicated and requires the development of assays that are not typical and occasionally not commercially available.

Obviously, as with all new drugs, the risk benefit ratio for the initial patient population and indication must be carefully considered and thoughtfully justified. This is particularly critical in the case of gene editing, where potential for genetic mutation as an adverse event must be considered.  This and the other regulatory challenges mentioned exist for all new drugs, but in the case of gene editing, require a different thought process and approach to these issues.

WuXi: How will gene editing technology evolve over the next five years?

Dirk Thye: The patent landscape for CRISPR-Cas9 is particularly complicated right now, with two different groups claiming victory for the foundational IP. We believe that over the course of the next five years, the patent landscape will become clear and pathways for rational licensing will be established. Simultaneously, the technology will continue to evolve rapidly in the areas of novel nucleases, preclinical model systems, bioanalytical assays and delivery platforms. We believe gene editing technology will be used in clinical trials, some of which will be successful and others which will not, just like any new technology.

For Agenovir specifically, over the next five years, we expect to complete clinical studies in more than one indication, demonstrating our innovative approach to treating persistent viruses to be successful.