Adeno-Associated Virus Gene Therapy Development: Early Planning and Regulatory Considerations to Advance the Platform Vector Gene Therapy Program

Abstract

Gene therapy development presents multiple challenges, and early planning is vital in the successful implementation of such programs. The Platform Vector Gene Therapy (PaVe-GT) program is a National Institutes of Health (NIH) initiative developing adeno-associated virus (AAV) gene therapies for four low-prevalence rare diseases. Utilizing the platform-based approach, the program aims to incorporate efficiencies throughout the preclinical and clinical development processes followed by public dissemination of scientific and regulatory learnings. Early in development, the establishment of a Target Product Profile (TPP) by the research team is a critical step to guide product development and align preclinical studies to clinical objectives. Based on the specific needs of the investigational product as defined in the TPP, an overall regulatory strategy can then be outlined to meet the regulatory requirements for the first-in-human clinical trials. During the preclinical phase of development, sponsors may request meetings with the Food and Drug Administration (FDA) to gather feedback on the planned studies and regulatory strategy. To pave the way for PaVe-GT's first investigational AAV gene therapy lead candidate, AAV9-hPCCA, we sought early feedback from the FDA utilizing an INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meeting. Here, we elaborate on the value of establishing a TPP and the FDA INTERACT meeting by including our initial AAV9-hPCCA TPP, detailing our INTERACT meeting experience, providing all corresponding regulatory documentation, and highlighting lessons learned. The regulatory documents along with templates developed by our program can also be found on the PaVe-GT website (https://pave-gt.ncats.nih.gov/). This communication aims to provide stakeholders with resources that can be applied to drug development programs in establishing a viable regulatory path to clinical trial initiation.

Keywords: AAV9; INTERACT meeting; PCCA; PaVe-GT; gene therapy; propionic acidemia; rare diseases; target product profile.

Figure 1.

Platform Vector Gene Therapy (PaVe-GT) approach. (A) To test the PaVe-GT hypothesis, our approach includes utilizing AAV as a platform vector, similar preclinical development processes, study designs, regulatory pathway and common clinical protocol elements, wherever possible. The diseases under study in the PaVe-GT platform include four rare diseases. The two organic acidemias under study are propionic acidemia (caused by PCCA deficiency) and isolated methylmalonic acidemia (MMAB deficiency/cobalamin type B methylmalonic acidemia). The two congenital myasthenic syndromes under study are COLQ deficiency and DOK7 deficiency. The outcomes of the program are being publicly shared on the PaVe-GT website. (B) The PaVe-GT team is comprised of basic researchers, disease and drug development experts supported by a strong project management team as depicted in the figure. All disciplines work in coordination, and the coordinated efforts of all team members are instrumental for the success of the program.

Figure 2.

Regulatory milestones and TPP. (A) This figure highlights how each component of a TPP can inform various aspects of the preclinical development program and assist in the study design and implementation to maximize program success and shorten the timeline. ROA: Route of administration. (B) After selection of a lead candidate, early establishment of a TPP as a guiding tool, in combination with stage appropriate regulatory interactions, can be instrumental for successfully moving a program through the various phases of development. Regulatory interactions can be initiated during early product development and continue until the IND submission, which is a significant milestone in the process and allows for the initiation of the FIH trial. Late-stage product development also entails the TPP and continued regulatory interactions (Note: late-stages not discussed in the article).

Figure 3.

Regulatory strategy for AAV9-hPCCA. (A) AAV9-hPCCA regulatory strategy is outlined. The first milestone was an INTERACT meeting and the feedback helped us move the program forward and prepare for a subsequent pre-IND meeting. For this program, FIH trials will commence after (FDA)’s review of our IND (with receipt of an FDA safe-to-proceed) and completion of other necessary clinical steps. (B) INTERACT meeting goals, timing and topics within scope are specified. (C) AAV9-hPCCA INTERACT package contents included in vivo POC study results, IND enabling Good Laboratory Practice (GLP) toxicology study plan, CMC, and clinical information. (D) Logistical information related to the procedures and timelines for an INTERACT meeting.

Figure 4.

Approach utilized by the PaVe-GT team for the INTERACT package preparation. (A) Our process for compilation of the package can be divided into three stages: strategy, implementation, and documentation. (B) FDA resources valuable for INTERACT package preparation and defining the drug development plan are included along with hyperlinks. (C) The core project management team led the drafting and package preparation working closely with the technical leads, regulatory experts, and clinicians. (D) Steps and timeline of AAV9-hPCCA INTERACT package preparation: Upon initial due diligence and planning, we held a kick-off meeting to inform all team members of the scope and content of an INTERACT meeting request and package. Subsequently, we discussed in smaller and larger groups to generate an initial draft of questions along with a supporting summary. Open dialogue and discussions were needed to solidify the development plan and finalize section drafts. The final stages included reviewing the complete package, editing, and formatting.

Figure 5.

Major takeaways from the AAV9-hPCCA INTERACT meeting experience. The left panel shows the major steps in the FDA process for review of the INTERACT meeting package. Upon reviewing our package, FDA provided feedback in the form of preliminary written responses (top panel). A few selected topics were discussed during the teleconference and major takeaways from the discussion during the INTERACT meeting are listed (bottom panel).

Figure 6.

Do’s and don’ts during early regulatory interactions. For a productive discussion, it is important to plan and prepare for regulatory interactions. These are suggested do’s and don’ts based on our experience.