In Vivo Gene Therapy

1. In vivo gene therapy has made major scientific progress. Where are we today in terms of commercial maturity vs. technical readiness?

VI: In vivo gene therapy is technically advanced, yet commercially immature. While the science has advanced enough to yield multiple approvals and robust clinical data, the industry's commercial readiness - including large-scale manufacturing, comprehensive chemistry, manufacturing, and controls (CMC), payer evidence, and sustainable launch models - is still evolving. The success of the next phase will depend as much on manufacturing and commercial execution as it will on biological innovation.

2. Is delivery advancing faster than manufacturing can support in in vivo gene therapy?

VI: Innovations in delivery, particularly in AAV capsid engineering and LNP refinement, are outpacing GMP manufacturing capacity and process development timelines. Upstream yields, downstream purification recovery rates, scalability, and analytical release testing remain bottlenecks that hinder the transition from discovery to clinic-ready supply chains. Although many programs demonstrate promising preclinical performance, scaling up, achieving process robustness, performing analytical characterization, and ensuring consistency remain significant challenges. Delivery innovation alone does not guarantee a commercially viable product.

3. At what point does manufacturing become the limiting factor for advancing programs to the clinic or market?

VI: Manufacturing usually becomes a limiting factor at the Phase II/III transition, when issues of scale-up, consistency, and cost constraints emerge. While early clinical supply can often be managed with less-optimized processes, regulatory expectations for comparability, scalability, product quality, and supply reliability increase substantially as programs approach registration and market launch. Programs also face avoidable delays in dose escalation, cohort expansion, and ultimately BLA/MAA submission timelines without robust process characterization and a qualified CDMO strategy in place prior to IND submission.

4. From a BD perspective, how do you balance CMC readiness vs. early clinical data when evaluating programs?

VI: Although clinical efficacy remains the primary value driver, CMC maturity is becoming an increasingly influential factor in risk-adjusted valuation. Although strong early data can justify investment despite manufacturing gaps, BD teams generally consider technical feasibility, platform maturity, and cost of goods (COGs) to be as important as clinical promise. The most attractive opportunities demonstrate differentiated clinical potential and a viable path to commercial manufacturing.

5. Do you see a real path to cost reduction, or is current pricing structurally tied to manufacturing constraints?

VI: Although there is a real path to cost reduction through better platforms, automation, and simplified processes, the economics are still structurally constrained by low volumes and complex release requirements. Near-term cost reduction is incremental, while transformative reduction depends on broadening indications, shared platform infrastructure, and regulatory harmonization around comparability. Reimbursement models will remain a major determinant of final pricing, but technology advances should reduce production costs over time.

6. What does recent experience tell us about the gap between innovation and reimbursement reality?

VI: The substantial gap is usually underappreciated at the inception of the gene therapy program. Reimbursement lags behind innovation due to uncertainty regarding long-term outcomes and high upfront costs. Even landmark clinical profiles do not guarantee access, as demonstrated by products like Zolgensma and Hemgenix, thus evidence generation frameworks must be co-developed with payers from Phase II onward. Payers also demand real-world evidence, which forces developers to bridge the gap with creative pricing models - such as annuities, or risk-limited access.

7. From a BD lens, what are the early warning signs that a gene therapy may struggle commercially post-approval?

VI: Warning signs include narrow differentiation from existing treatments, uncertain durability, complex administration requirements, limited pathways for physician adoption, and weak value propositions for payers. Manufacturing challenges that constrain supply or increase costs are potential significant concerns and weak post-market surveillance plans also indicate commercial vulnerability. Programs optimized solely for regulatory approval, without parallel development of a commercial infrastructure, consistently underperform revenue expectations post-launch.

8. How is the recent shift in investor sentiment influencing deal structures and partnership strategies in gene therapy?

VI: Risk aversion has significantly altered deal architecture as investors now demand proof of concept, preferably in the form of FIH results, in validated indications before committing. Upfront payments have decreased, and milestone-heavy, data-gated structures now dominate. This has prolonged preclinical development timelines and placed disproportionate pressure on biotech companies without platform differentiation or existing pharmaceutical industry relationships to bridge financial gaps. Companies are now expected to provide stronger evidence before receiving premium valuations - reducing tolerance for platform-only narratives without clinical support.

9. Are we moving toward new partnership models (e.g., staged payments, outcome-based deals) in this space?

VI: The field is moving toward staged payments, option structures, and outcomes-based economics - but the rate of adoption is slower than the discourse in the market suggests. Annuity-style installment payment agreements, which were piloted by Hemgenix, are the most operationally viable solution until more sophisticated risk-sharing infrastructure matures among payers and health systems. Outcome-based reimbursement arrangements are gaining attention, as long-term clinical durability is a central consideration for healthcare systems.

10. What needs to change first to unlock the next phase: biology, manufacturing, or business models?

VI: All three are important, but business models probably need to evolve first. The field has demonstrated significant biological potential - but scalable production and sustainable economics remain limiting factors. However, good biology and improved manufacturing alone cannot overcome reimbursement and adoption constraints. The next phase requires programs designed to generate evidence, scale CMC, and achieve payer acceptance from day one in the market. Improved access and reimbursement viability will also increase investor confidence in the sector.

11. What do companies most often underestimate in manufacturing planning for in vivo gene therapies?

VI: Companies often underestimate the time and resources necessary for process development, analytical method qualification, and regulatory alignment.  Initiating CDMO engagement too late and underinvesting in the process characterization studies required for IND filings is also a common mistake. So is underestimating the difficulty of transferring a process from research success to reproducible GMP execution. Manufacturing is often viewed as a downstream activity when, in reality, it influences development timelines, comparability strategies, and commercial feasibility. Investing early in CMC can significantly reduce the risk of execution later on.

12. Where do you see more value today: platform-based approaches or single-asset strategies?

VI: Today, platform-based approaches typically generate greater value because they mitigate technical risk and facilitate pipeline reuse. These approaches enable modular regulatory submissions, reusable analytical frameworks, and pipeline flexibility - which are not possible with single-asset programs. Although single-asset strategies may yield faster returns, they lack scalability and investor confidence in today’s risk-averse market. To compete for equivalent capital, single-asset strategies must demonstrate exceptional differentiation, clean CMC, and a clear reimbursement path.

13. What is one assumption about in vivo gene therapy that you think is wrong or outdated?

Vi: That gene therapy durability is a solved problem, while long-term expression data across approved products remains limited. Redosing, once considered clinically irrelevant, is now a serious scientific and commercial question. The "one-and-done" paradigm that underpins most current pricing and outcomes-based contract rationale is challenged by pre-existing immunity, vector seroprevalence, and waning expression in pediatric patients as they grow. Next-generation delivery requires tissue-specific, modular systems that can address efficacy, safety, and manufacturability simultaneously.

14. And as the last question, if you had to give one piece of advice to a biotech entering in vivo gene therapy today, what would it be?

VI: Invest in manufacturing process development as early and aggressively as you do in biology. Once clinical progression begins, regulatory and commercial timelines are unforgiving - and process-related CMC deficiencies are the most common cause of preventable program delay. Having a differentiated candidate means little if you cannot manufacture it, characterize it analytically, and supply it at a cost that supports a viable access model. The most successful programs are not necessarily the ones with the most innovative science - but the ones that can reliably deliver meaningful clinical value on a large scale.

--PFAm Issue 08--