By Rafael Escandon
Pfizer announced, surprisingly, on February 20, that they plan to discontinue commercial availability of Beqvez, their recently approved gene therapy (GT) for Hemophilia B. They also announced, in separate communications in mid and late 2024, their terminations of investments in a partnership for a Hemophilia A GT, and their discontinuation of a phase 3 study of their GT for Duchenne Muscular Dystrophy. This constellation of decisions made clear Pfizer’s conclusion of investments in Adeno-Associated-Viral (AAV) vector gene therapy programs across its portfolio. Despite this rare withdrawal and broad divestiture, opportunities for these programs remain, both for Pfizer and for those continuing to pursue GT as potentially transformative interventions for genetic diseases.
Beqvez is the first AAV GT to be second-to-market in a rare indication and is now the first approved GT to be simultaneously discontinued in the US, Canada and Europe. Pfizer cited challenges with its adoption (e.g., low demand) as leading the reasons for their decision. Discontinuing any approved drug or biologic program after such vast investments in research and development and multinational regulatory approvals is unusual, but shuttering an approved GT comes with additional and different implications to participants and patients than those for small molecules or biologics.
In particular, GTs offer, by nature, only a single opportunity to be dosed, and their effects may wear off over years or even decades, versus days to weeks for drugs. Importantly, GT effects cannot be increased, decreased or reversed, an underpinning of the common regulatory requirement for a decade or more of continued safety and efficacy monitoring after dosing. This translates to a heavier ethical weight and higher research burden, both for research participants and those sponsoring GT trials. Simply stopping or calling a GT trial complete at 30 days after the last participant’s dose would leave participants vulnerable to late-emerging safety events, as well as leaving the durability of any efficacy unmonitored. Failing to ensure a minimal threshold of long-term safety and efficacy monitoring if a program is abandoned compromises the balance and exchange of prospective benefit versus (long term) risk that GT research subjects accepted when consenting to trial participation.
With Beqvez, the FDA required Pfizer to monitor GT recipients for up to 15 years post-dosing. In BENEGENE-2, Beqvez’s pivotal trial, the majority of participants saw significant benefits in Factor IX expression, however some participants saw no either no benefit, or the benefits were small and temporary. In the Beqvez context, if long-term monitoring were to be discontinued, the absence of sponsor funding to support long-term data collection would compromise the ability to provide all stakeholders with long term safety and efficacy data and other valuable and generalizable knowledge from the research. Fortunately, it appears that Pfizer has committed to continuing follow-up.
This highlights the first opportunity. Setting the standard for responsible long-term monitoring of GT patients, even in discontinued programs, is as laudable as it is necessary. The combined use of new technologies and Pfizer’s internal know-how could produce a replicable, high fidelity, low cost and light-touch process which generates valuable data with low patient and investigator burdens. Such efficiencies could be shared with and adopted by past and any future companies who discontinue GT programs at any stage. This ensures useful and consistent future data collection by all at a lower cost and lower burden than a standard long-term clinical trial.
Next – since Beqvez is an AAV-GT, there is a high likelihood that a commercial supply was manufactured to support an efficient product launch, as well as to support the 200+ patient post-marketing trial required by the FDA. What will become of the expensive to produce GT supply slated for commercial and post-marketing study use is unknown. Will it sit in a freezer into perpetuity? Will it be returned to the company from which it was licensed? Or will it, tragically, be thawed and scrapped?
This is the second opportunity. Beqvez is an approved product in Canada, the USA and European Union, which have three of the most rigorous regulatory review processes in the world. While not zero, the probability of present or future catastrophic adverse events seems remote, and therefore, an opportunity to make the already manufactured supply available, without the $3.5 million USD cost per-[single]-dose, contains arguably less risk than it would for an investigational product. The impact of using this supply to, for example, unburden patients and the health care system(s) in (a) country(ies) afflicted with Hemophilia B without access to standards of care could hardly be higher. If such a gesture puts undue pressure on the first-to-market GT producer, then a region or a country with underserved patients where it and the western standard of care products are scarce or underutilized could be considered, assuming proper physician training in administration, immunosuppression and monitoring can be established and assured.
Third, since no further pursuit of R&D or commercial stage GT programs is planned by Pfizer, there is an opportunity to make available any trade secrets specific not just to Beqvez, but to their other recently discontinued GT programs. Myriad technical elements which are currently redacted from public documents and held as trade secrets could be shared broadly to benefit current and future GT programs in development. Any and all (among the dozens of) other companies who have discontinued GT programs could easily do the same, leading to greater transparency, potential efficiencies and optimization across the entire landscape of GTs. All these steps increase safety and potentially lower costs across the AAV GT platform.
The high risk and high cost of research, development and commercialization of AAV GTs is illustrated by the many programs that have recently struggled to raise the necessary capital to continue development or commercialization. Given the successes and potential of GT, and the observation that such interventions can be transformative to historically underserved rare disease populations is a success story. Giving up on these communities prematurely undervalues the sacrifices made by the clinical trial participants who didn’t benefit or only benefited transiently. An equally important part of capitalizing on clinical research successes is understanding the factors contributing to both failures and sub-optimal responses and not repeating them.
Benjamin Franklin refused to patent the designs for his stove, his lightning rod, and his bi-focal eyeglasses, despite all being his own innovations. Franklin’s belief was that “good ideas belong to humankind.” Jonas Salk believed the same for his polio vaccine. Thus, opportunities to share best practices, supplies of approved products, along with safety and technical information can, too, be such gifts – Ones received gratefully by patients and families with rare genetic diseases, wherever they may live.
Author: Rafael Escandon, DrPH, PhD, MPH, HEC-C
Affiliation: DGBI Clinical Research and Ethics Consulting, Bainbridge Island, WA, USA
Competing Interests: Principal and Founder of DGBI Clinical Research and Ethics Consultancy. No competing professional or financial interests to report.
Social media handles: Linkedin: https://www.linkedin.com/in/rafael-escandon-b23596/
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