The Vector
Editorial Team
Jon Brudvig, PhD – Editor, The Vector
Jessica Schneller, PhD – Associate Editor, The Vector
Wan Du, MD, PhD – Junior Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
The Policy Summit Starts Monday!
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Hello ASGCT Members,
I hope you’re looking forward to next week’s Policy Summit as much as I am! As a past attendee, I can confidently say this event has always been a great opportunity to share information about the regulatory side of the field and discuss how best to ensure timely access to CGTs for patients. The forum is unique, bringing together product developers, regulators, payors, advocacy organizations, and more, to address existing barriers to access for these therapies. This year’s program features high-profile speakers that you won’t want to miss, including: FDA’s Nicole Verdun, MD; CMMI’s Laura McWright, JD; and ARPA-H’s Renee Wegrzyn, PhD. The fireside chat format allows for more direct interaction with speakers, so be sure to bring your questions! Both in-person and virtual attendees can view the event on the virtual platform and can access on-demand recordings for 30 days. If you’ll be in person in Washington, D.C., join me at the networking reception at the end of the first day, September 18, to hear remarks from Congressman Scott Peters (CA-50). Take a look at the agenda and register today; I hope to see you there!
If you enjoy the Policy Summit and you’d be interested in spending a paid year shaping policy on Capitol Hill, consider applying for the Congressional Policy Fellowship. ASGCT and the American Association for the Advancement of Science (AAAS) will select one fellow each year to provide science-based guidance to federal policy makers and elevate awareness of ASGCT. For more information about the position, benefits, and application, visit this section of ASGCT’s website.
Finally, next month marks the return of ASGCT Insights! Registration is open for five, two-hour sessions the week of October 16. Check out the speaker lineup and register for one (or all) of the sessions:
I hope to meet many of you in Washington, D.C. next week.
Take care,
Jennifer Wellman
ASGCT Board of Directors
Breaking Through
Engineered arylsulfatase A with increased activity, stability and brain delivery for therapy of metachromatic leukodystrophy
Yaghootfam C, Sylvester M, Turk B, Gieselmann V, Matzner U
DOI: https://doi.org/10.1016/j.ymthe.2023.08.019
Summary by Jon Brudvig, PhD
Lysosomal storage disorders (LSDs), typically caused by genetic deficiencies in lysosomal enzymes, have been a productive area for therapeutic development. To date, 11 enzyme replacement therapies (ERTs) have been approved for use in the clinic, treating disease manifestations and improving quality of life for thousands of patients. For some LSDs, however, the development of effective ERTs has lagged due to numerous challenges inherent to the therapeutic modality. An effective ERT must reach widely distributed target cell populations following administration, circumventing humoral immunity and endogenous clearance mechanisms. Once in the vicinity of the target cells, it must be internalized and delivered to the lysosome in high enough concentrations to reduce accumulated substrate. Finally, the ERT must offer sustained activity in between infusions, even while residing in a catabolic organelle. In a recent study in Molecular Therapy, Claudia Yaghootfam et al. showcase innovative strategies for overcoming each of these obstacles, culminating in what appears to be a highly effective ERT for metachromatic leukodystrophy (MLD).
The authors started by engineering an increased lysosomal half-life for human arylsulfatase A (hASA), the enzyme that is deficient in MLD. Since hASA is proteolytically degraded by cathepsin proteases in the lysosome, the authors hypothesized that mutations that block cathepsin activity could lead to a longer-lived enzyme. Indeed, an E424A substitution increased the half-life of hASA by a factor of 3.4, but also abolished lysosomal targeting. To recover appropriate targeting, the authors tagged the protein with an ApoEII motif that facilitates cellular uptake via low-density lipoprotein receptors. This strategy recovered cellular targeting while also further increasing the serum half-life. Finally, the authors incorporated a previously reported triple substitution (M202V/T286L/R291) that has been shown to increase the specific activity of the enzyme. The resulting enzyme, called SuPerTurbo-ASA, had an increased half-life by 7-fold, increased cellular uptake by 118-fold, and increased specific activity by 3-fold as compared to wild type hASA.
Results in 12-month-old MLD mice were impressive, outperforming prior studies of MLD ERT by a wide margin. In the brain, SuPerTurbo reduced storage material by an impressive 60% following four weekly low-dose (10 mg/kg) intravenous injections, whereas the wild type hASA comparator achieved only an 8% reduction. Presumably, this was due not only to the enhanced stability and specific activity of the engineered hASA, but also from increased brain penetration from the ApoEII motif, which acts as a BBB shuttle. Importantly, the mutations introduced for engineering did not result in any signs of immunogenicity.
It remains to be seen whether these promising early results will hold in long-term studies, and whether the strategy will translate to the clinic. MLD is an extremely challenging disease that must be treated early to provide clinical benefit, as evidenced by the clinical trial data for Libmeldy, a recently approved ex vivo autologous HSC gene therapy for MLD. An engineered ERT, such as SuPerTurbo-ASA, could provide a much-needed option for rapid treatment following diagnosis, whether used alone or as a stopgap measure prior to treatment with a gene therapy.
From Molecular Therapy
Active Calls for Papers
RNA and epigenetic editing: A new generation of precision therapeutics
Novel therapeutic targets and biomarker development
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Society News
Carl June, Michel Sadelain Receive 2024 Breakthrough Prize
Congratulations to ASGCT Members Carl June, MD, and Michel Sadelain, MD, PhD, for receiving the 2024 Breakthrough Prize in Life Sciences! The Breakthrough Prize Foundation announced today that Drs. June and Sadelain were recognized for their work in CAR T-cell therapy to treat certain types of cancer. Learn more about the award and the winners here.
Oct. 16-17: NORD Breakthrough Summit in Washington, D.C.
Register now for the National Organization for Rare Disorders (NORD) Rare Disease and Orphan Products Breakthrough Summit, held in person in Washington, D.C. Oct. 16-17. This event brings together rare disease experts, patient advocates, and more from around the world to tackle the most pressing issues facing the rare disease community. Learn more on NORD's website.
Working Outside the U.S.? Take Our Survey by Oct. 31
As ASGCT continues to grow, so does our impact on the global gene and cell therapy community. ASGCT values your input and wants to know how the Society can better meet your needs to ensure that CGTs become a global reality. If you are working outside of the U.S., please fill out this survey by Oct. 31 to share your perspective on ASGCT's scientific programming, networking opportunities, and more.
Career Center
Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center for great opportunities with industry, government, and academic organizations. Sign up to receive alerts for open jobs in your area.
If you're from a recruiting institution, advertise in the Featured Jobs section to target the 6,000+ audience of The Vector.
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Featured Jobs
Public Policy
Don’t Miss Next Week’s Policy Summit!
ASGCT's Policy Summit, which takes place Sept. 18-19 in Washington, D.C., features regulatory-focused sessions on developing standards, patient-centered clinical development, FDA’s recent organizational changes, and more. Register to participate virtually or in person, and view all content on demand for 30 days.
1. Discuss CGT growth and innovation
Listen to the director of the FDA CBER Office of Therapeutic Products (OTP), Nicole Verdun, MD, discuss the new super office, including plans to accommodate substantial growth in the CGT field and how to support the development of novel products under their jurisdiction.
2. Gain invaluable insights into federal policy efforts
Hear about the Center for Medicare & Medicaid Innovation's (CMMI) recent Cell and Gene Therapy Access Model and other federal policy efforts impacting payment policy at a fireside chat with Laura McWright, JD.
3. Explore public-private partnerships and health system readiness for CGTs
Learn how public-private partnerships are fueling the transformative potential of cell and gene therapies. Chat with ARPA-H Director Renee Wegrzyn, PhD, about the new agency’s priorities and how these support CGT development.
ASGCT's Policy Summit connects you with policy and industry leaders. This year will feature networking opportunities including a Sept. 18 reception for in-person attendees with opening remarks from Congressman Scott Peters (CA-50). If you're attending virtually, find a full list of other attendees on the free ASGCT Events app (available on the Apple App Store and Google Play). You’ll hear and discuss a variety of stakeholder perspectives—and how they inform regulatory, legislative, and payment policies that impact gene and cell therapy development. It’s not too late to join your colleagues online or in Washington, D.C.!
CMS Releases IPPS Final Rule
The Centers for Medicare & Medicaid Services (CMS) has issued a final rule detailing Medicare payment rates and regulations for inpatient stays. CMS annually updates the rules and payment methods for Medicare fee-for-service payments and has completed this year’s rule-making cycle.
The final rule focuses on the Inpatient Prospective Payment System (IPPS) for fiscal year 2024 (FY24). The Society submitted comments earlier this year asking CMS to reconsider several of the new proposals. The IPPS final rule sets:
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New timelines for the New Technology Add-on Payment (NTAP), designed to encourage the use of new, more costly technologies when base payment rates haven't yet accounted for these expenses. CMS has finalized a change requiring FDA-approved new products to receive the add-on payment if approved in May rather than the previous deadline of July, effectively narrowing the window for manufacturers seeking this payment.
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ASGCT has significant concerns with CMS’ proposal to establish an earlier marketing authorization deadline for products as a part of eligibility for the NTAP. Restricting access to the NTAP for future gene and cell therapies could have significant implications for patients’ access to new, life-changing therapies arriving on the market. Modifying the deadline for FDA marketing authorization could jeopardize the ability of manufacturers to submit applications in a time that maintains their eligibility for the NTAP.
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Technical adjustments to the calculation of relative weights for MS-DRG 018, which is the DRG used to reimburse CAR T-cell therapies. These changes involve excluding certain claims with specific diagnosis and condition codes from the calculation of average costs for this DRG, and discontinuing the use of a standardized drug charge proxy for identifying clinical trials and expanded access use cases.
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CMS will eliminate the $373,000 proxy used to identify clinical trial claims. ASGCT is concerned that this change could lead to CMS inadvertently including inappropriate clinical trial cases in the calculation of the relative weight of MS-DRG 018. While coding accuracy has no doubt improved, the proxy amount remains a valuable way to ensure coding mistakes do not inadvertently lead to calculations that do not reflect CMS policy.
Several stakeholders have expressed concerns with these FY24 changes and may seek additional support from CMS in the coming months. ASGCT will continue to engage with CMS as opportunities arise.
Biden Administration Names First Drugs to Enter Pricing Negotiations Under Medicare
As part of President Biden’s Executive Order on lowering prescription drug costs, codified by the Inflation Reduction Act (IRA), the Secretary of Health and Human Services (HHS) will work to negotiate prices for selected high-cost prescription drugs for Medicare beneficiaries.
The Biden-Harris administration has announced the first 10 drugs that will undergo price negotiations under the IRA. HHS has released several fact sheets detailing timelines for negotiation and implementation. The pricing negotiations are set to take place before 2026, and companies failing to participate face penalties such as additional taxes or losing Medicare and Medicaid coverage. Concerns have been raised about potential unintended consequences and reduced innovation as a result of the price negotiations.
Appropriations Negotiations Heat Up as Congress Returns from Recess
Appropriations bills are expected to be negotiated as the U.S. House of Representatives and U.S. Senate return from the district work period. To date, the Senate Appropriations Committee has passed all 12 funding bills. These will move to a full floor vote this month and require a 60-vote majority to pass. The House Appropriations Committee has passed 10 of 12 bills, with the Labor-HHS bill still in sub-committee review. Currently, the House Labor-HHS and Agriculture-FDA bills propose lower funding levels than their Senate counterparts. This month, expect a significant debate in Congress over funding for the government, with current funding set to expire on Sept.30.
With just one month to pass bills in both chambers, plus time for reconciliation between House and Senate versions, a short-term continuing resolution (CR) is expected. Several members of the House have noted they will vote against a CR unless policy conditions are met, such as border security and lower overall funding levels. ASGCT will continue to report on funding packages and any policy riders included in the eventual CR.
Industry News
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