Jacques Galipeau, MD
President, ISCT (2022-2024)
Associate Dean for Therapeutics Development
UW-Madison School of Medicine and Public Health
The New York Times recently reported that Kendric Cromer, a 12-year-old boy in Washington, D.C., is the first commercial patient to begin the newly FDA-approved bluebird bio’s Sickle Cell Gene Therapyi. “Sickle cell always steals my dreams and interrupts all the things I want to do. I want to be cured,” he said. Kendric — whose family’s health insurance agreed to cover the procedure — began his treatment on May 1st, 2024, at Children’s National Hospital in Washington. Kendric’s journey and his chance of a one-and-done cure of a dreadful condition with a CGT (Cell and Gene Therapy) exemplify precisely what we as members of ISCT aspire to develop and deploy for catastrophic disease with unmet medical needs.
Beyond the great science and bluebird bio’s and Vertex’sii herculean efforts at navigating FDA marketing approval for their respective Sickle Cell gene therapies, we must appreciate the monumental obstacles to global access and deployment for this condition and other disorders for which curative commercial CGTs exist. These are in order of importance: payor, provider and patient.
Focusing on the Sickle Cell Disease (SCD) use case, there are roughly 100,000 individuals living with the disease in the US and 20 million worldwide. bluebird bio estimates it can treat only 85 to 105 patients each year — and that includes not just SCD, but also patients with a beta-thalassemia — who can receive a similar gene therapy. Medical centers also have the capacity to handle only a limited number of gene therapy patients. Each person needs expert and intensive care. After a patient’s stem cells have been modified and the patient treated, the patient must stay in the hospital for a month. For most of that time, patients are severely ill from powerful chemotherapy. For example, Children’s National can accept only about 10 of these gene therapy patients a year. Therefore, a very small fraction of 100,000 US SCD patients will be able to receive this treatment in the foreseeable future.
Bluebird lists a price of $3.1 million for its gene therapy, called Lyfgenia. It’s one of the highest prices ever for a treatment. The choice of who would go first came down to whose insurance comes through. In the US, one-third of patients with SCD have commercial health insuranceiii. Whether most plans are sufficiently robust to cover the cost of Lyfgenia as well as the additional clinical care – in essence, an autologous bone marrow transplant - which incurs an additional cost of at least $250,000 is an element of concern.
Most SCD patients without commercial insurance will have government-sponsored Medicare, Medicaid or are self-insured. Medicare is a federal health insurance program administered by the Centers for Medicare & Medicaid Services (CMS) for people age 65 years or older, as well as those with disabilities or End-Stage Renal Disease. 11,790 Medicare SCD beneficiaries were identified in a 2016 census and more than four out of five Medicare beneficiaries with SCD were non-elderly (less than 65 years old) and obtained Medicare coverage through disability insurance benefitsiv. CMS recently published FY 2025 Medicare Hospital Inpatient Prospective Payment System (IPPS) Proposed Rule where the proposed 75% New Technology Add-on Payment (NTAP) amount for sickle cell disease gene therapies does not come close to fixing the reimbursement concerns associated with delivering a product at that price point to CMS beneficiaries. Since CMS will cover no more than 75% of SCD gene therapy drug cost, this leaves healthcare enterprises facing colossal losses on seeking reimbursement for drug acquisition. Medicaid, which varies by State, is worse still in regard to reimbursement rate. Although there are more than 78 FACT accredited pediatric stem cell transplant centers in USA including the Southeastern States where most patients with SCD live, there will be substantial hesitancy for these centers to adopt and deploy this therapy for a local populace considering the unresolved financial downside risk for the healthcare enterprises. Therefore, the true total addressable market for SCD will be restricted to patients with adequate commercial insurance who live proximately to a select few urban clinical centers of excellence with sterling financial resilience.
Even though Kenric’s parents’ insurance was quick to approve the treatment, the insurance payments are only part of what it will cost his family in out-of-pocket expenses – and this latter financial toxicity may be an important element in patient hesitancy to engage in a one-and-done curative therapy even through the cost of the drug and clinical care are covered by a third party. However, real world deployment of CGTs requiring expert and intensive care from designated centers of excellence have important limitations regarding access. The evolving post marketing approval deployment of CAR-T in the real-world setting exemplifies this reality. To make CAR-T therapies, the patient’s own T cells are extracted during a two-day process called apheresis. Manufacturers then alter the cells for weeks before sending the final product back to the facility for treatment. After the infusion, patients are required to stay near the treatment center for up to a month to monitor for potentially life-threatening side effects. That one-month monitoring requirement presents the biggest logistics challenge for most patients. Indeed, the UK experience in real world deployment of commercial CGT speaks to this reality. The UK MHRA was an early adopter of SCD gene therapy with it being the first international jurisdiction to provide marketing approval, and distinct from the USA – MHRA approved therapies are eligible for full coverage by the NHS independently of patient socioeconomic status. Jacqueline Barry from UK Catapult presented at the Miami Advanced Therapy Forum in January 2024 highlights of a White Paper developed by The Advanced Therapy Treatment Centre network and the Cell and Gene Therapy Catapult to identify and analyze CAR-T patient referral pathways in the UK and make recommendations about how this might be improvedv. The UK was one of the first countries to approve CAR-T therapy in 2018 and licensed CAR-T have been made available in the UK through the Cancer Drugs Fund. There are 16 approved CAR-T centers across the UK and yet, as few of 35% of eligible patients in the UK receive MHRA licensed CAR-T products. The analysis reveals that an important variable is the lack of funding for support services such as travel, accommodation, caregivers etc. and this varies by hospital/region. Indeed, a scholarly analysis of access to commercially approved CAR-T products in USA also highlights concerns about the access of minority patients to these novel therapies. Known barriers to CAR-T access include travel distance, and akin to the UK experience, socioeconomic factors matter as well. Indeed, African American patients were less likely to receive CAR-T and that socioeconomic status, based on the median household income of less than $40,000, as well as lack of insurance or Medicare insurance were also associated with a lower likelihood of receiving a CAR-T treatmentvi. These findings foreshadow the difficulties that are likely to arise for access to CGTs that require meaningful and sustained engagement by patients, to receive and monitor outcome of these cures.
Once a CGT achieves marketing approval a distinct reality kicks in. Drug cost is now applied and a payor, let it be governmental, or insurer, needs to cover this first expense before eligible and willing patients can be considered for treatment. This exercise in securing drug cost payment is critical for industry’s return on their substantial investment in obtaining marketing approval. In US, application for NTAP coverage by CMS is such a first step for novel CGTs and publicly accessible applications made for recently approved Casgevy, Landitra and Lifileucel are an informative readvii. But this is parts, not labor. The squishier aspects of CGT deployment involves patient Social Determinants of Health (SDOH) and healthcare system clinical care bandwidth and financial risk, which explains in most part, the emerging reality of CGT deserts arising in first world healthcare systems.
Commercial developers invest large amounts of capital to secure marketing approval for novel therapies, including CGTs, and the sustainable commercial viability of one-and-done value pricing schemes – especially for orphan disorders - puts payors in a bind and their resistance to pre-authorize coverage may threaten the commercial viability and sustainability of current pricing and deployment schemes. The Provenge® precedent speaks to this reality. Approved by the US Food and Drug Administration in 2010, sipuleucel-T (Provenge®) was the first 'personalized' cancer cellular vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA priced at $93,000 for a course of treatment. From a deployment perspective, the patient underwent a leukapheresis, a product was manufactured in a centralized facility and he would then receive three outpatient intravenous injections over one month with manageable side effects. However, the demand for Provenge® never met projections and in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. In a salient analysis , the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. The financialization of Health in the USix and its influence on CGT commercial development is an on-going experiment where the outcome remains uncertain. Indeed, the narrative for one-and-done CGT value pricing involves not only the traditional recovery of cost of goods and development expenses, but also intends to capture future theoretical medical care cost avoidance arising from the curex. This latter component serves as the bulk justification of value pricing which is relevant in first world economies where lifetime medical care costs for SCD can exceed $1.4 million, but irrelevant in emerging economies where SCD patients suffer in silence. Let us hope that Provenge’s history of winning the battle of regulatory approval but losing the war of market adoption will not repeat itself with the most recent crop of approved CGT cures.
We are all excited about scientific advancement, but we must address the critical need for accessible, comprehensive care options for people living with SCD and other severe illnesses with unmet needs to make those advancements clinically relevant. The ISCT can meaningfully contribute to the understanding of SDOH and impact on access, mapping novel regulatory remedies to ease deployment as well as continuing to develop technical innovations that reduce cost and manufacturing time and most importantly devise pharmaceutical embellishments that offset the need for prolonged hospitalizations and life-threatening toxicities that discourage non-urban dwellers of modest means to even consider taking the cure.
These subject matters are center stage at our upcoming global meeting in Vancouver where we can robustly debate and innovate to deliver market-friendly harmless CGT cures to those in want.
Jacques Galipeau, MD
President, ISCT (2022-2024)
Associate Dean for Therapeutics Development
UW-Madison School of Medicine and Public Health
P.S: This is my capstone bimonthly “From The President’ Desk” Telegraft letter as I approach the end of my term as ISCT President on June 1 2024. Signing off but engaged I will remain as a regular member in advancing our Society’ mission.
[i] https://www.nytimes.com/2024/05/06/health/sickle-cell-cure-first.html
[ii] https://www.nejm.org/doi/full/10.1056/NEJMoa2309676
[iii] https://ashpublications.org/bloodadvances/article/7/3/365/485129/Lifetime-medical-costs-attributable-to-sickle-cell
[iv] https://www.cms.gov/about-cms/agency-information/omh/research-and-data/information-products/data-highlights/prevalence-of-sickle-cell-disease-among-medicare-fee-for-service-beneficiaries-in-2016
[v] https://www.theattcnetwork.co.uk/news/future-proofing-the-uk-car-t-patient-referral-pathway
[vi] https://www.sciencedirect.com/science/article/pii/S2666636722013653?via%3Dihub
[vii] https://www.cms.gov/medicare/payment/prospective-payment-systems/acute-inpatient-pps/new-medical-services-and-new-technologies
[vii] https://pubmed.ncbi.nlm.nih.gov/26403092/
[ix] https://www.nejm.org/doi/full/10.1056/NEJMms2308188
[x] https://icer.org/news-insights/press-releases/icer-publishes-final-evidence-report-on-gene-therapies-for-sickle-cell-disease/
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