Groundbreaking scientific advancement in gene replacement technologies [GTs] has resulted in an ever-increasing number of GTs set to penetrate rare disorder markets as the first viable treatment option targeting the root cause of disease. Even though 80% of the rare diseases are monogenic, implying a strong market potential in terms of growth and exclusivity, the therapy’s commercial success is not assured.
In this piece, we highlight the current state of play and, zooming into the U.S. market, use a case study in MPS II [Hunters Syndrome] to shine a light on the critical areas of commercial focus for GT developers who need to think beyond the normal market-shaping challenges.
The U.S. GT Market Is Evolving at Pace
The U.S. remains a key market for GT entrants due to the FDA’s willingness to exercise regulatory flexibility and the option to command premium pricing upon market entry. Eleven GTs have received FDA approval for rare disorders, half of which received approval in 2023, including the first topical [Krystal Biotech’s Vyjuvek] and CRISPR-based [Vertex’ Casgevy] GTs. Published FDA guidelines signal a favorable environment for building momentum, with five further approvals possible in 2024.
The disconnect between GT development and market adoption in rare-disorder markets has remained a hot topic for discussion since the first ATMP launch in 2016 [GSK’s Strimvelis in ADA-SCID], where GSK failed to make a return on its investment before handing over rights to Telethon in 2022. Although commercial markets have advanced in the last decade, the road ahead for GT has challenges as healthcare systems continue to evolve to keep pace with the recent scientific progress. With >7,000 rare disorders and growth in treatment-eligible patients increasing beyond 100,000, a tailored approach to tracking how payer, provider, and patient ecosystems adapt to new advancements is imperative to navigate this complex landscape.
Maximizing Opportunity in Patient-Limited Markets
The probability of success in rare-disorder markets is closely linked to the unmet need for new treatment options and an early genetic disease diagnosis. Early commercial success was witnessed in degenerative rare disorders, such as Duchenne muscular dystrophy. Despite a restricted label [600-800 eligible patients], Sarepta’s ELEVIDYS netted ~$200M U.S. revenue in the four months post-launch in August 2023, beating analyst consensus. Progress here has been due to an efficient site activation plan [~75 sites set up by YE 2023] and a “substantial demand” due to the lack of treatment competition and Sarepta’s capitalization on the urgency of treatment using a “time is muscle” slogan.
However, in well-managed disorders with an established standard of care [SoC], such as hemophilia, the risk-benefit payoff of first-generation GT isn’t as attractive [CSL Behring’s HEMGENIX and BioMarin’s ROCTAVIAN have had minimal commercial uptake], with patients waiting for next-generation modalities that offer more durable and long-lasting efficacy outcomes, and could have re-dosing potential. Future GT players who aim to enter markets with established SoCs should take these learnings forward to ensure a deep understanding of factors driving treatment uptake and the community’s risk tolerance for new GT technologies before moving an asset forward.
For the next wave of GT targeting low-incidence rare disorders [including REGENXBIO’s RGX-121 in MPS II and Rocket’s RP-L102 in Fanconi Anemia], achieving commercial success could first depend on investing in culturally relevant and educational rare disease resources [e.g., Takeda] that build community trust, improve equitable access to diagnosis, and highlight the urgency of treatment to commercial stakeholders. This should then be accompanied by a market-shaping strategy, which includes a robust patient identification network, a premium price narrative, a robust payer contracting strategy, and dedicated but targeted infrastructure at the point of care.
Five Pillars Underpinning a Successful Go-to-Market Strategy – a Case Study in MPS II
MPS II [Hunters Syndrome] is a degenerative X-linked disorder with a high disease burden. Multifaceted care requirements result in a large healthcare resource utilisation and a reduced quality of life. In patients with severe disease, life expectancy is between 20 – 30 years old.
Enzyme replacement therapy [ERT] has been the SoC therapy since 2006, following the approval of Takeda’s ELAPRASE. While ERT has shown benefits to the hepatic, lymphatic and musculoskeletal systems, it does not penetrate the blood-brain barrier [BBB] and, thus, does not cure the neurological disease consequences. Next-generation ERT, which aims to overcome this treatment limitation through using BBB transport vehicles [e.g., Denali’s DNL310], are expected to enter the market in 2026+. However, the patient treatment burden will remain high due to frequent QW IV infusions.
From 2025, GT [e.g., REGENXBIOs RGX-121] will interplay with ERT. Treatment with GT aims to build on the benefits of ELAPRASE by addressing neurological complications in patients with the severe disease form [U.S. prevalence of ~900 cases]. However, the competitiveness of ERTs will directly impact GT’s success, with GT positioned as an add-on to ERT in the near term, with the long-term goal for GT in MPS II to define an ERT discontinuation protocol and reduce the overall treatment burden.
1. Making premium pricing competitive. The net price of a single GT administration is just the starting point. Hidden treatment costs [e.g., immunosuppressive prophylaxis, monitoring], performance uncertainties, and insurance hurdles [e.g., patient-plan switching] may favor entry into novel payment models [e.g., PBMs, 340B] or value-based arrangements [VBA].
In MPS II, GT will enter the market as an add-on to ERT. The use of finance [e.g., Novartis five-year pay overtime for ZOLGENSMA] and/or outcomes [e.g., Bluebird’s LYFGENIA rebate model] models could increase the pricing competitiveness of MPS II GTs against ERT monotherapy and overcome coverage bottlenecks surrounding benefit: risk uncertainties [RGX-121’s initial dossier is expected to be based on a CSF biomarker]. However, these models typically favour large-cap pharma with additional revenue streams; small-cap players [like REGENXBIO] must balance the product risk and contractual risk of a VBA against available cash flows to ensure a sustainable business model.
A second consideration is that VBAs are still in the nascent stages within Medicaid state plans, many of which still prefer traditional rebates and/or require patient identification before policy development. Systems are adapting to overcome these challenges [e.g., CGT access model pilot for sickle cell], and upcoming players who may benefit from VBAs should consider a state-targeted launch plan, ensuring active and early communications with the selected state Medicaid leaders.
2. Early community engagement and education. Early community engagements, including those with patient advisory groups [PAGs] and target institutions [e.g., Takeda’s discovery program], are instrumental in ensuring players remain adaptable to the evolving and site-specific treatment barriers in MPS II, accelerating GT uptake.
Continued engagements with target institutions and PAGs should support a community-centric and data-driven education strategy. Engaging in institution-specific [e.g., LSD registry] or PAG registries is a cost-efficient approach to collecting real-world data, with continued key opinion leader [KOL] engagements necessary to tailor registry endpoint selection towards ensuring that the data addresses evolving community concerns and supports physician confidence in discontinuing ERT post-GT.
3. Cost-efficient support throughout the patient journey. Community outreach is central to GT’s success, with patient, patient-carer, and physician support necessary to gain community trust and simplify the patient journey through diagnosis, treatment, and follow-up monitoring. The subtle and non-specific onset of symptoms and the potential for a late genetic diagnosis are barriers to patient identification for GT in MPS II. Although direct engagements with patients before an Rx decision is complex, using unbranded platforms can support physicians and PAGs in providing the right education to patients, accelerating patient adoption.
Following an Rx decision, effective patient support programs [PSPs] can reduce the time to treatment by providing access support and logistics organisation, improving patient retention. While GT has some potential as a ‘one-and-done’ therapy, in most cases, GT is associated with a unique long-term patient journey and monitoring requirement. From a commercial perspective, an effective PSP can also provide a competitive advantage by supporting improved patient outcomes, which is a critical success factor for companies opting for an outcomes-based payor agreement.
However, for low-cap Biopharma, there is a need to ensure PSPs are cost-efficient. For companies like REGENXBIO or Ultragenyx [in MPS IIIA], who have multiple rare disorder programs, leveraging a multi-asset PSP [e.g., BioMarin RareConnections] can apply cross-functional expertise to increase patient reach and strengthen relationships across a broader range of KOLs and physicians, whilst reducing cash-burn across programs.
4. Tailored commercial site activation plans. Given the complexity and preparation needed for the GTs, the go-to-market model should shift to centralised care sites from diagnosis to treatment – regional, specialised centres that can make treatment recommendations to the suitable patients and scale up GT delivery to them.
For rare disorders, such as MPS II, where first-time GT entrants will interact with established SoCs, engaging sites early during clinical development is a feasible mechanism to increase familiarity with the GT’s specific management, procedures, and protocols. Tailoring site selection plans to include specialised research centers with existing revenue streams and GT infrastructure in place [e.g., CHOPs collaborative] can limit the burden of site set-up on hospital economics whilst ensuring regional coverage – further accelerating the time to site readiness.
5. Agile multifunctional field force deployment. With a sparse patient pool and limited geographical reach from activated clinical sites [REGENXBIO has sites in three states] compared to near-term ERT competitors [Denali has sites in nine states], an agile field-force deployment strategy is required to ensure real-time facility set-up and in-tandem education in the primary care setting, to support early diagnosis and referral to new and existing regional treatment centers.
For small-cap Biopharma competing against an established SoC, employing a coordinated, pan-rare disorder, territory-specific field force deployment strategy may streamline engagement with key stakeholders [e.g., local reimbursement agencies, key institutions, local physicians] and ensure adoption with physicians that would otherwise have a greater familiarity with ERTs [e.g., Children’s Hospital of Chicago], whilst reducing cash-burn across programs.
The ‘So What’ in Rare-Disorder GT Commercialization
Companies planning for future launches must continue to rethink their commercial strategy. There is no one-size-fits-all approach to GT commercialisation. Still, a commercial strategy should start with continuous stakeholder engagements to stay adaptable to community barriers through continuous understanding: how do we become central to the patient and physician experience?
From here, to improve the probability of success, Biopharma will need to deploy a high-performing market-shaping strategy that exercises attention to detail while assessing the evolution of competitive dynamics, adequate preparation to ensure that potential patients, providers, and payers are in place, and couples learnings from the pan-GT markets in terms of risk sharing and payment between Biopharma companies and providers.