Key Considerations for Cell and Gene Therapy Commercialization in Non-Orphan Indications
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Introduction
The field of cell and gene therapies (CGTs) presents significant transformative potential across a wide range of diseases including cancer, genetic disorders, and autoimmune conditions. Outside of oncology, CGT development has mainly focused on orphan and ultra-orphan indications. There has been an emerging trend toward developing CGTs in broader markets.
Commercializing CGTs in non-orphan indications will be fundamentally different than the experience to date. It is essential for companies developing (or planning to develop) CGTs in broader disease populations to understand the key differences between niche markets and broader indications.
This white paper will focus on the expansion of CGTs into non-orphan indications outside of oncology. It will examine the viability of developing a CGT in a non-orphan indication and address key considerations when evaluating the business case for a successful CGT product in a mainstream market.
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Non-Oncology CGT Development Is Expanding Beyond Ultra-Orphan Indications
Outside of oncology, early movers in the CGT space have heavily focused development on ultra-orphan conditions. One reason is that while more common diseases have diverse and often complex etiologies, many ultra-orphan diseases result from clearly defined monogenetic mutations or cellular flaws; developers can design therapies to address the condition at the genetic or cellular level. Additionally, gene therapy pricing has rested on rare disease price justification where high unmet need and small patient populations, coupled with durable response, allow for significant one-time spend.
Launched & Established CGTs (Non-Oncology)1
Market Size Key
While non-oncologic successes have thus far been limited to ultra-orphan and orphan indications,
near-registration and Phase III programs suggest a trend toward the development of CGTs in broader indications. This was exemplified by the late 2023 approvals of Lyfgenia (Bluebird Bio) and Casgevy (Vertex) for sickle cell disease, a condition with a United States (US) prevalence of approximately 100,000.2 Of 25 ongoing pivotal trials investigating novel CGTs, only a third are focused on ultra-orphan indications while nearly half are in orphan diseases; the remaining ~20% of trials are in non-orphan conditions, such as osteoarthritis, refractory angina, and urinary tract infections caused by E. coli. The catalog of diseases targeted by late-stage and pivotal CGTs indicates that companies are branching out from ultra-orphan diseases and seeking larger, more mainstream approvals.
Indication Segment Breakdown for CGTs in Development3
This trend appears to be advancing, evidenced by the early development pipelines for CGTs. Among over 150 Phase I and Phase II trials for CGTs included in the analysis, 30% of trials are conducted in non-orphan
indications, 50% are in orphan diseases, and only 20% are in ultra-orphan indications. Atherosclerosis, osteoarthritis, diabetic macular edema, and wet age-related macular degeneration are among those nonorphan indications seeing early CGT development.
Number of CGTs in Phase I or Phase II Development by Disease Group4
CGTs Face Commercial Challenges in Non-Orphan Indications
To date, CGTs have used the orphan disease model to fit into the healthcare ecosystem for a few main reasons. A small addressable patient population with limited or no access to treatment creates an environment of incredibly high unmet need that justifies high drug pricing to payers and can offset the cost of development and supply for manufacturers. Also, manufacturers of complex therapies used to treat rare diseases can afford to utilize high-touch, customized distribution methods and deploy through specialty treatment centers due to the limited patient population. Many of these choices are not available at scale.
As CGT development moves away from rare disease and into mainstream indications, companies must adopt new commercial and organizational strategies to find continued success within the established healthcare ecosystem. There are two important challenges for companies aiming to develop CGTs in mainstream indications:
- Reconciling orphan and non-orphan disease pricing models
- Scaling complex distribution and delivery to meet broader patient populations
CGT Pricing Considerations
CGT pricing to date has followed orphan disease price justification where high unmet need and small patient populations, coupled with durable response, allow for significant one-time spend. The prices of approved CGTs typically range from $2M to $3.5M for a single course of treatment; chronic ultra-orphan therapies can cost hundreds of thousands annually, sometimes exceeding $1M for certain patients. These prices are predicated on data that demonstrate strong and durable responses of at least three to five years.
In the US, payers accept these drug prices because the populations are rare, have significant unmet need, and in some cases, treatment has the potential to offset patients’ expensive chronic therapies. For ultra-orphan disease patients, treatment has historically either been unavailable or extremely expensive; in the case of the most severe β-thalassemia patients who require blood transfusions every two to five weeks for life, the burden of cost totals more than $6M in average lifetime spend. In these situations, manufacturers can make a compelling case to justify a high-cost, durable CGT intervention.
CGT Treatment Pricing5
5Nature; Manufacturer Press Releases; FiercePharma; AP News; NPR. 6Treatment may be directed to only subsets of patients based on eligibility and access considerations
CGT successes to date in treating orphan and ultra-orphan diseases at a high cost have highlighted the potential opportunity in developing CGTs. Novartis has treated more than 3,000 patients across 47 countries in which Zolgensma is approved. The small number of treated patients allows the budget impact to remain low even with a high price. In turn, the high price enables a viable business model whereby revenue can cover the significant cost of goods sold (COGS) and the required custom distribution approaches.
CGTs for broader populations would likely require lower pricing for payers to find them palatable. This may change the fundamentals of the CGT business.
CGT Delivery Ecosystem Considerations
CGTs typically require complex delivery systems to administer therapies to patients. CGTs often have strict storage and handling requirements, such as ultra-cold chain storage and very short shelf lives. Additionally, administration often requires specialized management. Some therapies have specific routes of administration, including sub-retinal or intrathecal delivery. Others have risk of immune reactions which require monitoring and preparedness to mitigate.
Due to these factors, CGTs are commonly delivered only in select treatment centers, typically associated with academic medical centers. And the product usually requires customized transportation logistics to ensure proper handling and protect the high value therapy.
These complex delivery systems are achievable in many cases where patient volumes are low. Custom systems can be economically built. Additionally, relatively few patients with severe course of disease can travel to treatment centers.
Manufacturers will need to consider the challenges of scale. CGTs for broader populations would necessitate administration in wider settings of care to ensure that there is sufficient facility capacity and that treatment is accessible to patients. Success will be driven by the ability to create efficient distribution systems that reach the broader target population.
Conclusions
As manufacturers move toward developing CGTs in broader indications, the established pricing model and treatment paradigm break down. The medical and economic system-wide impacts of non-orphan diseases are often much larger than orphan diseases, even if the per-patient impacts are lower. To be viable in more common diseases, manufacturers need to develop new business models. Neither the current CGT model nor traditional specialty models are likely to work in their present form.
Below are some key questions developers and manufacturers should ask themselves when considering investment in CGTs in larger patient populations.
Price and Value
- Have we established that a CGT intervention has clear economic value to the healthcare system?
- Are we targeting a population that we can clearly define and identify, and that has high-value unmet need that we can meet with a CGT?
- What price point is reasonably achievable given our target population?
Administration
- Do we have a strategy to administer our CGT in general healthcare settings without specialized
procedures? - For required adverse event mitigation: have we established a clear mitigation strategy that is easily achievable in our desired setting of care? Is that mitigation protocol part of our clinical trial?
Commercial and Distribution Model
- Have we considered our model for commercializing and distributing our CGT?
- Is our desired model economical given the expected price of our CGT?
- Knowing there may be novel elements to our model, have we vetted them with stakeholders to determine if they are viable?
- Does our CGT have handling and shelf-life characteristics that can enable broad use?
Manufacturing/COGS
- Can we manufacture our CGT with enough scale and efficiency to make it economical?
Authors:
Brad Ship,
Partner
William Haines,
Project Leader
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