From cell line development to protein purification, manufacturing high-value, low-volume biologic drugs for orphan indications may present numerous challenges. Given the inherently longer clinical trial times due to a limited number of patients in most orphan indications, it is vital that the manufacturing of biologic material does not add additional delays. The right contract development partner must provide access to manufacturing slots in a timely manner to cope with numerous, small volume manufacturing runs driven by clinical trial timing and needs.

Background
By the mid to late 1970s, it was clear to many drug developers that therapeutic candidates targeting low incidence and rare indications were not benefiting from drug development advances because their small patient size and limited prevalence acted as a barrier to entry for most commercial investments. The Orphan Drug Act (ODA), enacted in 1983 in the United States, was designed to provide financial and marketing incentives to overcome those barriers and stimulate the development of critically needed therapeutics addressing underserved rare or orphan diseases.

In the U.S., a rare or orphan disease affects fewer than 200,000 people. Collectively, however, rare diseases are not rare. There are approximately 7,000 rare diseases that represent about 10 percent of the U.S. population, but only five percent of rare diseases have an approved treatment, which means there is still a great deal of need and opportunity for these indications. Prior to the enactment of the ODA, only 38 drugs were specifically approved to treat orphan diseases.¹ By contrast, since 1983, more than 560 distinct drugs for orphan indications have been approved by the U.S. Food and Drug Administration (FDA).²

Biologics contribute significantly towards therapeutic solutions for rare or orphan indications. Between 1983 and 2017, 238 (36 percent) approved Orphan Drugs were biologics,³ and FDA studies indicate that the proportion of biologic products receiving Orphan Drug designation is increasing.

Despite some criticism, the ODA has largely been considered a success. Japan enacted similar legislation in 1993, and the European Union passed similar legislation in 1999. There are now considerably more options for patients facing rare diseases. For therapeutic developers, the global orphan drug market is projected to be $255 billion by 2026, representing approximately 18 percent of global prescription drug sales and up from $127 billion in 2019.⁴ 

Opportunity
Drugs for orphan or rare indications must follow the same early regulatory pathway as other pharmaceutical products, including evaluation of stability, safety, dosing, pharmacokinetics, pharmacodynamics and efficacy. However, the patient numbers and statistical burden for approval are often reduced in these indications to recognize that the numbers obtainable in more common indications cannot be achieved in rare indications. For example, it is not uncommon for an orphan drug to receive market approval after Phase 2 clinical testing. To further motivate pharmaceutical and biotech companies to invest in developing rare disease solutions, the ODA also provides a range of other incentives, including:

• Market exclusivity for seven years post-approval for the first orphan drug approved for a given indication;
• The Orphan Drug Tax Credit (ODTC), which allows for a tax credit of up to 25 percent for research and clinical drug testing expenses;
• Waiver of new drug application (NDA)/biologics license application (BLA) application fees (approximately worth $2.9 million); and,
• An Orphan Product Grant program, can provide funding for clinical testing of new therapies to treat and/or diagnose rare diseases.

When developed effectively, orphan drugs, in addition to providing desperately needed drugs to patients with few options, can improve return on investment for developers. Studies indicate that when effectively managed and developed, the costs of developing orphan drugs can be lower, the timeline shorter with a higher probability of regulatory success.⁵ 

Challenges to biologics orphan drug development
There can be a myriad of challenges to organizations embarking on developing a biologic therapeutic for an orphan drug indication. Often the disease biology and course of progression are less well understood than more common diseases, and as a result, there is often limited experience for these indications among regulatory agencies. Clinical trial design and patient recruitment can be challenging, requiring recruitment across small and geographically dispersed populations. For example, the SHEPHERD Phase 3 trial, which supported approval of eculizumab for paroxysmal nocturnal hemoglobinuria (PNH), had 97 patients across 33 study sites internationally⁶ and the N-Momentum Phase 2/3 clinical trial leading to the approval of inebilizumab-cdon (anti-CD19) for neuromyelitis optica spectrum disorder (NMOSD) had 230 patients across 98 clinical sites internationally.⁷

Not surprisingly, given these logistical challenges with patient access and recruitment in these rare indications, having a solid development and manufacturing strategy and appropriate manufacturing capacity is critical to ensuring supply security for these critical studies. Otherwise, the shortened timeline advantage available under the orphan drug designation is lost.
Critical issues with biologic production for rare disease indications include:

• Developing a manufacturing and product stability strategy that accounts for the slow and unpredictable patient recruitment timeline can support many clinical sites. Depending on the molecule type and its mode of action, the product need may be quite small. At the same time, there is a greater focus on the cost of goods (COGs) for orphan drugs due to the small market. This can be a burden and not achievable for some contract development and manufacturing organizations (CDMOs);
• Ensuring that the cell line platform can produce a wide range of molecules and can utilize sophisticated cell engineering tools to address intractable product quality, secretion, and potency challenges. Flexibility in manufacturing scale and access to manufacturing queues on time are essential as the product advances throughout the development process;
• Experienced analytical method development and validation given the limited quantity of drug substance; and,
• The need for a custom clinical supply strategy to accommodate the large number of clinical sites across the globe even during Phase 2 of clinical development.

Selexis and KBI Biopharma, two JSR Life Sciences companies, have a strong history of working with clients on biologic therapeutics for orphan indications. Thirty-two biologics for rare diseases have been generated using Selexis cell lines, three of which are now marketed products and KBI has developed and manufactured 42 biologics targeted for rare diseases.

Since 2012, Selexis and KBI have been partners and have streamlined development and current good manufacturing practice (cGMP) workflows between their organizations. This has resulted in shortened development timelines that can significantly benefit orphan drug development. For example, Selexis and KBI can develop and manufacture most monoclonal antibody therapeutics in nine months from DNA transfection to drug substance.

The typical antibody titers in bioreactors are between 3-10 g/L. For many clients completing the initial toxicology study is the most urgent and rate-limiting step in drug development. Selexis and KBI have delivered >30 gm of purified product within 15 weeks of transfection of the cell line for multiple orphan drug development programs.   

The range of biologic therapeutics classes for orphan indications is vast. Selexis and KBI have extensive experience in cell line and process development and manufacturing of monoclonal antibodies, enzymes, receptors, structural proteins, Fc-fusion proteins, and bi-specific antibodies with varying degrees of complexity. Given the diversity of molecule type and associated expression challenges and the importance of high titer needed for small-batch manufacturing, access to technologies and capabilities that address difficult-to-express proteins is critical for success. For example, Selexis had a client whose orphan drug candidate was a multimeric protein that had proved impossible for other organizations to sufficiently express, multimerize and fold using standard CHO cell technologies. The Selexis team used its SURE CHO-Mplus Libraries to overcome multimerization and folding issues and generate enough material to advance to the clinic. Without this solution, the product would have been shelved.

Recognizing the importance of flexibility in manufacturing and as a leader in analytical and formulation services, KBI has built an infrastructure and an organization able to customize programs to fit the specific needs of each manufacturing campaign. For its clients with small-batch manufacturing needs, KBI offers low cell culture working volume (< 100L); custom piping, assemblies, and vessels to minimize dead legs and line losses; tailored viral clearance and method qualification strategies to reduce material usage; and, regulatory consultancy and authoring services based on the extensive experience in successful regulatory submissions for rare disease therapeutics. Based on experience from more than 600 programs, the analytical team created analytical and formulation solutions for orphan drugs that minimize material need while delivering robust outcomes.  

Conclusion
Orphan drugs currently account for approximately 17 percent of all worldwide prescription sales8 and about one-third of all new FDA drugs approved,⁹ and the likelihood for success is much higher than for drugs for large indications. Both smaller biotech companies and large pharma organizations are trying to take full advantage of the ODA legislation for biologics development can benefit from working with CDMOs with experience in orphan drug manufacturing.

Engaging organizations with a track record of generating high-producing, high-quality production cell lines, flexibility to readily adapt between small- and large-volume manufacturing, high-quality analytics, in-depth orphan drug regulatory experience and access to global manufacturing sites can de-risk the manufacturing process and set up companies to take advantage of the benefits of developing biologics for orphan indications, thereby bringing new solutions to patients in need. 

References

1. https://en.wikipedia.org/wiki/Orphan_Drug_Act_of_1983#cite_note-14
2. https://rarediseases.org/wp-content/uploads/2021/03/orphan-drugs-in-the-united-states-NRD-2020.pdf
3. Miller and Lanthier. Orphanet Journal of Rare Diseases (2018) 13:183
4. https://info.evaluate.com/EvaluatePharma-World-Preview-2020.html
5. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247853
6. BLOOD (2008) 111(4):1840-7
7. https://pubmed.ncbi.nlm.nih.gov/31495497/(Lancet. 2019 Oct 12:394(10206):1352-63
8. http://info.evaluategroup.com/rs/607-YGS-364/images/EPOD17.pdf
9. https://www.raps.org/news-and-articles/news-articles/2020/1/fda-2019-continues-uptick-in-orphan-drug-approval

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Dirk Lange is CEO of Selexis SA and president and CEO of JSR Life Sciences’ member company, KBI Biopharma. Previously, he served as KBI’s chief operating officer following several roles of increasing responsibility, including senior vice president of operations and site head of KBI’s Boulder, Colorado facility. He also held vice president positions in operations and business development.