FDA Releases Draft Guidance On CMC For Individualized ASO Therapies

By Neil DiSpirito, Esq.; Adam M. Schoen, Esq.; Symin J. Charpentier, Esq., Pharm.D.; and Robert B. Ruh, Esq.; Brown Rudnick

Personalized medicine continues to be at the cutting edge of healthcare, pharmaceuticals, and biotechnology. For patients afflicted with a unique disease state or those with diseases resistant or inadequately treated by existing therapies, personalized treatments are a last, best hope.  However, for pharmaceutical companies, the safe and ethical development of individualized treatments is, as with any new pharmaceutical, an expensive and time-intensive endeavor. This creates a conflict between the need for these therapies and the lack of a large patient population that may participate in clinical trials and ultimately purchase an approved treatment to offset the initial development costs.

Recognizing this conflict, on Dec. 7, 2021, the FDA published a new draft guidance, IND Submissions For Individualized Antisense Oligonucleotide Drug Products For Severely Debilitating Or Life-Threatening Diseases: Chemistry, Manufacturing, And Controls Recommendations, Guidance For Sponsor-Investigators.¹ This chemistry, manufacturing, and controls (CMC) guidance acknowledges the difficulties inherent in manufacturing these individualized treatments and offers researchers and manufacturers the opportunity to create policies and procedures that are more likely to be condoned by the FDA in an IND submission.

This draft guidance complements a simultaneously issued draft guidance on clinical recommendations for individualized antisense oligonucleotide (ASO) genetic treatments² which we covered in this article. The clinical recommendations draft guidance focuses on the structure of an investigational trial for an individualized ASO treatment and notes the limited applicability of these very small investigational trials to broader patient populations. Buttressing the clinical recommendations guidance, the CMC guidance addresses the unique issues that arise when manufacturing small batches of new personalized treatments.

The design of antisense oligonucleotide therapies is intensive and particular; that particularity is critical to the success of the therapy.³ After decades of research and development, ASO therapies have shown success in treating certain conditions. Development of ASO therapies requires careful consideration to ensure that these nucleotide therapies do not provoke an uncontrolled immunogenic response. The risk is acute, especially because the immune system is designed to recognize and target unrecognized or foreign nucleotide sequences. Thus, when designing an ASO, the backbone of the oligonucleotide sequence, the inclusion of any exons and the sequence itself must all be considered and controlled for in the manufacture of the investigational drug product.

Given the risks, any potential deviations and impurities must be carefully investigated and eliminated.

As the patients who participate in these investigational trials are afflicted with severely debilitating and life-threatening diseases, it is critical that the first instance of the trial be as successful as possible, with any adverse effects caused by the therapeutic itself, and not due to failures during manufacture that impact the quality, purity, stability, or sterility of the drug product.

Key Takeaways Of The Draft Guidance

The draft CMC guidance is offered for sponsor manufacturers that are producing an individualized ASO drug product to treat a severely debilitating or life-threatening disease.⁴ Such a disease must be caused by unique or vanishingly rare genetic variation to fall under the purview of the guidance.

The FDA cautions that the draft guidance does not apply to the development of ASO products for disease states that are not severely debilitating or life threatening. Similarly, the draft guidance does not apply to disease states caused by genetic mutations that are present in a wider population. The draft guidance likewise does not apply to commercial products. Rather, for now, FDA is reserving this treatment of investigational treatments to patients with an exigent need and for which practicality necessitates a less regulated approach.

One of the initial words and themes of the draft guidance is flexibility. The draft guidance seeks to balance a flexible and practical approach to personalized ASO investigations with the necessity of preserving appropriate safeguards ensuring the efficacy of the treatment.

According to the guidance, the sponsor must ensure that the investigational drug product covered in the submission is properly identified and is of sufficient quality, purity, and strength. The drug product must be manufactured using current good manufacturing practices (cGMP). Nevertheless, because the drug product is not expected to undergo the traditional phases of drug development, e.g., the well-known Phase 1, 2, and 3 investigational trials, the drug product is exempted from certain cGMP regulations.

One of the more explicit recommendations in the draft guidance is that the same batch of drug product be used for both non-clinical and the initial clinical investigations. In fact, the guidance explains that if a sponsor needs to manufacture additional drug product, then the previously exempted cGMP regulations are noted to apply to any secondary batch of drug product. Furthermore, per the guidance, using different batches for the non-clinical and clinical phases of an investigational trial requires that an investigator provide a description of any differences between the processes for those batches. This includes any analytical data indicating that the different batches have similar quality, purity, and strength.

The draft guidance requires a description of the method of preparation of the investigational drug product. The IND should also contain a flow diagram that includes all of the steps required to obtain the drug product. The flow diagram should be accompanied by a narrative description that includes any unique or critical manufacturing steps. The investigator should also provide a list of the materials used to manufacture the antisense oligonucleotide therapeutic.

The draft guidance recommends confirmation of the chemical structure of the drug substance using physical and chemical techniques. The guidance also recommends monitoring the stability of the investigational drug product, as well as recommendations for the confirmation of the drug product after extended storage.

Analysis

This guidance provides investigational sponsors and drug manufacturers with a template of the chemistry, manufacturing, and controls that are required in the investigational new drug application. That template gives some latitude to manufacturers that is usually not a feature of an investigational new drug application.

The draft guidance does not provide information that is completely unfamiliar to manufacturers at this time. In fact, the European Pharma Oligonucleotide Consortium (EPOC) was formed years ago by pharmaceutical companies that agreed to collaborate to identify areas for harmonization of oligonucleotide CMC development and regulatory strategies and to propose good practices and solutions to influence the external regulatory environment.⁵ Through presentations and white papers, the consortium has thus far focused on starting materials, identity testing, solution drug substance, and impurity purging of the drug substance of the oligonucleotides, reflecting shared challenges and opportunities in the oligonucleotide therapeutic area. One example of the consortium’s work is in recommending providing the active pharmaceutical ingredient (API) in solution rather than as a dry drug product;⁶ using API in solution can eliminate the lyophilization step in the manufacturing process, thereby streamlining the manufacture of the drug product. It is demonstrative of the challenges in manufacturing oligonucleotides especially for uniquely small populations that corporations that are normally competitors are working together to share knowledge and best practices. Corporations in the consortium include Biogen, Amgen, Pfizer, Novartis, Roche, Janssen, AstraZeneca, Sanofi, GSK, and Ionis.

Another recognized area where different manufacturers may be able to rely on the same foundational science is in the identification and designation of the oligonucleotide starting materials, such as deoxyamidites, methoxyethyl amidites, constrained ethyl amidites, or other starting materials that will be used for formulation.⁷ The draft guidance does not address what starting materials should be used, nor does it distinguish among them. However, the draft guidance does advise that the manufacturers clearly state the starting materials. This will allow the FDA to more clearly compare and contrast trials using those starting materials.

The draft guidance yields more information to those who need to design protocols in oligonucleotide manufacturing. It will also help the FDA compare individualized antisense oligonucleotide trials against each other, by seeing whether manufacturers that are utilizing similar techniques in chemistry, manufacturing, and controls are producing drug products of similar quality or utility.

However, the FDA does not answer some questions that are critical to manufacturing oligonucleotides.⁸ The draft guidance does not define whether oligonucleotides should be treated as small or large molecule drug substances. Nor do its recommendations solve some of the manufacturing difficulties that challenge manufacturers at this time. For example, the FDA recommends using HPLC to verify the drug product between batches, but HPLC stratifies molecules based on molecular weight, not the identity of the oligonucleotides. The draft guidance also does not address what are acceptable deviations from the given quality or purity of the drug product.

Further critical issues are yet unresolved, such as the environmental hazards that can be caused by the manufacture of these oligonucleotides.⁹ The draft guidance does not mention waste or environmental protection concerns. Large amounts of organic and aqueous waste, hazardous reagents, and the use of non-renewable source materials present significant sustainability challenges to larger-scale manufacture of oligonucleotides. While these trials are small, there is potential for wider application, wherein environmental concerns will grow exponentially as the number of doses being manufactured increases.

In the future, the FDA may be able to protect patients by ensuring that individualized antisense oligonucleotide trials or other trials with one or very few patients with similar IND applications are utilizing practices that have been successful in the past. Alternatively, a trial that unfortunately proves unsuccessful can be compared to other similar trials. This may have utility in the future because the small number of treated patients within these trials, either one or just a few, makes it difficult for these trials to have external validity. A trial for a unique patient has potentially unlimited confounders, with too many patient-specific variables and disease-specific variables for success or failure of the investigational new drug to definitively be ascribed to the drug product itself.

However, for the goal of ensuring that future research is as high quality as possible, this framework of chemistry, manufacturing, and controls recommendations from the FDA will be helpful in making sure that trials with similar drug products are conducted with a drug product that is at least of high quality and purity. This FDA draft guidance, and any final guidance that might issue from it, will therefore be critical in making sure that these individualized trials are as helpful as possible to future patients.