Stakeholders ask FDA to harmonize oligonucleotide-based therapeutics guidances

Key stakeholders representing drugmakers, generics manufacturers, and biotechnology companies have asked the US Food and Drug Administration (FDA) to harmonize recent guidances related to developing oligonucleotide-based therapeutics (ONT).

In November, FDA published a draft guidance on nonclinical safety assessments of oligonucleotide-based therapeutics (ONT) detailing its expectations for pharmacology and pharmacokinetic characteristics and conducting different toxicity studies. In response, several stakeholders have written to the agency recommending that it not only harmonize the guidance with a recent FDA final guidance, but also with international guidelines. (Related: FDA proposes guidance for nonclinical safety assessment of oligonucleotide-based drugs, Regulatory Focus 13 November 2024)

The pharmaceutical lobby group PhRMA asked FDA to harmonize its guidance globally and pointed to the work already done by the International Council for Harmonisation (ICH). The group noted that ICH recently developed guidelines on non-clinical safety evaluation of ONTs, and ICH’s working group is developing a question-and-answer document that aims to address some issues regarding QTc and proarrhythmic risk assessment for some ONTs.

“Pharmaceutical development is a global enterprise and minimizing unique regional requirements, to the extent possible, helps promote more efficient supply chains and increased patient access to medicines,” said PhRMA.

The biotechnology lobby group BIO similarly asked FDA to ensure the guidance was aligned with ICH’s document on “Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential” and the upcoming ICH S13 draft guideline on “Non-clinical Safety Evaluation of Oligonucleotide-based Therapeutics.” The group also asked the agency not to finalize its guidance before ICH S13 was adopted.

PhRMA and BIO asked FDA to ensure that the final version of the guidance aligns with a June 2024 final guidance that the agency published on clinical pharmacology considerations for developing ONTs.

The Association for Accessible Medicines (AAM), which represents generic drugmakers and biosimilar manufacturers, also brought up FDA's June 2024 final guidance on clinical pharmacology considerations when developing ONTs. The group stated that it was unclear how the principles in both guidances would be applied to abbreviated new drug applications (ANDA).

"We noted that neither of the guidances appears to have been developed with input from the Office of Generic Drugs (OGD)," said AAM. "We request that FDA publish guidance for oligonucleotide product development for ANDAs—in particular, for topics that are not included in published product-specific guidances (e.g., recommendations for immunogenicity and inflammation risk assessments and for demonstration of comparability of impurities)."

"Such guidance would support early product development decisions for generic oligonucleotide drug products," the group added. "Our members have experienced challenges in obtaining clarity on FDA’s expectations with regard to immunogenicity for peptides, and we would like to avoid such issues with regard to the oligonucleotide class of drug products."

AAM also asked FDA to harmonize its guidances with regulatory requirements from the European Medicines Agency (EMA). Specifically, it asked the agency to harmonize with EMA's draft guideline on developing and manufacturing ONTs, which is open for public consultation until 31 January.

"Additionally, we recommend that FDA be forward-looking and consider recommendations for follow-on oligonucleotides developed with a drug substance of recombinant DNA origin," said AAM. "We urge FDA to accept nonclinical immunogenicity assessments for such products, helping to ensure that submission through the ANDA pathway is feasible."

Other considerations

In the draft guidance FDA outlines its thinking on off-target hybridization-dependent effects.

“Given their ability to form Watson-Crick-Franklin base pairs, ONTs have the potential to bind to nontargeted RNA or DNA sequences that share partial or complete complementarity with the base sequence present in the ONT, which can lead to adverse effects in humans that might not be detected in toxicology studies,” said FDA. “Therefore, sequence-dependent off-target assessments should be conducted for ONTs using appropriate in silico and in vitro methodologies to identify potential off-target hybridization.”

The agency listed several factors to consider when conducting sequence-dependent off-target assessments, such as the ONT's risk factor and sensitivity, elements of the ONT and its predicted metabolites, potential hybridization to the transcriptome and nuclear and mitochondrial genome, and more.

In response, PhRMA asked FDA to clarify that such assessments should be focused on longer metabolites.

“Longer metabolites are likely to be covered to a large degree by the standard assessments, given allowances for up to 3 mismatches is typically made in in-silico analyses whereas shorter metabolites are much less likely to exert an effect given the consequent reduction in potency of shortmers,” said the group. “Additionally, metabolites may be present at relatively low levels in comparison to the parent and the probability of exerting detectable off target pharmacology may be low.”

BIO noted that there is not enough concentration of many ONT metabolites to be efficient in on- or off-targeting, and therefore, their effects are likely negligible compared to intact, protected, and longer-lived ONTs. Based on its observations, the group said evaluating off-target hybridization-dependent effects is only useful until n-2 on the 3’-end, as long as there is no significant endonuclease-mediated cleavage and asked that the final guidance takes that into account.

PhRMA also asked FDA to update the guidance so that sponsors are allowed more flexibility to decide whether potential hybridization to the transcriptome and nuclear and mitochondrial genome is worth considering when designing sequence-dependent off-target assessments.

PhRMA addressed several other issues in their letter to FDA including in vitro human ether-a-go-go-related gene (hERG) assay testing. It asked the agency to revise the text to explicitly state that ONT testing in hERG assays was not recommended. The group also said it supports the use of surrogates during certain phases of ONT development consistent with the 3Rs of toxicology, which are replacement, reduction, and refinement; asked for flexibility to use alternative non-animal testing; and recommended updating how first-in-human dosing is determined.

Guidance comments

Stakeholders ask FDA to harmonize oligonucleotide-based therapeutics guidances

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