Mechanism of Action: Step Up & Be Heard in Rare Disease

In a crowded market, your drug’s mechanism of action (MOA) is more than a scientific formality – it’s strategic. Although MOA cannot be used promotionally to support efficacy or safety, is it time to rethink this paradigm, particularly as it relates to individualized therapy for rare disease?

In a market increasingly shaped by precision, elevating your MOA in your rare disease strategy can potentially play an instrumental role.

Leverage New Thinking on the Evolving Perception of Product Value

The U.S. Food and Drug Administration (FDA) is signaling a new, broader view of product value for rare diseases with clear molecular or cellular root causes. In a recent draft guidance, the FDA noted that, in some situations, approval based on a single adequate and well-controlled study with confirmatory evidence could be sufficient.

What counts as “confirmatory evidence”? Among several options, one of them is MOA.

According to the guidance, “Confirmatory evidence would likely come from clinical or nonclinical data sources and may include but is not limited to mechanistic or pharmacodynamic data, confirmation of target engagement based on nonclinical or clinical data, or exposure-response on biomarkers and clinical outcomes.” Furthermore, approval via this pathway could be achieved through the traditional approval pathway or the accelerated approval pathway.

The context for this guidance is relatively narrow and only pertains to individualized therapies. These therapies are based on genomic editing or RNA targeting, and in some cases, can be tailored to the specific genetic variant causing disease in individual patients.

If confirmatory evidence can be based in part on mechanistic, pharmacodynamic, or target engagement data, then claims based on these data seem warranted for effective communication to the marketplace. This issue is especially relevant for accelerated approval products, where biomarker endpoints often serve as the basis for approval.

The guidance reviews the criteria and conditions for biomarkers to “support effectiveness as either surrogate endpoints or confirmatory evidence.” Key characteristics include:

• The biomarker has been established to predict clinical benefit
• The biomarker reflects disease pathology or has previously been used to support drug approval
• The methods used for biomarker assessments should be validated, and preanalytical specimen handling should be well defined

The guidance emphasizes that biomarkers measuring target engagement and primary pharmacodynamics are likely essential as confirmatory evidence, and that sponsors should plan for comprehensive biomarker assessments throughout the course of treatment.

As a draft, the new guidance is open for public comment, and one group that has commented is the American Society of Gene + Cell Therapy. The ASGCT had several recommendations:

• Clarify the scope of the guidance, which seems to bounce from very rare and ultra-rare diseases to individualized therapies that target a specific pathway.
• The full scope of evidentiary expectations, particularly natural history and clinical outcomes, in the guidance may be difficult to meet, at least all at once. ASGCT suggests, “Instead of presenting lines of evidence as all contributing in every case, we recommend FDA clarify that, depending on the strength of the plausible mechanism arguments and reliability of early measures, some lines of evidence may not be needed.”
• The guidance should address the mismatch between strong biological evidence of effect, which may emerge relatively quickly, versus clinical outcomes that may take longer to read out.

What does this mean for product teams in rare disease? It’s time to talk with your medical, legal, and regulatory (MLR) team about the implications of this guidance for making promotional claims.

• Engage your MLR team on the new draft guidance
• Discuss the applicability of the guidance to your brand
• Address the scope of the guidance and implications for claims
• Discuss the nature of the mechanistic data in the draft label and what claims, if any, can be made from them

This guidance can open a more nuanced discussion with MLR about what MOA messaging means in this new environment in the rare disease market.

Ready to Elevate Your MOA Strategy in Rare Disease?

At Precision AQ, our Advertising and Branding team partners with biotech and pharmaceutical companies to develop disease awareness programs, brand strategies, and launch narratives that elevate science to the center of your story. From behavioral mapping and patient journey work to omnichannel campaign execution, we offer the services your product needs to succeed. If you’re ready to elevate your MOA strategy, connect with our team today.