Iberdomide's FDA approval: a milestone for molecular glues, CELMoDs and targeted protein degradation

Over the last few years, targeted protein degradation (TPD) has evolved into one of the most active fields of drug discovery and biotechnology. Much of the recent attention has focused on emerging modalities such as PROTACs, molecular glues and a growing range of next-generation degrader technologies, which we explored in our recent blog series.

The FDA's recent accelerated approval of Bristol Myers Squibb's iberdomide (Zenbexus™) in combination with daratumumab and dexamethasone for relapsed or refractory multiple myeloma marks an important milestone for this field. It’s the first approved cereblon E3 ligase modulator (CELMoD), and it gives patients with multiple myeloma another treatment option while providing further clinical validation for degradation-based therapeutic strategies.

A new class built on established biology

We explored molecular glues in our previous article. Molecular glues are small molecules that promote or stabilise an interaction between an E3 ubiquitin ligase and a neosubstrate (the target of interest). Many modern molecular glue discovery programmes focus specifically on identifying compounds capable of inducing entirely new protein-protein interactions. But some of the field’s biggest early wins weren’t designed at all. They were found by accident, long before anyone was deliberately designing molecular glues.

That story starts with the discovery of the immunomodulatory drug (IMiD) thalidomide, and later with lenalidomide (Revlimid®) and pomalidomide (Pomalyst®), both also from Bristol Myers Squibb, which have long been central to multiple myeloma treatment. Thalidomide, lenalidomide and pomalidomide are now understood to function through binding to cereblon, a substrate receptor within the CRL4 E3 ubiquitin ligase complex. Upon binding cereblon, these molecules promote recruitment of specific neosubstrate proteins, specifically the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), bringing them close enough to cereblon that the ligase can ubiquitinate them and send them to the proteasome for degradation.

CELMoDs can be viewed as the next generation of this molecular glue concept. CELMoDs still bind cereblon and work by promoting interaction between cereblon and degradation targets, but they have been specifically engineered to achieve more potent and selective modulation of the cereblon complex. Iberdomide, for example, drives particularly efficient degradation of IKZF1 and IKZF3. Degradation of these transcription factors not only suppresses tumour cell survival but also switches on T-cell and natural killer cell activity, contributing to broader anti-tumour immune responses. Critically, iberdomide has demonstrated activity in some patients who have already developed resistance to earlier IMiDs. As lenalidomide-based regimens continue to move into earlier treatment settings, therapies capable of overcoming resistance mechanisms are becoming increasingly valuable.

What does this mean for patients?

Multiple myeloma remains an incurable disease despite substantial progress in treatment options over the last two decades. Patients relapse, move to the next line of therapy and eventually run out of options, which is why new options for treatment are important here.

The EXCALIBER-RRMM trial enrolled patients who had already received one or two prior lines of treatment, including both a proteasome inhibitor and an IMiD. In that population, iberdomide in combination with daratumumab and dexamethasone produced an MRD-negative complete response rate of 41%, compared with 21% for the comparator regimen. This is a significant improvement and it’s the basis on which the FDA granted accelerated approval, using MRD-negative complete response as a surrogate endpoint, with longer-term follow up still to come. This brought a desperately needed new therapy to patients sooner.

Broader trends across the degradation landscape

The past few years have seen multiple degradation platforms progress through late-stage clinical development and while iberdomide represents the first approved CELMoD, other degradation modalities are also beginning to achieve important milestones.

Perhaps the most prominent example is vepdegestrant, the ER-targeting PROTAC developed by Arvinas and Pfizer, which has become something of a flagship for heterobifunctional degraders in late-stage trials (explored in our previous blog).

Meanwhile, companies like Monte Rosa Therapeutics, Neomorph and Ambagon are investing heavily in molecular glue discovery, trying to widen the pool of proteins that can be manipulated by inducing new protein-protein interactions.

These programmes suggest that the field is not converging on a single degrader architecture or discovery strategy. Instead, we are beginning to see the emergence of a diverse toolkit of degradation technologies, each with its own advantages, limitations and therapeutic opportunities.

CELMoDs have carved out a distinctive niche in that landscape. They're not heterobifunctional bridges like PROTACs, physically tethering target to ligase, and they differ from many modern molecular glue discovery approaches that aim to identify entirely new neosubstrate interactions. Instead, CELMoDs build upon one of the best-understood and most clinically validated degradation pathways in biology: cereblon-mediated substrate degradation.

The IP implications

For CELMoDs and other degradation technologies, the interesting patent territory may relate to novel E3 ligase binders beyond cereblon, substrate degradation profiles (target and tissue specificity), Markush formulae around novel degrader architectures, biomarkers predictive of responses in certain patients, dosing regimens, combination therapies and platform technologies that enable future degrader discovery.

Iberdomide’s approval will probably sharpen the focus on the competitive landscape surrounding cereblon biology as cereblon remains one of the most clinically validated E3 ligases available to drug developers, and companies continue to explore new binders, substrate profiles and degradation mechanisms that build upon this biology. As increasingly potent cereblon modulators enter development, expect more disputes over patent scope, freedom to operate and how clearly a new CELMoD can be differentiated from existing IMiD and CELMoD portfolios that came before it.

More broadly, CELMoDs face the same open questions as the wider degradation sector. How far can protection extend beyond an individual degrader molecule as the space becomes increasingly crowded? To what extent can claims rely on functional degradation characteristics when the mechanisms of action are not entirely clear and are likely similar within each class? How should applicants support claims directed to degradation profiles, substrate selectivity or platform technologies? The answers to these questions will develop as the field matures.

Outlook – what’s next?

Iberdomide is not the only CELMoD in the Bristol Myers Squibb's pipeline. Mezigdomide, its next-generation CELMoD, is designed to achieve even more potent degradation of IKZF1 and IKZF3. Mezigdomide has already demonstrated encouraging activity in heavily pre-treated multiple myeloma and recently generated positive Phase III data in the SUCCESSOR-2 trial, where the combination of mezigdomide, carfilzomib and dexamethasone significantly improved progression-free survival relative to the comparator regimen. Thus mezigdomide may offer a future treatment option for patients who have exhausted multiple existing therapies.

Beyond Bristol Myers Squibb's own pipeline, the broader significance of iberdomide's approval may be that it provides further clinical validation for cereblon-mediated degradation as a therapeutic strategy. Molecular glues, CELMoDs and heterobifunctional degraders are often discussed as distinct modalities, but they are all contributing to the same growing pile of clinical evidence demonstrating that targeted protein degradation can deliver meaningful patient benefit across multiple disease settings.

From where we sit on the patent side, the foundational IP around cereblon biology, IMiDs and first-generation CELMoDs is already well mapped out. So the next wave of competitive advantage may depend less on simply identifying a cereblon-binding molecule and more on identifying genuinely new target classes and from developing smarter combination strategies, patient stratification approaches and discovery platforms.

That points to a slow shift in what kind of patent actually creates value in this space. Composition-of-matter protection will remain critically important, but companies are increasingly seeking to build broader portfolios around mechanism-based discoveries, biomarkers, treatment regimens, target selectivity and platform technologies that can keep the pipeline fed. As clinical validation accumulates and more competitors enter the space, such secondary layers of protection may become increasingly significant components of overall IP strategy.

If you have any questions about patent strategies in the protein degrader field, please do get in touch.