Moderna–Recordati Strike Global Deal on mRNA-3927 for Propionic Acidemia

Moderna–Recordati Strike Global Deal on mRNA-3927 for Propionic Acidemia

Moderna and Recordati Partner to Bring First mRNA Treatment for Rare Metabolic Disorder to Patients

BLUF (Bottom Line Up Front): Moderna has partnered with Italian pharmaceutical company Recordati to develop and commercialize mRNA-3927, an investigational mRNA-based treatment for propionic acidemia (PA)—a devastating rare genetic disorder affecting metabolism. This marks a significant expansion of mRNA technology beyond vaccines into treating genetic diseases, with the therapy currently in Phase 1/2 clinical trials. The agreement provides Moderna with up to $160 million in upfront and near-term payments, while Recordati will handle global commercialization once approved. For patients with PA and their families, this represents the first potential disease-modifying treatment for a condition that currently has only supportive care options.

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Understanding Propionic Acidemia: A Devastating Genetic Disorder

Propionic acidemia (PA) is an ultra-rare inherited metabolic disorder that affects approximately 1 in 100,000 to 150,000 newborns worldwide. The condition is caused by mutations in genes that produce enzymes necessary for breaking down certain proteins and fats in the body—specifically, the PCCA and PCCB genes that encode the propionyl-CoA carboxylase (PCC) enzyme.

Without functional PCC enzyme, toxic levels of propionic acid and related compounds accumulate in the blood and tissues, leading to severe, life-threatening complications. Children born with PA typically show symptoms within the first few days to weeks of life, though some milder forms may not appear until later in childhood.

The devastating symptoms of PA include:

• Metabolic crises: Episodes of vomiting, lethargy, seizures, and potentially life-threatening complications including coma
• Feeding difficulties: Poor appetite, failure to thrive, and chronic vomiting
• Developmental delays: Intellectual disabilities and delayed motor skills development
• Neurological problems: Seizures, movement disorders, and cognitive impairment
• Cardiac complications: Cardiomyopathy (weakening of the heart muscle) and arrhythmias
• Immune system dysfunction: Increased susceptibility to infections
• Growth problems: Stunted growth and poor weight gain
• Organ damage: Progressive damage to the liver, kidneys, and pancreas

Even with current management—which consists primarily of strict dietary protein restriction, specialized medical formulas, and emergency protocols during metabolic crises—many patients experience repeated hospitalizations, progressive organ damage, and significantly shortened lifespans. There is currently no FDA-approved disease-modifying treatment for PA; care focuses entirely on managing symptoms and preventing crises through dietary control and supportive measures.

Many children with PA require liver transplantation in an attempt to reduce toxic metabolite production, but this invasive procedure carries significant risks and doesn't fully correct the underlying metabolic defect in other tissues.

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How mRNA Therapy Could Transform Treatment

Moderna's mRNA-3927 represents an entirely new approach to treating PA. Rather than simply managing symptoms, the therapy aims to address the root cause of the disease by delivering genetic instructions to produce the missing or defective PCC enzyme.

Here's how the mRNA therapy works:

The treatment uses messenger RNA (mRNA)—the same technology platform that enabled the rapid development of COVID-19 vaccines—but for a fundamentally different purpose. Instead of instructing cells to make a viral protein to trigger immune response, mRNA-3927 provides the genetic code for producing functional propionyl-CoA carboxylase enzyme.

The mRNA is encapsulated in lipid nanoparticles (tiny fat bubbles) that protect it and help deliver it to cells, particularly in the liver, where much of the body's protein metabolism occurs. Once inside cells, the mRNA serves as a temporary template for producing the missing enzyme, potentially restoring the body's ability to properly break down proteins and fats.

This approach offers several theoretical advantages:

1. Disease modification, not just symptom management: By restoring enzyme function, the therapy could prevent the accumulation of toxic metabolites rather than simply trying to manage their effects
2. Potentially reduced dietary restrictions: Patients might be able to tolerate more normal diets if their bodies can properly metabolize proteins
3. Prevention of organ damage: Early intervention could prevent the progressive damage to heart, liver, kidneys, and brain that characterizes PA
4. Avoiding transplantation: An effective enzyme replacement therapy could eliminate or delay the need for risky liver transplantation

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The Moderna-Recordati Partnership: What It Means

The collaboration announced between Moderna and Recordati Rare Diseases brings together complementary strengths: Moderna's mRNA technology platform and manufacturing capabilities with Recordati's expertise in rare disease commercialization and patient support.

Key terms of the agreement include:

• Moderna retains responsibility for all clinical development, regulatory filings, and manufacturing of mRNA-3927 through approval
• Recordati assumes global commercialization rights, including marketing, distribution, and patient support programs once the therapy receives regulatory approval
• Financial structure: Moderna receives up to $160 million in upfront and near-term milestone payments tied to development and regulatory achievements, plus additional commercial milestone payments and tiered royalties on future sales
• Geographic scope: The partnership covers worldwide rights

For Moderna, this partnership provides validation of its rare disease pipeline while allowing the company to focus on its core strengths in research, development, and manufacturing. The upfront funding helps offset the high costs of clinical development for rare diseases, where patient populations are small but development costs remain substantial.

For Recordati, which specializes in rare and specialty diseases, this adds a potentially transformative therapy to its portfolio. The company has experience navigating the complex rare disease landscape, including working with patient advocacy groups, securing reimbursement in multiple countries, and providing comprehensive patient support services.

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Current Clinical Development Status

mRNA-3927 is currently being evaluated in a Phase 1/2 clinical trial (NCT05130437) investigating its safety, tolerability, and preliminary efficacy in patients with propionic acidemia. The study, which began enrolling patients in 2021, is designed to:

• Assess the safety profile of escalating doses
• Evaluate how the body processes and clears the therapy
• Measure biomarkers indicating whether the therapy is increasing enzyme activity
• Monitor for reductions in toxic metabolites
• Track clinical outcomes including frequency of metabolic crises, hospitalizations, and quality of life measures

While detailed results from this trial have not yet been publicly disclosed, the fact that Moderna has moved forward with this major commercialization partnership suggests the company has seen encouraging data supporting continued development. Typically, pharmaceutical companies seek commercialization partners when they have confidence in a therapy's potential, as partners conduct extensive due diligence before committing to such agreements.

The Phase 1/2 trial design includes both pediatric and adult patients, recognizing that PA is most severe when it manifests in infancy but that treatment could benefit patients diagnosed at any age.

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The Broader Context: mRNA Beyond COVID-19

This partnership represents a significant milestone in demonstrating that mRNA technology—which gained widespread attention through COVID-19 vaccines—has applications far beyond infectious disease prevention.

Moderna's platform uses the same core technology across multiple therapeutic areas:

In rare genetic diseases like PA, mRNA can potentially provide the genetic instructions for missing or defective proteins, offering disease modification for conditions that currently have no effective treatments.

In oncology, Moderna is developing personalized cancer vaccines that train the immune system to recognize and attack tumor-specific mutations. The company has partnerships with Merck for melanoma treatment and is exploring applications in multiple cancer types.

In infectious diseases beyond COVID-19, the company is developing vaccines for influenza, RSV (respiratory syncytial virus), cytomegalovirus, and other pathogens.

In cardiovascular disease, Moderna is investigating mRNA therapies that could stimulate the growth of new blood vessels or regenerate damaged heart tissue.

The PA partnership with Recordati demonstrates growing pharmaceutical industry confidence that mRNA technology can be successfully translated from the vaccine space—where Moderna generated billions in revenue from its COVID-19 vaccine—into therapeutic applications with different manufacturing, delivery, and regulatory requirements.

However, this transition faces real challenges. Unlike vaccines given as one or a few doses to healthy individuals, mRNA therapeutics for chronic conditions like PA may require repeated dosing over years or lifetimes. This raises questions about:

• Long-term safety: How well will patients tolerate repeated mRNA administrations?
• Sustained efficacy: Will the therapy continue working over time, or will effectiveness decline?
• Immune responses: Could the body develop reactions to the lipid nanoparticle delivery system or the produced enzyme?
• Practical delivery: What dosing frequency will be required to maintain therapeutic benefit?

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Rare Disease Economics and Patient Access

The rare disease space presents unique economic and ethical challenges that will influence mRNA-3927's path to patients.

With only an estimated 1,000-1,500 PA patients in the United States and perhaps 3,000-5,000 globally, the potential patient population is extremely small. Developing drugs for such rare conditions costs hundreds of millions of dollars, with the same regulatory requirements as drugs for common diseases, but dramatically smaller revenue potential.

This economic reality typically results in very high prices for approved rare disease therapies—often $300,000 to over $1 million annually—which raises critical questions about patient access, insurance coverage, and healthcare system sustainability. Some rare disease therapies have faced significant coverage restrictions or denials, leaving patients without access despite regulatory approval.

For PA specifically, the value proposition of an effective disease-modifying therapy could be substantial:

• Prevented hospitalizations: Metabolic crises requiring ICU admission are extremely costly
• Avoided transplants: Liver transplantation costs $500,000+ initially, plus lifelong immunosuppression
• Improved outcomes: Better quality of life, reduced disability, and potentially longer survival
• Reduced burden: Decreased need for specialized medical formulas and intensive dietary management

Patient advocacy groups for PA and related metabolic disorders have been actively involved in supporting research and clinical trial recruitment. Organizations like the Propionic Acidemia Foundation work to raise awareness, connect families, and advocate for treatment development. These groups will play crucial roles in ensuring patients can access mRNA-3927 if approved, navigating insurance coverage challenges, and providing support for clinical trial participation.

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Regulatory Pathway and Timeline Considerations

For mRNA-3927 to reach patients, Moderna must successfully complete clinical development and navigate regulatory approval processes in multiple countries.

The therapy may qualify for several regulatory designations that could accelerate development and review:

Orphan Drug Designation has already been granted by the FDA, providing incentives including seven years of market exclusivity, tax credits for clinical trial costs, and waiver of the FDA's new drug application fee.

Rare Pediatric Disease Designation could provide an additional priority review voucher, which can be sold or used to expedite review of another drug.

Fast Track Designation may be available, allowing more frequent interactions with regulators and rolling submission of application components as they're completed.

Breakthrough Therapy Designation could be granted if preliminary evidence suggests substantial improvement over existing treatments—though for PA, there are no disease-modifying treatments for comparison.

The regulatory standard for approval in rare diseases can be more flexible than for common conditions, given the impracticality of large randomized controlled trials with tiny patient populations. Regulators may accept smaller studies with biomarker endpoints and observational data if they demonstrate clinically meaningful benefit with acceptable safety.

Based on typical development timelines, and assuming the ongoing Phase 1/2 trial shows positive results:

• Additional Phase 2/3 studies might be needed: 2-3 years
• Regulatory review after filing: 6-12 months for priority review
• Potential earliest approval: 2027-2028 timeframe

However, these timelines could be accelerated if data are particularly compelling and regulators grant the most expedited pathways, or extended if additional studies are required to address safety or efficacy questions.

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What This Means for Patients and Families

For families affected by propionic acidemia, this development represents the first real hope for a treatment that could modify the disease course rather than simply manage symptoms.

If mRNA-3927 proves safe and effective, it could transform what PA means for diagnosed children:

• Potentially fewer life-threatening metabolic crises and emergency hospitalizations
• Reduced need for extremely restrictive diets that severely limit protein intake
• Better growth and development outcomes
• Prevention or slowing of progressive organ damage
• Improved quality of life for both patients and caregivers
• Possible avoidance of liver transplantation

However, significant questions remain to be answered through ongoing clinical trials:

• How much enzyme function can the therapy restore?
• What dosing schedule will be required—weekly, monthly, or other intervals?
• Will effectiveness be maintained with long-term treatment?
• What side effects might emerge with repeated dosing?
• Will the therapy work equally well in patients of different ages and disease severities?
• Can it reverse existing damage, or only prevent future progression?

Families interested in potentially participating in clinical trials should discuss with their metabolic disease specialist whether their child might be eligible for current or future studies. Clinical trial information can be found at www.clinicaltrials.gov by searching for "propionic acidemia" and "Moderna" or trial identifier NCT05130437.

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Looking Ahead: The Future of mRNA Therapeutics

The Moderna-Recordati partnership for PA is part of a broader transformation in how the pharmaceutical industry views mRNA technology. What began as a vaccine platform has rapidly expanded into a potential treatment modality for genetic diseases, cancer, cardiovascular disease, and more.

Beyond PA, Moderna has disclosed mRNA programs for other rare metabolic disorders including:

• Methylmalonic acidemia (MMA), a related organic acid disorder similar to PA
• Phenylketonuria (PKU), an inability to break down the amino acid phenylalanine
• Glycogen storage disease type 1a, a disorder of glucose metabolism

Other companies are also advancing mRNA therapeutics:

• BioNTech, Moderna's main mRNA vaccine competitor, has multiple cancer immunotherapy programs
• Intellia Therapeutics and Beam Therapeutics are developing mRNA-based gene editing approaches
• Translate Bio (acquired by Sanofi) has programs in cystic fibrosis and other pulmonary diseases

The next several years will be critical in determining whether mRNA can fulfill its promise beyond vaccines. Success in PA and other rare diseases could validate the platform for broader applications, potentially revolutionizing treatment for genetic diseases that have historically had few or no therapeutic options.

For patients with rare diseases and their families, the expansion of mRNA technology into therapeutics represents a new frontier of hope—one grounded in the same science that enabled the rapid development of COVID-19 vaccines, now being applied to some of medicine's most challenging problems.

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Verified Sources and Formal Citations

1. Moderna, Inc. "Moderna and Recordati Enter into Strategic Collaboration for mRNA-3927 for the Treatment of Propionic Acidemia (PA)." Press Release, January 21, 2026. https://feeds.issuerdirect.com/news-release.html?newsid=8361946056927408&symbol=MRNA

2. Recordati Rare Diseases. "Recordati and Moderna Announce Strategic Collaboration for mRNA-3927, an Investigational Treatment for Propionic Acidemia." Press Release, January 21, 2025. https://www.recordati.com/

3. ClinicalTrials.gov. "A Study to Learn About the Study Medicine (mRNA-3927) in People With Propionic Acidemia (PA)." Identifier NCT05130437. National Library of Medicine. https://clinicaltrials.gov/study/NCT05130437

4. Genetics and Rare Diseases Information Center (GARD), National Institutes of Health. "Propionic Acidemia." Updated 2024. https://rarediseases.info.nih.gov/diseases/7596/propionic-acidemia

5. National Organization for Rare Disorders (NORD). "Propionic Acidemia." Rare Disease Database. https://rarediseases.org/rare-diseases/propionic-acidemia/

6. Baumgartner, M.R., et al. "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia." Orphanet Journal of Rare Diseases 9:130 (2014). doi: 10.1186/s13023-014-0130-8. https://ojrd.biomedcentral.com/articles/10.1186/s13023-014-0130-8

7. Pena, L., et al. "Natural history of propionic acidemia." Molecular Genetics and Metabolism 105(1): 5-9 (2012). doi: 10.1016/j.ymgme.2011.09.022. https://pubmed.ncbi.nlm.nih.gov/22079268/

8. U.S. Food and Drug Administration. "Orphan Drug Designations and Approvals: mRNA-3927 (Propionic Acidemia)." Orphan Drug Database. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/

9. Propionic Acidemia Foundation. "About Propionic Acidemia." Patient advocacy organization. https://www.pafoundation.com/

10. Moderna, Inc. "Rare Diseases: Addressing the Genetic Root Cause of Disease with mRNA." Pipeline Overview. https://www.modernatx.com/research/product-pipeline

11. Fraser, J.L., et al. "Neurological Complications of Propionic Acidemia." Molecular Genetics and Metabolism 113(1-2): 39-45 (2014). doi: 10.1016/j.ymgme.2014.07.007. https://pubmed.ncbi.nlm.nih.gov/25066111/

12. Deodato, F., et al. "Methylmalonic and propionic aciduria." American Journal of Medical Genetics Part C: Seminars in Medical Genetics 142C(2): 104-112 (2006). doi: 10.1002/ajmg.c.30090. https://pubmed.ncbi.nlm.nih.gov/16602102/

13. Heringer, J., et al. "Impact of age at onset and newborn screening on outcome in organic acidurias." Journal of Inherited Metabolic Disease 39(3): 341-353 (2016). doi: 10.1007/s10545-015-9906-y. https://pubmed.ncbi.nlm.nih.gov/26643078/

14. Recordati Group. "Recordati Rare Diseases: Our Approach." Corporate website. https://www.recordati.com/en/rare-diseases/

15. Guenzel, A.J., et al. "The Biochemistry, Molecular Genetics, and Clinical Phenotypes of Propionic Acidemia." In: Valle, D., et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Available from: https://ommbid.mhmedical.com/

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About This Article: This patient-friendly overview was prepared for the Informed Prostate Cancer Support Group (IPCSG) newsletter to inform members about significant developments in mRNA therapeutics for rare diseases. While this article focuses on propionic acidemia rather than prostate cancer, it demonstrates the broader applications of mRNA technology beyond the COVID-19 vaccines many patients are familiar with. Understanding these advances helps contextualize the ongoing research into mRNA-based cancer therapeutics, including personalized cancer vaccines being developed by Moderna and other companies for various malignancies.