 of a Biologics License Application (BLA) for imsidolimab in generalized pustular psoriasis (GPP) was announced, the 

 editorial team spoke in an interview with a dermatology leader regarding this move’s significance for patients with GPP.

Vanda Pharmaceuticals' investigational interleukin (IL)-36 receptor inhibitor could potentially add to the limited armamentarium of agents implemented within the GPP patient population. The medication is currently under formal review by the agency as a potential addition to the emerging class of IL-36–targeted drugs in the dermatology space.

Neal Bhatia, MD, a dermatologist at Therapeutics Clinical Research whose location served as an investigator site for the development of spesolimab (Spevigo; Boehringer Ingelheim), the first IL-36 receptor inhibitor approved for GPP, spoke in this Q&A interview about this new announcement regarding imsidolimab:

I wanted to ask you a little bit about the FDA’s acceptance of the BLA for imsidolimab and the significance of this move. What might this mean for patients with generalized pustular psoriasis, and how significant would you say it is for clinicians to see another therapy targeting the IL-36 pathway?

 I think it's actually very novel and well-timed. We were an investigator site for the Boehringer Ingelheim drug, which is now spesolimab. That was the first IL-36 to make it to dermatology for us, which was great to have another molecule, which is even better, and adds to the significance. Leo Pharma now brings spesolimab map to the market for us and they've done a good job with that. That being said, Vanda makes good drugs, from what I understand. I think this is another one where the GEMINI trials. 53% of the patients got to clear or almost clear by Week 4.

For many of these patients who suffer in a prison of misdiagnosis or just not having options, it is really some game-changing stuff for them. More importantly, we're understanding how rapidly the disease can be mitigated with the onset of the intravenous dosage. We saw that with the Effisayil 2 trials and the Effisayil 1 trial as well, and it brought them both to relevance. The Effisayil 2 trials, specifically with the SubQ to keep things away…I think what imsidolimab is showing us is that it's got a very similar destiny, if you will. Clinically, thinking about durability, the 2-year maintenance period without flares is a significant improvement from what we know from a patient's quality of life standpoint.

My biggest take home point is that I hear a lot about a lot of dermatologists say, ‘Well, my patients got better with a 17 inhibitor or a 23 inhibitor.’ From a psoriasis pathway, there is always a little bit of overlap. What interleukin-17, what IL-23 does, and what some crossovers like IL-22 are involved with is that they're all intermixed into it. There's going to be a little impact from what targeting those cytokines can do. But GPP is well established in an interleukin-36 milieu, where that cytokine is the main driver. You see a lot of neutrophils and a lot of reactive oxygen species, a lot of tissue damage. All of that is unique to the IL-36 pathway, and by inhibiting that, just like we saw with spesolimab, we'll see that with imsidolimab. We can make real headway in keeping the disease away. Not just making it go away.

You mentioned to the 53% of patients attained clear or almost clear skin by Week 4. How meaningful would you say that level of rapid response is for clinicians managing acute GPP flares?

You can look at it from the dermatologist's side as well as the patient's side. Obviously, from the patient side, if they have had no relief of the pain of the visceral symptoms, the fevers, the misery that they go through with the pustules, this will be a godsend for them. I would say that first and foremost, a lot of these patients just live in fear of their next flare. Even when their flare is put out, the first thing they do is worry about when the next one is. Again, that is the nature of the disorder. I think even more so, to see some quick onset of relief, it should take away the thought process of turning to a 17 inhibitor or 23 inhibitor, when that isn't the pathway of choice, and it's not really what we see under the hood for GPP. With the label of psoriasis under generalized pustular psoriasis, there's going to be a mindset that says, ‘Sure, these psoriasis drugs should work.’ But I think we've seen enough data, as well as seen enough mechanism of action discussion, that we know that the inhibition of the 36 pathway is really the key to success for these patients.

 From a clinical perspective, how important is the reported durability of response over the roughly 2-year maintenance period with flares in the active treatment arm?

If we can put out the flares and give patients some relief of their potential onset, that's a very significant win for how this drug could impact the market. Understanding 2 years [of maintenance] for patients who have had this disease, you can imagine what that does to quality of life. We talk about quality, like for eczema, psoriasis, and other disorders like hidradenitis, and these are all very significant. But from what we've seen of GPP, we haven't had an option that has really been a benefit. We've seen cyclosporine and some of these other Th1 drugs go after that process, which is incomplete. They're slow-acting, and they come with their own baggage. So, to see where we can get some real relief from what the GEMINI trials showed us, as well as what we can see in the 2-year data, I think we have a lot of opportunities to put out fires that didn't get put out before.

 If it is approved by the FDA, where do you think imsidolimab could fit within the current treatment landscape for GPP?

If you look at, you know, spesolimab against the current market-approved treatments, it would probably be side-by-side with that. I would hope that the dermatologists are understanding that that pathway is not the pathway that affects GPP, even though there may be some anecdotal evidence. A lot of dermatologists will say, ‘Oh, sure, my patients do better on 17, 23,’ as I said, and for me, that makes sense, because you have easy access to it. You have easy access to a sample of it to get them started. But if that is the way to get the ball rolling and then get them on an IL-36-modifying treatment, I think that would be a paradigm that would actually make a lot of sense.

Given the rarity and the severity of GPP, how might a therapy with a favorable safety profile and low incidence of anti-drug antibodies influence treatment decision-making in clinical practice?

 I think the first key is just making the diagnosis. Get that diagnosis confirmed. I would give the patient their own path report so that they carry it around in case they run into trouble, or they get into an emergency room or urgent care where they can't get treated. They can show whoever has seen them that this is their diagnosis. I think the other key to the equation, too, is to get them to a place where infusion can be as easy as possible, or at least have access to the drug within a day or 2, to try to get them out of the flare.

Really thinking about the big picture for the dermatologist is being an advocate for these patients, saying, ‘Look, this is a rare disease. This is not just a variant of psoriasis that I can try to knock down with other therapies that I have samples of.’ I think even more so, just to support the research as well as the approval of some of these newer therapies and say, ‘Well, we're going to welcome those into dermatology and not give these away to rheumatologists and oncologists.’ Because that's where we lose our edge on our specialty. That would just be a shame.

The quotes contained in this summary were edited for the purposes of clarity.

Bhatia reported serving as an advisor, consultant, and investigator for AbbVie, Almirall, Arcutis Biotherapeutics, Beiersdorf, Biofrontera, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant Sciences, EPI Health, Ferndale, Galderma, Incyte, ISDIN, Johnson & Johnson, La Roche-Posay, LEO Pharma, Lilly, Ortho Dermatologics, Pfizer, Regeneron Pharmaceuticals, Sanofi, Sun Pharma, and Verrica Pharmaceuticals.

Smith T. FDA Accepts BLA for Imsidolimab as Generalized Pustular Psoriasis Treatment. HCPLive. February 25, 2026. Accessed April 28, 2026. 

https://www.hcplive.com/view/fda-accepts-bla-imsidolimab-generalized-pustular-psoriasis-treatment.

Vanda Pharmaceuticals Announces FDA Acceptance of Biologics License Application Filing for Imsidolimab for the Treatment of Generalized Pustular Psoriasis. Vanda Pharmaceuticals, Inc. February 25, 2026. Accessed April 28, 2026. 

https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-fda-acceptance-of-biologics-license-application-filing-for-imsidolimab-for-the-treatment-of-generalized-pustular-psoriasis-302696991.html

Articles

FDA acceptance of a BLA places imsidolimab, an investigational IL‑36 receptor inhibitor, under review as a second targeted option for generalized pustular psoriasis alongside spesolimab. GEMINI results showed 53% achieving clear/almost clear skin by week 4, supporting rapid control of painful systemic flares. Reported durability with roughly two years of maintenance without flares could meaningfully improve quality of life versus slower, toxic immunosuppressants. Emphasis remains on correct diagnosis, timely infusion access, and prioritizing IL‑36 over IL‑17/23 off‑pathway use in routine practice.

In this Q&A interview, Bhatia discusses the FDA's recent acceptance of BLA for imsidolimab for generalized pustular psoriasis (GPP).

Plaque Psoriasis

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Q&A: Discussing Imsidolimab for Generalized Pustular Psoriasis, With Neal Bhatia, MD

Andrea Cipriani, MD, PhD, from the University of Oxford.

PETRUSHKA Tool Improves Antidepressant Persistence in MDD, With Andrea Cipriani, MD, PhD

A recent study found that the PETRUSHKA decision-support tool improved antidepressant treatment persistence in 

. In an accompanying interview, Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford, emphasized its potential to extend personalized treatment into primary care and other nonpsychiatric settings through structured, shared decision-making.

“If you don't have a psychiatric or specific knowledge in the field, like family doctors or other specialties—neurology, cardiology, oncology, whatever—using the tool is much better than the clinical judgment of the known specialist.” Cipriani told 

Antidepressant selection in routine care often reflects clinician familiarity rather than individualized prediction, particularly in primary care where most prescriptions originate. This pattern has limited implementation of guideline-recommended personalization strategies, despite longstanding recognition of heterogeneity in treatment response and tolerability.

The PETRUSHKA platform generates a ranked list of antidepressants using routinely collected clinical and demographic variables, including symptom severity, comorbidities, and prior treatment history, combined with patient preferences regarding adverse effects. This approach supports a 2-fold strategy of broadening pharmacologic consideration while actively incorporating patient priorities into treatment selection.

The multicenter PETRUSHKA randomized clinical trial enrolled 540 adults with MDD across 47 sites in Brazil, Canada, and the UK.¹ Participants were randomized 1:1 to a web-based decision-support system or usual care. The primary endpoint, all-cause treatment discontinuation at 8 weeks, occurred in 17% (41/241) of the PETRUSHKA group versus 27% (69/252) under usual care (adjusted relative risk, 0.62; 95% CI, 0.44-0.88; 

 =.007). This absolute difference of approximately 10 percentage points reflects a clinically relevant improvement in early treatment persistence.

Secondary outcomes further supported clinical benefit at 24 weeks. Mean PHQ-9 scores were 7.1 (SD, 5.4) in the PETRUSHKA group versus 9.2 (SD, 6.5) in usual care (adjusted mean difference, −1.92; 95% CI, −3.06 to −0.78; 

 <.001). Anxiety symptoms improved similarly, with GAD-7 scores of 4.6 versus 5.8 (adjusted mean difference, −1.39; 95% CI, −2.26 to −0.52; 

 =.002). These findings suggest downstream clinical benefit associated with improved early treatment matching and persistence.

Treatment discontinuation due to adverse events at 8 weeks occurred in 9% (n = 22) of the PETRUSHKA group compared with 16% (n = 39 in usual care (adjusted relative risk, 0.59; 95% CI, 0.36-0.97; 

 =.04). No new safety signals were identified, and serious adverse events were not attributed to the intervention or selected treatments.

Cipriani emphasized the broader significance of these findings in a field constrained by limited biomarkers. He noted the tool demonstrates meaningful gains using routinely available clinical and demographic inputs, improving prediction without reliance on advanced biological markers. He added that future development efforts aim to integrate additional data layers, including genetic and imaging information, to further refine treatment selection.

The study reinforces a shift toward shared decision-making in mental health care. The PETRUSHKA tool facilitates real-time collaboration between clinician and patient, incorporating individual preferences related to tolerability into final treatment selection. Cipriani described this as a move away from clinician-centered prescribing toward a more collaborative model, with particular relevance in primary care, neurology, cardiology, and oncology settings.

Limitations include the open-label design and missing data for some secondary outcomes, which may affect interpretability. In addition, findings may not fully generalize to specialty psychiatric settings, although subgroup analyses suggested greater benefit in primary care environments.

“The big challenge is what we call external validity, so to use the prediction for people that are not included in the building up of the prediction model. That's one word of caution for people not to trust automatically any kind of tool. We need to raise the bar in the level because we need to prove that these tools are effective in delivering what we want,” Cipriani said. “The second thing [that] is crucial is a shared decision-making process.”

Cipriani has no relevant reported disclosures.

Cipriani A, Fernandes KBP, Mulsant BH, et al. A Decision-Support System to Personalize Antidepressant Treatment in Major Depressive Disorder: A Randomized Clinical Trial. 

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Study showed the PETRUSHKA decision-support tool reduced antidepressant discontinuation, supporting personalized treatment approaches.

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Major Depressive Disorder

Major Depressive Disorder condition center page, resources on the topics of medical news and expert insight into depression can be found. Content includes articles, interviews, videos, podcasts, and breaking news on MDD research, treatment, and drug development.

Victoria Johnson joined MJH Life Sciences in 2020 and has written for NeurologyLive, CGTLive, and is now an assistant managing editor for HCPLive and RheumatologyLive. She doesn’t have enough time for her numerous hobbies. You can reach her at vjohnson@mjhlifesciences.com.

The United States Food and Drug Administration (US FDA) has approved budesonide/glycopyrrolate/formoterol fumarate (BGF; BREZTRI Aerosphere, AstraZeneca) as the first single-inhaler triple-combination maintenance therapy for 

 in adult and pediatric patients 12 years of age and older, the company announced April 28, 2026. The decision marks the second approved indication for BGF, which received FDA clearance for chronic obstructive pulmonary disease (COPD) in adults in 2020.¹

"Despite the availability of dual maintenance therapy, many patients are still at risk for exacerbations and experience daily breathing difficulties, reduced lung function and the ongoing fear of worsening symptoms," said Njira Lugogo, MD, Clinical Professor in the Division of Pulmonary and Critical Care Medicine at the University of Michigan.

 The approval represents a potential option for the estimated half of the 27 million US asthma patients who remain inadequately controlled on existing inhaled corticosteroid/long-acting beta₂-agonist (ICS/LABA) regimens.

 KALOS & LOGOS, Phase III, ~4,300 patients

 Significant FEV₁ improvement vs dual ICS/LABA

 Increased risk of serious asthma events with LABA monotherapy

The FDA approval was supported by data from the KALOS and LOGOS trials, twin Phase III, randomized, double-blind, double-dummy, parallel-group, multicenter studies enrolling approximately 4,300 patients with asthma, including those with and without a recent exacerbation.

 Both trials had variable treatment durations of 24 to 52 weeks.

For the US regulatory submission, the primary efficacy endpoint was change from baseline in forced expiratory volume in 1 second (FEV₁) area under the curve from 0 to 3 hours (AUC₀₋₃) at week 24, compared with PT009, an Aerosphere-formulated budesonide/formoterol fumarate dual comparator. The least squares mean differences in morning pre-dose trough FEV1 and FEV1 AUC0–3 over 24 weeks for BGF 28.8 versus the pooled budesonide–formoterol comparators were 76 mL (95% CI, 57–94; 

 <.0001), respectively, with BGF 28.8 favored across all regulatory comparisons for both lung function endpoints. In the primary pooled exacerbation analysis, BGF 28.8 reduced the annualized severe exacerbation rate versus the combined budesonide–formoterol arms (incidence rate ratio, 0.86; 95% CI, 0.76–0.97; 

 = .012) and versus the suspension formulation specifically (IRR, 0.82; 95% CI, 0.71–0.94; 

 = .0043); the comparison versus the Aerosphere co-suspension formulation alone did not reach significance (IRR, 0.90; 95% CI, 0.78–1.03; 

Adverse events were reported in 53.2% of BGF 28.8 recipients, 60.0% with BGF 14.4, 55.2% with budesonide–formoterol Aerosphere, and 58.4% with the suspension formulation; no treatment-related deaths occurred.

 The investigators noted that benefits were observed regardless of recent exacerbation history, suggesting BGF may be appropriate for escalation in inadequately controlled patients without requiring a preceding acute episode on ICS–LABA.

Asthma affects approximately 262 million people globally and 27 million in the US, with nearly 10 million acute attacks occurring annually in the US alone.

 A substantial proportion of patients with moderate-to-severe asthma remain inadequately controlled on standard ICS/LABA dual therapy, sustaining persistent airflow limitation, exacerbations, and diminished quality of life. Uncontrolled asthma carries risks of hospitalization and, in severe cases, death. The approved asthma indication for BGF targets patients whose disease burden persists despite dual inhaled maintenance therapy, a population with recognized unmet need.

BGF for asthma (BGF 320/18/9.6 µg) combines budesonide, an inhaled corticosteroid (ICS), with formoterol fumarate, a long-acting beta₂-agonist (LABA), and glycopyrrolate, a long-acting muscarinic antagonist (LAMA), delivered via pressurized metered-dose inhaler (pMDI) using Aerosphere technology. The ICS/LABA combination addresses airway inflammation and bronchoconstriction, while the addition of the LAMA provides further bronchodilation through a complementary, anticholinergic mechanism. BREZTRI for COPD (BGF 320/36/9.6 µg) received FDA approval in July 2020 and has since been prescribed to more than 6.8 million patients globally.¹ Regulatory submissions for the asthma indication are currently under review in the EU, Japan, and China.

The comparator used in the FDA submission was a dual ICS/LABA in Aerosphere formulation (PT009), which limits direct extrapolation to other ICS/LABA devices or formulations. Long-term data beyond 52 weeks, pediatric-specific subgroup outcomes, and performance relative to biologic therapies remain areas for future investigation. Regulatory filings in the EU, Japan, and China are pending review.

AstraZeneca. BREZTRI Aerosphere approved in the US for the maintenance treatment of COPD. Press release. July 24, 2020. 

https://www.astrazeneca.com/media-centre/press-releases/2020/breztri-aerosphere-approved-in-the-us-for-copd.html

Papi A, et al. Budesonide/glycopyrronium/formoterol fumarate dihydrate in uncontrolled asthma (KALOS and LOGOS): twin phase 3, randomised, double-blind, double-dummy, parallel-group, multicentre trials. 

US Centers for Disease Control and Prevention. Most Recent Asthma Data. 

https://www.cdc.gov/asthma-data/about/most-recent-asthma-data.html

US FDA approval expands budesonide/glycopyrrolate/formoterol (BREZTRI Aerosphere) to asthma maintenance in patients ≥12 years, establishing the first single-inhaler triple therapy for this population and adding to its 2020 COPD indication. KALOS/LOGOS (n≈4,300; 24–52 weeks) showed statistically significant improvements in trough FEV₁ and FEV₁ AUC₀₋₃ versus budesonide–formoterol comparators, with modest severe-exacerbation rate reductions in pooled analyses. Adverse-event rates were comparable across arms, with no treatment-related deaths. Remaining gaps include >52-week outcomes, pediatric subgroups, and comparisons versus biologics.

The FDA has approved budesonide/glycopyrrolate/formoterol fumarate as the first single-inhaler triple therapy for asthma.

FDA News

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FDA Approves BGF Triple Therapy for Asthma in Patients 12 and Older

Tim Smith joined the MJH Life Sciences team in 2022 and is currently an associate editor for HCPLive. He is also the executive producer of two podcasts: Skin of Color Savvy and The Medical Sisterhood. Previously, he was the producer of the Lungcast podcast. He graduated from UC Berkeley and worked in multimedia journalism as a staff writer prior to joining MJH. You can contact him at tsmith@mjhlifesciences.com.

AbbVie announced on April 28, 2026, the submission of a supplemental new drug application to the 

 for upadacitinib (Rinvoq) for the treatment of severe alopecia areata in adult and adolescent patients.¹

The upadacitinib FDA submission for alopecia areata is supported by a pair of replicate phase 3 studies from the UP-AA clinical program evaluating 15 mg and 30 mg once-daily doses.

"In the UP-AA clinical program, upadacitinib showed early and substantial scalp hair growth, including complete scalp hair coverage, which is a significant outcome for those living with this often-overlooked disease," Kori Wallace, MD, PhD, vice president and global head of immunology clinical development at AbbVie, said in a statement.¹

If approved, upadacitinib would become the second JAK inhibitor available for alopecia areata in the United States, joining baricitinib (Olumiant), which received FDA approval for severe alopecia areata in 2022. According to AbbVie, upadacitinib is the first JAK inhibitor to meet a ranked secondary endpoint of complete scalp hair regrowth, defined as a Severity of Alopecia Tool (SALT) score of 0, at Week 24 in a phase 3 program.¹

UP-AA Phase 3 Trial Design and Primary Efficacy Results

The UP-AA program (NCT06012240) comprises two replicate, randomized, double-blind, placebo-controlled phase 3 studies conducted across 248 sites worldwide.¹ The trials enrolled 1,399 participants aged 12 to 63 with severe alopecia areata. Mean baseline SALT score across both studies was 84, and approximately 51% of participants (716 of 1,399) had SALT scores of 95 or higher at baseline, indicating near-total or total scalp hair loss.¹

In Period A, participants were randomized to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 24 weeks. Period B extended the blinded treatment through Week 52, with descriptive reporting of results.¹

Upadacitinib met the primary endpoint of SALT score of 20 or lower at Week 24 in both studies using nonresponder imputation. In Study 1, 45.2% of patients receiving upadacitinib 15 mg and 55.0% receiving 30 mg achieved SALT of 20 or lower, compared with 1.5% on placebo.¹ Study 2 results were concordant: 44.6% for the 15 mg dose and 54.3% for the 30 mg dose versus 3.4% for placebo.¹ Response rates continued to improve through Week 52, reaching 59.3% and 63.8% for the 15 mg and 30 mg groups in Study 1 and 55.0% and 63.3% in Study 2, respectively.¹

Complete Scalp Hair Regrowth, Safety Profile, and Regulatory Outlook

On the key ranked secondary endpoint of complete scalp hair coverage (SALT = 0) at Week 24, upadacitinib 15 mg and 30 mg demonstrated clear separation from placebo in both studies. In Study 1, 14.1% of patients on 15 mg and 20.3% on 30 mg achieved SALT of 0, compared with 0% on placebo.¹ In Study 2, corresponding rates were 13.1% and 22.5% versus 0.7%.¹ By Week 52, complete scalp hair regrowth rates rose to 28.5% and 35.8% in Study 1 and 26.6% and 37.0% in Study 2 for the 15 mg and 30 mg doses, respectively.¹

According to AbbVie, the safety profile of upadacitinib 15 mg and 30 mg through Week 52 was consistent with observations at Week 24 and with previously reported data.¹ The company did not disclose new safety signals in this announcement. The class-level boxed warning for JAK inhibitors, which includes risks of serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality, applies to the existing upadacitinib label across its approved indications.²

The application is also under review by the European Medicines Agency.¹ AbbVie is additionally studying upadacitinib in phase 3 trials for hidradenitis suppurativa, Takayasu arteritis, systemic lupus erythematosus, and vitiligo.¹

AbbVie. AbbVie submits application to FDA for upadacitinib (Rinvoq) for adults and adolescents with severe alopecia areata. Published April 28, 2026. Accessed April 28, 2026. 

https://www.prnewswire.com/news-releases/abbvie-submits-application-to-fda-for-upadacitinib-rinvoq-for-adults-and-adolescents-with-severe-alopecia-areata-302754816.html

Rinvoq [package insert]. North Chicago, IL: AbbVie Inc.; 2025.

AbbVie filed an FDA supplemental NDA for upadacitinib 15 mg and 30 mg once daily for severe alopecia areata in adults and adolescents. Two replicate global, randomized, double-blind phase 3 trials (n=1,399; mean baseline SALT 84; 51% with SALT ≥95) met the primary endpoint (SALT ≤20 at week 24) with ~45% (15 mg) and ~54%–55% (30 mg) versus 1.5%–3.4% on placebo, improving through week 52. Complete regrowth (SALT 0) occurred in 13%–23% at week 24 and 27%–37% at week 52, without newly disclosed safety signals.

AbbVie submitted an sNDA to the FDA seeking approval of upadacitinib for severe alopecia areata in adults and adolescents.

Alopecia

Upadacitinib sNDA Submitted to FDA for Severe Alopecia Areata

Yao Wei Lu, PhD, assistant professor of medicine and member of the Hastings Center for Pulmonary Research at the Keck School of Medicine of USC

yao wei lu.jpeg

A study in murine and human cardiomyocyte models found PCBP1 loss disrupts AARS2 function and mitochondrial activity, identifying a potential target in infant cardiomyopathy.

New Target Emerges for AARS2-Related Cardiomyopathy With Early-Life Mortality

AARS2-related cardiomyopathy, a rare inherited disorder driven by mutations in the alanyl–transfer RNA synthetase 2 (AARS2) gene, is associated with onset at birth and high mortality within the first year of life, with no approved disease-modifying therapies. Prior investigational approaches have focused on correcting the underlying mutation, but progress has been limited by incomplete understanding of upstream regulatory mechanisms.

PCBP1 Identified as Upstream Regulator of AARS2 Function

 identify poly(rC)-binding protein 1 (PCBP1) as a potential therapeutic target, functioning as a regulator of AARS2 activity independent of direct gene correction.

Preclinical Models Recapitulate Disease Phenotype

In murine models, cardiomyocyte-specific deletion of PCBP1 reproduced key features of AARS2-related cardiomyopathy, including mitochondrial dysfunction and activation of maladaptive stress signaling. Parallel studies in human induced pluripotent stem cell–derived cardiomyocytes demonstrated similar mitochondrial impairment following PCBP1 suppression, supporting cross-species relevance.

Mechanistic Link to Mitochondrial Dysfunction

Mechanistically, loss of PCBP1 disrupted post-transcriptional processing of AARS2, resulting in reduced functional protein output. This was associated with impaired mitochondrial energy production and compensatory stress pathway activation, consistent with the metabolic phenotype observed in affected infants.

Translational Implications and Broader Relevance

Investigators also developed a novel mouse model of AARS2-related cardiomyopathy, enabling further therapeutic exploration. These findings suggest that targeting upstream regulators of gene function may offer a viable strategy in monogenic cardiomyopathies. Given the central role of mitochondrial dysfunction across cardiac and systemic diseases, the PCBP1–AARS2 axis may have broader therapeutic relevance beyond this ultra-rare condition.

 spoke with Yao Wei Lu, PhD, assistant professor of medicine and member of the Hastings Center for Pulmonary Research at the Keck School of Medicine of USC, who explained that this represents the first evidence linking PCBP1 to the pathogenesis of AARS2-related cardiomyopathy.

HCPLive: Can you walk us through the background of why past efforts to treat AARS2-related cardiomyopathy focused on repairing mutations in the AARS2 gene, and what prompted investigators to look beyond it?

Lu: AARS2 has long been established as the causal gene in infantile mitochondrial cardiomyopathy, so most efforts logically focused on correcting coding mutations, through gene replacement or editing. More broadly, mitochondrial disease research has been gene-centric. What shifted our thinking was growing evidence from the field of RNA biology that certain genetic mutations can affect alternative splicing, implicating RNA-binding proteins as crucial upstream players. This prompted us to look for upstream regulators rather than the gene alone.

HCPLive: How did PCBP1 first emerge as a gene of interest in your investigation?

Lu: We took an unbiased approach to identify RNA-binding proteins that regulate AARS2 transcripts in cardiomyocytes. PCBP1 stood out because of its known role in poly(C)-rich RNA binding and splicing regulation, and its strong interaction with AARS2 pre-mRNA. While PCBP1 has been studied in RNA metabolism and stress responses, it hadn’t been definitively linked to cardiac mitochondrial biology, making it an unexpected but compelling candidate.

HCPLive: Can you walk us through how PCBP1 influences AARS2 at the molecular level, particularly in terms of RNA processing and mitochondrial function?

Lu: PCBP1 ensures proper inclusion of a critical exon in AARS2 during pre-mRNA splicing. Loss of PCBP1 leads to aberrant splicing and premature transcript termination, effectively reducing functional AARS2. Because AARS2 is essential for mitochondrial protein translation, this disrupts oxidative phosphorylation and mitochondrial proteostasis, triggering downstream stress pathways. This connects RNA processing directly to mitochondrial function.

HCPLive: When you deleted or inhibited PCBP1 in your mouse and iPSC models, how closely did the resulting phenotype mirror AARS2-related cardiomyopathy?

Lu: Strikingly well. In both our mouse models and human iPSC-derived cardiomyocytes, PCBP1 loss reproduced the key hallmarks of AARS2-related disease: impaired mitochondrial respiration, activation of integrated stress response, and severe defects in cardiac development and survival. Importantly, the phenotypes we observed in both our mouse models and human iPSC-derived cardiomyocytes were highly concordant with those in human COXPD8 patients with mitochondrial cardiomyopathy, supporting a shared disease mechanism.

HCPLive: Given that mitochondrial dysfunction underlies many rare diseases, how do you see this PCBP1–AARS2 pathway informing therapeutic strategies beyond this specific cardiomyopathy?

Lu: Our work supports a shift from a purely gene-centric view to an RNA-regulatory framework for mitochondrial disease. Many mitochondrial disorders lack effective treatments despite known genetic causes. Targeting RNA processing—such as splicing regulators or specific transcript isoforms—could offer a more flexible therapeutic strategy, not only for AARS2-related cardiomyopathy but also for other disorders in which mitochondrial dysfunction is driven by defective gene expression rather than irreversible DNA mutations. Additionally, there are similarities in the downstream pathways affected by mitochondrial dysfunction that underlie many rare diseases; our findings will therefore inform therapeutic strategies beyond this specific cardiomyopathy.

Lu YW, Liang Z, Dorr K, et al. PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy. 

https://doi.org/10.1038/s44161-026-00798-3

Study points to new treatment target for fatal infant heart disease. EurekAlert! Published April 20, 2026. Accessed April 28, 2026. 

https://www.eurekalert.org/news-releases/1124804

AARS2-driven infantile mitochondrial cardiomyopathy presents at birth with frequent mortality in the first year and lacks disease-modifying therapy. An RNA-regulatory mechanism has now been implicated: PCBP1 acts upstream of AARS2 by enforcing correct exon inclusion during pre-mRNA splicing. PCBP1 loss causes aberrant AARS2 transcript processing, reduced functional AARS2 protein, impaired mitochondrial translation and oxidative phosphorylation, and activation of maladaptive stress programs. Cardiomyocyte-specific PCBP1 deletion in mice and PCBP1 suppression in human iPSC-cardiomyocytes recapitulate core disease phenotypes.

Lu explains findings that link PCBP1 to the pathogenesis of AARS2-related cardiomyopathy. 

Cardiology

Cardiology condition center page is a comprehensive resource for clinical news and insights on cardiovascular and cardiometabolic diseases. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for heart disease and cardiovascular events, as well as associated diabetes, renal failure, and more...

Ryan Livingston joined the MJH Life Sciences team in March of 2025, shortly after graduating from TCNJ with a bachelor’s degree in English. He enjoys creative writing, reading, and scuba diving. He can be reached at rlivingston@mjhlifesciences.com.

The FDA granted Fast Track Designation to coramitug, an investigational anti-TTR antibody designed to clear existing amyloid deposits in ATTR cardiomyopathy.

Cardiomyopathy

FDA Grants Fast Track to Coramitug for ATTR-CM, Supporting Amyloid-Clearing Phase 3 Trial

Abigail Brooks is an assistant managing editor for 

She joined MJH Life Sciences in August 2023 shortly after graduating from Monmouth University where she earned her BA in Communication with a concentration in Public Relations/Journalism and later an MA in Interactive Digital Media. She enjoys traveling, running, and reading books. She can be reached at abrooks@mjhlifesciences.com.

The FDA has accepted bepirovirsen's NDA for Priority Review and granted Breakthrough Therapy designation, with a PDUFA date of October 26, 2026.

Hepatology

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FDA Grants Bepirovirsen Breakthrough Therapy Designation, Priority Review for Chronic Hepatitis B

The phase 3 trials enrolled frequent exacerbators regardless of eosinophil count or smoking status.

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The HCPFive: Top News for Healthcare Providers from the Week of 04/19

These Week 16, phase 2a findings from the EVERLAST-A study assessing ORKA-001 highlight the treatment's potential in those with plaque psoriasis.

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Diana Isaacs, PharmD, is an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic.

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Viral Shah, MD, joins the show to break down his AACE 2026 presentation on the benefits of using GLP-1 RAs in patients with T1D.

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Type 2 Diabetes

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Strategic Alliance Partnership

Diabetes Dialogue: Expanding GLP-1 Usage Into Type 1 Diabetes With Viral Shah, MD

David Kass, MD, is the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine.

Kass explains recent findings from a study that suggest myocardial dysfunction in HFpEF may be reversible with weight loss. 

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HFpEF Myocardial Dysfunction May Be Reversible With Weight Loss, With David Kass, MD

Funke Pickering, MD, senior medical director at Inovalon.

Pickering discusses data linking social risk factors to hospitalization and costs in MDD and implications for screening and care models.


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