Breakthrough Clinical Results
Napo Pharmaceuticals, a Jaguar Health family company, plans to meet with the FDA to discuss the clinical development program for crofelemer in treating microvillus inclusion disease (MVID), an ultrarare pediatric disorder. Initial proof-of-concept results from an investigator-initiated trial showed crofelemer reduced total parenteral nutrition in an MVID patient by up to 27%. This data will be presented at the NASPGHAN 2025 Annual Meeting. Napo aims to explore expedited regulatory pathways for crofelemer given the ultrarare nature of MVID and the positive initial results. The company is supporting an investigator-initiated trial in Abu Dhabi and conducting a Phase 2 study in the U.S., EU, and Middle East/North Africa.
Key Highlights
- FDA meeting planned to discuss crofelemer's development for MVID.
- Initial proof-of-concept data shows up to 27% reduction in total parenteral nutrition in an MVID patient.
- Data to be presented at NASPGHAN 2025 Annual Meeting.
- Napo aims to explore expedited regulatory pathways for crofelemer in MVID.
Incidence and Prevalence
Latest Estimates of Incidence and Prevalence of Microvillus Inclusion Disease (MVID)
Microvillus inclusion disease (MVID) is characterized as a rare congenital diarrheal disorder across multiple sources spanning from 1998 to 2023. Despite its recognition in medical literature for decades, specific global incidence and prevalence data for MVID remain undocumented in the available research.
The condition is described as having a broad spectrum of disease severity with two distinct disease phenotypes - one affecting both intestine and liver, and another affecting the liver alone. MVID is considered life-threatening and often has a poor prognosis.
While comprehensive epidemiological studies are lacking, several indicators point to the extreme rarity of this condition:
- A 2022 publication notes that only five cases of STX3 abnormalities resulting in MVID have been described to date
- Limited case reports exist in the literature, including isolated reports from Thailand (2002) and Korea (1998)
- A more recent study identified ten individuals with biallelic STX3 loss-of-function variants from diverse geographic origins
Interestingly, a 1998 publication suggested that "Microvillus inclusion disease may be the most common congenital secretory diarrhea," though no specific prevalence figures were provided to support this claim.
The prevalence is higher in countries with a high degree of consanguinity, suggesting geographic variation in disease frequency. This pattern is consistent with the genetic basis of the disorder, which is primarily caused by loss-of-function mutations in the myosin Vb gene (MYO5B). More recently, mutations in syntaxin 3 (STX3) and Munc18-2 (STXBP2) proteins have also been identified as causative.
The clinical presentation of MVID is severe, with patients experiencing intractable watery diarrhea often beginning in the first days of life and excreting stools up to 200 ml/kg per day. This leads to permanent intestinal failure and dependency on parenteral nutrition.
In regions with high consanguinity rates, such as Oman, there is recognition of the need to identify the prevalence of MVID through appropriate diagnostic investigations.
In summary, while MVID is recognized as a rare congenital disorder worldwide, the current literature does not provide specific global incidence or prevalence statistics. The disease's genetic basis, association with consanguinity, and limited case reports suggest significant geographic variation in its occurrence, but quantitative epidemiological data remain absent from the published research.
Key Unmet Needs and Target Populations for Microvillus Inclusion Disease (MVID)
Target Population
MVID primarily affects the neonatal population, with symptoms typically presenting shortly after birth. The disease is characterized by refractory diarrhea, metabolic acidosis, and has a poor prognosis. The early onset of symptoms requires rapid diagnosis and intervention capabilities in neonatal intensive care settings.
Diagnostic Challenges
A significant unmet need is improved genetic diagnosis. Recent case studies have identified that MVID can be caused by compound heterozygous variants of the MYO5B gene, such as c.1591C>T (p.R531W) and deletion of exon 9. Essential diagnostic techniques include Whole exome sequencing (WES), Sanger sequencing, and multiple ligation-dependent probe amplification (MLPA).
Mortality and Treatment Concerns
The mortality concern is extremely high. In one documented case, a neonate died at just 2 months old despite active symptomatic treatment. The survival rate is alarmingly low - out of 188 patients reported worldwide, only one was cured. In China specifically, of seven children with MVID reported, one was lost during follow-up and six deceased.
Critical Unmet Needs
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Effective Treatments: Current symptomatic treatments are largely ineffective, highlighting a critical need for novel therapeutic approaches.
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Specialized Care Protocols: The extremely high mortality rate indicates an urgent need for specialized care protocols and innovative treatment strategies for this rare disease.
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Genetic Services: The genetic basis of MVID provides opportunities for genetic counseling and prenatal diagnosis, which are important services needed for affected families, especially given the genetic inheritance pattern demonstrated in cases where variants are inherited from both parents.
The combination of early onset, difficult diagnosis, and ineffective treatments makes MVID a particularly challenging condition that requires significant advances in medical research and clinical practice to improve outcomes for affected neonates and their families.
Crofelemer Clinical Trials Beyond MVID
HIV/AIDS-related Diarrhea
Crofelemer is currently FDA-approved for the symptomatic relief of non-infectious (secretory) diarrhoea in adult patients with HIV/AIDS on antiretroviral therapy (ART). This approval was based on the ADVENT study, a large (n = 376 randomized patients), multicentre, phase III trial. The intervention model was a placebo-controlled trial with a 4-week placebo-controlled phase followed by a 5-month placebo-free extension phase. The recommended dosage is 125 mg twice daily. The ADVENT trial demonstrated that crofelemer significantly improved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01) in HIV-seropositive patients with chronic diarrhea.
Irritable Bowel Syndrome with Diarrhea (IBS-D)
A clinical trial evaluated the effect of crofelemer on abdominal pain in women with IBS-D. The intervention model was a randomized, placebo-controlled trial where women received either crofelemer (125 mg) or placebo twice daily for 12 weeks. A total of 240 women were enrolled in this study. The primary efficacy endpoint was overall change in percentage of abdominal pain/discomfort-free days. In post hoc analysis, FDA abdominal pain monthly responders were significantly more likely during months 1 through 2 (58.3% vs 45.0%, P = 0.030) and during the entire 3 months (54.2% vs 42.5%, P = 0.037) in the crofelemer group compared with placebo. However, there was no significant difference in the primary endpoint of overall percentage of pain/discomfort-free days between the groups.
Other Indications
Crofelemer has been evaluated in clinical trials for various types of secretory diarrhea, including:
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Traveler's diarrhea: Studies showed crofelemer significantly brought about faster symptom resolution with lower rates of treatment failure compared to placebo.
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Cholera-related and acute infectious diarrhea: Preliminary studies indicate that crofelemer may reduce watery stool output in patients with infectious diarrhea such as cholera.
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Cancer treatment-related diarrhea: Crofelemer was used off-label to successfully control treatment-related diarrhea in a patient with metastatic papillary renal cell carcinoma receiving tyrosine kinase inhibitor (TKI) therapy (cabozantinib), allowing resumption and partial dose increase of the cancer treatment.
However, it's worth noting that in a rat model study, crofelemer worsened dacomitinib (a tyrosine kinase inhibitor)-induced diarrhea, suggesting antisecretory drug therapy may be ineffective in this specific setting.
Across these trials, crofelemer was generally well tolerated with infections and GI disorders being the most frequently reported treatment-emergent adverse events (TEAEs). The overall incidence of TEAEs was similar in the crofelemer and placebo groups during controlled trial phases.