In order to assess the relationship between age and AEs associated with HPIs, we divided the AE reports into three subgroups based on age: children (aged < 18 years), adult (aged 18-65 years), and elderly (aged > 65 years). In patients with sonidegib, the occurrence of ageusia, dyspepsia, gastritis and localized infection was more prevalent in the adult group than in the elderly group. Decreased appetite, urinary tract infection, therapy interrupted, sepsis and 20 other AEs were found to be more common in the elderly group of sonidegib. In patients with vismodegib, high-risk AEs associated with children included epiphyses premature fusion, asthenia, and death. Adult are more prone to develop dehydration, embolism, pneumonitis during vismodegib treatment. The elderly were more commonly affected by cholestasis, anosmia, duodenal ulcer, acute hepatitis, B-cell lymphoma and deafness (Supplementary Table S5).
Our study expands the safety profile of HPIs vismodegib and sonidegib by searching and analyzing the real-world data from a large population. Overall, sonidegib displays a relatively higher safety profile with lower risk of AEs, partly due to differences of pharmacokinetics between the two HPIs. Recent drug approvals of the two drugs (2012 for vismodegib, 2015 for sonidegib) mean limited real-world patient exposure time. This prevents capture of rare or very late-onset AEs in FAERS, as insufficient time has passed for them to occur and be reported, leading to an incomplete safety profile. To overcome this inherent limitation and build a more complete safety profile, ongoing pharmacovigilance and long-term observational studies are essential. As SMO inhibitors, sonidegib and vismodegib have similar demographic characteristics. More reports from male patients and patients aged > = 65 were expected, which is consistent with BCC epidemiological research. More indications were observed in patients with vismodegib than in patients with sonidegib, which are associated with multiple clinical trials of vismodegib. This disparity introduces potential confounding by indication and reporting biases that must be considered when comparing their safety profiles. As shown in Table 1, our study was predominantly comprised of reports from the United States and Europe. Extrapolating these findings to global populations should be done with extreme caution. Moreover, a substantial proportion of adverse event reports (23.30% for sonidegib and 18.31% for vismodegib) in FAERS lacked a specified indication for drug use. This missing information poses a significant challenge to the interpretation of our findings, as it is undetermined if the drug usage in these instances was appropriate, in the right dosages, or abused. Notably, about a half of reports of HPIs in this study were submitted by consumers, which can introduce bias into the analysis results. Supplementary Table S6 revealed that FAERS reporting rates of AEs were significantly lower than clinical trial incidence, suggesting that there is a significant under-reporting in FAERS for these highly prevalent AEs. It is recommended that clinicians proactively counsel patients on expected AEs, manage symptoms to improve quality of life and adherence, and regularly assess at visits.
The results of this study indicated that AEs associated with sonidegib involved fewer SOCs than those of vismodegib (16 vs. 25 SOCs). Further disproportionality analysis showed that sonidegib had fewer AEs and a lower incidence of most AEs compared with vismodegib, which aligns with previous research. It is important to note that spontaneous reporting systems like FAERS are primarily hypothesis-generating and cannot establish definitive causal relationships between drug exposure and reported AEs. Findings from clinical studies suggest that the three most common AEs of HPIs are muscle spasms, alopecia and dysgeusia. The mechanisms of muscle spasms caused by HPIs are not yet fully understood, which are hypothesized to occur because of calcium influx into the muscle cells. Studies have reported that noncanonical Hh signaling promotes the opening of plasma membrane calcium channels in muscle cells. Therefore, calcium channel blocker amlodipine can greatly reduce occurrence of muscle spasms in patients treated with vismodegib. Other studies suggest that increased actin expression may play a significant role in the occurrence of muscle spasms related to HPIs. Muscle spasms can be relieved by dose reduction or interruption of HPIs, massage, heating, stretching and gentle exercise.
HPIs-induced alopecia, manifesting as gradual hair thinning, has a longer onset time compared with hair loss induced by chemotherapy. The Hh signaling pathway is a critical regulator of hair follicle development and cycling. Inhibition of Hh signaling pathway blocks transition to anagen phase in the hair follicle after hair shedding in telogen phase, resulting in hair thinning and alopecia. The alopecia is reversible, but regrowth takes many months. In addition to alopecia, vismodegib could cause a variety of skin and subcutaneous tissue disorders, such as hair growth abnormal, hypotrichosis, and unexpected AEs, including madarosis, actinic keratosis, and ingrown hair. Sonidegib exhibited fewer AEs, fewer report numbers, and lower signal intensity, implying that sonidegib may pose a lower risk in skin and subcutaneous tissue.
Taste disturbance (dysgeusia and ageusia) is among the most common AEs associated with HPIs. The mechanisms by which HPIs induce taste disturbances are Hh pathway blockade leads to disruptions in taste papillae, taste buds and neurophysiological taste function. After stopping Hh pathway inhibition, taste buds and sensory responses recover. Nutritional management and using vismodegib at a reduced dose with milder side effects could make oral Hh pathway inhibition treatment more tolerable. At the PT level, we identified a number of unexpected AEs involving the sensory organs, such as eye, ear, nose, and tongue. Further studies showed that vismodegib exhibited stronger toxicity than sonidegib to special sensory organs. Hh pathway has been reported to be a modulator of development and maintenance of special sensory organs, including eye, ear, and nose. It is remarkable that atrophic glossitis was found to be the unexpected AE of vismodegib with the strongest signal, which occurs almost exclusively in females (Supplementary Table S4). This finding represents a exploratory signal with strong biological plausibility, aligning with the known class effects of HPIs on taste bud loss and taste disturbance. While the biological rationale is strong, FAERS data cannot definitively prove causation. Therefore, this signal warrants further confirmation through more studies. It is necessary for clinicians to pay more attention to the AEs involving sensory organs in patients receiving vismodegib.
Unexpected neoplasm-related AEs after sonidegib treatment included TNBC, squamous cell carcinoma, acute myeloid leukaemia, and vismodegib was associated with malignant neoplasm of eye, squamous cell carcinoma, metastatic squamous cell carcinoma, ocular neoplasm, neuroendocrine carcinoma of the skin, nasal neoplasm. The mechanisms of secondary malignancies post HPIs therapy are still uncertain. The possible mechanisms may involve inhibition of Hh signaling pathway leads to alternative activation of the RAS-MAPK pathway, thereby driving tumor growth and enhancing metastatic behavior. Studies have demonstrated that canonical Hh signaling contributes to TNBC growth and metastatic spread by enhancing tumor angiogenesis. Moreover, administration of sonidegib reduces xenograft proliferation and vascularization in TNBC angiogenesis by inhibiting Hh signaling. Furthermore, the EDALINE study (GEICAM/2012-12) is a phase Ib clinical trial investigating sonidegib in combination with docetaxel in triple-negative advanced breast cancer patients, suggesting that some of those patients already had TNBC when they received sonidegib. This supports the explanations of reverse causality. The Hh pathway plays a critical and complex role in eye development, maintenance, and various ocular diseases. Both inhibition and activation of Hh signaling can result in eye abnormalities. This is a possible mechanism for the occurrence of malignant neoplasms of the eye after treatment with vismodegib. Although our data imply the potential of HPIs to induce or promote second primary malignancies, it is illogical to determine whether second primary tumors are caused by HPIs only by AE signals due to the limitations of this study. Therefore, these findings should be interpreted as preliminary signals rather than definitive evidence. The identified potential drug-adverse event pairs warrant further rigorous research using study designs capable of assessing causality. Early recognition of neoplasm-related AEs is essential because these AEs may be life-threatening.
It is noteworthy that the long-term use of sonidegib was associated with a risk of complete atrioventricular block, which appears to occur only in females. In contrast, the relevant SOCs for vismodegib did not include cardiac disorders, suggesting that vismodegib seems to have better cardiac safety. This finding may have particularly clinical preventive significance for females with cardiac disorders.
Our study indicated that the majority of AEs associated with sonidegib and vismodegib occurred within 3 months (56.07% vs. 61.91%), with the highest incidence in the first month (30.84% vs. 34.99%). Vismodegib caused adverse events earlier than sonidegib (56 vs. 67 days). It is crucial to monitor AEs within the first 3 months after HPIs treatment, and sonidegib-treated patients should be observed for longer. A significant limitation of our TTO analysis is the inherent reporting delay between AE occurrence and reporting present in FAERS. This delay means that the calculated TTO reflects the time from drug initiation to the reported onset, not necessarily the actual biological latency. AEs with longer true latencies are disproportionately less likely to be reported, or their reports may be significantly delayed, leading to a potential truncation of the observed TTO distribution. The delay, plus under-reporting of long-latency events, shortens observed TTO making drugs appear to have quicker effects than reality. This biases TTO findings towards acute events and can miss important chronic or late-onset safety signals. Gender differences in AEs associated with HPIs have not been comprehensively investigated before. In our study, males were more likely to experience AEs than females. We identified the unexpected significant gender-specific AEs associated with HPIs such as female-specific TNBC and complete atrioventricular block for sonidegib, as well as female-specific atrophic glossitis for vismodegib. Only children receiving vismodegib were at risk of epiphyses premature fusion and death. Consequently, our findings suggest that it is necessary to monitor the occurrence of AEs in specific population subgroups, especially in children with vismodegib, which is the only subgroup with death reports.
This study has the following limitations: Firstly, FAERS is a spontaneous reporting system, and information collection is not restricted in health care professionals, which may lead to the accumulation of incomplete or inaccurate information. The passive nature of surveillance also results in substantial and non-random underreporting, capturing only a small fraction of all AEs. Serious AEs, those associated with newly marketed drugs, or events receiving significant public attention are disproportionately reported, which can inflate signals for these events while potentially obscuring signals for more common or less severe AEs. Moreover, most reports originated from the United States, potentially limiting the generalizability of our findings and providing an incomplete picture of the drugs' global safety profile. The differing number of indications and associated clinical trial activities between vismodegib and sonidegib represent a major challenge for direct safety profile comparisons using FAERS data. Vismodegib's broader therapeutic reach implies exposure to a more diverse and potentially sicker patient cohort, which can inflate its raw adverse event counts and disproportionality signals due to confounding by indication. Indication bias occurs when a drug is administered to patients at high baseline risk for an adverse event, thereby creating a spurious drug-event association or masking a true risk, as the observed effect is actually due to the underlying condition. Secondly, the US FDA does not require a proof of causal relationship when reports are submitted. The results from the FAERS database only represent statistical correlation between a particular drug and the corresponding adverse reaction, so further clinical observations, trials, and studies are needed to determine causality. Thirdly, FAERS database lacks comprehensive details for complete causal or epidemiological analysis. For example, FAERS provides the numerator (i.e., the number of adverse event reports for a drug) but lacks a reliable denominator (i.e., the total number of patients exposed to the drug). Consequently, it is impossible to calculate the incidence rate of an AE. This inability to quantify frequency precludes any robust risk quantification or meaningful comparison of risks between drugs. Likewise, the absence of a direct control or comparator group (e.g., BCC patients not treated with HPIs or receiving other therapies) limits the ability to contextualize the relative safety of sonidegib and vismodegib. Future studies with active comparators or population-based cohorts are needed to confirm our findings. Furthermore, lacking data on potential confounders, including polypharmacy, comorbidities, and treatment duration means FAERS signals are prone to spurious associations (e.g., confounding by indication, drug-drug interactions), making it hard to determine if the drug itself caused the AE or if other patient factors/medications were responsible. Despite the limitations of the FAERS database, the comprehensive analysis of AEs associated with HPIs in this study lays the ground for the safe usage of HPIs in clinics and further clinical research.