Last week, Ventyx Biosciences (Nasdaq: VTYX) announced the results from a Phase 2a study with its oral CNS-penetrant NLRP3 inhibitor, VTX3232, in obese patients with cardiovascular risk factors. The data showed that VTX3232 did not affect weight loss, whether used as monotherapy or in combination with semaglutide. During the company’s call, CEO Raju Mohan, when discussing the lack of weight-loss efficacy for VTX3232, emphatically proclaimed that the data, “…showed conclusively that NLRP3 inhibition has no effect in humans in promoting weight loss.” It is unusual to hear such a blunt admission of a drug’s failure from a biopharma company’s CEO. However, VTX3232’s failure to induce weight loss didn’t concern Ventyx, nor did it seem to matter to investors, both of whom found other study data far more compelling.
Fleeting Optimism
In our initial note on Ventyx in June 2024, we discussed Ventyx’s intriguing entry into the obesity arms race. In later notes, we highlighted Ventyx’s conflicted relationship with obesity and CEO Mohan’s occasional frustration with investors’ focus on it. We believe the company, after raising $100 million early in 2024 during the frothy obesity market, felt compelled to conduct a study in obese patients, even though the evidence for NLRP3 inhibition and weight loss was “thin.” To be clear, we aren’t suggesting the company lacked optimism about VTX3232 in obesity at the start. Instead, between their 2024 financing and last week’s data, there were indications that NLRP3 inhibition was unlikely to succeed for weight loss, including the company’s own underwhelming diet-induced obesity mouse model data (see The Mouse Giveth and Taketh Away) and mixed Phase 1b obesity study results from NLRP3 peer NodThera. Regardless, the company had a backup plan for its Phase 2a study beyond weight loss, measuring several cardiovascular disease (CVD)-related biomarkers, where there was more optimism that VTX3232 could show a benefit.
Momentum & Timing
The key CVD-related biomarker measured in the Phase 2a was high-sensitivity C-reactive protein (CRP). In fact, the company’s clinicaltrials.gov study description doesn’t even list weight loss as an outcome measure, only CRP after safety. CRP, a biomarker that measures systemic inflammation, has been gaining momentum among the cardiology community, with the American College of Cardiology (ACC) recently advocating for universal CRP screening for both primary and secondary prevention of CVD.
With momentum building behind CRP, the timing was perfect for Ventyx to dismiss an obesity miss and celebrate a CRP hit. In last week’s clinical data, Ventyx reported a robust, rapid, and statistically significant reduction in CRP levels with VTX3232 compared to placebo. The impressive CRP results are the impetus for the company’s new, yet-to-be-fully-elucidated plan to explore CVD indications with VTX3232. This strategic shift toward CVD could complicate its relationship with Sanofi and its pipeline.
A Biomarker Looking For An Indication
As we mentioned, CRP has been gathering momentum within the cardiology community, as part of the broader systemic inflammation conversation. Earlier this month, the ACC published a paper on inflammation and CRP, stating, “…residual inflammation, measured with high-sensitivity C-reactive protein (hsCRP) remains strongly predictive of recurrent events…”, adding, “… the evidence linking inflammation with atherosclerotic CVD is no longer exploratory but is compelling and clinically actionable.”
Elevated CRP is linked to numerous CVD conditions, including atherosclerosis, atrial fibrillation, congestive heart failure, and recurrent pericarditis (RP). Despite growing interest in CRP screening, the FDA has not approved it as a surrogate endpoint for drug approval.
Downstream Validation
NLRP3 is upstream of interleukin 1ꞵ (IL-1ꞵ) and interleukin 6 (IL-6) in the inflammatory cascade that can lead to cardiovascular disease. Several drugs approved in both classes have shown a clear link between inhibiting IL-1 and/or IL-6 and a reduction in CRP. Kiniksa Pharmaceuticals’ (Nasdaq: KNSA) IL-1 inhibitor Arcalyst (rilonacept) is the only approved medication for recurrent pericarditis (RP). Among the IL-6 drugs, none are approved for CVD, though all significantly impact CRP. Notably, in September this year, Novartis acquired Tourmaline Bio (Nasdaq: TRML), which was developing an IL-6 inhibitor for CVD, for $1.4 billion. It is worth noting that all approved IL-1 and IL-6-targeting drugs are injectables, whereas Ventyx is developing oral NLRP3 inhibitors. Although no NLRP3 inhibitor has been approved yet, the commercial success and M&A activity around mechanisms just downstream of NLRP3 are promising.
***Novel Insights Into the NLRP3 Inflammasome in Atherosclerosis, JAHA June 11, 2019
Pipeline Complication
As we highlighted earlier, Ventyx reported very promising biomarker data last week for VTX3232 in obese patients with cardiovascular risk factors. In addition to the statistically significant reduction in CRP compared to placebo, VTX3232 also showed statistically significant decreases in IL-6 and lipoprotein(a). These biomarker results offer encouraging evidence of VTX3232’s potential to regulate systemic inflammation. However, remember that VTX3232 is a CNS-penetrating compound, meaning it was developed for diseases requiring NLRP3 inhibition in the brain, such as neuroinflammatory conditions like Parkinson’s disease (PD) and Alzheimer’s. For systemic inflammation, Ventyx developed an orally administered, peripherally restricted NLRP3 inhibitor, VTX2735.
Ventyx is currently enrolling an open-label Phase 2 study involving 30 RP patients treated with VTX2735, with CRP as a key endpoint. In addition to CRP reductions from baseline, investors should also focus on changes in pain scores as a crucial endpoint. Decreases in CRP levels are strongly associated with symptom relief, particularly pain, in RP patients, which should reassure investors. Moreover, as mentioned above, IL-1 inhibition with Arcalyst is already approved for RP, indirectly supporting NLRP3 inhibition as a valid mechanism. Top-line results from the Phase 2 RP study are expected before the end of the year.
Ventyx appears committed to pursuing CVD indications with VTX3232. At the same time, the company is testing VTX2735 in RP, another CVD indication. Can two NLRP3 inhibitors targeting CVD coexist within the same pipeline?
Obesity (CVD) Complication
In September 2024, Sanofi invested $27 million in Ventyx for the rights of first negotiation (ROFN) for VTX3232. During subsequent corporate presentations, CEO Mohan highlighted that Sanofi’s primary interest was in VTX3232 for neuroinflammatory conditions. At the time of the ROFN announcement, Ventyx was conducting a PD study with data expected in 2Q2025, which clearly aligned well with Sanofi’s therapeutic focus. However, we found it challenging to reconcile Sanofi’s interest in VTX3232 and obesity, given that the company had no active R&D programs in that area. In a June note, ahead of the PD results, we referred to it as the “obesity complication” for a potential Ventyx-Sanofi collaboration.
Ventyx disclosed topline PD data in June of this year. The company released limited details from the small ten-patient open-label study, mainly stating, “This was a thorough and well-conducted trial demonstrating clear evidence of target engagement in the CSF and plasma, with significant reduction to near-normal levels or the limit of quantitation (LOQ) in downstream biomarkers of NLRP3 inhibition, including IL-1b, IL-6, and high-sensitivity C-reactive protein (hsCRP). Our investigators also noted clinically significant reductions in MDS-UPDRS Parts II and III.” Investors were left wanting more information, and the stock had a lackluster response to the results. Since the June press release, Ventyx has shared some additional data, notably promising results from the Unified Parkinson’s Disease Rating Scale (UPDRS). However, the company hasn’t put much emphasis on the PD data, and investors generally seem indifferent towards them. The real question, though, is what does Sanofi think?
Partnering Complication
Following positive biomarker data from the Phase 2a obesity study, Ventyx appears emboldened to pursue inflammatory CVD indications with VTX3232. Similar to neurodegenerative diseases, the CVD indications Ventyx has proposed—atherosclerosis, atrial fibrillation, and heart failure—are typically the domain of large biopharma companies, which have the financial resources to fund the extensive studies often needed in CVD. Sanofi fits this profile, especially if VTX3232’s focus was on neurodegenerative diseases. As a departed BioTwitter legend commented;
However, Sanofi currently lacks an active CVD pipeline, raising questions about whether it remains the ideal licensing candidate for VTX3232. If Sanofi does not license VTX3232, Ventyx would likely need another partner to step up.
This new, yet-to-be-fully-elucidated plan for VTX3232 in CVD might also complicate VTX2735’s development. We have always believed that RP was an indication that Ventyx could handle on its own. Kiniksa’s Phase 3 study for Arcalyst in RP involved only 86 patients, a trial that a company of Ventyx’s size could fund independently. However, it’s difficult to envision a partner licensing VTX3232 for its wide-ranging CVD uses while allowing Ventyx to develop a peripherally restricted NLRP3 inhibitor in an adjacent CVD indication. If VTX2735 proves successful in RP, it seems likely that the two drugs will be difficult to differentiate, which might prompt VTX3232 licensing talks to turn into potential acquisition discussions.
Good Complications
Last week’s data from VTX3232 may temporarily complicate Ventyx’s partnering path. The VTX3232 data could also complicate Ventyx’s plans to develop VTX2735 independently, especially if the company generates robust CRP data in the ongoing RP study. In the meantime, the stock appears poised to go higher, with investors willing to bet on VTX2735’s success in RP later this quarter and the optionality of potential business development on the horizon. The various scenarios that could play out for Ventyx are complicated, but sometimes complications are good.