FirstWord Pharma

Vivace Therapeutics raised a $35-million series D on Wednesday to advance its lead candidate, VT3989, into a Phase III trial for mesothelioma.RA Capital Management led the round, and other existing investors Canaan Partners and Cenova Capital also participated. VT3989 is a potentially first-in-class small molecule that targets the Hippo pathway by inhibiting palmitoylation of members of the transcriptional enhanced associate domain (TEAD) protein family."Hippo signaling has been recognised as a key tumour suppressor," CEO Sofie Qiao told FirstWord. "Dysfunction of the pathway promotes uncontrolled cellular proliferation… [and] is particularly common in mesothelioma, which is why it’s the first indication we are targeting with VT3989."She added that, unlike other cancer indications that have "a plethora of targeted therapies available to them," the only approved treatments for mesothelioma are immunotherapy and chemotherapy combinations, like Merck & Co.'s Keytruda (pembrolizumab). VT3989 is currently in an open-label Phase I study, and according to the company, has demonstrated "particularly notable" results in patients with mesothelioma who have failed chemotherapy and immuno-oncology combination regimens. Vivace will present the data at a major medical conference next half.  With Wednesday's financing, Vivace is planning to launch a randomised, registrational Phase III study of VT3989; the firm hopes to discuss the potential trial with the FDA later this year.

Hotly anticipated late-stage data for Pfizer and Arvinas' oral oestrogen receptor-degrader vepdegestrant (ARV-471) debuted on Tuesday, with positive results seen in breast cancer patients with an ESR1 mutation. However, the drug failed to demonstrate benefit in those without the mutation, sending Arvinas shares down as much as 50%.While a number of oral selective oestrogen receptor degraders (SERDs) have delivered similarly mixed data — such as Menarini's Orserdu (elacestrant) and Eli Lilly's imlunestrant — hopes were high for vepdegestrant in the broader population. UBS analysts recently said "we think the potential for success in ESR1 [wild type] patients is greater than appreciated" for vepdegestrant, partially due to the design of the VERITAC-2 study.The trial enrolled 624 patients with oestrogen receptor-positive, HER2-negative advanced or metastatic breast cancer whose disease progressed following prior treatment with CDK 4/6 inhibitors and endocrine therapy. Participants were randomised to receive once-daily vepdegestrant or fulvestrant.PFS exceeded targetTop-line results showed that in patients with an ESR1 mutation, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to fulvestrant, meeting the trial's primary endpoint in this population. Pfizer and Arvinas noted that PFS exceeded the pre-specified target hazard ratio of 0.60 in this group.However, the companies said that in the wider trial population, which also included those with ESR1 wild type, the study failed to reach statistical significance on improvement in PFS.OS data immaturePfizer and Arvinas noted that less than a quarter of the required number of events have occurred for the overall survival (OS) analysis — a key secondary endpoint — with the study continuing in order to evaluate this goal."The first Phase III data readout for a PROTAC degrader represents a significant achievement and these data show that vepdegestrant has the potential to provide clinically meaningful outcomes for…patients with metastatic breast cancer whose tumours harbour [ESR1] mutations," remarked John Houston, CEO at Arvinas. The companies noted that the data will be shared with global regulatory authorities, and presented at a medical conference later this year. Meanwhile, the Phase III VERITAC-3 study investigating vepdegestrant in combination with Pfizer's CDK 4/6 inhibitor Ibrance (palbociclib) in the first-line setting is also ongoing.Back in 2021, Pfizer paid $650 million upfront for rights to co-develop vepdegestrant, which utilises Arvinas' PROTAC (PROteolysis TArgeting Chimera) protein degrader platform.The VERITAC-2 results Tuesday follow a positive Phase III readout for AstraZeneca's oral SERD candidate camizestrant last month, showing a significant PFS benefit when paired with a CDK4/6 inhibitor in first-line patients with HR+/HER2- advanced breast cancer whose tumours have an emergent ESR1 mutation. In a recent interview with FirstWord to discuss the SERENA-6 study, key opinion leader Azka Ali described the results as a win-win for both safety and efficacy, and would likely hasten the shift from aromatase inhibitors to oral SERDs in patients with ESR1 mutations. For the rest of that conversation, see – KOL Views Q&A: Battle for oral SERD supremacy in HR+ breast cancer boils down to efficacy.

Genmab and Johnson & Johnson are no longer developing an anti-CD38 antibody the partners had hoped to market as a next-generation version of their megablockbuster cancer drug, Darzalex (daratumumab) — which rose to the number one spot on the pharma's top-sellers list last year, and was the seventh biggest revenue generator across all pharmaceuticals (see – Spotlight On: J&J's Darzalex joins the $10 billion club and Vital Signs: Top ten drugs of 2024).The decision comes more than a decade since the pair first teamed up on Darzalex, a CD38-targeted monoclonal antibody (mAb) that won its first full FDA approval for multiple myeloma (MM) in 2016. Three years later, J&J and Genmab agreed to use the latter's HexaBody technology to design a follow-on drug against CD38. At the time, Genmab CEO Jan van de Winkel had commented that "preclinical data suggest that HexaBody-CD38 could be superior to [Darzalex] for certain tumour cell types." He has previously described the HexaBody technology to FirstWord as "super-charged molecules with a much higher ability to kill target cells in the context of cancer by promoting clustering behavior." See – ViewPoints: What’s next for Genmab?As part of the collaboration, Genmab funded R&D activities for the candidate, GEN3014, through clinical proof-of-concept studies in MM, after which J&J could opt for a global license. But on Monday, Genmab disclosed that the pharma has decided not to exercise its option for GEN3014, and without J&J's backing, the biotech said that, "following a thorough evaluation of the data, the market landscape, and Genmab’s rigorous portfolio prioritisation," it wouldn't continue development. The biotech's stock dropped more than 8% in Copenhagen on the news.Safety woesEarly data from a Phase I/II trial might shed some light as to why J&J decided not to move forward with GEN3014. Though Genmab said the results "showed robust clinical efficacy," the intravenous HexaBody programme did not seem to significantly improve overall response rate (ORR) compared with subcutaneous Darzalex. Of 84 evaluable patients with relapsed or refractory MM or another blood cancer, half received GEN3014 and half took the flagship drug. Patients in the GEN3014 arm saw an ORR of 55% and a complete response rate of 7%, compared with rates of 52% and 2% for Darzalex recipients.Moreover, GEN3014 was associated with a notably higher rate of severe related treatment-emergent adverse events (TEAEs), with 73.3% of patients experiencing Grade 3 or higher events compared to 18.6% with Darzalex, and related serious TEAEs occurring nearly twice as often at 22.2%. Treatment interruptions due to TEAEs were reported in 51.1% of GEN3014 patients versus 4.7% for Darzalex, while dose delays occurred in 75.6% and 34.9% of cases, respectively."While we are disappointed that J&J has decided not to advance HexaBody-CD38, the data confirms the clinical potential of the HexaBody platform, reinforcing its value for future applications," Winkel said in a company release Monday, adding that Genmab is "confident in the potential of our existing pipeline of innovative antibody therapeutics."