Ipatasertib Dihydrochloride

Dive Brief:Terremoto Biosciences, a San Francisco-area biotechnology company, on Wednesday announced it raised $108 million from a Series C financing round to help develop its medicines for cancer and rare diseases.New investors include RA Capital Management, Deep Track Capital, Osage University Partners and BeOne Medicines. Existing investors OrbiMed, Third Rock Ventures, Novo Holdings and Cormorant Asset Management also participated.The latest funding follows a Series B financingthat raised $175 million in 2023 and a Series A haul that brought in $75 million the year before. The company is led by Charles Baum, the founder and previous CEO of Mirati Therapeutics, which Bristol Myers Squibb acquired through a $4.8 billion deal that closed two years ago.Dive Insight:Terremoto, whose name translates to earthquake, trumpets that its science offers a seismic shiftin drug discovery and development. The companys goal is to create oral medicines with better efficacy and safety using novel covalency technologies.Terremoto focuses on drugs that aim to block an enzyme known as AKT, which regulates cell division, growth and survival. Its looking particularly at the enzymes role in spurring cancer and a rare bleeding disorder known as HTT, or hereditary hemorrhagic telangiectasia.AKT has drawn the interest of several drugmakers in recent years. AstraZeneca was the first to bringan AKT inhibitor to market, winning Food and Drug Administration approval in 2023for capivasertib, or Truqap, as part of a combination treatment for certain breast cancer patients. Roche, meanwhile, moved a medicine called ipatasertib into Phase 3 trials, but gave up on itthree years ago following mixed results in cancer studies. Terremoto hopes its drug offers better and longer response times with fewer side effects than others in its class. Researchers are testing the biotechs lead therapy, TER-2013, in a Phase 1 program for solid tumors that have certain genetic alterations. Another drug, TER-4480, should enter the clinic this year in patients with HHT, the company said. HHT currently has no approved therapies.Terremotos latest financing comes at a time when venture funding rounds for drug developers have grown larger.Its a signal that these earlier backers are concentrating resources around companies they believe have the best chance at success. Drugmakers focused on cancer, like Terremoto, have been particularly popular, drawing in roughly $15 billion from the most prolific life sciences venture capitalists over the past four years, according to data compiled by BioPharma Dive. '

The lack of showing for Truqap in gene-altered patients was disappointing as the AstraZeneca AKT inhibitor was expected to work better in this subgroup. As if a limited initial FDA approval was not bad enough, AstraZeneca’s Truqap has recorded a pivotal trial flop that could raise additional doubts around the first-in-class AKT inhibitor. From AZ’s perspective, a company executive argued the failure was probably a one-off.Through and through, the phase 3 CAPItello-290 study was a bust. Truqap, when added to the chemotherapy paclitaxel, failed to extend the lives of patients with newly diagnosed metastatic triple-negative breast cancer or those in a subgroup with alterations in one of the PIK3CA, AK1 and PTEN genes.It was not a close call at all. The death risks between chemo and the Truqap-chemo combo were roughly the same in both analyses, according to data presented at the European Society for Medical Oncology Congress 2024. Patients in the Truqap arm lived a median 17.7 months, versus 18 months for control. In patients with the gene-altered tumors, the median overall survival was the same at 20.4 months between the two arms.While the study was designed to measure the drug’s survival benefits as the primary endpoint, Truqap did show a numerical advantage in reducing the risk of disease progression or death. The AZ drug reduced this risk by 28% compared with paclitaxel in the overall trial population and 30% in the gene-altered subgroup. Apparently, that didn’t translate into any life-extension benefit.The lack of showing in gene-altered patients was particularly disappointing as Truqap was expected to work better in this subgroup. The drug’s initial FDA nod in HR-positive, HER2-negative breast cancer, obtained in November, is limited to gene-altered patients because the FDA saw the most convincing effects there. The addition of Truqap to chemotherapy led to new toxicities in CAPItello-290. Notably, among adverse events that are grade 3 or above, the rates of diarrhea were 12.7% and 0.7% for Truqap and control, respectively. The rate of neutropenia was also slightly higher for AZ's medicine. Adverse events led to an 8.5% rate of treatment discontinuations in the experimental arm, compared with 4.9% in control.Cristian Massacesi, AstraZeneca’s chief medical officer and oncology chief development officer, argued that safety wasn’t the reason behind Truqap’s defeat in TNBC. Instead, he said that the data speak to “the fact that the practice is changing.” Although Massacesi didn’t elaborate, new therapies such as Gilead Sciences’ Trodelvy have emerged as later-line treatments for TNBC since CAPItello-290 commenced in 2019. Strong subsequent therapies may sometimes muddy the effect of a first-line drug, especially around overall survival.The control arm in CAPItello-290 performed markedly better than the control group in the phase 2 PAKT trial, which prompted AZ to move Truqap into phase 3 testing in first-line TNBC. Patients who received chemo alone lived a median 12.6 months in that phase 2 trial but 18 months in the new phase 3 study. In control patients with gene-altered tumors, the median progression-free survival time was 3.7 months in phase 2, versus 5.6 months in phase 3.TNBC was not meant to be Truqap’s core indication, and the CAPItello-290 failure does not affect AZ’s understanding of the drug in other ongoing phase 3 trials, including in HR+/HER2- breast cancer and prostate cancer, Massacesi told Fierce.The CAPItello-292 study was intended to move Truqap one line earlier in the treatment sequence than its existing U.S. indication. Unlike TNBC, the relevance of the PI3K/AKT pathway is very well-established in HR+/HER2- breast cancer, Massacesi noted. There, Novartis’ PI3K inhibitor Piqray has been approved in patients with PIK3CA-mutated tumors.As for prostate cancer, the CAPItello-281 trial, which could read out this year, is only being conducted in metastatic hormone-sensitive prostate cancer that’s PTEN-deficient. In addition, the phase 3 CAPItello-280 trial is testing the addition of Truqap to docetaxel in metastatic castration-resistant prostate cancer (mCRPC). That study was started because AKT activation seems to be a rescue mechanism prostate cancer develops to evade docetaxel, Massacesi explained. The idea is to block that alternative pathway and maximize the effect of docetaxel. Nevertheless, AKT inhibitors’ track record in prostate cancer has not been great. Roche previously dropped development of its AKT inhibitor ipatasertib. The drug showed a tumor progression benefit in a phase 3 trial in mCPRC with PTEN loss but didn’t move the needle on overall survival. Like Truqap, ipatasertib had also failed in TNBC in the IPATunity-170 trial.Truqap might have a different fate; after all, ipatasertib had also missed the mark in HR+/HER2- breast cancer, where Truqap was successful at least in the gene-altered population.Truqap didn’t have the best start when the FDA’s initial approval in HR+/HER2- breast cancer left out patients without mutations along the PI3K/AKT pathway despite a positive phase 3 trial readout in the overall population. AZ is still following the phase 3 CAPItello-290 trial for a longer overall survival analysis, and Massacesi said the company will share more data when the time is right.