Itovebi Drug's Side Effects on Hyperglycemia Are 31% Lower Than Piqray!

Given the highly competitive environment for Roche in breast cancer, the company is banking on a new drug, inavolisib, to add 2 billion Swiss francs of value to its prestigious portfolio. The drug has been approved by the U.S. Food and Drug Administration (FDA) as part of a first-line treatment regimen for HR-positive, HER2-negative breast cancer with PIK3CA mutations that are resistant to adjuvant endocrine therapy. The oral drug will be used in combination with Pfizer's Ibrance and Astrazeneca's Faslodex, further strengthening its market position.

Inavolisib, which will be marketed under the brand name Itovebi, poses a direct challenge to Novartis' PI3K inhibitor Piqray and Astrazeneca's AKT inhibitor Truqap. Despite intense market competition, Roche Pharmaceuticals head Teresa Graham is confident about Itovebi's market prospects, predicting maximum sales potential of CHF 2 billion ($2.3 billion).

Graham elaborated on this sales forecast during an investor call in April, noting that PIK3CA mutations account for about 40 percent of HRD-positive breast cancers, and he firmly believes that inavolisib has superior performance compared to Piqray. Charlie Fuchs, MD, global head of product development for oncology and hematology at Roche's Genentech, also stressed in an interview with the media that although the PIK3CA mutation has been known for decades, it has long plagued the medical community due to its difficulty in treatment, limited drug efficacy and poor tolerance. He further noted that Itovebi showed best-in-class potential in terms of both efficacy and safety.

Itovebi's superior performance is supported by strong clinical data. In the Phase 3 INAVO120 trial, the combination of Ibrance, Faslodex and Itovebi significantly reduced the risk of disease progression by 57%. Specifically, patients in the Itovebi group achieved progression-free survival of 15 months, compared to 7.3 months in the control group. The study specifically targeted a population of tumor patients with PIK3CA mutations who rapidly deteriorated after receiving postoperative endocrine therapy and showed significant resistance to endocrine therapy.

In terms of security, Itovebi's performance is also noteworthy. While 6.2% of patients stopped Itovebi due to adverse events, only 0.6% of patients in the control group stopped matching placebo for similar reasons. The incidence of serious adverse events was 24.1% and 10.5%, respectively. Notably, a common side effect of PI3K drugs was high blood sugar, with 5.6% of patients in the Itovebi group recording grade 3 or 4 high blood sugar levels, compared with none in the control group. In contrast, Novartis' Piqray caused grade 3 or 4 hyperglycemia in 36.6 percent of patients in the Phase iii trial of SOLAR-1, compared to just 0.6 percent in the control group.

Dr. Fuchs attributed Itovebi's advantages in efficacy and tolerability to its increased specificity of the mutant PI3K-α subunit, rather than its widespread inhibition of wild-type PI3K. He further noted that hyperglycemia may be the result of the degradation of normal PI3K, but Itovebi reduces this risk through its specific inhibitory effect. "We are committed to providing a treatment that provides both meaningful efficacy and is well tolerated, ensuring that patients can continue to take the drug," he stressed. This is the key to targeting PI3K."

However, Itovebi still faces some challenges in the current line-up of first-line therapies. In particular, in the INAVO120 interim analysis, which had a median follow-up of 21.3 months, data on whether Itovebi extended patients' lives were premature. Although preliminary results showed a 36 percent reduction in the risk of death, the number was not statistically significant. The FDA said it will release overall survival results after the trials accumulate to the 63 percent of deaths required for the final analysis. Dr. Fuchs is optimistic about Itovebi's overall survival data and promises to share mature data as soon as it becomes available.

Second, treatment strategies for early-stage HR+/HER2- breast cancer are undergoing significant change. It is worth noting that Novartis' Kisqali and Eli Lilly's Verzenio have been approved for use as an adjunct to endocrine therapy, and not just for endocrine therapy itself. This development then raises the important question of whether the Itovebi-Ibrance Faslodex triple therapy is still significant for patients who have received Kisqali or Verzenio as adjunctive therapy, especially since these two drugs are believed to outperform Pfizer's Ibrance in efficacy.

The data from the INAVO120 study were insufficient to answer questions about post-treatment with cdk4/6 inhibitors, because only four of the 325 participants in the trial had previously received adjuvant CDK4/6 inhibitors.

In addition, Dr. Fuchs referred to another Phase 3 study called INAVO121, underscoring Roche's strong confidence in Itovebi. Roche has initiated a head-to-head trial of Piqray in a second-line setting in patients with advanced or metastatic breast cancer following cdk4/6 inhibitor and endocrine combination therapy. The trial officially started in June 2023 and is expected to take several years to complete.

Notably, Itovebi is also facing competitive pressure from Astrazeneca's AKT inhibitor Truqap. Truqap was approved by the FDA about a year ago in combination with Faslodex to treat HR+/ HER2-breast cancer patients with alterations in the PIK3CA, AKT1 and PTEN genes.

However, market data shows that since the sixth year of Truqap's launch in late 2023, sales of Piqray have shown a downward trend. Specifically, in the first half of 2024, Piqray's sales declined 7% year-over-year to $229 million.

Roche is similarly confident in the value of AKT inhibitors, despite the failure of its previously studied AKT inhibitor, ipatasertib, in multiple Phase 3 trials, which led to the project being shelved.

Dr. Fuchs noted that targeting PI3K, whether by targeting mutations or downstream pathways like AKT, provides important treatment options for patients. But he also stressed that Itovebi is the only drug that currently has evidence to support its use in first-line therapy.

Outside of the endocrine resistance area, Roche has also initiated a Phase 3 trial, coded INAVO123, to evaluate Itovebi in endocrine-sensitive HR+/HER2- patients. In addition, the INAVO122 study focused on the combination of Itovebi and Roche Phesgo in the first-line treatment of HER2-positive pik3ca mutated breast cancer. Roche is also exploring the potential of the drug in adjuvant therapy for breast cancer and other PI3K-mutated tumor types.

Itovebi is part of an important product line that Roche has crafted to revitalize its breast cancer business. With the expiration of the Herceptin patent period, Roche's former HER2 franchise has dimmed slightly. Kadcyla faces stiff competition from Astrazeneca (AZ) and Daiichi Sankyo's star antibody drug conjugate Enhertu.

In addition to Itovebi, Roche is also actively advancing development of giredrant, an oral SERD for HR+/ HER2-breast cancer, with key Phase 3 clinical data expected in 2025.

Last week, Roche announced an $850 million pre-stage deal with Regor Pharmaceuticals, adding the potential for early-stage CDK4/2 inhibitors and a Phase I CDK4 drug to its portfolio.