Novartis gets CDSCO panel nod to study Alpelisib for early (prophylactic) and sustained improvement of hyperglycemia

New Delhi: Pharmaceutical major Novartis has got a conditional nod from the Subject Expert Committee (SEC) of the Central Drugs Standard Control Organization (CDSCO) to conduct the phase II trial of Alpelisib to investigate the management strategies that offer earlier (prophylactic) and sustained improvement of hyperglycemia than what is achieved with Metformin and/or Dapagliflozin as initial therapy after hyperglycemia has been observed.

This approval was made after the drug-maker presented the proposed Phase II global clinical trial study protocol no. CBYL719C2202, Version: 01, dated August 6, 2021, before the Committee.

This nod came with multiple conditions, including that the firm should provide continuous glucose monitoring (CGM) to the trial site for the continuous monitoring of each subject's flash glucose in addition to the protocol-defined fasting blood glucose (FBG) monitoring, to safeguard the trial subjects.

Furthermore, the firm has been directed that at screening, a DEXA bone scan will be conducted, and individuals who are found to have a high fracture risk (FRAX) would be excluded.

Alpelisib, an orally available phosphatidylinositol 3-kinase (PI3K) inhibitor with specific activity against PI3K alpha (PI3Kα)-is being developed by Novartis for the treatment of breast cancer.

Alpelisib has demonstrated efficacy in combination with fulvestrant as treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer in patients with a PIK3CA mutation and was recently approved for this indication in the USA.

Alpelisib specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

Furthermore, analysing the risk-benefit ratio, the expert panel observed, "The non clinical and clinical studies with Alpelisib (BYL719) were approved by USFDA, India, EU and other countries in combination with Fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. The Dapagliflozin and Metformin are anti-diabetic and both were approved. Thus it justifies the conduct of trial."

In addition, evaluating the innovation vis-a-vis existing therapeutic options, the SEC meeting minutes added, "This is a Phase II, multicenter, randomized, open-label, active-controlled trial designed to assess the safety and efficacy of the combination of Dapagliflozin plus Metformin XR compared with Metformin XR during treatment with Alpelisib plus Fulvestrant in participants with HR-positive, HER2- negative advanced breast cancer with a PIK3CA mutation following progression on or after endocrine-based therapy."

After detailed deliberation, the Committee recommended the conduct of the proposed study with the following conditions:

1) The firm should provide continuous glucose monitoring (CGM) to the trial site for the continuous monitoring of each subject's flash glucose in addition to the protocol defined fasting blood glucose (FBG) monitoring, to safeguard the trial subjects.

2) DEXA Bone scan to be performed at screening and those found with high fracture risk (FRAX) should be excluded.

3) Regular clinical investigation/test to be performed to control the UTI risk with the trial subjects.

4) The trial should have atleast 50% Govt. site. 5) The study team should mandatorily have one DM-Endo. / MD (Diabetologist or Medicine) as Co Investigator/SubInvestigator at each site.