Low-grade gliomas (LGG) are incurable, slow-growing malignant brain tumors commonly found in young adults between the ages of 20-40. Patients diagnosed with this type of cancer can expect to survive for up to 14 years with treatment.
Even after surgical intervention, these tumors have a knack for reappearing and eventually evolving into more aggressive types like glioblastomas and anaplastic gliomas. Once this stage is reached, patient survival rates plummet to under two years.
In the grand scheme of things, LGGs are relatively rare in adults, accounting for just 3.75% of all new brain cancer cases reported each year in the United States (roughly 3,000 out of 80,000). More than 80% of all LGG patients carry a unique IDH mutation (isocitrate dehydrogenase).
While IDH mutations make gliomas slower and easier to treat, patients still face significant challenges during their treatment journey. Surgeries often fail to completely remove the tumors, which can lead to frequent bouts of chemotherapy and radiation for maintenance.
While some patients can make it to 10 years without cancer progression, in other instances, the tumor can become aggressive in just a couple of years despite surgical intervention. The psychological, physical, and emotional toll of living with an LGG can be significant.
Now, a drug developed specifically to target the IDH mutation is offering new hope to thousands of patients who are forced to live with low-grade gliomas. The name of this targeted drug is Vorasidenib. Let us take a deep dive into its history and mode of action.
The Story Behind the Evolution of Vorasidenib
Vorasidenib (brand name Voranigo) was developed by Agios Pharmaceuticals, a biotechnology company based in Cambridge, Massachusetts. Agios specializes in developing treatments for rare cancers and genetic diseases and is a pioneer in the field of IDH inhibitors.
Apart from their role in 80% of all gliomas, IDH1 and IDH2 mutations are also linked to aggressive blood cancers like acute myeloid leukemia. Blocking the activity of the abnormal proteins created by mutated IDH genes can help slow the progression of these cancers.
In the 2010s, Agios successfully developed two IDH blockers to treat acute myeloid leukemia. Enasidenib and Ivosidenib, the groundbreaking drugs were designed to selectively target aberrant IDH1 and IDH2 proteins respectively. They received FDA approval circa 2017-2018.
However, both these drugs were not suitable for the treatment of IDH-mutated LGGs as they could not effectively cross the blood-brain barrier. Vorasidenib was designed to specifically overcome this limitation. Instead of targeting just one protein, it is capable of blocking both IDH1 and IDH2 proteins.
In 2021, Agios Pharmaceuticals decided to switch from oncology to rare genetic diseases as part of a strategic pivot. The oncology assets, including drugs like ivosidenib and vorasidenib, were sold to the French biotechnology firm Servier.
A phase 3 clinical trial for the evaluation of Vorasidenib was already in its third year when the sale occurred. Servier continued the trial, called INDGIO, and its final findings were reported in 2023 in the New England Journal of Medicine.
The Key Findings of the INDIGO Clinical Trials
The phase 3 trials for Vorasidenib involved 331 patients from 10 countries including the United States and the UK. It was a large double-blind trial where patients were randomly assigned either 40 mg of vorasidenib or a placebo over several cycles lasting 28 days each.
Researchers noted the following findings at the end of the trial:
- Patients who received vorasidenib enjoyed a median progression-free survival (PFS) of 27.7 months. In contrast, the PFS of the placebo group was just 11.1 months.
- Patients also had an 83% chance of not requiring an additional cancer treatment (surgery, chemo, or radiation) after 2 years of taking vorasidenib, compared to just 27% for the placebo group.
- While some adverse effects like fatigue, headache, and signs of liver damage were reported in 22.8% of the patients, the drug was found to be generally very safe and well tolerated.
Overall, the results of the INDIGO trial were so positive that it was stopped earlier than planned due to meeting all the targets. Consequently, patients in the placebo group were also offered a chance to switch to vorasidenib due to the proven benefits.
Bolstered by these results, FDA approval was formalized in August 2024. In the US, vorasidenib can be used to treat grade 2 astrocytoma/oligodendroglioma with IDH mutation in patients aged 12 and over. The daily approved dose is 40mg for patients weighing more than 88lbs, and 20mg for those under the threshold.
Understanding IDH Mutation and Vorasidenib’s Method of Action
IDH 1 and 2 are genes that play a vital role in regulating the production of energy in our cells through the production of various enzymes. In their mutated form, these genes produce an abnormal metabolite called 2-hydroxyglutarate (2-HG).
The human brain requires over 20% of the body’s total energy output, despite weighing just 2% of the total mass. Glial cells are responsible for ensuring the energy supply to the neurons in the brain. Their role and abundance across the brain make them more vulnerable to IDH mutations.
2-HG metabolites disrupt normal cellular processes in glial cells, paving the way for the formation of abnormal, slow-growing gliomas. Vorasidenib works by blocking the action of both IDH1 and IDH2 enzymes, decreasing the levels of 2-HG in glial cells.
IDH mutations have a strange dual role – on the one hand, they prevent the tumors from growing aggressively, reducing the risk of early death. However, the tumors also become harder to treat, as the 2-HG creates a fertile environment for the spread of tumor cells even after surgical treatment.
LGG patients tend to be young adults with families and careers. Vorasidenib is the first-ever targeted drug developed to improve the lives of these patients in the last few decades. It can help thousands of young LGG patients live longer, healthier lives.
There are at least 120 different types of brain tumors, each with varying levels of severity and lethality. However, the total number of brain cancers only accounts for about 2% of all reported malignancies. The lower number of patients often makes drug development for rare tumors challenging.
The dramatic success of targeted drugs like Vorasidenib indicates that change could soon be on the horizon. Molecular targeting of known mutations is an effective approach that can be replicated in other types of lethal cancers like glioblastomas (EFGR mutation) and colorectal cancer (KRAS mutation).
