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Breakthrough Results from the INDIGO Trial of Vorasidenib in Low Grade Glioma (LGG)
Great news for IDH-mutant LGG patients…and an object lesson in investable theses for brain cancer
Over the past several days, the American Society for Clinical Oncology (ASCO) annual meeting has been underway in Chicago. ASCO is the focal point each year for important announcements regarding all things cancer, and this year is no exception.
The INDIGO Trial Results Represent Great News for IDH-mutant Low Grade Glioma Patients
Back in March, Servier issued a press release summarizing top line results from the INDIGO pivotal trial of vorasidenib in LGG patients. The full data presentation occurred at ASCO on 4-Jun, and was accompanied by a more detailed Servier press release, a New England Journal of Medicine paper, and general media articles. In summary, the results unambiguously demonstrated that vorasidenib provides Progression Free Survival and Overall Survival advantages for patients with Grade 2 gliomas harboring an IDH-1/2 mutation. Given the long history of almost no progress in developing therapeutic alternatives for these patients, the INDIGO data can only be viewed as a major success.
Congratulations to the Servier, the trial investigators and the patients who participated in the study.
What Can We Learn from the Vorasidenib Story?
The Neuro-Oncology field and leading healthcare investors had high confidence that the INDIGO trial would yield positive results for two critical reasons:
Vorasidenib targets LGG driver mutations in a validated target (IDH-1/2). The target has previously been validated in multiple cancers, and it can serve as a biomarker to identify likely responders. When one is developing targeted oncology drugs, this is the profile that one is seeking. Drug developers are confident that if (a) the drug is tolerable; and (b) enough of the drug can be delivered to the tissue harboring the target, then the drug is very likely to work…at least until the cancer cells generate compensatory pathways to circumvent the selective pressure from the targeted drug.
Vorasidenib was specifically engineered to cross the Blood-Brain Barrier (BBB) and be brain-penetrant. This is a key point that we cannot emphasize enough. If adequate levels of the drug do NOT get to the tumor, then one should not expect a therapeutic benefit. The BBB erects a challenging barrier to drug transport into the brain. In fact, analysis of several dozen clinical trials by our investment group has reached the conclusion that the vast majority of HGG clinical studies fail because the therapeutic agent under study is not getting across the BBB and to the tumor site in sufficient concentrations and with sufficient dwell times to yield the desired pharmacodynamic action(s).
For those readers keeping score at home, you will undoubtedly notice that the above two criteria are also satisfied by tovorafenib from Day One Biopharmaceuticals (Ticker: DAWN). As a result, several leading healthcare investors poured both private and public capital into DAWN. This is what we call an Investable Thesis.
Are There Analogous Investable Theses in GBM and other High Grade Gliomas (HGG)?
The majority of HGGs, and especially GBM, are low Tumor Mutational Burden (TMB) cancers. Genetic analyses of resected tumor samples show very few mutations, and most are not validated as primary drivers. In addition, some of the mutations observed are very difficult to drug. Oncogenic drivers in GBM are often amplified copy number wild type genes like EGFR and CDK 4/6. Moreover, many of these driver oncogenes (a) are located on extra-chromosomal DNA (ecDNA), and their inheritance characteristics do not follow chromosomal inheritance patterns; and (b) research shows that the cancer cells can modulate the ecDNA oncogenes (and possibly immune regulatory genes) in a couple of cell divisions in order to avoid selective pressure. Taken together, these characteristics make it very difficult to develop single agent, targeted drugs for HGGs.
In addition, the field has not paid adequate attention to engineering drug molecules that can traverse the BBB. Our investment group sees proposal-after-proposal (after proposal, after proposal, after proposal!) in which the investigators show single target in vitro cellular growth inhibition assays and one or two xenograft animal models (often with cherry-picked cells lines unrepresentative of primary human HGGs and chosen to over-emphasize the target under study) with no attempt to measure brain penetrance of the drug candidate.
As Einstein was reported to have commented, “Insanity is doing the same thing over and over again and expecting different results.”
HGG clinical research is not alone in disregarding the assessment of brain penetrance. The Alzheimer’s field has been guilty of the same practices. The area is currently dominated by monoclonal antibodies against Tau and A-Beta, which independent studies have shown usually traverse the BBB only in the 0.1-0.5% of administered dose range. It is difficult to prove the validity of the amyloid plaque hypotheses, if almost no drug gets to the target. Nonetheless, tens of billions of dollars have been invested over 20 years repeating the same experiment over-and-over again with largely the same results.
A Concluding Thought
While research will continue in targeted drugs for GBM and HGGs, we expect that meaningful progress will come from combination protocols invoking immuno-oncology or immunotherapeutic mechanisms with specific attention devoted to transport of therapeutic agents across the BBB or circumvention of the BBB by neurosurgically-installed techniques. The heterogenous, highly aggressive and invasive characteristics of HGGs would appear to tilt the solution space in that direction.