Isocitrate dehydrogenase 1

But then we also looked into the co-mutational landscape of these tumors, because some of these tumors actually harbor some other actionable alterations.

And we did find KRAS mutations, quite a few IDH1 mutations in diastrocytomas, the N-TRAC or PIKT3CA mutations.

So this could hopefully inspire others to go down to look into combination therapies to combine a PRM25 inhibitors with like a PIK3CA inhibitor or a RAS inhibitor in this population of CNS tumors with a highly unmet need for

treatment.

But these are small subgroups that tell us that somatically something is going on.

Others include like IDH1 and 2 or EZH2.

But there are also other mutations that are present less frequently than in MDS and AML.

but still explain the heterogeneous outcome of these patients that makes the treatment algorithm so challenging, but can help in triple negative patients to see is it more aggressive disease or is it also just a bit somatic burden with bit constitutional symptoms.

So for example, inhibition of the TET-mediated DNA methylation process, which can occur because of a mutant isocitrate dehydrogenase.

This is where 2-hydroxyglutarate, which can be generated from alpha-ketoglutarate because of a mutant IDH1,2, will competitively inhibit the function of alpha-ketoglutarate-dependent enzymes.

Now, I didn't mention, now I will, the TET enzyme requires alpha-ketoglutarate.

So in fact, the TET enzyme is an alpha-ketoglutarate-dependent enzyme, such that the TET2 and then the histone demethylases all function in a coordinated manner.

Targeted drugs, targeting certain proteins and certain gene mutations are another avenue.

For example, some patients with MDS may have something called an IDH1 or IDH2 mutations.

We have drugs that can target these mutations, and there's still more research going on to how to optimize that type of targeted therapy.

There is a lot of thought that inflammation is a unique part of MDS, meaning inflammation can lead to the development and progression of MDS and inflammation can cause your blood counts to be lower.

And it's best in patients under the age of 60 with less than 5% blasts and if they have PNH clone that is positive.

And then IDH mutated lower risk after failure of ESAs, you can also consider the IDH1 inhibitor ivosidenib or enasidenib, which is a IDH2 inhibitor.

Definitely.

So I have to laugh because even though we've taken our boards now five years ago, when you, when I read or when you read the lenalidomide for deletion 5q low-risk MDS, I immediately thought, "I know that because there was a question on it." [laughs]

So that's azacitidine, which is 75 milligram per meter squared for seven days every four weeks, category one, and it's the only agent with a phase 3 survival benefit, or decitabine 20 milligrams per meter squared for five days every four weeks for at least four to six cycles.

And then there's also oral decitabine, cedirotinib, which is an acceptable substitute, uh, for the IV decitabine.

And then venetoclax may be added to the hypomethylating backbone in select patients, as well as IDH inhibitors, the ones we just talked about, ivosidenib, as well as here is olutasidenib for mutated IDH1, and then enasidenib for mutated IDH2.

And then transplant-eligible patients may go directly to transplant or receive hypomethylating chemo agents to bridge to get the blast under 5%.

Wow, that is.

Um, but at the same time, that person in, uh, uh, uh, got a sporadic mutation called a, uh, IDH1 mutation.

Uh, it's been known for a long time that this mutation, you know, it happens spontaneous, like a gift from God.

Um, it's sl- uh, people who, who, uh, acquire that mutation in the growth of their tumor, it just happens by chance, live longer.

You know, the other portion that was part of the passion project for me is they came to me originally for gliomas and brain cancer mutations.

And so we have a product called NeuroInsight that's for IDH1, IDH2.

IDH2 doesn't have a really good IHC around it, so immediately we would add 15% market share to a couple companies that already have IDH drugs out.

And our initial studies in that show that we're better than the IHC, very quickly.