Orphan Drug Designation Granted for VGT-1849A, a Novel and Selective Antisense Oligonucleotide Candidate for the Treatment of PV

[Manouche]

« The molecular targeting strategy of VGT-1849A addresses a critical medical need in PV treatment. The 95% prevalence of JAK2 V617F mutations in PV patients provides a clear rationale for this targeted approach. The antisense oligonucleotide technology offers precise genetic intervention, potentially reducing the systemic effects seen with traditional kinase inhibitors.

The therapeutic concept is particularly compelling because it targets the disease's root cause - aberrant JAK2 signaling - rather than just managing symptoms. For non-technical readers, think of it as precision-guided therapy that specifically targets the problematic protein while leaving related proteins unaffected, similar to using a sniper rifle instead of a shotgun.

This approach could be especially valuable for patients who experience adverse effects from current treatments or require long-term therapy, potentially offering a better balance of efficacy and tolerability ».

stocktitan.net/news/VNDA/va...

[hunter5582]

The use of ASOs to target the underlying mechanism of aberrant JAK2 signalling via altering RNA function is an interesting and hopeful approach. The theory is that by binding to JAK2 mRNA, VGT-1849A reduces its activity, leading to decreased downstream signaling and inhibition of JAK2-driven autonomous cell proliferation. If it works, then this gene therapy would selectively reduce JAK2 activity, hopefully having fewer off-target effects than other treatment options.

Thanks for posting this. It will be interesting to see whether this treatment option is viable.

[EPguy]

This part of a suddenly expanding line of better targeted Jak inhibitors.

prnewswire.com/news-release...

"By specifically targeting JAK2, Vanda seeks to reduce the risk of infection and toxic effects that are seen with inhibitors also blocking JAK1, JAK3, TYK2" (Tyk2 has also been called Jak4)

For Rux this is most relevant to Jak1, which Rux substantially targets along with Jak2. Their quote here also has new info: the immune suppresive effects of Rux are increased because of the non-Jak2 targets.

But some of the allele reductions with Rux have been proposed to be a result of its anti-inflammatory effect. Could it be these off targets are part of that? When VGT-1849A enters trials we will might out if they choose to track the mutation. To be fair they are not looking to reduce the clone, rather to reduce the disease causing events via Jak2 in the JakStat path. Also this is the 1st new Jak-i for PV indication vs MF. Us PV'ers will welcome any new options.

The context of the above is they don't claim this agent is selective for V617F, only that it is selective for any Jak2, as is Rux (albeit with Jak1 added). Like Rux, to the extent Jak2 wild type (unmutated) does something useful, will there be negative effects from less of that happening.

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A contrast is INCB160058 discussed in (too much) detail below, and AJ1-11095 in prior posts. These claim to not only be selective for Jak2, but additionally only the mutation of it (V617F). It would suggest the other two agents are more on the point. But info on VGT-1849A remains skimpy, there may be more to the story.

prnewswire.com/news-release...