cccDNA destabiliser as a new therapy for HBV cure

In my last topic i pondered about Gene Editing being a potential cure, which in my opinion is. We also touched on NAPs as @availlant provided great and detailed insight. Many thanks to him. This is a great place for us all involved in this disease. Thanks to @ThomasTu .

As a mean to brighten us all let me mention about another promising molecule developed by Dicerna in collaboration with Roche. This product is a short interfering RNA which can inhibit HBV gene expression for HBsAg production. This is already in Phase 2 Clinical trial as a combination therapy with others.

Information about Dicerna’s Drug Candidate DCR-HBVS (RG6346) | Dicerna Pharmaceuticals

But what has been kept secret i dont know for what reason is another product in development by Roche. Im not sure whether they have scrap its development or maybe i have not been upto date with the latest info. I think in 2019 or earlier they discovered a small molecule that can destabilize the HBV cccDNA in mouse models.

A first-in-class orally available HBV cccDNAdestabilizer ccc_R08 achieved sustainable HBsAgand cccDNAreduction in the HBVcirclemouse model

Perhaps, and i hope, this molecule is still in secret development and one day Roche will provide the related information.

While it is at times suffocating for many of us, the end of our anxieties is in sight. Dont know when but it will come to pass and Hepatitis B, like Hepatitis C will be curable. Many products are currently in development simultaneously, atleast one of them will knock Hep B down.

1 Like

Hi @KWr

I hope they can complete the trial soon. I am one of the patient who is waiting for this cure so long.

I will be one of the first people to get the treatment.

1 Like

Dear @KWr

These are indeed interesting molecules. In the interest of keeping the community well informed, the following should be noted:

RG6346 (aka RO7445482) is a GalNAc siRNA very similar to the three other compounds also in development: JNJ-3989, VIR-2218 and AB-729. The performance of RG-6346 was very similar to these other three GalNAc-siRNA in phase IIA studies and demonstrated that a significant proportion of HBsAg persists despite repeated dosing. Longer duration combination trials with NUCs + CAMs + GalNAc-siRNA, including a large phase IIB trial by J&J have not been able to achieve any functional cure.

A recent combination trial with VIR-2218 + pegIFN demonstrated 30% HBsAg loss after 48 weeks but in this trial, patients with very low HBsAg were enrolled and it is in these patients where most of the HBsAg loss occurred. We will also have to wait to see how durable these HBsAg losses are after removal of therapy. For some reason, a control group of pegIFN alone was not included in this study which is unfortunate since pegIFN can also achieve > 30% HBsAg loss in patients with low baseline HBsAg. As such is it difficult to understand the contribution that VIR-2218 made in the HBsAg loss observed in this study. The community also needs to be aware that HBsAg levels < 1000 IU/mL occur in ~5% of patients (the average is ~10,000 IU/mL) so HBsAg loss rates made in studies that include patients with low HBsAg cannot be extrapolated to the patient population at large. Hopefully subsequent trials which recruit patients with low baseline HBsAg and use pegIFN will include a control group with pegIFN.

It has indeed been ~4 years since we heard from Roche regarding ccc_R08.

I encourage community members to search for clinical trials at to see what trials are ongoing with these agents. J&J, Arbutus and Roche all have trials underway with their GalNAc-siRNA in combination with pegIFN. There are no current listings for ccc_R08.

1 Like