For the community at large I would like to provide some clarifications on the very well intentioned (and appreciated) comments on NAPs which were made by John in this podcast.
NAPs have certainly had an unusual development history. The reasons for this have been discussed elsewhere in this forum here.
It is important to understand that international studies or studies with a significant component of (or all) patients enrolled from international locales outside the US are the norm in the development of HBV medications. This is to access patients with different HBV genotypes and disease states (such as HDV co-infection) or allow access to patients which are HBeAg positive and or treatment naive (these are hard to find in North America and Western Europe). Many studies with other investigative antiviral agents for HBV and HDV have included study centers in Moldova (where Replicor’s latest studies were performed), some even using the same centers and investigators. No clinical trials with NAPs have been performed in Romania.
John discussed the absence of “immunological” data from Replicor’s trials which is true but is also true for many other clinical studies for investigational agents in HBV. Immunological data for some investigational agents like the RNAi AB-729, the antisense bepirovirsen (due to acknowledged off target effects) and therapeutic vaccines (immunostimulation is their primary mechanism) have been generated but these have not identified any conclusive linkage between the immune markers examined and functional cure of HBV. Indeed we have very little understanding about which immunological processes ultimately participate in the establishment of functional cure, except that the ALT flares they generate (from removal of infected liver cells) are an important component of this process in non-cirrhotic patients (see here, here and here for recent reviews / studies addressing this).
It is important to note that the only recognized primary efficacy endpoints for all HBV drugs in development are still HBsAg decline and loss and the sustained loss of HBV DNA and HBsAg and normal liver function (ALT) in the absence of all therapy (functional cure). As John pointed out, the clinical trials with NAPs are the only ones to achieve HBsAg loss during therapy functional cure of HBV (and HDV) in a high proportion of patients to date. What should also be recognized is that trials with NAPs are the only trials to provide high resolution mapping of HBsAg and ALT responses and to present these data on an individual patient basis (which is rarely done with other trials). Importantly, these trials are also the only trials to have excluded patients with low baseline HBsAg (< 1000 IU/mL) which represent only 5-10% of patients and in which functional cure is much easier to achieve with approved agents. All other trials include these patients and it is in these niche patients where HBsAg loss (mostly transient off therapy) have been reported with other agents. Replicor’s studies are the only studies to have completed and disclosed very long follow-up assessment demonstrating persistent functional cure of HBV and HDV with continual reversal of liver fibrosis and excellent long term safety in the absence of antiviral therapy for more than seven years.
Replicor’s initial small studies conducted in Bangladesh starting in 2009 were done as investigator sponsored trials by a clinician who believed in the strength of our animal model data. This pre-clinical data, even though conducted by a well known expert investigator in HBV and now widely published and reproduced and accepted, was not accepted by the field at the time - see the previous post cited above. Importantly these trials were conducted in the most difficult population in which to achieve functional cure (HBeAg positive patients who acquired HBV infection at birth with very high HBsAg loads). These initial trials allowed us to confirm the activity of NAPs, the safety of ALT flares that John discussed in the podcast and the ability to achieve functional cure. At first this was in a small but significant proportion of patients with NAP monotherapy but much larger with the introduction of pegIFN (an immunotherapy that all companies are now attempting to incorporate into their combination regimens for HBV).
Replicor’s first small study conducted in Moldova allowed us access to clinicians well experienced with ALT flares in HBV infection (a key event required for functional cure - see above) as well as to an ethnically distinct, treatment naive population of patients which confirmed the activity of NAPs not only in HBV but HDV as well.
However, Replicor’s latest clinical study (also in Moldova) was a fully randomized controlled study enrolling 40 HBV monoinfected patients with the most difficult to treat HBV genotype (genotype D - where TDF + pegIFN cannot achieve any functional cure of HBV) and was similar in size to all other phase IIA studies which have been conducted for other investigational agents. The high rate of functional cure now observed in this study (exceedingt 50%) comes after more than 5 years of treatment-free follow-up analysis.
The reproducibility of the safety and antiviral effects of NAPs against HBV and HDV observed in Bangladesh and in Moldova continue to be confirmed in the currently ongoing compassionate use of NAPs in a cohort of 18 French patients at 8 different centers in France with diverse ethnic backgrounds with very advanced liver disease (some awaiting liver transplant) the latest results of which were presented at the EASL 2023 meeting in June. Many more patients from diverse locations worldwide will be presented in the coming months at upcoming meetings.
No doubt additional trials are required for approval of NAPs but at this point the activity of NAPs has been well established in diverse ethnic groups with different HBV infection status and in several countries. This is now widely accepted amongst the clinical community.
Although the net effect of NAPs is the inhibition of secretion of HBV subviral particles (> 99.99% of circulating HBsAg) as John has indicated, this effect is a result of direct inhibition of subviral particle assembly (published here and here) leading to immediate reduction in intracellular HBsAg via increased HBsAg degredation. This process is driven by the via interaction of NAPs with a novel host chaperone (DNAJB12) which is involved in the formation of subviral particles (see here). The molecular mechanism continues to be refined for NAPs with HBV and these updates as well as the first data on the direct antiviral mechanism of NAPs in HDV infection, will be presented at upcoming meetings.