Inside Barinthus Biotherapeutics' Combination Immunotherapy Platform

By Tyler Menichiello, contributing editor

Millions of people are living with chronic hepatits B infections globally. While antiviral treatments are available to manage these infections, there’s still no functional cure — but Barinthus Biotherapeutics is on a mission to change that. Barinthus (formerly Vaccitech) is a clinical-stage biopharma company developing immunotherapies to treat chronic infectious diseases and autoimmunity, and it’s lead infectious disease program, VTP-300, is being developed for hepatitis B.
VTP-300 is built on a two-pronged immunization approach with the company’s proprietary platforms — ChAdOx1 (chimpanzee adenovirus Oxford) and modified Vaccinia Ankara (MVA). According to Barinthus CEO, Bill Enright, stepwise administration of ChAdOx1 and MVA leads to an improved, more durable T-cell immune response, and thus a functional cure for HBV. I met with Enright to learn more about the company’s combination immunotherapy platform and its approach towards developing this potentially curative treatment for HBV.
* The following Q&A has been edited for length and clarity. *
Please give a little background about VTP-200 and VTP-300.
VTP-300 for HBV is the lead asset, and we presented some really promising Phase 2 data at EASL this year that showed we’re the first immunotherapy to show a significant decline in surface antigen levels and the first molecule we’re aware of that really showed a sustained reduction in surface antigen. So, nine months after the first dose was given, the patients that responded still had low levels of surface antigen.
A lot of people are looking at reducing surface antigen levels using siRNAs, asRNA, or monoclonals — a number of different approaches — and they’ve done that pretty successfully. You can get to two and a half log reduction in surface antigen levels. The problem is, once you stop giving patients these molecules, the surface antigen levels rebound. So, in our case, it was very promising to see those levels stay down in the people that responded.
Please explain the combination dosing approach Barinthus uses with its proprietary ChAdOx and MVA platforms.
The key thing about adenoviruses is they stimulate the highest level of T cells out of any viral platform out there — bar none. So, you get a very high-magnitude T-cell response that lasts for a long time. With the adenovirus itself, the T-cell response comes down, but when you then stimulate with the poxvirus as a second dose, then you get an even higher T-cell response that lasts for a long time. You probably heard a lot about this in the COVID-19 era — this mix and match approach, where you’re using two different platforms to get a better overall immune response. That’s really what our scientific co-founders, Sir Adrian Hill and Dame Sarah Gilbert, have been studying at the University of Oxford for the last 25 to 30 years.
They did this empirically. They looked at a ton of different platforms and viral platform combinations. They looked at viral platforms in combination with DNA, in combination with RNA, and in combination with protein, and they showed in Phase 1 clinical trials that the best combination of platforms is giving a first dose of ChAdOx (chimpanzee adenovirus) and coming back with a second dose of MVA. Thereby, you not only get a high-magnitude response — primarily CD8 killer T cells, which are a part of the immune system that recognize infected or mutated cells and destroys them — but a response that lasts a long time, and they showed that it’s very polyfunctional, so it’s doing what you want it to do.
Can you share some insights on the regulatory guidelines around combination therapies?
Regulatory agencies have seen these platforms a lot. The ChAdOx platform is the same one that AstraZeneca used. In fact, we were co-inventors and were involved in the early development of AstraZeneca’s COVID-19 vaccine, Vaxzevria, which has been in millions of people. So, the agencies really understand the safety profile and the attributes of the platform.
Similarly, the MVA base platform was an approved product against smallpox that has been in hundreds of thousands of people. So, you really have good safety validation and good efficacy validation for these platforms. It’s kind of like the flu vaccine — you change the flu vaccine every year, but you don’t have to go through an entirely new approval process because you’re only changing the inserts. You’re only changing specific sequences related to the circulating strain that year.
Barinthus’s lead assets are in Phase 2 now. What have been the biggest challenges the company’s had to overcome thus far?
I mean, drug development isn’t easy. It’s a long, expensive process with a lot of technical, regulatory, and commercial hurdles that you have to overcome to bring something effectively to market, and we’re going through that process. Take VTP-300 as an example. We’ve said for a long time that there will be three components to a functional cure for HBV, and VTP-300 is just one piece of that puzzle. Part of the challenge is not just finding the optimal dosing for VTP-300, but also how that fits into an overall functional cure regimen, and we’re seeing really exciting results so far in the HBV003 and IM-PROVE II trials.
The key for us is to always have a plan A, B, and C, to have contingency plans. So, we have multiple products moving forward in different disease areas.
What is SNAP-TI, and how does it compare to Barinthus’s other platforms?
In addition to the viral platform we have, we’ve got a pretty unique platform, something we call SNAP-TI — a self-assembling nanoparticle platform. So, it’s not LNP based; it’s not lipids at all. It’s a peptide-based technology where we can control the size of the particle and the different antigens that go within the particle. We can control where the particle goes — whether it’s to stimulate the antibody side of the immune system or the T-cell side of the immune system. And we can combine it with other molecules — immunomodulators — to help stimulate further CD8+ T cells or Tregs, depending what indications we’re going after. So, this is really an innovative platform.
It's been known for a long time that peptides may be important in this kind of approach, but peptides that have the highest avidity and affinity for binding other things are generally those that are most highly charged, or those with very hydrophobic or hydrophilic domains. Those peptides are the hardest to manufacture — so the things that probably work the best, you can’t make. So, they came up with a way to make a large number of sequences, and that allows us to get into some areas where no one else can.
The peptide sequences in SNAP-TI are synthesized individually with a hydrophobic end and an immunomodulator end. So, upon dilution in an aqueous buffer, they assemble to form a sphere. For early-stage clinical trials, individual peptides are manufactured in smaller batches for speed using peptide synthesizers, or we can use the standard synthetic peptide chemistry approach for commercial use.
One example would be our first indication for SNAP, celiac disease. And again, it’s the peptide sequence that’s important here, so we’re combining SNAP with an immunomodulator that really helps to stimulate the Treg arm of the immune system —the arm of the immune system that dampens the autoimmune response.
What are the differences in developing immunotherapies for infectious diseases versus for cancer, and how do they compare to this autoimmune disease indication?
There’s some overlap because we believe that T cells are important to the cure. The key for us is to have platforms that stimulate T cells to a high magnitude and that last for a long time, which we know from the CAR-T space means we can impact cancer. So, the goal is having a platform that allows us to get a really high, sustained response of T cells for a long period of time without having to generate new CAR-Ts for every disease indication. This essentially allows us to rebalance the immune system so that we attack diseased cells in the instance of cancer and stop attacking normal cells in the instance of immune tolerance.
It’s all about the regulatory endpoint, which is showing that the disease is cured, and showing that to regulators. In HBV, that’s a functional cure. You want to get people off these antivirals they are currently taking. If you can get these people a treatment where you can get them off their antivirals and show there’s no virus from a surface-antigen perspective after months of being off antivirals, that’s what the regulatory agencies are considering a functional cure. In HPV, it’s different, because we’re trying to clear the virus before it causes cervical cancer. We’re going after the very early stages and looking at viral clearance as the regulatory endpoint there.