To fight COVID-19, more than eleven vaccines are currently being tested. As the vaccine race continues in the world, promising startups could make a difference. One of them, Abivax, announced that the first patient in the Phase 2/3 trial of his solution ABX464 against COVID-19 was treated at the Centre Hospitalier Universitaire de Nice, France, during last summer. As a matter of fact, this investigational drug could "promote recovery or, prevent the severe form of Covid-19 disease," says its founder. The floor was given to Philippe Pouletty, Founder & Chairman and Prof.

Hartmut Ehrlich, CEO of Abivax to discuss this innovation within our BlastingTalks project, which consists of focusing on the challenges that companies face during the evolution of the digital world and during this unprecedented period of health crisis.

Your company helps to treat people with inflammatory, viral diseases and cancer by mobilizing the body’s natural immune system. Could you explain in general terms what your technology is and how it is supposed to help patients?

Answer Hartmut Ehrlich: Abivax’s current core program focuses on the treatment of chronic inflammatory diseases. A chronic inflammatory disease occurs when your immune system is spinning out of control and is therefore unable to slow an inflammation down.

Our lead product candidate ABX464 is a highly differentiated oral drug candidate, with a completely novel mechanism of action. To simplify how it works, you could say that it triggers the over-expression of a specific microRNA, called miR-124, a key chief conductor in limiting and containing inflammation. With the increase in miR-124, a cascade of events leads to a strong anti-inflammatory effect which seems to have the capacity to put “a brake” on inflammation.

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Many patients suffering from inflammatory diseases do not respond or stop responding to currently available treatments. There is a significant unmet medical need for therapies that show a long-term effect to improve the lives of patients suffering from these often very disabling diseases. In ulcerative colitis, an inflammatory bowel disease, ABX464 generated very promising and durable safety in efficacy data in patients treated for two years.

This study is still ongoing, and we hope to further confirm the long-lasting positive effect it has shown so far. With its unique mechanism of action, ABX464 has a broad potential as a novel anti-inflammatory therapeutic agent, which could have a positive effect in various inflammatory diseases.

Our second drug candidate, the immune enhancer ABX196, is also in clinical development to treat patients with hepatocellular carcinoma, the most common form of liver cancer. ABX196 is currently being tested in the United States in combination with a checkpoint inhibitor to boost its activity and potency in patients suffering from liver cancer. ABX196 was selected for development because of its ability to stimulate the immune response towards tumors that don’t respond well to anti-PD1 antibodies alone.

How does your innovation distinguish itself from other therapeutic approaches?

Answer Hartmut Ehrlich : As mentioned before, the unmet medical need in inflammatory diseases, and notably in inflammatory bowel diseases such as ulcerative colitis and Crohn’s diseases, is still very high. For biologics and other recently introduced therapies, the rate of clinical remission (when the patient is symptom free) is very low. And actually, many patients stop responding to these products within a year of continued treatment.

By contrast, from the clinical study data we have been able to generate with ABX464 so far, we could make the following observations which clearly differentiate ABX464 from current therapies:

  • Patients can take ABX464 orally, once a day, which makes it very easy to administer, so there is no need for injections
  • It has been shown to start being effective as early as 14 days after initiation of the therapy, which is very rapid compared to other treatments
  • ABX464 appears to be working equally well in patients who have never been exposed to biologic treatments and in patients who stopped responding to these treatments
  • At the end of induction treatment, so after 2 months, the rate of clinical remission (or being symptom free) is around 20 to 25%, after subtraction of the rate observed in placebo patients, so about double of what we see with currently available treatments. Several key opinion leaders in this field consider this as transformative or breakthrough efficacy
  • And similarly important, after two full years of continued treatment with ABX464, the percentage of patients in clinical remission was still at 69%, whereas with biologics, it is between 20 and 30%.
  • These exciting efficacy data are coming on top of a very good clinical safety and tolerability profile, as seen in the over 400 patients and volunteers treated with ABX464 so far
  • The longest treated patients are now on daily oral dosing for 3 years, without any treatment interruptions

Of course, these observations need to be validated and confirmed in the ongoing Phase 2b and upcoming Phase 3 studies.

But we are very excited about these encouraging results, and given our robust study designs, we are confident that ABX464 will also show a similar safety and efficacy profile in these large-scale studies.

You created ABX464 to fight against inflammatory diseases, such as ulcerative colitis and rheumatoid arthritis. Could you tell us more about it? How did it come to where it is now?

Philippe Pouletty : Abivax was founded by my fund, Truffle Capital, in 2013, by merging three of our biotech companies. The strategy was always to identify projects coming from great sciences in academia, and then to start a company based on that intellectual property already generated, while continuing to work with the inventors who would stay in academia.

ABX464, Abivax’s lead molecule, was initially derived from the platform technology coming from the French National Centre for Scientific Research.

At the very beginning, ABX464 was tested in HIV patients and we observed that the molecule could substantially reduce the viral reservoirs, and thus potentially deliver a long-lasting reduction in the viral load of HIV patients. However, as research and development with ABX464 was progressing, we realized that ABX464 had also a very strong and potent anti-inflammatory effect. After some supplementary preclinical studies and a proof-of-concept clinical study in ulcerative colitis, we felt that this molecule could really make a big difference for these patients because of the large unmet need in this disease, so we decided to shift our focus to the treatment of inflammatory diseases.

That was in September of 2018 and since then the clinical short- and long-term results of the Phase 2a study in ulcerative colitis patients confirmed our decision. We are looking forward to additional results from the ongoing Phase 2b study in ulcerative colitis as well as from a Phase 2a study in rheumatoid arthritis with expected results for both in the second quarter of 2021. Further, a clinical Phase 2b/3 trial is being planned in Crohn’s disease and we are also taking the required steps to get ready for a subsequent Phase 3 trial in ulcerative colitis.

Today, over 1.3 million deaths have been attributed to COVID-19. Last week both Pfizer and BioNTech and Moderna said their vaccines were more than 95% effective.

Now your technology is not a vaccine, but a therapy - can you explain the difference and how your therapy will fight the virus?

Philippe Pouletty : The objective of a vaccine is to prevent people from getting infected with Covid-19. A therapy, such as ABX464, treats patients that are already infected to promote recovery or, in our case, to prevent the severe form of Covid-19 disease that leads to lack of oxygen and the need for intensive care. Elderly patients or patients with pre-existing conditions, such as diabetes, hypertension or obesity, are more vulnerable to becoming severely ill, and our trial particularly targets this high-risk population. Even with availability of vaccines, many patients will suffer from Covid-19 infection.

ABX464 is the only drug candidate which shows a desirable and complementary triple action to effectively treat Covid-19 patients:

  • An antiviral effect: ABX464 showed the capacity to reduce or eliminate the viral reservoirs in clinical HIV trials. This antiviral effect has now also been shown in a preclinical model where ABX464 was able to inhibit the replication of SARS-CoV-2 (the Covid-19 virus) at a magnitude similar to Remdesivir. ABX464 could therefore potentially deliver a reduction in the viral load of Covid-19 patients.
  • An anti-inflammatory effect: ABX464 has demonstrated impressive efficacy in a severe inflammatory disease, ulcerative colitis. We know that hyper-inflammation in the lungs is the primary cause of the respiratory distress and death of Covid-19 patients. ABX464’s molecular mechanism of action supports the rationale to prevent and treat this potentially fatal hyper-inflammation observed in severely ill Covid-19 patients.
  • Tissue repair properties: ABX464 has also been proven to heal inflammatory lesions in ulcerative colitis patients. This means that Covid-19 patients may not only benefit from the anti-inflammatory effect of ABX464 but also from its tissue repair properties, to prevent potential longer-term pulmonary dysfunction following the infection.

Our Phase 2b/3 study in Covid-19 specifically differs from most of the other studies, by the fact that we are trying to treat high-risk patients as early as possible.

Once they are diagnosed, they have to be on the trial within 48 hours because our main objective is to prevent the start of acute respiratory distress syndrome that leads to lack of oxygen and the need to put the patient on a respirator. This is why we are treating these patients early before they have pulmonary problems which means that patients can typically be treated at home. This is possible with ABX464 because it is an oral treatment and patients take one capsule a day.

Obviously, at this stage we do not claim victory of ABX464 for Covid-19, which is a complex disease, where you have a short window to be efficacious. But, of course, we hope that the study results will show a beneficial effect.

Even if potent vaccines will start to be available in the next couple of months, there will not be enough vaccine shots available in the short- and mid-term and many people cannot or will not want to get vaccinated. So, an effective treatment stays a top priority to fight the virus.

Abivax is currently conducting seven clinical trials to test the tolerability, safety and efficacy of its two product candidates ABX464 and ABX196, in several indications, from Ulcerative Colitis, to Cancer and to COVID-19? What are the positions of these projects?

Hartmut Ehrlich : Our clinical trials, except for the open label extension studies in ulcerative colitis and rheumatoid arthritis, are all randomized, double-blind and placebo controlled.

This means that a certain percentage of randomly selected study participants do not get the active drug, but a placebo, and that neither the patient nor the treating physician know if they are in the active or the placebo group. This is necessary to makes sure there is no bias in the generated study data.

Our ulcerative colitis and rheumatoid arthritis studies consist of two parts respectively: An 8-weeks induction study to see short-term effects of ABX464, followed by a maintenance study where patients are kept on treatment for several months and years to evaluate the long-term safety and efficacy of the drug. In our most advanced indication, ulcerative colitis, the Phase 2a maintenance study is still ongoing, with some patients that have now been on daily treatment with ABX464 for 3 years with very encouraging results. In addition, our clinical Phase 2b trial is ongoing in the same indication. We are planning to complete recruitment for the induction phase of this study by the end of this year and then continue with another subsequent maintenance study to get more long-term data in a larger set of patients.

For rheumatoid arthritis, the recruitment of the induction study will also be completed before year end and the maintenance study is being conducted in parallel.

As indicated before, our focus is on the treatment of inflammatory bowel diseases, mainly ulcerative colitis and Crohn’s disease. As these two diseases show many clinical similarities, our clinical trial consultants and investigators recommended to directly initiate a pivotal Phase 2b/3 study in Crohn’s disease. So, if this study is successful, we could speed-up the marketing authorization for this indication significantly. We are planning to start the trial sometime in 2021.

The Phase 2b/3 trial in Covid-19 is ongoing in Europe and Latin America and will include 1,034 patients; we are planning to complete recruitment in the course of the first quarter 2021 and would then communicate first high-level results timely.

Last, but not least, the Phase 1/2 study with ABX196 in liver cancer is running in the U.S. and we are currently in the “dose escalation phase”, which means that we are carefully investigating which dose of ABX196 is safe, well-tolerated and efficacious at the same time.

What are your thoughts as a doctor, chairman and scientist about this recent “race for vaccines”?

Philippe Pouletty : As a scientist, the most important lesson learned in the past month is the following: Don't try to bend science and data, the scientific evidence about the clinical safety and efficacy of a potential Covid-19 vaccine should be key and in the center of our interest.

As a doctor, I trust our regulatory authorities will continue to uphold their high standards and only grant approval for a safe and effective vaccine. Safety, tolerability and a certain level of meaningful clinical benefit are the pillars that Abivax has committed to and we would not compromise our standards on patient safety.

In my role as chairman and entrepreneur, I was quite pleased to see that during the crisis, the various players are able to work hard together towards a common goal – a vaccine and a treatment against Covid-19. We could observe that companies and governments, together with KOLs, regulatory and grant agencies all over the world worked five or ten times faster than in normal times. I would like to see that this continues in the future to optimize and potentially speed up the development of new drugs for other urgent healthcare needs. I would also like to see Europe to get better organized like the US are, for regulatory approvals and project funding. This could be one of the positive takeaways once the virus is hopefully under control with safe and efficacious vaccines and treatments.

We have been living for 7 months in an unprecedented crisis causing health to be placed at the top of the concerns of many governments around the world. How did you face this time with your teams in terms of work arrangement?

Hartmut Ehrlich : Of course, the safety of the team was our priority which means that everyone was working from home, we reduced presence in the office during the summer months and are now back to work from home with the pandemic picking up again in France and all over the world. With 27 employees, Abivax is a very small and very flexible company, we were able to adapt very quickly to the new situation and kept-up business as usual in a very efficient manner. The proof of this is that we managed to kick-off our Covid-19 trial during the Covid-lockdown in record time. For the colleagues working in the labs, the situation was different, but we managed to find appropriate solutions for all of them and no one was left behind.

Fortunately, there were only very minor impacts on the recruitment pace of our running clinical trials, and we will be able to keep all the timelines for recruitment and the communication of the upcoming data read-outs.

You recently won the Mediscience Award for “Best Technology”. Are you looking to further develop ABX464 for any additional clinical or scientific programs for your patients?

Hartmut Ehrlich : With Covid-19 we showed that we were able to assess a potential benefit of ABX464 for a new indication and to take immediate actions to launch a clinical trial program.

Of course, Covid-19 was a particular situation, but obviously we are fully aware of the large opportunities that ABX464 offers through the different characteristics that we described. Therefore, Abivax is constantly exploring further indications where ABX464 might be beneficial and we are very keen to develop the full potential of our drug candidate for the benefit of all patients in need of novel therapeutic management options.