Updates on Dupilumab: Atopic Dermatitis in Children as Young as 6 Months

Recent press releases from Regeneron and Sanofi¹ presented the results of a pivotal phase 3 trial of dupilumab in children aged 6 months to 5 years with moderate to severe atopic dermatitis (AD). The findings show that dupilumab is the first biologic to show positive results and remains the only approved biologic medicine in this population. In this exclusive interview, Naimish Patel, MD, head of global development, immunology and inflammation at Sanofi Genzyme, and Bola Akinlade, MD, therapeutic area head, immunology & inflammation at Regeneron, shared insights into the promising results of the trial.

How did dupilumab show superior efficacy vs standard of care alone when treating patients aged 6 months and older with AD?

Dr Naimish Patel: What we studied in this trial were the kids who had moderate to severe, or the worst forms, of AD. Many of these patients - babies and children - had almost 60% of their skin covered with rash and severe itching. In this patient population, topical medicines are standard of care but the other medicines that are available are immunosuppressants, which have a lot of side effects. Many patients have improvements in their AD as they get older but in a subset of patients, especially if they are severe, it can continue into adulthood. You want to take a medicine that is not going to have long-term side effects, but many of the immunosuppressant medicines do.

On that backdrop, this study followed children aged 6 months to less than 6 years. We compared children receiving standard of care (SOC) therapy plus dupilumab vs patients treated with placebo and SOC therapy.

Essentially, the results looked fantastic, with 28% of children having clear or almost clear skin vs 4% in the placebo group. Over half the patients had 75% disease improvement in the dupilumab group vs 11% in the placebo group. There are also improvements in other outcomes, such as sleep, pain and quality of life.

Dr Bola Akinlade:  We had about 16 endpoints in a statistical hierarchy that were tested, and all showed robust statistical efficacy, including Investigator Global Assessment response, Eczema Area and Severity Index 75 response, itch response, patient- or caregiver-reported outcomes, and skin infections.

I would say that this is probably the first biologic that has shown such efficacy in this young group of children. As you know, we started off with adults with the SOLO1, SOLO2, and the CHRONOS studies, wherein we showed clearly dupilumab had robust efficacy and safety. We have gone down now to the youngest children and shown that the same type of robust efficacy and safety that we've seen in adults.

How has dupilumab positively influenced these patients, from the burden of itch to health-related quality of life? How about the impact of the therapy for their caregivers?

Dr Akinlade:  Itch is an important aspect of the symptomatology of AD. It's what bothers a lot of patients all the time. The itch is intense; it's year-round, 24 hours a day, and certainly has a huge burden not only to the patients but also to the caregivers. I had a younger brother who had AD. It was bad, and the impact it had on the family was unbelievable.

In this trial, we showed that dupilumab improved the itch and also demonstrated an improvement in caregivers' perception of disease improvement. These types of responses have not been seen before because, like I said, this is the one study that we've had a randomized control trial with a biologic in these children. The results are certainly very impressive and robust.

The patients enrolled in our trial had to show a certain threshold of disease activity with moderate to severe AD. Even though they had been on what is considered SOC, they still had bad disease. For a parent to enroll his or her child in the trial, one can assume that the need for effective treatment of their child was profound. The results of this trial are very exciting, not just for us but more importantly for patients who experience this dreadful disease.

Dr Patel:  We did include specific questionnaires—both for children who could fill it out and also their caregivers—around sleep, skin pain, and quality of life. These general questions touched on the impact and treatment of the disease and living with the diseases in their daily life. We saw a significant impact that most of these things have scores attached to them, such as an itch score, pain score, or sleep score, and we saw a significant improvement across these outcomes both for the patients and their caregivers.

It is the first time any drug has been measured for whether they affect these factors in this age group. We are excited because there are not many advanced therapy options available to these kids right now. Beyond topicals, immunosuppressive drugs can have long-term side effects. These results demonstrate that dupilumab potentially could change the way AD is treated.

During this trial, were there any adverse events that clinicians should keep in mind before considering dupilumab in this young patient group?

Dr Akinlade:  The gratifying thing with the study is that, even in this age group, we didn't see any safety issues that were peculiar. The safety profile was similar to what we know about dupilumab.

We didn't see an excess risk of infection, which plays to what we know about dupilumab. It does not really immunosuppress to a point that we need to worry about infections. We saw a lower incidence of skin infections with dupilumab compared with patients who were on the placebo and topical corticosteroids.

The side effect profile that we saw from the study was in line with what we had seen in previous trials involving adolescents and younger children in addition to adults. Remember, in drug development, the paradigm is to start with adults first before you go into children, just because of the unknown side effects that may come up in children. We didn't see anything at all in this younger group of patients that is any different from what we see in adults.

Dr Patel: The profile we see is pretty similar to the profile we see in other age groups, which is important.

One of the issues in AD is that the skin gets colonized with certain bacteria that can cause skin infections. If you're taking medicines that suppress immune function, they could make skin infections worse by allowing colonization of bacteria that make the disease worse or can lead to other systemic illnesses.

One of the key aspects of the way dupilumab works is that it specifically targets the immune response of type 2 inflammation, which is thought to attack parasites. It doesn't affect the immune response to bacteria and viruses. Largely, in most places, parasitic infections aren't really a big issue anymore and there are lots of theories on why, but that immune response has become hyperactive. Since dupilumab is so specific to just targeting that type 2 inflammation, the type 2 immunity leaves those other immune responses intact. If you can get rid of the type 2, the other immune responses can fight off bacteria and infections.

That response is the scientific rationale behind the use of dupilumab. While some immunosuppressant drugs are somewhat nonspecific in the way they inhibit the immune system, those things can increase susceptibility to infections. Because we do not see an increase in infections with dupilumab, we can add to the evidence that dupilumab specifically targets a type of immune response that causes the disease but isn't necessary for other things. Some types of immunosuppression could also predispose to cancer or other diseases, and you don't want to predispose a patient to those types of things.

Is there anything else notable about this phase 3 dupilumab data that you would like to share?

Dr Akinlade:  We have talked about our 16 endpoints in the statistical hierarchy. It is unusual to have a study in which you have all of the endpoints in your hierarchy be so statistically significant with a P value of .001. That just tells you how powerful an effect dupilumab has in improving these patients’ AD.

I also talked about skin infections and how there is a lower incidence of skin infections in dupilumab-treated patients. We know that patients with AD are prone to skin infections. Remember, the skin acts as a barrier to skin infections; people with AD have an impaired skin barrier, and that makes them prone to skin infections. Dupilumab reduced the incidence of skin infections by approximately 70% in this study compared with patients who were on the topical corticosteroids.

It is gratifying now to see the youngest of children experiencing the same robust efficacy and remarkable safety profile of dupilumab as compared with adults.

Dr Patel: Children in the study group, especially those younger than 1 year, who have AD are at increased risk of developing other type 2 inflammatory conditions such as asthma or food allergy. What is not known is if early intervention with a therapy in this age group reduces the chances of still developing these other atopic diseases. We will have long-term follow-up data from this study because we will follow the babies and the children over a couple of years to see how they do on dupilumab. We look forward to that data because it may tell us if these children are developing the same sort of type 2 comorbidities.

Reference

1. Dupixent^® (dupilumab) pivotal trial meets all primary and secondary endpoints becoming first biologic medicine to significantly reduce signs and symptoms of moderate-to-severe atopic dermatitis in children as young as 6 months. News release. Regeneron Pharmaceuticals, Inc.; Published Aug 30, 2021. Accessed September 1, 2021. https://www.prnewswire.com/news-releases/dupixent-dupilumab-pivotal-trial-meets-all-primary-and-secondary-endpoints-becoming-first-biologic-medicine-to-significantly-reduce-signs-and-symptoms-of-moderate-to-severe-atopic-dermatitis-in-children-as-young-as-6-months-301364919.html