by Reynald Castaneda in London

Evelo Biosciences’ Phase II EDP1815 still has a long road in demonstrating clinical value in mild-to-moderate psoriasis and atopic dermatitis (AD), experts said. This is despite an intriguing mechanism and an early efficacy signal in both conditions, they added.

EDP1815, by stimulating the gut cell wall, downregulates the systemic inflammation cascade. This approach is supported by preclinical investigations showing gut microbiome changes could do the same, experts noted. However, there are still many EDP1815 mechanism gaps yet to be filled to clearly connect the gut with the skin, they added.

While EDP1815 has Phase Ib data in both indications that signal potential for efficacy, such data is both too short-term and too small a sample size. EDP1815 is in a 225-patient, 16-week Phase II trial (NCT04603027) recruiting mild-to-moderate psoriasis patients, with results anticipated mid-2021. This Phase II is a better barometer to validate EDP1815’s mechanism, they said. Further trials in AD are yet to be detailed.

Due to EDP1815’s unprecedented mechanism in dermatology, its efficacy bar might be low, as experts said stronger efficacy data would help bolster its mechanism rationale. Yet, the challenge in running trials in mild-to-moderate dermatology patients is that it is hard to notice improvements in the milder cohort. Moderate patients are susceptible to a placebo effect, even if this is less of an issue in psoriasis than AD, they noted.

Evelo, which did not respond to a comment request, has indicated it would use Phase II data in determining next steps for EDP1815 in psoriasis and other inflammatory diseases. It has a $419.9m market cap.

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Mechanism encouraging though many narrative holes

Many preclinical investigations show that the gut microbiome can have an impact in both local inflammation in the intestine as well as systemic inflammation, in organs such as the liver, heart, lung and brain, said Dr James Versalovic, director, Texas Children’s Microbiome Center, Houston. However, it is currently hard to say which is a more relevant target for therapy—changing the gut microbiome or targeting the gut cells directly, added Dr Brian Kim, associate professor of medicine, Division of Dermatology, Washington University School of Medicine, St Louis, Missouri.

EDP1815 is designed to interact with cells in the small intestine, to impact systemic inflammation, such as cytokine signaling and T-cell trafficking. Nevertheless, targeting either the microbiome or the gut itself could still lead to an effect on the inflammation cascade to ease skin disease severity, noted Kim. In fact, in preclinical investigations wherein gut microbiota changes are mimicked in a particular way, such changes lead to immune system modulation, he added.

In preclinical murine model studies, EDP1815 can limit systemic production of a variety of inflammatory cytokines. Although there are targeted therapies in moderate-to-severe AD and psoriasis, the rationale behind an approach like EDP1815’s is to potentially mimic what a healthy gut looks like, Kim explained. But work is still ongoing to paint the full picture of what constitutes a healthy gut microbiome, Versalovic noted.

EDP1815 features a nonliving, noncolonizing bacteria called Prevotella histicola, which is not intended to change the gut microbiome composition but rather influence the gut cells. It is possible that a bacterium’s metabolites or cell components can influence distant sites like the skin, Versalovic added. But, while this has been observed in preclinical studies, the exact mechanism on how this works is still a mystery, he added. While there may be a bevy of preclinical data linking the gut microbiome to dermatological issues, there are no therapies that are able to modulate the gut to have an impact on the skin, said Dr George Han, assistant professor, Department of Dermatology, Mount Sinai Beth Israel, New York.

And so, it is currently challenging to imagine EDP1815 having a role in dermatology, said Dr Brett King, associate professor of dermatology, Yale University School of Medicine, New Haven, Connecticut. Evidence showing the gut is the driver of inflammation is limited, King added. In fact, it is possible that gut-related effect on the skin could be more of a bystander effect, he noted, adding more understanding is needed on how relevant the gut is in dermatology.

Since EDP1815 is a gut-directed therapy, its efficacy could be impeded by not only microbiome variation among people but also variation in the intestine of the same person, Versalovic noted. The Phase II psoriasis trial is investigating three doses. There should be a correlation between dose and efficacy, as generally observed in microbiome gut investigations, he added. Nevertheless, any therapy that aims to influence the gut cells needs to maintain potency in low pH environments in the gut, as well as being able to interweave itself in the matrix of the existing microbiome, he said.

There could be the argument that the skin microbiome may be a more important target than targeting the gut, Kim said. In psoriasis, there are different bacterial populations in the skin during flares, compared with patients who do not have flares, Versalovic said. But it is still unclear what these disease flares mean, Han added. A systemic approach is still attractive in more systemic issues like AD, Kim said.

Early data draws interest but only a faint sign

As for EDP1815’s Phase Ib (NCT03733353) data in patients with either psoriasis or AD, it provides an early efficacy signal worthy of additional exploration in both, experts said. The percent point difference between the treatment and placebo arms in psoriasis is encouraging for further investigations, added Dr Raja Sivamani, dermatologist, Pacific Skin Institute, Sacramento, California. However, longer-term data of around three to six months is needed to fully understand this approach’s efficacy profile, Sivamani added. The Phase II psoriasis trial runs for 16 weeks (four months).

In 12 psoriasis patients who received the low dose (1.6×10^11 bacterial cells) and 18 patients who received high dose (8.0×10^11), the baseline mean Psoriasis Area and Severity Index (PASI) score was 9.5, whereas this was 6.2 and 6.7 with the high dose and placebo, respectively. In the secondary efficacy endpoint, both therapeutic arms had a 16% reduction in PASI versus 1% with placebo at day 28, though at day 42, the high-dose improvement increased to 21% but not in the low dose at 10%, according to data presented at the European Academy of Dermatology and Venereology (EADV) Congress in October (abstract no 2039). In the Phase II psoriasis trial, the primary endpoint is a mean reduction in PASI.

As well as in psoriasis, more data in AD is needed to fully understand this approach’s efficacy potential, said Dr Amy Paller, chair, Department of Dermatology, Northwestern University, Chicago. Phase Ib results are from a small number of patients, she added. The Phase II psoriasis trial is enrolling 225 patients, with Kim noting this should be large enough to support the drug’s efficacy profile.

On 9 December, Evelo reported positive Phase Ib data in AD, though it is only from 23 patients. In AD, the difference between EDP1815 and placebo arms was 62% in the percentage change in the Eczema Area and Severity Index (EASI) secondary efficacy endpoint (p=0.034) at day 56. Improvements were observed as early as day 14, with participants not allowed topical treatments and not required to use emollients.

Efficacy bar may be low, but changes in mild-to-moderate hard to show

While analyst reports have mentioned Amgen’s Otezla (apremilast) as an efficacy bar, Sivamani said this might not be appropriate as Otezla is approved in moderate-to-severe psoriasis. Mild-to-moderate patients do not go straight to systemic therapies, he explained.

That said, the efficacy bar for EDP1815 might be low in both psoriasis and AD because even if results are modest, it could help validate its mechanism, Han said. In fact, once its MOA is validated, its efficacy could be boosted by diet change, he added.

Still, the Phase II psoriasis trial’s success could hinge on how many mild or moderate patients are recruited, King said. In mild patients, it is hard to demonstrate efficacy because even if their disease severity is cut in half, they would still be classified as mild, he noted. In moderate patients, the transition to mild is more visible, he added.

Phase II will recruit patients with more active disease scores than Phase Ib, ones with PASI score between 6–15. The score ranges from 0–72, with more than ten translating to moderate-to-severe. The psoriasis trial is recruiting patients with plaque covering body surface area of ≥3% and ≤10%. While this range is ideal for a systemic approach, this window could have been reduced to between 5% and 10% to have fewer mild patients, Kim noted.

As for moderate patients, the main challenge in clinical trials is the placebo effect, King said, adding this is particularly true in AD. In some dermatology indications, placebo effect should be expected in one-fourth of both mild and moderate patients, he noted, adding this could even go up to a third. Placebo effect is less of a problem in psoriasis than in AD, Kim noted. This is because in AD, patients have different levels of severity within a period, whereas in psoriasis, patient profiles are a bit more consistent throughout the year, he said.

To accommodate for the possible placebo effect, there needs to be a dramatic difference between arms, not just statistical significance, King said. In psoriasis, for example, there could be a need of at least 5%–10% point difference between the treatment and placebo arms, Sivamani said.

EDP1815 so far has a positive safety profile, which is encouraging, Paller said. In the Phase Ib safety primary endpoint, EDP1815 was well-tolerated at daily doses of up to 8.0×10^11 cells administered for up to 28 days. Still, gastrointestinal issues should be monitored, as well as more side effects yet to be described as its mechanism implies far-reaching systemic impact, Kim said.

Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.