Combos, New MOAs, And Oral Formulations Of Injectables: Lilly’s Immunology Strategy

Eli Lilly is relatively young in immunology, but it has demonstrated a strategic commitment to growing its pipeline and presence in rheumatologic, dermatologic and gastroenterologic indications. Its first market entrant in this category was Taltz (ixekizumab) in 2016, and it now has four approved immunology drugs, but Lilly’s relative greenness in immunology “gives us a unique opportunity to continue to expand” in these three areas, Mark Genovese, Lilly’s SVP of immunology development since October 2023, recently told In Vivo in an exclusive interview.

“But above and beyond that, we’re looking to see if we can expand some of the treatable populations, and in some situations, move into potentially earlier disease, and how we can utilize combinations of biologic agents and combinations of oral agents to achieve higher levels of efficacy with reasonable safety profiles,” said Genovese, who came to Lilly from Gilead Sciences, where he was SVP of inflammation development.

A look at the company’s recent immunology approvals, late-stage pipeline assets and recent M&A activity demonstrates this strategy in action.

Strong Launch For Omvoh As It Awaits Crohn’s Approval

Lilly’s IL-23p19 antagonist Omvoh (mirikizumab) is approved in the US and EU for ulcerative colitis and is so far faring well, with sales jumping from $9.4m in Q1 2024 to $25.6m in Q2 and $41m in Q3, as the sales product has been available in more geographies. Citeline’s Biomedtracker projects $158m in total sales of the drug this year.

Now, the company is awaiting label expansion for Crohn’s disease after data from the pivotal 52-week Phase III VIVID-1 study showed the drug bested both placebo and Johnson & Johnson’s Stelara (ustekinumab) in histologic response rates.

“[W]e’re looking to see if we can expand some of the treatable populations, and in some situations, move into potentially earlier disease, and how we can utilize combinations of biologic agents and combinations of oral agents to achieve higher levels of efficacy with reasonable safety profiles."

Mark Genovese

As Genovese explained, up to 25% of patients who appear to have mucosal healing during endoscopic evaluation have underlying histologic inflammation, meaning the illness is active. Both in clinical practice and in the study setting, histologic evaluation provides “a better understanding of what’s actually taking place in the bowel,” which is why the company used the “comprehensive, five-bowel segment assessment, which aligns with a recent [European Crohn’s and Colitis] position statement on Harmonization of Crohn’s Disease Mucosal Histopathology,” as Genovese told sister publication Scrip.

“This is the first Phase III study of any treatment in Crohn’s disease, approved or investigational, to implement this rigorous evaluation of both histologic and combined endo-histologic outcomes. These analyses of microscopic mucosal healing may set a new standard for the evaluation of therapeutic response,” he said.

Indeed, emphasizing the drug’s ability to induce histologic remission may partly explain why Omvoh’s launch has been going well.

A US FDA approval for Crohn’s disease – which Genovese hopes could be given in Q1 2025—would boost Omvoh revenues. Berenberg analyst Kerry Holford expects sales of the drug to grow to $700m in 2025 and to peak at nearly $2bn for both inflammatory bowel disease indications.

Expanding Dermatology Portfolio

The company’s dermatology sales force will be busy this year as it encourages ongoing uptake of Taltz (ixekizumab), its IL-17A inhibitor for plaque psoriasis. Sales of Taltz increased in the US and internationally 18% and 19%, respectively, in Q3 2024, compared to Q3 2023. The company continues to encourage prescribing of Olumiant (baricitinib), its Janus kinase 1/2 inhibitor for alopecia areata, which was approved in 2018.

However, the dermatology team will now have another integrin-targeting agent to market, namely Ebglyss (lebrikizumab), an IL-13 inhibitor for the treatment of moderate-to-severe atopic dermatitis patients not adequately controlled with topical agents. That was launched in the US in September 2024 after an earlier launch in the EU and Japan.

Ebglyss is approved as a first-line biologic treatment option for moderate-to-severe atopic dermatitis and the company’s commercial team is likely educating prescribers about two main characteristics that differentiate Ebglyss from its competitors, such as Sanofi and Regeneron Pharmaceuticals’ Dupixent (dupilumab). While the two drugs have similar efficacy, Ebglyss is administered once monthly, while Dupixent is injected every other week. Additionally, Ebglyss’s wholesale acquisition cost in the US is slightly lower than that of Dupixent.

Given those advantages, analysts expect strong sales of the drug. In a Guggenheim Securities note from 30 September 2024, the drug was estimated to generate $1.8bn in annual sales by 2031, further highlighting the growing importance of immunology to Lilly’s overall revenue.

Morphic And DICE Acquisitions Increase Options

The recent acquisitions of Morphic Therapeutics and DICE Therapeutics have brought molecules with both novel and proven mechanisms of action into Lilly’s pipeline, most immediately for psoriasis and inflammatory bowel disease (IBD). This provides opportunities to expand into populations of patients currently not receiving Lilly agents.

The Morphic acquisition was one of the largest M&A deals of 2024. It was based partly on data from the small, open-label Phase IIa EMERALD-1 study of MORF-057, an oral, selective integrin α4β7-targeting compound, in ulcerative colitis patients. That showed a 25.7% rate of endoscopic improvement at week 12 and 45.7% clinical response rate, and no serious side effects. Readout from the Phase IIb EMERALD-2 study in the same patient population is expected in the first half of 2025 and Morphic is also studying the agent in Crohn’s disease in Phase IIb.

If MORF-057 proves successful, it has the potential to be used more expansively than the typical moderate-to-severe disease label that most biologics or oral small molecules are indicated for. Genovese believes it has promise to be administered either as monotherapy in mild or more moderate patients, or as part of a combination approach in more refractory patients.

“We’re waiting to see the results of the EMERALD-2 trial from Morphic, which we believe will come in the first half of 2025.”

Mark Genovese

“We’re waiting to see the results of the EMERALD-2 trial from Morphic, which we believe will come in the first half of 2025,” Genovese said. “Pending those results will depend on how we move forward with a variety of assets, particularly as it relates to what the programs will look like with MORF-057.”

Genovese said mild-to-moderately ill IBD patients with symptoms of bleeding and diarrhea are “inadequately treated with period courses of corticosteroids for flares, and there is potential that safe and effective oral α4β7 may be able to provide significant benefit to these patients.”

“This will be considered as an option in our development program,” he said.

According to Leering Partners analyst Thomas Smith, the acquisition of Morphic is in line with Lilly’s strategy of bringing to market oral forms of successful injectable biologics, in this case Takeda Pharmaceutical’s Entyvio (vedolizumab). If the agent reaches the market for both UC and CD, it could generate an estimated $2.9 to $3.6bn in peak annual revenues, Smith estimates.

Shareholders will hope those forecasts materialize, as the cost of the Morphic acquisition recently played a part in Lilly lowering its full-year earnings guidance to a range of $13.02 to $13.52, down from $16.10 to $16.60, as previously forecast.

Reprioritized Dice Program

Confirming Smith’s assessment of Lilly’s modus operandi, Genovese told In Vivo that the DICE Therapeutics acquisition reflects Lilly’s pipeline curation strategy of balancing the development of drugs for novel targets with drugs that have a known and validated mechanism of action.

At a cost of roughly $2.4bn, the purchase brings with it DICE’s DELSCAPE discovery platform, which has produced a number of oral IL-17 inhibitors and several other preclinical programs for gastrointestinal, dermatologic and fibrotic diseases.

Lilly recently deprioritized the lead DICE program for the oral IL-17 inhibitor, DC-806, which was in a Phase IIb trial for moderate-to-severe plaque psoriasis at the time, choosing to shift focus to DC-853, a “fast follower” IL-17 inhibitor, which was designed to have higher potency and metabolic stability than DC-806, balanced with a good safety profile.

"While the efficacy and safety data we saw in the DC-806 Phase II trials were encouraging, it did not hit our prespecified criteria to move forward."

Mark Genovese

“While the efficacy and safety data we saw in the DC-806 Phase II trials were encouraging, it did not hit our prespecified criteria to move forward,” he noted.

DC-853 is now being studied in several Phase I trials and the company recently initiated a Phase II trial in moderate-to-severe plaque psoriasis. The drug could ultimately take over for Taltz, which will go off patent between 2032 and 2036. DC-853 also fills in a gap left when Lilly halted the development of its own oral IL-17 inhibitor, LY3509754 after liver toxicity issues arose in a Phase I trial.

The significance of an oral IL-17 inhibitor, Genovese said, is that it delivers the same level of efficacy as Taltz “in a convenient fashion,” and “potentially opens up the opportunity for oral combinations and for “broadening the treatable population to both earlier as well as to more refractory patients.”

Combination Plays

One combination Lilly is examining is Omvoh with eltrekibart, a novel monoclonal antibody that binds to the ligands that signal CXCR1 and CXCR2, which affects neutrophil trafficking.

Eltrekibart has shown promise in Phase II studies in patients with hidradenitis suppurativa (HS), a chronic inflammatory skin condition thought to occur due to inflammation around hair follicles, and Genovese believes combining it with Omvoh “could potentially deliver transformative efficacy in ulcerative colitis.”

“We’re looking to better understand whether that combination can deliver really meaningful improvements and potentially even higher levels of response in those patients that have high neutrophils in the bowel,” despite a clinical response, Genovese said. “Because ultimately our goal is not just response but to drive more patients to the opportunity to have a remission in their disease.”

Genovese said physician comfort levels with combination immunologics still “vary meaningfully between disease specialties and between combination approaches,” suggesting the company could need to provide physician education on the safety of these approaches.

Tirzepatide In Immunology?

Along with other companies developing incretins, the company is beginning to act on preclinical and preliminary data suggesting that incretins have a role in modulating inflammation. To that end, Lilly is studying its mega-blockbuster tirzepatide (Mounjaro for diabetes and Zepbound for obesity) with Taltz to see if it can increase the likelihood of response in plaque psoriasis patients who are also obese or overweight. They are studying the same combination in patients with psoriatic arthritis who are overweight or obese.

If Lilly can demonstrate higher levels of response and better management of comorbidities and reduced risk over time, it will carve out a new niche for its incretins.

“Patients with chronic disease often have higher levels of inflammation and while most inflammation can be treated through immunomodulation, there’s opportunity to reduce the inflammation that comes from adiposity,” noted Genovese. “Each of these approaches may offer us an opportunity to have iterative, additive or synergistic benefits. Of course, you have to weigh that against the potential safety profiles to ensure we’re delivering the right approach to the right patient.”