MoonLake Immunotherapeutics operates as a clinical stage biotechnology company.
The company is advancing therapies to address significant unmet needs in inflammatory skin and joint diseases. The company is a single asset company focused on the development of SLK, a novel tri-specific IL-17A and IL-17F inhibiting Nanobody, that the company exclusively licensed from MHKDG and that has the potential, based on response levels seen in clinical trials, to drive disease modification in dermatology and...
MoonLake Immunotherapeutics operates as a clinical stage biotechnology company.
The company is advancing therapies to address significant unmet needs in inflammatory skin and joint diseases. The company is a single asset company focused on the development of SLK, a novel tri-specific IL-17A and IL-17F inhibiting Nanobody, that the company exclusively licensed from MHKDG and that has the potential, based on response levels seen in clinical trials, to drive disease modification in dermatology and rheumatology patients.
SLK is a proprietary Nanobody that was discovered by Ablynx N.V., Belgium, a Sanofi company (‘Ablynx’), and previously studied by MHKDG and Avillion LLP (‘Avillion’) under a 2017 co-development agreement. The terms ‘Nanobody’ and ‘Nanobodies’ used herewith are registered trademarks of Ablynx. Nanobodies are able to bind selectively to a specific antigen with high affinity. Nanobodies have a fraction of the molecular weight compared to traditional antibodies. They offer a number of potential advantages over traditional monoclonal antibodies, including the potential to create multivalent molecules with enhanced ability to penetrate inflamed tissue, especially when containing an additional albumin binding domain, such as SLK, an easier manufacturing process and a higher thermostability.
The company develops SLK in inflammatory diseases in dermatology and rheumatology where the pathophysiology is known to be driven by IL-17A and IL-17F. This group of diseases comprises the company’s initial target diseases, hidradenitis suppurativa (‘HS’) and psoriatic arthritis (‘PsA’), and several other inflammatory conditions (including axial spondyloarthritis (‘axSpA’) and psoriasis (‘PsO’). The company’s initial target diseases affect millions of people worldwide, and there is a need for improved treatment options. SLK has a differentiated mechanism of action and that its purposefully designed molecular characteristics, including its small size and its albumin binding site, facilitate deep tissue penetration in the skin and joints. The company envisions SLK as a key therapeutic alternative in the company’s initial target indications and potentially in multiple other IL-17 driven inflammatory conditions.
In May 2022, the company initiated a Phase 2b trial of SLK in patients with moderate-to-severe HS (the MIRA trial (M1095-HS-201)). In June 2023, the company announced positive top-line results from this trial, which met its primary endpoint of Hidradenitis Suppurativa Clinical Response (‘HiSCR’) 75. In October 2023, the company announced positive 24-week top-line results showing that the maintenance treatment with SLK led to further improvements in HiSCR75 response rates and other clinically relevant outcomes in patients with moderate-to-severe HS. In February 2024, the company announced the successful outcome of the company’s end-of-Phase 2 interactions with the U.S. Food and Drug Administration (‘FDA’), as well as positive feedback from the company’s interactions with the E.U. European Medicines Agency (‘EMA’), with both regulatory bodies unanimously supporting the company’s proposed approach for advancing the company’s Phase 3 program of SLK in HS. In December 2022, the company initiated a Phase 2b trial in patients with active PsA (the ARGO trial (M1095-PSA-201)), and in November 2023, the company announced positive top-line results from this trial, which met its primary endpoint of American College of Rheumatology (‘ACR’) 50. The company expects to announce 24-week top-line results of the ARGO trial in the first quarter of 2024. SLK was also studied in a Phase 2b trial in PsO patients where it showed a significant improvement in the primary end point as compared with placebo and for which results were presented in peer-reviewed scientific publications and conferences.
All three Phase 2b trials were conducted with active reference arms. In the HS and PsA trials, patients randomized to the active reference arm were treated with adalimumab (also known as Humira), and in PsO, with secukinumab (also known as Cosentyx), both drugs being considered the current standard of care in the respective indications. In all three trials, patients on the active reference arm achieved outcomes consistent with those achieved in previous studies for those molecules, demonstrating the validity of the company’s own trial results. In addition, SLK numerically outperformed the active reference arms, highlighting SLK’s promise as a treatment for inflammatory diseases.
In addition to the three Phase 2b trials, Phase 1 single ascending and multiple ascending dosing trials were previously completed, bringing the total number of patients in SLK-related trials to more than 700.
Building on the robust clinical data generated as of December 31, 2023, the company intends to further pursue the clinical development of SLK. The company expects to commence Phase 3 clinical trials in HS in the first half of 2024, and in PsA in the second half of 2024. The company also expects to commence clinical trials of SLK in other indications to be announced in 2024.
Strategy
The company’s strategy is centered on developing SLK as, to the company’s knowledge, the first ever Nanobody in clinical development for the company’s selected indications. The company seeks to accomplish this strategy by completing the development of SLK in the company’s initial focus indications, HS and PsA; broadening the company’s portfolio of indications; strengthening the differentiation elements for future SLK patients; building the company’s manufacturing and commercial capabilities; deepening the company’s intellectual property portfolio to support the company’s Nanobody technology and product candidates; and licensing/broadening the company’s portfolio.
Focus: Inflammatory Diseases Involving IL-17A and IL-17F
SLK is an inhibitor of IL-17A and IL-17F that modulates cytokine activity in a fashion that is founded in current understanding of the importance of IL-17 biology in inflammatory disease. IL-17 cytokines can potently promote inflammation and also play a role in protection against some infectious agents. The inflammatory effects of IL-17 can be targeted directly by blocking the cytokine or its receptor, or indirectly by blocking cytokines upstream of IL-17-producing cells. IL-17 contributes to various lesions that are produced by Th17 cells, one subset of helper T cells, by gamma delta T cells, and by innate lymphoid cells. In healthy tissue, IL-17A is largely absent, but is significantly upregulated in inflamed lesions in the company’s focus indications. While IL-17F is present in healthy and non-lesional tissue at detectably higher concentrations than IL-17A, it is also significantly upregulated in inflamed tissue in the company’s focus indications. The current view is that IL-17F contributes to inflammatory conditions such as HS and PsA, which is why IL-17A and F inhibition could well exert an increased anti-inflammatory therapeutic potential compared to just IL-17A inhibition.
Pipeline
The company is developing a portfolio of therapeutic indications for SLK.
Clinical Development of SLK
Phase 2b Clinical Trial in HS: The MIRA Trial
The MIRA trial (M1095-HS-201) is a global, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of SLK, administered subcutaneously, in the treatment of adult patients with active moderate-to-severe HS. The trial recruited 234 patients, with the aim to evaluate two different doses of SLK (120mg and 240mg) with placebo control and adalimumab as an active reference arm. The primary endpoint of the trial is the percentage of participants achieving HiSCR75, defined as a =75% reduction in total abscess and inflammatory nodule (‘AN’) count with no increase in abscess or draining tunnel count relative to baseline. The trial also evaluated a number of secondary endpoints, including the proportion of patients achieving HiSCR50, the change from baseline in International Hidradenitis Suppurativa Severity Score System (‘IHS4’), the proportion of patients achieving a Dermatology Life Quality Index total score of =5, and the proportion of patients achieving at least 30% reduction from baseline in Numerical Rating Scale in the Patient’s Global Assessment of Skin Pain.
In June 2023, the MIRA set a landmark milestone as the first placebo-controlled randomized trial in HS to use HiSCR75 as the primary endpoint which it met with a significantly greater proportion of patients treated with both SLK 120mg and 240mg achieving HiSCR75 compared to those on placebo at week 12. The primary analysis was based on a very stringent type of analysis for such trials, intent-to-treat non-responder imputation (‘ITT-NRI’). Both doses performed similarly, with the 120mg dose providing the highest delta on HiSCR75 and HiSCR50. The 120mg dose achieved a 29 percentage points (‘ppt’) delta to placebo on HiSCR75 (p=0.0002) and a 38 ppt delta to placebo on HiSCR50 (p<0.0001). The results suggest that, as early as week 12, SLK, relative to placebo, reaches the highest clinical activity among all other therapies tested in similarly stringent pivotal-like trials.
In October 2023, 24-week results were presented, showing that ongoing treatment with SLK 120mg and 240mg dosed Q4W further increased HiSCR75 response rates compared to week 12. 57% of patients continuously treated with 120mg achieved a HiSCR75 response (more than 10 ppt improvement from week 12) and 38% achieved HiSCR90 (more than 14 ppt improvement versus week 12). The IHS4 score, which encompasses changes in all active HS lesions (nodules, abscesses, draining tunnels), decreased by 65% in patients treated with the 120mg maintenance dose.
Rates of complete resolution of inflammatory nodules and abscesses (AN 100) together with complete resolution of draining tunnels (DT 100) also increased between week 12 and 24 (31% and 49% of patients achieving this high level of response at week 24 with 120mg respectively, an increase of up to 15 ppt). Complete inflammatory remission (IHS4-100) was achieved in 1 in 4 patients (24%) treated with 120mg at week 24. Clinical responses translated to profound improvements in patient-reported outcomes at 24 weeks including quality of life, pain, and patient global impression of severity. 43% of patients reached self-reported absent or minimal disease activity on the PGI-S scale.
Results obtained with placebo patients re-randomized to SLK 120mg or 240mg in Part B, after the primary analysis, replicated the dose responses observed in Part A. Difficult-to-treat subgroup analysis (e.g., in Hurley stage III patients or those previously exposed to biologics) confirms the advantage of the 120mg dose. Similarly, PK analysis support the use of the monthly maintenance 120mg dose. For patients who were inadequate responders to adalimumab at week 12 switching to SLK resulted in HiSCR75 response rates similar to responses in those randomized to SLK at baseline. SLK provided better durability of response compared to that observed with adalimumab in other studies.
The safety profile of SLK was consistent with that observed in previous studies. Overall, SLK continues to show a favorable safety profile, in line with the known profile of IL-17 inhibitors. Based on the efficacy and safety results, Q4W maintenance dosing of SLK 120mg has been confirmed in the company’s view as the optimal dose, in terms of speed and depth of response, and overall benefit-risk profile, for progression into Phase 3 development.
Phase 2b Clinical Trial in PsA: the ARGO Trial
The ARGO trial (M1095-PSA-201) is a global, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of SLK, administered subcutaneously, in the treatment of adult patients with active PsA. The trial was designed to evaluate different doses of SLK, with placebo control and adalimumab as an active reference arm. The primary endpoint of the trial is the percentage of participants achieving =50% improvement in signs and symptoms of disease from baseline, compared to placebo, as measured by ACR50 response. The trial also evaluates a number of secondary endpoints, including improvement compared to placebo in ACR20, complete skin clearance as measured by at least a 100% improvement in PASI (PASI100), physical function as measured by the Health Assessment Questionnaire-Disability Index, enthesitis as measured by the Leeds Enthesitis Index and pain as measured by the Patients Assessment of Arthritis Pain. Important composite scores, such as ACR50+PASI100, measuring both joint and skin improvement in the same patients were also studied.
In November 2023, the ARGO trial, which enrolled 207 patients, met its primary endpoint with a statistically significant greater proportion of patients treated with either SLK 60mg or 120mg (with induction) achieving an ACR50 response compared to those on placebo at week 12. Specifically, for the 60mg and 120mg doses with induction, respectively, 46% and 47% of patients treated with SLK achieved ACR50 (p<0.01 versus placebo); 78% and 72% of patients achieved ACR20; and 29% and 26% achieved ACR70. The primary analyses were based on a very stringent type of analysis for such trials, ITT-NRI. As expected, the 60mg dose without induction did not reach statistical significance, confirming the 60mg and 120mg with induction as the potential dose regimens to carry forward into Phase 3. All key secondary endpoints were met for the 60mg and 120mg doses with induction. The key secondary endpoint PASI90 was met for all doses with induction. 77% of patients achieved a PASI90 response at week 12 to the 60mg dose (ITT-NRI, p<0.001 versus placebo). For this dose, 58% of patients achieved complete skin clearance (PASI100) at week 12. PASI responses across dose arms were consistent with the previously reported Phase 2b data of SLK in moderate-to-severe plaque-type PsO, with the 120mg dose achieving the highest responses for PASI100 (close to 60% of patients at week 12, ITT-NRI) in patients with more severe skin lesions (PASI score = 10 at baseline). Up to 33% of patients achieved both ACR50 and PASI100 at week 12. Other clinically relevant secondary endpoints, such as Minimal Disease Activity (MDA), the modified Nail Psoriasis Severity Index (mNAPSI), the Leeds Enthesitis Index (LEI) and the patient self-reported Psoriatic Arthritis Impact of Disease (PsAID-12), each show promising levels of response at week 12. Adalimumab was used as an active reference to validate responses across arms (not powered for statistical comparisons to active treatment). SLK 60mg and 120mg (with induction) numerically outperformed adalimumab on the primary endpoint and all key secondary endpoints, with the observed deltas further supporting the potential for SLK as a future leading therapy.
The safety profile of SLK in ARGO was consistent with previously reported studies with no new safety signals. Overall, SLK continued to show a favorable safety profile.
The results suggest that, as early as week 12, SLK reaches levels of clinical response at or above those seen with other therapies tested in similarly stringent trials. 24 weeks data of the ARGO trial is expected to be presented in March 2024. The high performance of SLK and its favorable safety profile continue to support the plan for progression into Phase 3 development in 2024.
Phase 2b Clinical Trial in Psoriasis
In May 2021, data for the Phase 2b trial of SLK in PsO was published. This trial was conducted by Avillion under a 2017 co-development agreement with MHKDG. The randomized, double-blind, placebo-controlled, multi-center trial was designed to assess efficacy, safety and tolerability of SLK in patients with moderate-to-severe chronic plaque-type PsO, over a total period of 52 weeks (inclusive of a 40-week follow-up assessment). In all cases, patients were administered SLK via subcutaneous injection.
The primary objective of the trial was to evaluate the efficacy of four dose regimens of SLK compared to placebo on achievement of an Investigator’s Global Assessment (‘IGA’) score of 0 or 1 after 12 weeks of treatment in patients with moderate to severe chronic plaque-type PsO. The secondary objectives were to evaluate the efficacy of four dose regimens of SLK compared to placebo during a 12-week treatment period on secondary endpoints: PASI 75, PASI 90, PASI 100, change in mean PASI and shift in IGA, to assess the dose-regimen efficacy relationship for SLK after 12, 24, 36, and 48 weeks of treatment, to evaluate the longer-term efficacy of SLK at week 24 and at weeks 36 and 48, and to assess the safety and tolerability of SLK. Other exploratory objectives were also considered.
Primary and secondary end-points, associated with the described objectives were achieved. Doses up to 120 mg showed rapid and significant differences in PASI 100 compared with placebo. In the highest dosage group, nearly six out of ten patients (57%) achieved total skin clearance (PASI 100 response) after 24 weeks. Rapid response was demonstrated with one of three patients already achieving nearly clear skin (PASI 90 response) by week four. Analysis of an individualized dosing scheme including off-drug periods in controlled patients revealed durable responses over one year. SLK was generally well tolerated, with a safety profile similar to the active control, secukinumab, and an overall Candida infection rate of 2.9% from week 0 to week 12 and 6.4% in the period from week 12 to week 52 across all doses.
Ongoing and Planned Clinical Development
The company expects to present 24 weeks data of the ARGO trial in the first quarter of 2024.
The company expects to commence Phase 3 clinical trials in HS in the first half of 2024, and in PsA in the second half of 2024, with primary endpoint data expected in mid 2025 and early 2026, respectively. In February 2024, the company announced the successful outcome of the company’s end-of-Phase 2 interactions with the FDA, as well as positive feedback from the company’s interactions with the EMA, with both regulatory bodies unanimously supporting the company’s proposed approach for advancing the company’s Phase 3 program of SLK in HS.
The company expects to announce details on which indications the company intends to pursue during 2024, and intends to initiate one or more trials of SLK in such indications in 2024.
Manufacturing
The company partners with third-party CMOs for both drug substance and finished drug product, through established contracts.
The company’s drug substance supplier is Richter-Helm Biologics GmbH & Co. KG (‘RHB’) based in Bovenau, Germany. Effective July 1, 2021, the company entered into a contract manufacturing agreement with RHB with respect to the manufacture of SLK.
MHKDG (Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany) produced the drug product supply for the company’s Phase 2 clinical trials, the MIRA trial and the ARGO trial. In 2022, the company successfully transferred the drug product process to Vetter Pharma International GmbH as part of the company’s strategy to ensure sufficient supply for potential commercialization following all regulatory and related requirements.
In May 2023, the company entered into a collaboration agreement with SHL Medical to develop an autoinjector for clinical and potential subsequent commercial supply of SLK.
Intellectual Property
As of December 31, 2023, the company had the exclusive license to a patent family directed to Il-17 Nanobodies, including SLK, and methods of making and using the same derived from International Patent Application PCT/EP2012/058313, published as WO 2012/156219, entitled ‘Amino Acid Sequences Directed Against IL-17A, IL-17F and/or IL17-A/F and Polypeptides Comprising the Same.’ Applications in this family have been filed in the United States, the European Patent Office (EPO), the Eurasian Patent Organization (EAPO), Australia, Brazil, Canada, Chile, China, Hong Kong, India, Israel, Japan, Korea, Malaysia, Mexico, New Zealand, Philippines, Singapore, and South Africa. As of December 31, 2023, 24 patents have issued and several applications are pending. Three patents have been issued in the United States in this family thus far (U.S. Patent Nos. 10,017,568, 10,829,552 and 11,773,159), all three providing protection until May 2032, without taking into account any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity and other governmental fees. There are several non-U.S. patents that have been granted or are pending in this family, all of which are expected to have similar expiration dates, absent any extensions that may be available through supplementary protection certificates or similar mechanisms. Additional data exclusivity rights may be applicable.
The Merck Healthcare KGaA (Darmstadt, Germany) License Agreement
On April 29, 2021, the company entered into a license agreement with MHKDG (the ‘License Agreement’). The License Agreement is a sublicense of a license agreement between MHKDG and Ablynx, dated September 3, 2008 (the ‘Initial License Agreement’), pursuant to which MHKDG developed SLK, and subsequently acquired exclusive right and title to SLK, including the right to further develop and commercialize (and grant sublicenses to further develop and commercialize) SLK. Pursuant to the License Agreement, the company acquired (i) a royalty- and milestone-bearing exclusive (even as to MHKDG), sublicensable right and license under MHKDG’s controlled patents, materials, and exclusive know-how to develop, manufacture, use, sell, offer for sale, export and import and otherwise commercialize SLK on a world-wide basis, (ii) a royalty- and milestone-bearing non-exclusive, sublicensable, right and sublicense under Ablynx’s and certain others’ controlled patents, materials, and know-how to develop, manufacture, use, sell, offer for sale, export and import and otherwise commercialize SLK on a world-wide basis, in each case subject to certain restrictions and compliance with the terms and conditions of the Initial License Agreement; and (iii) a royalty- and milestone-bearing non-exclusive, sublicensable right and sublicense under Research Cooperation Technologies (‘RCT’) patents and know-how related to the manufacturing process using the underlying yeast strain Pichia pastoris, to develop, manufacture, use, sell, offer for sale, export and import and otherwise commercialize SLK on a world-wide basis, in each case subject to certain restrictions and compliance with the terms and conditions of the underlying license granted to MHKDG from RCT. Under the terms of the License Agreement, the company have the first right to file, prosecute and maintain the licensed patents as well as the first right to attempt to resolve any third party infringement.
The License Agreement includes a development plan, subject to specified periodic updates, which describes the plan for developing the licensed products in the initial target indications of HS and PsA, including the plan for conducting clinical trials to obtain regulatory approval in the major European markets, Japan, and the United States (the ‘Major Markets’). In accordance with the foregoing, the company, among other requirements, are obligated to use commercially reasonable efforts to develop one licensed product in at least two indications, including initiating certain Phase 2 trials for the licensed product within a specified period following conclusion of the License Agreement, and launching and commercializing the same in each of the Major Markets a certain period following receipt of regulatory approval in such respective markets.
On May 12, 2023, the company entered into an agreement with RCT and MHKDG, effective as of June 1, 2023, pursuant to which the company were granted a royalty-bearing, nonexclusive, sublicensable right and license under RCT’s patents and know-how related to a manufacturing process using an underlying yeast strain, Pichia pastoris, to develop, manufacture, use, sell, offer for sale, and import and otherwise commercialize SLK on a world-wide basis, subject to certain restrictions. This agreement replaces the company’s sublicense for similar rights under the License Agreement with MHKDG.
Government Regulation
The FDA, and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of biologics such as those the company is developing.
Any products manufactured or distributed by the company pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing user fee requirements, under which the FDA assesses an annual program fee for each product identified in an approved BLA. Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMPs, which impose certain procedural and documentation requirements upon the company and its third-party manufacturers.
Research and Development
The company’s research and development expenses were $31.8 million for the year ended December 31, 2023.
History
MoonLake Immunotherapeutics was founded in 2021.
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