N E W S & A N A LY S I S
IL‑17 antibodies gain momentum A Phase III trial for a first‑in‑class psoriasis drug provides encouraging data, but the emerging agents still have to prove their worth in a crowded autoimmune market. Man Tsuey Tse Novartis is on track to file its interleukin-17A (IL‑17A) inhibitor secukinumab for approval by the end of the year, following the presentation of encouraging Phase III psoriasis data last month at the European Association of Dermatology and Venerology (EADV) meeting. The first‑in‑class biologic met all primary and key secondary end points and was superior to Amgen and Pfizer’s tumour necrosis factor (TNF) inhibitor etanercept, a current standard biologic therapy for this lifelong inflammatory skin disease. In pursuit are Amgen and Eli Lilly and Company, which also have IL‑17-targeting monoclonal antibodies (mAbs) in Phase III development for psoriasis. Amgen’s brodalumab and Lilly’s ixekizumab both achieved similar efficacy as secukinumab in Phase II trials. “IL‑17 is one of the best targets we’ve ever had,” says Craig Leonardi, a physician scientist at St Louis University Medical School, Missouri, USA, who has been involved in trials of all three drugs. This new wave of therapies for psoriasis patients dates back to 1993, when IL‑17 (initially identified as cytotoxic T lymphocyteassociated antigen 8, now formally known as IL‑17A) was first reported. Subsequent work discovered other members of this cytokine family, IL‑17B to IL‑17F, and their receptors, IL‑17RA to IL‑17RE. In 2005, researchers identified a new T lymphocyte subset, the T helper 17 (TH17) cell, as the primary source of IL‑17A and IL‑17F. It is now known that the IL‑17–TH17 cell pathway mediates many inflammatory and autoimmune diseases and has a prime role in host defence, thus expanding the number of cytokines that could be the pathogenic drivers of autoimmune and inflammatory conditions. “The discovery of IL‑17 was a major breakthrough in immunology,” says Ajay Nirula, Executive Medical Director of Global Development at Amgen. “Industry paid a lot of attention, as the biology of the IL‑17 pathway was very rich: there were a number of different cytokines and receptor complexes that could
be targeted.” (See FIG. 1 for a summary of the homodimers, heterodimers and various points of interventions in this pathway.)
Cytokine versus receptor Industry has focused much of its attention on IL‑17A and IL‑17RA. But a key question was whether to target the cytokine or the receptor? Novartis targeted the cytokine more because of circumstance than design. “The receptor wasn’t even known when we started our programme,” says Dhavalkumar Patel, Global Head of the Autoimmunity, Transplantation and Inflammation Disease Area at the Novartis Institutes for BioMedical Research. Nevertheless, Patel says that in retrospect Novartis is happy that it is targeting the cytokine and not the receptor. Cytokines are readily available in the circulation, whereas with the receptor you have to gain access to the relevant tissue before the receptor can be neutralized. Consequently, from a pharmacokinetic point of view it is easier to block the cytokine than the receptor. Mike Heffernan, Distinguished Medical Fellow at Lilly, agrees: “Going after the ligand is often more straightforward than the receptor.” Lilly’s ixekizumab also targets IL‑17A. Amgen, by contrast, pursued the receptor. “What we noted was that most of the receptor complexes in the IL‑17 pathway had a common signalling subunit: IL‑17RA,” says Nirula. “And so we felt it was an effective way to disrupt the pathway: if multiple IL‑17 cytokines were contributing to a disease rather than a particular cytokine, then this would be a good strategy.” In psoriasis, the lead indication for these drugs, it is not yet clear whether the different approaches translate into different results. “When you’re using them in the clinic, they feel very similar to each other,” says Leonardi. “All three are capable of being high-performance psoriasis-clearing drugs.” The published Phase II data on these three mAbs back this view. In trials of brodalumab, secukinumab and ixekizumab involving ~125–200 patients, each drug helped around 80% of treated patients achieve a 75%
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 12 | NOVEMBER 2013 | 815 © 2013 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Inhibitors of IL-17A • Ixekizumab • Secukinumab
IL-17A
IL-17RC Target tissue
IL-17F TH17 cell or other cells
Biological effects • Inflammation • Matrix destruction • Cell migration
IL-17RA IL-17A–IL17F
Inhibitors of TH17 cell generation
Inhibitors of IL-17A–IL-17F
Inhibitors of IL-17RA • Brodalumab
Figure 1 | IL‑17–TH17 pathway and points of intervention. The interleukin-17 (IL‑17)–T helper 17 (TH17) pathway is a rich source of targets for inflammatory disease drugs. The most advanced are Nature Reviews | Drug Amgen’s brodalumab, Lilly’s ixekizumab and Novartis’s secukinumab. Figure modified fromDiscovery Nature Rev. Drug Discov. 11, 763–776; 2012.
reduction in the Psoriasis Area and Severity Index (PASI 75; see N. Engl. J. Med. 366, 1181–1189; 2012; N. Engl. J. Med. 366, 1190–1199; 2012; and Br. J. Dermatol. 168, 412–421; 2013, respectively). The Phase III data on secukinumab, presented at the EADV meeting last month, offer further encouragement. Around 1,300 patients were treated with placebo, secukinumab or etanercept, a fusion protein that acts as a decoy receptor to mop up excess TNF and is indicated for a broad range of inflammatory disorders including psoriasis. The trial met its primary end point, with secukinumab besting both placebo and etanercept on both the PASI 75 and other measures of disease activity at 12 weeks. Secukinumab also seemed to offer faster resolution of symptoms than etanercept (2 weeks versus 8 weeks) and better long-term efficacy (65% of secukinumab-treated patients achieved PASI 90 at 52 weeks versus 33% of etanercept-treated patients). No new major safety signals were identified in the Phase III trial compared with the Phase II trial. These and earlier data suggest that the safety profile of these three mAbs may be a particularly promising aspect of this class of agents. “The traditional issues that we worry about are serious infection and malignancy, and we didn’t see any of that in the Phase II data,” says Leonardi. “It was really quite stunning.” Phase III data for ixekizumab (in a head-to-head trial versus etanercept) and brodalumab (in a head-to-head trial versus
ustekinumab, an approved mAb that inhibits IL‑12 and IL‑23 signalling) are expected next year, which will enable better comparison of the relative benefits and safety profiles of these agents.
Entering the autoimmune market In the first instance, Amgen, Lilly and Novartis hope to muscle into the lucrative psoriasis biologics market, which BioMedTracker analysts estimate is worth up to ~US$4 billion worldwide. Etanercept currently takes the largest slice, with ~30% of this market. In addition to psoriasis, etanercept is approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis, and had worldwide sales of ~$8 billion in 2012. Owing to the entrenchment of current biologics and the arrival of biosimilars, BioMedTracker predicts that uptake of secukinumab will be slow — despite the encouraging Phase III data — and that its initial use will probably be after TNF failure. Analysts at Datamonitor have forecasted sales of secukinumab in psoriasis of ~$10 million in 2014, increasing to ~$360 million in 2018 for the United States, Japan and the five major EU markets. But Novartis and Lilly see potential for their IL‑17 mAbs in other indications as well. Novartis has Phase III trials of secukinumab in psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis. “As soon as the TH17 story broke and it was shown that this cell was important for specific diseases, we went into
816 | NOVEMBER 2013 | VOLUME 12
all those diseases in parallel,” says Patel. For rheumatoid arthritis, Datamonitor predicts sales of ~$400 million for secukinumab in 2018 for the United States, Japan and the five major EU markets. Lilly, similarly, is developing its ixekizumab for psoriatic arthritis, ankylosing spondylitis and other autoimmune conditions. However, not everybody is convinced that IL‑17 inhibitors will be as successful in some of these indications as they are in psoriasis. “For either rheumatoid or psoriatic arthritis, the published data would suggest that they’re not going to be doing a great job,” says Leonardi. According to Pierre Miossec, a professor of clinical immunology at Claude Bernard University Lyon, France, and a pioneer in the IL-17 field, the underlying biology is more complex with arthritic indications and treatment is made more difficult by irreversible changes in mesenchymal cells and by the tissue destruction in bone and cartilage that comes along with disease. Indeed, Amgen stopped developing brodalumab in rheumatoid arthritis owing to lack of efficacy, although Miossec notes that the ligand-targeting agents may fare better than the receptor-targeting agents in arthritic settings. To overcome the effect of tissue destruction, he adds, two approaches could help. IL‑17 inhibitors might be more effective if they are deployed earlier on in the disease than have been tested. In addition, as IL‑17 and TNF have synergistic effects, another approach is to take out both TNF and IL‑17. AbbVie is testing such an approach with its Phase I candidate ABT‑122, a bispecific mAb that binds TNF and IL‑17A. Researchers are also working on other tractable targets in the IL‑17 pathway that they hope could potentially address the shortfalls of the first batch of IL‑17 inhibitors. NovImmune and Genentech are developing a mAb against IL‑17A and IL‑17F (NI‑1401/RG7624), which is currently in Phase I. Others are targeting retinoic acid-related orphan receptor γt (RORγt), which is a master regulator of TH17 cell development. Small-molecule RORγt inhibitors could block the development of TH17 cells, preventing the secretion of IL‑17 and modulating other pro-inflammatory cytokines. This transcription factor could also provide an opportunity to target IL‑17 signalling with oral rather than injectable therapies, and has formed the basis of several recent preclinical deals (Nature Med. 19, 1078; 2013). “It’s bubbling,” says Miossec regarding the pipeline of these inhibitors. “It’s too early to tell what the net effect will be, but it’s a highly active and competitive area.”
www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved
IL‑17 antibodies gain momentum A Phase III trial for a first‑in‑class psoriasis drug provides encouraging data, but the emerging agents still have to prove their worth in a crowded autoimmune market. Man Tsuey Tse Novartis is on track to file its interleukin-17A (IL‑17A) inhibitor secukinumab for approval by the end of the year, following the presentation of encouraging Phase III psoriasis data last month at the European Association of Dermatology and Venerology (EADV) meeting. The first‑in‑class biologic met all primary and key secondary end points and was superior to Amgen and Pfizer’s tumour necrosis factor (TNF) inhibitor etanercept, a current standard biologic therapy for this lifelong inflammatory skin disease. In pursuit are Amgen and Eli Lilly and Company, which also have IL‑17-targeting monoclonal antibodies (mAbs) in Phase III development for psoriasis. Amgen’s brodalumab and Lilly’s ixekizumab both achieved similar efficacy as secukinumab in Phase II trials. “IL‑17 is one of the best targets we’ve ever had,” says Craig Leonardi, a physician scientist at St Louis University Medical School, Missouri, USA, who has been involved in trials of all three drugs. This new wave of therapies for psoriasis patients dates back to 1993, when IL‑17 (initially identified as cytotoxic T lymphocyteassociated antigen 8, now formally known as IL‑17A) was first reported. Subsequent work discovered other members of this cytokine family, IL‑17B to IL‑17F, and their receptors, IL‑17RA to IL‑17RE. In 2005, researchers identified a new T lymphocyte subset, the T helper 17 (TH17) cell, as the primary source of IL‑17A and IL‑17F. It is now known that the IL‑17–TH17 cell pathway mediates many inflammatory and autoimmune diseases and has a prime role in host defence, thus expanding the number of cytokines that could be the pathogenic drivers of autoimmune and inflammatory conditions. “The discovery of IL‑17 was a major breakthrough in immunology,” says Ajay Nirula, Executive Medical Director of Global Development at Amgen. “Industry paid a lot of attention, as the biology of the IL‑17 pathway was very rich: there were a number of different cytokines and receptor complexes that could
be targeted.” (See FIG. 1 for a summary of the homodimers, heterodimers and various points of interventions in this pathway.)
Cytokine versus receptor Industry has focused much of its attention on IL‑17A and IL‑17RA. But a key question was whether to target the cytokine or the receptor? Novartis targeted the cytokine more because of circumstance than design. “The receptor wasn’t even known when we started our programme,” says Dhavalkumar Patel, Global Head of the Autoimmunity, Transplantation and Inflammation Disease Area at the Novartis Institutes for BioMedical Research. Nevertheless, Patel says that in retrospect Novartis is happy that it is targeting the cytokine and not the receptor. Cytokines are readily available in the circulation, whereas with the receptor you have to gain access to the relevant tissue before the receptor can be neutralized. Consequently, from a pharmacokinetic point of view it is easier to block the cytokine than the receptor. Mike Heffernan, Distinguished Medical Fellow at Lilly, agrees: “Going after the ligand is often more straightforward than the receptor.” Lilly’s ixekizumab also targets IL‑17A. Amgen, by contrast, pursued the receptor. “What we noted was that most of the receptor complexes in the IL‑17 pathway had a common signalling subunit: IL‑17RA,” says Nirula. “And so we felt it was an effective way to disrupt the pathway: if multiple IL‑17 cytokines were contributing to a disease rather than a particular cytokine, then this would be a good strategy.” In psoriasis, the lead indication for these drugs, it is not yet clear whether the different approaches translate into different results. “When you’re using them in the clinic, they feel very similar to each other,” says Leonardi. “All three are capable of being high-performance psoriasis-clearing drugs.” The published Phase II data on these three mAbs back this view. In trials of brodalumab, secukinumab and ixekizumab involving ~125–200 patients, each drug helped around 80% of treated patients achieve a 75%
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 12 | NOVEMBER 2013 | 815 © 2013 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S Inhibitors of IL-17A • Ixekizumab • Secukinumab
IL-17A
IL-17RC Target tissue
IL-17F TH17 cell or other cells
Biological effects • Inflammation • Matrix destruction • Cell migration
IL-17RA IL-17A–IL17F
Inhibitors of TH17 cell generation
Inhibitors of IL-17A–IL-17F
Inhibitors of IL-17RA • Brodalumab
Figure 1 | IL‑17–TH17 pathway and points of intervention. The interleukin-17 (IL‑17)–T helper 17 (TH17) pathway is a rich source of targets for inflammatory disease drugs. The most advanced are Nature Reviews | Drug Amgen’s brodalumab, Lilly’s ixekizumab and Novartis’s secukinumab. Figure modified fromDiscovery Nature Rev. Drug Discov. 11, 763–776; 2012.
reduction in the Psoriasis Area and Severity Index (PASI 75; see N. Engl. J. Med. 366, 1181–1189; 2012; N. Engl. J. Med. 366, 1190–1199; 2012; and Br. J. Dermatol. 168, 412–421; 2013, respectively). The Phase III data on secukinumab, presented at the EADV meeting last month, offer further encouragement. Around 1,300 patients were treated with placebo, secukinumab or etanercept, a fusion protein that acts as a decoy receptor to mop up excess TNF and is indicated for a broad range of inflammatory disorders including psoriasis. The trial met its primary end point, with secukinumab besting both placebo and etanercept on both the PASI 75 and other measures of disease activity at 12 weeks. Secukinumab also seemed to offer faster resolution of symptoms than etanercept (2 weeks versus 8 weeks) and better long-term efficacy (65% of secukinumab-treated patients achieved PASI 90 at 52 weeks versus 33% of etanercept-treated patients). No new major safety signals were identified in the Phase III trial compared with the Phase II trial. These and earlier data suggest that the safety profile of these three mAbs may be a particularly promising aspect of this class of agents. “The traditional issues that we worry about are serious infection and malignancy, and we didn’t see any of that in the Phase II data,” says Leonardi. “It was really quite stunning.” Phase III data for ixekizumab (in a head-to-head trial versus etanercept) and brodalumab (in a head-to-head trial versus
ustekinumab, an approved mAb that inhibits IL‑12 and IL‑23 signalling) are expected next year, which will enable better comparison of the relative benefits and safety profiles of these agents.
Entering the autoimmune market In the first instance, Amgen, Lilly and Novartis hope to muscle into the lucrative psoriasis biologics market, which BioMedTracker analysts estimate is worth up to ~US$4 billion worldwide. Etanercept currently takes the largest slice, with ~30% of this market. In addition to psoriasis, etanercept is approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis, and had worldwide sales of ~$8 billion in 2012. Owing to the entrenchment of current biologics and the arrival of biosimilars, BioMedTracker predicts that uptake of secukinumab will be slow — despite the encouraging Phase III data — and that its initial use will probably be after TNF failure. Analysts at Datamonitor have forecasted sales of secukinumab in psoriasis of ~$10 million in 2014, increasing to ~$360 million in 2018 for the United States, Japan and the five major EU markets. But Novartis and Lilly see potential for their IL‑17 mAbs in other indications as well. Novartis has Phase III trials of secukinumab in psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis. “As soon as the TH17 story broke and it was shown that this cell was important for specific diseases, we went into
816 | NOVEMBER 2013 | VOLUME 12
all those diseases in parallel,” says Patel. For rheumatoid arthritis, Datamonitor predicts sales of ~$400 million for secukinumab in 2018 for the United States, Japan and the five major EU markets. Lilly, similarly, is developing its ixekizumab for psoriatic arthritis, ankylosing spondylitis and other autoimmune conditions. However, not everybody is convinced that IL‑17 inhibitors will be as successful in some of these indications as they are in psoriasis. “For either rheumatoid or psoriatic arthritis, the published data would suggest that they’re not going to be doing a great job,” says Leonardi. According to Pierre Miossec, a professor of clinical immunology at Claude Bernard University Lyon, France, and a pioneer in the IL-17 field, the underlying biology is more complex with arthritic indications and treatment is made more difficult by irreversible changes in mesenchymal cells and by the tissue destruction in bone and cartilage that comes along with disease. Indeed, Amgen stopped developing brodalumab in rheumatoid arthritis owing to lack of efficacy, although Miossec notes that the ligand-targeting agents may fare better than the receptor-targeting agents in arthritic settings. To overcome the effect of tissue destruction, he adds, two approaches could help. IL‑17 inhibitors might be more effective if they are deployed earlier on in the disease than have been tested. In addition, as IL‑17 and TNF have synergistic effects, another approach is to take out both TNF and IL‑17. AbbVie is testing such an approach with its Phase I candidate ABT‑122, a bispecific mAb that binds TNF and IL‑17A. Researchers are also working on other tractable targets in the IL‑17 pathway that they hope could potentially address the shortfalls of the first batch of IL‑17 inhibitors. NovImmune and Genentech are developing a mAb against IL‑17A and IL‑17F (NI‑1401/RG7624), which is currently in Phase I. Others are targeting retinoic acid-related orphan receptor γt (RORγt), which is a master regulator of TH17 cell development. Small-molecule RORγt inhibitors could block the development of TH17 cells, preventing the secretion of IL‑17 and modulating other pro-inflammatory cytokines. This transcription factor could also provide an opportunity to target IL‑17 signalling with oral rather than injectable therapies, and has formed the basis of several recent preclinical deals (Nature Med. 19, 1078; 2013). “It’s bubbling,” says Miossec regarding the pipeline of these inhibitors. “It’s too early to tell what the net effect will be, but it’s a highly active and competitive area.”
www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved
