All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, OPEN SUPERSTAR Helping millions, 10 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 34 lakh plus VIEWS on this blog in 225 countries, 7 CONTINENTS The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent, ……………………A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, I have lot to acheive
DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email firstname.lastname@example.org, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
International non-proprietary name (INN) or common name
Therapeutic area (MeSH)
Anatomical therapeutic chemical (ATC) code
Bimzelx 160 mg solution for injection in pre-filled syringe Bimzelx 160 mg solution for injection in pre-filled pen
The active substance in Bimzelx, bimekizumab, is a monoclonal antibody, a protein designed to attach to interleukins IL-17A, IL-17F and IL-17AF, which are messenger molecules in the body’s immune system (the body’s natural defences). High levels of these interleukins have been shown to be involved in developing inflammatory diseases caused by the immune system, such as plaque psoriasis. By attaching to these interleukins, bimekizumab prevents them from interacting with their receptors (targets) on the surface of the epidermis (outer layer of the skin), which reduces inflammation and improves the symptoms related to plaque psoriasis.,,, https://www.ema.europa.eu/en/documents/overview/bimzelx-epar-medicine-overview_en.pdf
Antipsoriatic, Anti-IL-17A/IL-17F antibody, Monoclonal antibody Treatment of moderate to severe plaque psoriasis
The most common side effects include upper respiratory tract infections (nose and throat infection) and oral candidiasis (thrush, a fungal infection in the mouth or throat).
Bimekizumab was approved for medical use in the European Union in August 2021.
Drug:bimekizumab Company: UCB Used for: psoriasis Est. 2026 sales: $1.63 billion
Monoclonal antibody treatments for psoriasis are stacking up—but UCB hopes to muscle into the market with bimekizumab this year. The anti-IL-17A and IL-17F injection showed up both Johnson & Johnson’s Stelara and Novartis blockbuster Cosentyx in trials.
UCB’s Stelara head-to-head, the Be Vivid study presented in June at the American Academy of Dermatology and later published in The Lancet, found 85% of bimekizumab patients had a 90% or greater reduction in the area and severity of their psoriasis symptoms at 16 weeks. Complete skin clearance, indicated by a score of PASI 100, happened in 59% of patients.
Stelara, for its part, helped just half of patients reach PASI 90 and 21% achieve complete skin clearance over the same time period.
That Be Vivid readout raised expectations of a potentially favorable outcome in UCB’s head-to-head study with Novartis blockbuster Cosentyx (secukinumab), called Be Radiant.
In July, UCB announced that in that phase 3 study, its candidate had “demonstrate(d) superiority to secukinumab for complete skin clearance at both weeks 16 and 48.” The full study results will be presented “in due course,” UCB promised.
The data from the Cosentyx trial could be worth a lot to UCB, Evaluate wrote in June, adding that Jefferies analysts at the time expected annual sales of bimekizumab to top out around $1.5 billion. If bimekizumab beats Cosentyx, the sales forecast could rise to above $2 billion, it said at the time.
Without specific Cosentyx-topping data from the Be Radiant study in hand, Evaluate pegs consensus sales estimates at $1.63 billion in 2026.
One concern for UCB is whether the smaller pharma will be able to compete with the big marketing budgets in psoriasis. AbbVie’s Skyrizi and Humira, Novartis’ Cosentyx, Eli Lilly’s Taltz and Amgen’s Otezla are just a handful of the psoriasis drugs that have spent millions on mainstream TV ads to build brand names.
In September, the FDA and EMA accepted UCB’s biologics license application (BLA) for bimekizumab for adults with moderate to severe plaque psoriasis, the company reported. Ongoing phase 3 trials are evaluating the drug to treat a variety of other conditions, including psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa.
In the meantime, more competition is on the way. South San Francisco biotech DiCE Molecules, for its part, last month nabbed new funding to the tune of $80 million to roll its oral small molecule IL-17 program into a clinical trial in psoriasis and build out preclinical programs.
In addition to IL-17 rivals, others are also looking to get in on the action—particularly, several TYK2 inhibitors. Bristol Myers Squibb’s deucravacitinib recently bested Otezla in a study, while both Pfizer and Nimbus Therapeutics are in phase 2 studies with prospects of their own.
Psoriatic arthritis (PsA) is a complex and heterogeneous inflammatory disease that affects 20% to 30% of patients with psoriasis and is associated with substantial disability, impaired quality of life (QoL), and several comorbidities.1–3 It involves diverse clinical domains that extend beyond musculoskeletal manifestations (peripheral and axial arthritis, enthesitis and dactylitis): eg, nails, gut, and eyes, in addition to latent or manifest psoriasis.
Although there is still a huge gap in knowledge on the pathophysiology of PsA, what is known has fortunately turned into new treatment approaches that have improved symptoms and outcomes for PsA patients over the last two decades. Pro-inflammatory cytokines have been recognized as potential treatment targets in inflammatory diseases and have led to the creation of a number of anti-cytokine monoclonal antibodies that have revolutionized its treatment, such as TNFα and IL-12/23 inhibitors.4 More recently, the IL-17 pathway has been shown to play an important role in the pathophysiology of psoriatic disease and its blockage has shown to be clinically beneficial, as demonstrated with IL-17A inhibitors secukinumab and ixekizumab.4 Some patients, however, still do not respond, stop responding over time or suffer from side effects, leading to drug discontinuation, and other times combination strategies are required to control all PsA’s disease domains. Thus, there is still a great need for novel therapeutic options.5
Dual inhibitor antibodies target two different cytokines simultaneously potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have a similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F.
Bimekizumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.
This drug is being developed by Belgian pharmaceutical UCB. Phase III trials have demonstrated that bimekizumab is superior to not only adalimumab but also secukinumab for the treatment of plaque psoriasis.
The Role of Interleukin (IL)‑17A and IL‑17F in Psoriatic Arthritis
The IL-17 cytokine family comprises six different members (from A to F), of which IL-17A is the most studied. Known to be produced by a wide range of immune cells, IL-17A is involved in the pathophysiology of several inflammatory diseases including spondyloarthritis.6–8
Most non-hematopoietic cells possess IL-17 receptors, including fibroblasts, epithelial cells and synoviocytes,8 but despite this ubiquitous presence, IL-17 seems to have only moderate inflammatory capability per se, rather recruiting and amplifying other pathways, such as IL-6, IL-8, TNF and inflammatory-cell attracting chemokines.6,7,9,10
Still, evidence supporting the centrality of the IL-17 pathway in both PsO and PsA is available from a wide range of data.11 Th17 cells, IL-17 protein and related genes are elevated in both skin, blood and synovial fluid of PsO and PsA patients.11,12 In PsA, increased levels of IL-17+ CD4 and CD813,14, as well as IL-17A+Tγδ cells, have been found in the synovial fluid compared with peripheral blood. Specifically, the levels of IL-17+CD8+ cells in the synovial fluid distinguish PsA from rheumatoid arthritis (RA) and correlate with increased DAS28 scores, C-reactive protein levels, power-doppler findings of activity and prevalence of erosions.13 Inhibition of this pathway is capable of normalizing almost four times more disease-related genes than anti-TNFα treatments.11,15
Within the entire IL-17 family, IL-17F is the most structurally homologous (~50%) to IL-17A8 (Figure 1). They can both be secreted as homodimers (ie IL-17A/A or IL-17F/F) or as heterodimers of IL-17A/IL-17F,9 sharing signaling pathways through the same heterodimeric complex of IL-17 receptors A and C (IL-RA/RC) and biologic function.7–9
Figure 1 Summarized schematic of inhibition of the IL-17 cytokine family. *Not approved for psoriatic arthritis. Notes: Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, BioDrugs, Reis J, Vender R, Torres T. Bimekizumab: the first dual inhibitor of interleukin (IL)-17A and IL-17F for the treatment of psoriatic disease and ankylosing spondylitis, COPYRIGHT 2019.6Abbreviations: IL, interleukin; IL-17RA, IL-17 receptor A; IL-17RB, IL-17 receptor B; IL-17RC, IL-17 receptor C; IL-17RE, IL-17 receptor E.
The role of both IL-17A and F in psoriasis pathogenesis has been previously addressed.6,9,16
In enthesitis, a central pathologic process in PsA, Tγδ cells have recently been described that are capable of producing both IL-17A and IL-17F even independently of IL-23 stimulation.17 IL-17A and F had already been shown to promote osteogenic differentiation in in vitro models of human periosteum activated through the use of Th17 and Tγδ cells or through culture with serum from patients with ankylosing spondylitis,18 a mechanism potentially implied in the development of enthesitis. Importantly, both cytokines seem to be equipotent in this role, unlike in inflammatory processes where IL-17F seems to be less potent.18
Both IL-17A and IL-17F, when synergized with TNF, lead to increased production of pro-inflammatory cytokines, such as IL-8 and IL-6 in synoviocytes of PsA patients.9 IL-17A seems to be the most pro-inflammatory of the two cytokines.9,19 However, despite some inconsistencies in the literature regarding IL-17F detection levels which might be attributable to differences in methodology,19 IL-17F levels have been reported to be 30–50 times higher in some cytokine microenvironments, such as in psoriatic skin lesions of PsA patients20 or the synovium,21 which might dilute differences in relative potency. Additionally, IL-17F seems to be significantly increased in the synovium of PsA compared to osteoarthritis (OA) patients, unlike IL-17A.21 Dual neutralization of both IL-17A and IL-17F (using bimekizumab) resulted in greater downregulation of pro-inflammatory cytokine production than a single blockade in synovial fibroblasts.9,19 Critically, in in vitro models, anti-TNF blockade alone did not reduce the production of IL-8 as much as both IL-17A and F neutralization or even just anti-IL17A alone.9,19 In in vitro models of human periosteum dual blockade of IL-17A and F was also more effective in suppressing osteogenic differentiation than the blockade of either cytokine individually.18
Interestingly, in Tγδ cells, the predominant IL-17 production seems to be the F subtype.18 Also of note is the recent description that the IL-17receptorC (IL-17RC) competes with IL-17RA for IL-17F, IL-17A and IL-17A/F heterodimers,22 suggesting the possibility of IL-17RA-independent signaling pathways (and thus not targeted by brodalumab, an anti-IL17RA monoclonal antibody).
Bimekizumab is a humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. In in vitro models, bimekizumab appears to be as potent as ixekizumab at inhibiting IL-17A (also more potent than secukinumab)8 but, unlike those drugs, also possesses the unique ability to inhibit IL-17F as well, functioning as a dual inhibitor. Unlike brodalumab, an IL-17 receptor A blocker – which targets not only IL-17A and F signaling but also IL-17 C, D and E – bimekizumab spares IL-17E (also known as IL-25), for example, which is believed to have anti-inflammatory properties.6
Bimekizumab demonstrates dose-proportional linear pharmacokinetics, with a half-life ranging from 17 to 26 days, and its distribution is restricted to the extravascular compartment.23 Currently, bimekizumab is in advanced clinical development for psoriasis, but also for psoriatic arthritis, and ankylosing spondylitis (both currently in phase III).
Bimekizumab in PsA – Efficacy
The first bimekizumab clinical trial in PsA was a phase Ib randomized, double-blind, placebo-controlled clinical trial that included 53 patients (39 treated with bimekizumab, 14 with placebo) with active psoriatic arthritis who had failed conventional disease-modifying antirheumatic drugs (DMARDs) and/or one biologic DMARD. Patients in the active treatment arm were randomized to four different treatment regimens of varying loading doses (ranging from 80 to 560 mg) and maintenance doses (from 40 to 320 mg) at weeks 0, 3 and 6. Patients were followed for up to 20 weeks.9
Patients treated with bimekizumab had a faster response, compared to placebo. This was first detected at week two, with maximal or near-maximal responses maintained up to week 20, for both arthritis and skin psoriasis. ACR20, 50 and 70 responses were maximal at week 8 (80%), week 12 (57%) and week 16 (37%), respectively. For patients with skin involvement, PASI75 and PASI100 responses at week 8 were 100% and 87%, respectively (Table 1).
Table 1 Results from Published Trials Involving Bimekizumab in Psoriatic Arthritis
BE ACTIVE10 was a 48-week multicentric, international, phase 2b dose-ranging, randomized, double-blind placebo-controlled trial to assess the efficacy and safety of bimekizumab. Two hundred and six adult patients (out of 308 screened) with active (tender and swollen count >3) PsA (diagnosed according to CASPAR criteria) were enrolled in 5 treatment arms (placebo, 16 mg, 160 mg with single 320 mg loading dose, 160 mg, 320 mg bimekizumab dose, with SC injections every 4 weeks). Concurrent use of TNF inhibitors was not permitted but conventional DMARDs (if on a stable dose and kept throughout the study), corticosteroids (equal or less 10mg/day) and NSAIDs were allowed. Sixteen-milligram bimekizumab (a much lower dose than other treatment arms) was tested with a programmed re-randomization at week 12 to either 160 or 320 mg dosing (meaning no placebo arm after 12 weeks). All patients received treatment up to week 48.
The primary outcome was ACR50 response at 12 weeks, a much more stringent outcome than used for other IL-17 inhibitors. The prespecified analysis was not possible due to the absence of a statistically significant difference versus placebo for the 320 mg group at week 12. All other outcomes were thus considered exploratory, rendering this a failed primary endpoint with no active comparator group.
At 12 weeks, significant ACR50 responses were present for every bimekizumab group, although lower in both the 16 mg and 320 mg dose group (Table 1 reports average values for all bimekizumab treatment groups). The 160 mg dosing had the greatest ACR and PASI response rates. These were confirmed to be increasing response rates up to week 24 and stability thereafter up to week 48, where the results of both 160 and 320 mg were similar. There were also responses in PASI scores, enthesitis, HAQ-DI and SF-36 across all bimekizumab doses. There was no loss of efficacy by week 48.
At the recent American College of Rheumatology (ACR) congress, additional data on BE ACTIVE were reported. BASDAI scoring was improved on the 93 patients in the treatment arm (160–320 mg bimekizumab) who had a baseline score >4 (mean 6.2 ± 1.42). BASDAI50 response rates were 43% and 56% at week 12 and 48, respectively.24
Regarding patient-reported outcomes (PROs), the Health assessment questionnaire Disability Index (HAQ-DI) and the psoriatic arthritis impact of disease-9 (PsAID-9) questionnaire developed specifically to assess health-related quality of life (QoL) in PsA were used on 206 patients from the BE ACTIVE trial. Rapid improvement was registered by week 12 and this response was sustained up to 48 weeks. Better QoL was associated with the better clinical outcomes reported in that study.25,26
Open-Label Extension Study (OLE)
Results from the 108 weeks of follow-up in the open-label extension study of BE ACTIVE (BE ACTIVE2, NCT03347110) have been recently presented.27,28 All patients who completed all 48 weeks of the BE ACTIVE trial were enrolled and switched to the 160 mg dosing regardless of previous treatment dose regimen. Over 108 weeks (an additional 60 weeks of OLE study over the 48 of the original BE ACTIVE trial) there was a 66.7% and 75.4% ACR 50 and body surface area (BSA) 0% response, respectively. Dactylitis and enthesitis were also significantly improved completely resolving in 65.9% and 77.9% of patients, respectively.27 Regarding week 12 responders, ACR20/50/70 and BSA 0% responses were maintained until week 108 in 80/78/81% and 72%, respectively.27 MDA/VLDA responses and DAPSA remission were maintained by 81/72/76% of Week 12 responders, respectively, to Week 120 (MDA/VLDA), and Week 108 (DAPSA remission).
Bimekizumab in PsA – Safety
Over 90% of reported adverse events, in both arms, were mild or moderate. In the treatment arm, two fungal infections (oropharyngeal and vulvovaginal candidiasis) were reported, both treated with oral medication. There was no increased incidence of other infections. There were no deaths or severe adverse events resulting from treatment, and no patient discontinued bimekizumab.9
No difference was found in the frequency of adverse events between placebo and treatment arms by week 12 in the BE ACTIVE trial. After reallocation (after week 12) and up to the 48 weeks of the trial 151 (74%) of the total 204 patients who ever received bimekizumab reported some AE (exposure adjusted incidence rate 166.8/100 patient-years). Most AE were mild or moderate (the most frequently reported were nasopharyngitis and upper respiratory tract infections) and there was no direct association with bimekizumab dose.
Nine patients (8 of which received bimekizumab) had serious adverse effects. These included one patient with drug-induced liver injury. Another patient also had severe liver enzyme elevation. Both had been given the 320 mg dosing. From the hepatic point of view, the other 11 patients were noted to have increased liver enzymes (>3x ULN). There was no relation with bimekizumab dose, and most were on DMARDs and one was on TB prophylaxis. At least two serious adverse events were related to infections across the entire study period (28 weeks) – 1 hepatitis E infection, 1 cellulitis (both with the 160 mg dosing). Non-severe Candida infection was reported in 7% of the patients, none led to treatment discontinuation. Other serious AEs reported were melanoma in situ (160 mg), suicidal ideation (160 mg loading dose), and neutropenia (320 mg dosing) (only in one patient each).10 In summary, this safety profile overlaps with those of other anti-IL17 therapies.29
In the OLE study, at week 108, serious adverse events occurred in 9.3% of patients (no deaths or major adverse cardiac events) and a total of 8.8% of patients withdrew from the study due to side effects. Full publication is still pending but the authors share that the safety profile observed in the OLE study reflected previous observations.27
Dual inhibitor antibodies represent a novel therapeutic strategy, and a logical extension of the success monoclonal antibodies has had over the last couple of decades.
Here we review the most recent information on IL-17A and F inhibition in psoriatic arthritis through the first-of-its-class bimekizumab, a dual inhibitor of both cytokines.
The importance of the IL-17 pathway in psoriatic arthritis, already suggested by preclinical data, was reinforced by the excellent results obtained by secukinumab30 or ixekizumab31 in the control of the disease in the last few years.
Indeed, IL-17 seems to be involved in all of the clinical domains of psoriatic arthritis. In preclinical trials, it has been shown that both IL-17A and F are capable of inducing pro-inflammatory cytokines, like IL-8 or IL-6, in synoviocytes, periosteum and the skin,23 and that this activation was greatly suppressed by blocking both these cytokines simultaneously. Research is expanding on the differential role of IL-17F in different environments,18,21 compared with the more studied IL-17A, as well as possible alternative signaling pathways.22 Taken together these findings could potentially explain different clinical phenotypes in PsA and treatment responses to anti-IL17A (secukinumab, ixekizumab) and IL-17RA (brodalumab) inhibitors furthering support for the use of dual cytokine blockade such as with bimekizumab (Figure 1).
Phase II trials, specifically BE ACTIVE results, have been encouraging. Bimekizumab has shown to be relatively fast-acting, with initial improvements detected by week 8 and well established by week 12. Additionally, at a dose of 160 mg every 4 weeks, bimekizumab has shown to be capable of retaining this level of response in a high percentage of patients for at least 2 years. These results are independent of prior exposure to anti-TNF therapy.10
As with all new drugs, there are still pending questions regarding its optimal use. In BE ACTIVE,10 in which patients received four different dosages through the first 12 weeks, the 160 mg seemed most effective. The initial lower response in the 320 mg group might have been produced by a higher proportion of refractory patients in which bimekizumab took longer to work. This impression is reinforced, in the author’s opinion, by the fact that response rates were different as early as week 4 in both 160 mg (loading dose) and 320 mg dose groups although by that time period both groups had received the same dose. Co-medication was balanced between both groups.
Whichever dose proves best, these results were achieved with mostly mild side-effects that did not lead to treatment discontinuation – most commonly nasopharyngitis, upper respiratory infections and candidiasis. Overall the available data have not revealed any unexpected adverse events. Nonetheless, the number of patients included in the trials is still small. Thirteen out of the 204 patients (6,4%) receiving any dose of bimekizumab in the BE ACTIVE trial had some hepatic adverse effect, raising the need for attentive monitoring by treating physicians. Co-medication needs to be well pondered in this setting as well, but if real-world outcomes of bimekizumab prove as beneficial as in the trials there might be a reduced need for concomitant use of other DMARDs. Although IL-17F has been shown to be associated with increased susceptibility in many forms of human cancer, it has shown a protective role in colon tumorigenesis in mice,32,33 mainly by regulating tumor angiogenesis.6 Longer and bigger trials will be needed to fully ascertain the safety of bimekizumab.
Overall the available results for this new therapeutic option in psoriatic arthritis are encouraging, although it is still early to completely understand the added value offered by bimekizumab. As of yet, however, there are no head-to-head trials directly comparing it to other treatment options in PsA. Anti-IL17A monoclonal antibodies have been evaluated against other therapies, such as anti-TNF inhibitors in the treatment of PsA with mixed results (using different endpoints).34,35
Right now we can only look to early reports from the more advanced Phase 3 trials in psoriasis, where bimekizumab was first studied, which already encompass hundreds of patients and compare bimekizumab with other biologics. A head-to-head comparison with ustekinumab was recently published36 involving 567 patients (321 randomized to bimekizumab, 163 to ustekinumab and 83 to a placebo arm that was switched to bimekizumab at week 16). Using a 320 mg dose of bimekizumab every 4 weeks (and not the 160 mg shown in BE ACTIVE to be the most efficacious in PsA) bimekizumab was superior to ustekinumab (85% vs 49.7% PASI 90 responses at week 16, p<0.001). This response was also sustained throughout the 52-week duration of the study (81.6% vs 55.8%, p<0.001). Similar responses (86.2% vs 47.2% PASI 90 at week 16, p<0.001) in the BE SURE trial comparing bimekizumab (320 mg every 4 weeks or 320 mg until week 16 and then every 8 weeks) and adalimumab (80 mg week 0, 40 mg week 1 and every 2 weeks) were recently presented.37 Switching adalimumab patients to bimekizumab resulted in increased response rates, comparable to rates in bimekizumab-randomized patients at week 56. UCB, the company developing bimekizumab, have also reported the superiority of bimekizumab against secukinumab.38
If nothing else, bimekizumab is a proof-of-concept for a novel avenue in treating inflammatory diseases. Up until now the clinical practice in inflammatory diseases has been to steer clear of the combination of monoclonal antibodies. The results of the trials reported here using bimekizumab to simultaneously inhibit two cytokines, even if related ones, are an important reminder of the redundant and overlapping nature of the immune system and of the multiple pathways through which one arrives at inflammatory disease.
As of yet, however, there are no head-to-head trials directly comparing bimekizumab to conventional DMARDS or other bDMARDs in PsA although the results reported here seem encouraging. Upcoming trials (see Table 2) will hopefully fill this gap in knowledge.
Table 2 Ongoing Trials of Bimekizumab in Psoriatic Arthritis
Psoriatic arthritis can be a severe and disabling disease. Although improvements in its treatment have been achieved in the past decade, its pathogenesis is not completely known, and its treatment is still difficult particularly throughout all disease domains.
The IL-17 pathway has been implicated in disease pathogenesis and targeting IL-17A with secukinumab and ixekizumab has shown good results, although there is still a large proportion of patients that respond only partially. The simultaneous blockade of both IL-17A and IL-17F seems to have a synergistic benefit, with IL-17F inhibition contributing with a differentiated role in both osteogenesis and skin inflammation, important domains of PsA.
Bimekizumab uses a novel approach to biologic treatment in psoriatic arthritis through dual cytokine blockade. Mounting evidence from early trials has shown a good safety and efficacy profile, with rapid onset and sustained response, with results now extending to 108 weeks of follow-up. Moreover, clinical trials in skin psoriasis have also shown that bimekizumab is highly effective, confirming the importance of inhibiting these two cytokines in psoriatic disease.
In the near future, phase III trials will help to better understand the potential of bimekizumab in the treatment of psoriatic arthritis.
Phase IColorectal cancer; Malignant melanoma; Pancreatic cancer
No development reportedMultiple sclerosis
22 May 2021Pepinemab is still in phase I trials for Colorectal cancer and Pancreatic cancer in USA (NCT03373188)
17 May 2021Phase-I/II clinical trials in Squamous cell cancer (Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater) in USA (IV) (NCT04815720)
17 May 2021Vaccinex plans a phase I/II trial for Alzheimer’s disease (In volunteers), in H2 2021
Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to the pathophysiology of neuroinflammatory/neurodegenerative diseases. SEMA4D is, therefore, a uniquely promising target for therapeutic development.
Pepinemab is a novel monoclonal antibody that blocks the activity of SEMA4D, and preclinical testing has demonstrated the beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.
Note: Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. It has not been demonstrated to be safe and effective for any disease indication. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.
Mechanism of ActionInterferon alpha beta receptor antagonists
RegisteredSystemic lupus erythematosus
Phase IILupus nephritis
DiscontinuedRheumatoid arthritis; Scleroderma
02 Jul 2021Phase-III clinical trials in Systemic lupus erythematosus in USA (SC) (NCT04877691)
25 Jun 2021AstraZeneca plans a phase III trial in Systemic lupus erythematosus (Adjunctive treatment) in the China, Hong Kong, South Korea, Philipines, Taiwan and Thailand (IV, Infusion), in July 2021 (NCT04931563)
02 Jun 2021Pharmacokinetic, efficacy and adverse events data from a phase II TULIP-LN1 trial in Lupus nephritis presented at the 22nd Annual Congress of the European League Against Rheumatism (EULAR-2021)
Anifrolumab was approved for medical use in the United States in August 2021.
Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus.
Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.7,11 The standard therapy for systemic lupus erythematosus consists of antimalarials like hydroxychloroquine, glucocorticoids like dexamethasone, and disease modifying antirheumatic drugs like methotrexate.8,11
Three monoclonal antibodies (anifrolumab, rontalizumab, and sifalimumab) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved.3
The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism.3 The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial.3
Anifrolumab has also been investigated for the treatment of Scleroderma.1
Anifrolumab was granted FDA approval on 30 July 2021.11
The most common adverse effect was shingles, which occurred in 5% of patients in the low-dose group, to 10% in the high-dose group, and to 2% in the placebo group. Overall adverse effect rates were comparable in all groups.
The drug was developed by MedImmune, a unit of AstraZeneca, which chose to move anifrolumab instead of sifalimumab into phase III trials for lupus in 2015.
Clinical trial results
Anifrolumab failed to meet its endpoint of significant reduction in disease as assessed by the SLE Responder Index 4 instrument in the TULIP 1 phase III trial. This multi-center, double-blind, placebo-controlled study followed adults with moderate to severe SLE over the course of one year. Preliminary results were announced on 31 August 2018.
Anifrolumab is the international nonproprietary name (INN).
Goldberg A, Geppert T, Schiopu E, Frech T, Hsu V, Simms RW, Peng SL, Yao Y, Elgeioushi N, Chang L, Wang B, Yoo S: Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014 Feb 24;16(1):R57. doi: 10.1186/ar4492. [Article]
Peng L, Oganesyan V, Wu H, Dall’Acqua WF, Damschroder MM: Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-alpha receptor 1 antibody. MAbs. 2015;7(2):428-39. doi: 10.1080/19420862.2015.1007810. [Article]
Massarotti EM, Allore HG, Costenbader K: Editorial: Interferon-Targeted Therapy for Systemic Lupus Erythematosus: Are the Trials on Target? Arthritis Rheumatol. 2017 Feb;69(2):245-248. doi: 10.1002/art.39985. [Article]
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S: Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. [Article]
Tummala R, Rouse T, Berglind A, Santiago L: Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus Sci Med. 2018 Mar 23;5(1):e000252. doi: 10.1136/lupus-2017-000252. eCollection 2018. [Article]
Riggs JM, Hanna RN, Rajan B, Zerrouki K, Karnell JL, Sagar D, Vainshtein I, Farmer E, Rosenthal K, Morehouse C, de Los Reyes M, Schifferli K, Liang M, Sanjuan MA, Sims GP, Kolbeck R: Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus. Lupus Sci Med. 2018 Apr 5;5(1):e000261. doi: 10.1136/lupus-2018-000261. eCollection 2018. [Article]
Trindade VC, Carneiro-Sampaio M, Bonfa E, Silva CA: An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. Paediatr Drugs. 2021 Jul;23(4):331-347. doi: 10.1007/s40272-021-00457-z. Epub 2021 Jul 10. [Article]
Koh JWH, Ng CH, Tay SH: Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials. Lupus. 2020 Dec;29(14):1845-1853. doi: 10.1177/0961203320959702. Epub 2020 Sep 22. [Article]
FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]
//////////Anifrolumab, Saphnelo, FDA 2021, APPROVALS 2021, peptide, Monoclonal antibody, アニフロルマブ (遺伝子組換え) , MEDI 546, AstraZeneca, Medarex, MedImmune
Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13, and is designed for the treatment of asthma and other inflammatory diseases. Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354 and taken through pre-clinical and early clinical development. After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis. This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.
Discovery and development
Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists using protein optimization based on Ribosome Display. They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims. In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005. On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.
In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued. In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.
A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.
On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.
Society and culture
On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.
The applicant for this medicinal product is LEO Pharma A/S.
Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions – including involvement in the regulation of lipid metabolism – which have made them desirable therapeutic targets in recent years.2 Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.3
In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name “Evkeeza”.8 Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.
Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.
Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 slows the function of certain enzymes that break down fats in the body. Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol. Evinacumab was approved for medical use in the United States in February 2021.
Injection, solution, concentrate
Regeneron Pharmaceuticals, Inc.
Injection, solution, concentrate
Regeneron Pharmaceuticals, Inc.
The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH). In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo. Participants were taking other lipid-lowering therapies as well.
The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24. At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.
The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.
Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.
During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.
In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.
The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.
Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.
FDA granted the approval to Ridgeback Biotherapeutics, LP.
Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.
The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.
Ansuvimab was approved for medical use in the United States in December 2020.
Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity. Other functional killing tests have not been performed.
Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.
In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.
In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived. Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.
Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.
On December 21, 2020, the US Food and Drug Administration approved Ebanga (ansuvimab-zykl) for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga had been granted US Orphan Drug designation and Breakthrough Therapy designations. Ansuvimab is a human IgG1 monoclonal antibody that binds and neutralizes the virus.
The safety and efficacy of Ebanga were evaluated in the multi-center, open-label, randomized controlled PALM trial. In this study, 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.
Ebanga is the 12th antibody therapeutic to be granted a first approval in the US or EU during 2020.
Immunoglobulin G1, anti-(calcitonin gene-related peptide) (human-oryctolagus cuniculus monoclonal ALD403 heavy chain), disulfide with human-oryctolagus cuniculus monoclonal ALD403 kappa-chain, dimer
Approved 2020 fda
Humanized anti-calcitonin gene-related peptide (CGRP) IgG1 antibody for the treatment of migraine.
Eptinezumab, sold under the brand name Vyepti, is a medication for the preventive treatment of migraine in adults. It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta. It is administered by intravenous infusion every three months.
Eeptinezumab-jjmr was approved for use in the United States in February 2020.
^Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. (November 2014). “Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial”. The Lancet. Neurology. 13 (11): 1100–1107. doi:10.1016/S1474-4422(14)70209-1. PMID25297013.
Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively. In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.
Alder announced one-year results from the PROMISE 1 studyin June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients. In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018. These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.
Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).
FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020
Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.
“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”
Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.
Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.
The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).
The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.
Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, non-small cell lung cancer and sarcoma. Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.
In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis. In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED. On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.
Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.
Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo. Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers.3 It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link.3 It is similar to brentuximab vedotin, another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4.
The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics2 and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.3
The most common side effects for patients taking enfortumab vedotin were fatigue, peripheral neuropathy (nerve damage resulting in tingling or numbness), decreased appetite, rash, alopecia (hair loss), nausea, altered taste, diarrhea, dry eye, pruritis (itching) and dry skin. Enfortumab vedotin (AGS-22M6E) is an antibody-drug conjugate designed for the treatment of cancer expressing Nectin-4.Enfortumab refers to the monoclonal antibody part, and vedotin refers to the payload drug (MMAE) and the linker.
The fully humanized antibody was created by scientists at Agensys (part of Astellas) using Xenomice from Amgen; the linker technology holding the antibody and the toxin together was provided by and licensed from Seattle Genetics.
Results of a phase I clinical trial were reported in 2016.
In December 2019, enfortumab vedotin-ejfv was approved in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.
Enfortumab vedotin was approved based on the results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response. The median duration of response was 7.6 months.
Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.3
Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.3 Patients with moderate to severe hepatic impairment should not use enfortumab vedotin – though it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.3 Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.3
Mechanism of action
Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.3 It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein which is highly expressed in urothelial cancers,1 attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.3
Cancer Research (2016), 76(10), 3003-3013.
Hanna KS: Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma. Drugs. 2019 Dec 10. pii: 10.1007/s40265-019-01241-7. doi: 10.1007/s40265-019-01241-7. [PubMed:31823332]
McGregor BA, Sonpavde G: Enfortumab Vedotin, a fully human monoclonal antibody against Nectin 4 conjugated to monomethyl auristatin E for metastatic urothelial Carcinoma. Expert Opin Investig Drugs. 2019 Oct;28(10):821-826. doi: 10.1080/13543784.2019.1667332. Epub 2019 Sep 17. [PubMed:31526130]
FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]
(enfortumab vedotin-ejfv) for Injection, for Intravenous Use
Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.
Figure 1: Structural Formula
Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis.
PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL [see DOSAGE AND ADMINISTRATION]. After reconstitution, each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0.
///////////////Enfortumab vedotin, AGS-22M6E, エンホルツマブベドチン (遺伝子組換え) , protein Based Therapies, Monoclonal antibody, mAb, FDA 2019
Romosozumab was originally discovered by Chiroscience, which was acquired by Celltech (now owned by UCB). Celltech entered in a partnership with Amgen in 2002 for the product’s development.
In 2016 results from 12 months of a clinical study were reported.
Some results from the FRAME and ARCH clinical studies were reported on in 2017.
Japan’s Ministry of Health, Labor and Welfare has granted a marketing authorization for romosozumab (EVENITY)for the treatment of osteoporosis in patients at high risk of fracture. Developed by Amgen and UCB, romosozumab is a humanized IgG2 monoclonal antibody that targets sclerostin. The approval in Japan is based on results from the Phase 3 FRAME and BRIDGE studies, which included 7,180 postmenopausal women with osteoporosis and 245 men with osteoporosis, respectively.
A biologics license application (BLA) for romosozumab as a treatment of osteoporosis in postmenopausal women at high risk for fracture was submitted to the U.S. Food and Drug Administration (FDA) in July 2016, but additional safety and efficacy data was requested in the FDA’s complete response letter, as announced by Amgen and UCB in July 2017. In July 2018, Amgen and UCB announced that the BLA had been resubmitted. In addition to data from early-stage clinical studies, the original BLA included data from the Phase 3 FRAME study. The resubmitted BLA includes results from the more recent Phase 3 ARCH study, an alendronate-active comparator trial including 4,093 postmenopausal women with osteoporosis who experienced a fracture, and the Phase 3 BRIDGE study. The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee is scheduled to review data supporting the BLA for romosozumab at a meeting on January 16, 2019.
The European Medicines Agency is also currently reviewing a marketing application for romosozumab.
Commercial production of cell culture-derived products (for example, protein-based products, such as monoclonal antibodies (mAbs)), requires optimization of cell culture parameters in order for the cells to produce enough product to meet clinical and commercial demands. However, when cell culture parameters are optimized for improving productivity of a protein product, it is also necessary to maintain desired quality specifications of the product such as glycosylation profile, aggregate levels, charge heterogeneity, and amino acid sequence integrity (Li, et al., 2010 , mAbs., 2(5):466-477).
For instance, an increase of over 20% volumetric titer results in a significant improvement in large-scale monoclonal antibody production economics. Additionally, the ability to control the glycan forms of proteins produced in cell culture is important. Glycan species have been shown to significantly influence pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic proteins such as mAbs. Moreover, the ability to modulate the relative percentage of various glycan species can have drastic results over the behavior of a protein in vivo. For example, increased mannose-5-N-acetylglycosamine-2 (“Man5”) and other high-mannose glycan species have been shown to decrease mAb in vivo half-life (Liu, 2015 , J Pharm Sci., 104(6):1866-84; Goetze et al., 2011 , Glycobiology, 21(7):949-59; and Kanda et al. 2007 , Glycobiology, 17(1):104-18). On the other hand, glycosylated mAbs with mannose-3-N-acetylglycosamine-4 (“G0”) glycan species have been shown to impact antibody dependent cellular cytotoxicity (ADCC).
Bioreactors have been successfully utilized for the cell-based production of therapeutic proteins using fed-batch, immobilized, perfusion and continuous modes. Strategies, such as the use of temperature, media formulation, including the addition of growth inhibitors, autocrine factors or cyclic mononucleotides, and hyperstimulation by osmolarity stress, have been used to enhance protein production by cells in culture. To the extent that they have worked at all, these approaches have shown only marginal success.
As such, there is a particular need for improved compositions for use in cell culture for the production of medically or industrially useful products, such as antibodies. Ideally, such compositions and methods for utilizing the same would result in higher titers, modulated (e.g. decreased) high and low molecular weight species, as well as a more favorable glycosylation profile of the derived products in cell culture.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.