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Martins, A.C.; Albericio, F.; De La Torre, B.G. Therapeutic Indications and Mechanisms of Action in Biologics. Encyclopedia. Available online: https://encyclopedia.pub/entry/44313 (accessed on 23 June 2024).
Martins AC, Albericio F, De La Torre BG. Therapeutic Indications and Mechanisms of Action in Biologics. Encyclopedia. Available at: https://encyclopedia.pub/entry/44313. Accessed June 23, 2024.
Martins, Alexander C., Fernando Albericio, Beatriz G. De La Torre. "Therapeutic Indications and Mechanisms of Action in Biologics" Encyclopedia, https://encyclopedia.pub/entry/44313 (accessed June 23, 2024).
Martins, A.C., Albericio, F., & De La Torre, B.G. (2023, May 15). Therapeutic Indications and Mechanisms of Action in Biologics. In Encyclopedia. https://encyclopedia.pub/entry/44313
Martins, Alexander C., et al. "Therapeutic Indications and Mechanisms of Action in Biologics." Encyclopedia. Web. 15 May, 2023.
Therapeutic Indications and Mechanisms of Action in Biologics
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The year 2022 witnessed the control of the COVID-19 pandemic in most countries through social and hygiene measures and also vaccination campaigns. It also saw a decrease in total approvals by the U.S. Food and Drug Administration (FDA). Nevertheless, there was no fall in the Biologics class, which was boosted through the authorization of 15 novel molecules, thus maintaining the figures achieved in previous years. Indeed, the decrease in approvals was only for the category of small molecules. Monoclonal antibodies (mAbs) continued to be the drug class with the most approvals, and cancer remained the most targeted disease, followed by autoimmune conditions, as in previous years. Interestingly, the FDA gave the green light to a remarkable number of bispecific Biologics (four), the highest number in recent years. Indeed, 2022 was another year without the approval of an antimicrobial Biologic, although important advancements were made in targeting new diseases, which are discussed herein. This work analyzes the Biologics authorized in 2022. Furthermore, the orphan drugs authorized was considered. A quantitative analysis was applied to this year’s harvest, the efficacy of the Biologics with those authorized in previous years was compared. On the basis of their chemical structure, the Biologics addressed fall into the following classes: monoclonal antibodies; antibody-drug conjugates; and proteins/enzymes.

FDA Biologics anacaulase eflapegrastim

1. Cancer

Of the 15 Biologics approved in 2022, six were indicated for the treatment of a diversity of cancers (Table 1). Comparatively, there were four Biologics approved indicated for cancer approved in 2019, eight in 2020, and six in 2021 [1]. From 2019, there has clearly been a growth aimed at cancer in the Biologics market.
Table 1. Biologics for cancer approved by the Food and Drug Administration in 2022.
The first-in-class Biologic, namely the bispecific fusion protein KimmtrakTM (tebentafusp), which is intravenously administered, is the first drug to date specifically for the treatment of metastatic uveal melanoma in HLA-A-positive patients, leading the immune system directly to the cancer cell [3]. One arm of tebentafusp (anti-CD3 effector) binds to T lymphocytes, later dragging the T cell to the cancer cell. This immune cell must bind to glycoprotein 100 (gp100), which may be inside the tumor cell, and therefore needs to be presented to the tumor cell surface through the human leukocyte antigen (HLA). The other arm of tebentafusp (T-cell receptor arm) then targets gp100, binding to the melanoma cell and activating the T cell, which then kills the melanoma cell. Other Biologics have previously been approved for the treatment unresectable or metastatic melanomas, namely YervoyTM (ipilimumab) in 2011, KeytrudaTM (pembrolizumab) and OpdivoTM (nivolumab) in 2014 [12], TecentriqTM (atezolizumab) in 2016 [1], and OpdualagTM (relatlimab and nivolumab) in 2022. However, tebentafusp is the first Biologic indicated for metastatic uveal melanoma. This type of cancer is very different from other melanomas as it shows distinct patterns, pessimistic prognosis, and a high likelihood of metastasis [13]. These characteristics thus make KimmtrakTM an important breakthrough. Overall Survival (OS) was the main measure found in the literature for KimmtrakTM, with a median OS of 21.7 months vs. 16 months for the control group [3][13]. For OpdualagTM, which is intravenously administered, the main measure found was Progression-Free Survival (PFS) vs. nivolumab alone, with a PFS of 10.1 months for OpdualagTM vs. 4.6 months for nivolumab [5].
As shown in Ref. [14], the combination of mAbs such as OpdualagTM (nivolumab and relatlimab), which was approved this year, offers the interesting advantage of simultaneously targeting multiple pathways. OpdualagTM provides a first-in-class mechanism of action by carrying two fully human mAbs, the first one targeting LAG-3 receptors and the second one PD-1 receptors, thereby increasing T-cell activation [5]. Bispecific mAbs can also target more than one pathway. However, three distinct mAbs can be combined, as is the case of PhesgoTM, in which all the mAbs target the glycoprotein (GP) of Zaire ebolavirus but in distinct ways. In this regard, between 2015 and 2022, only three combinations of mAbs have received approval, namely the aforementioned PhesgoTM (pertuzumab, trastuzumab, and hyaluronidase) for Ebola vírus, InmazebTM (atoltivimab, maftivimab, odesivimab) to treat early or metastatic breast cancer, both approved in 2020 [1], and OpdualagTM, which received authorization this year [5].
Of note, the last fusion protein approved by the FDA was in 2018, with tagraxofusp, indicated for the treatment of blastic plasmocytoid dendritic cell neoplasm [1]. While the two cancer drugs tagraxofusp and tebentafusp received Orphan Drug Status, tebentafusp is the first bispecific fusion protein to get the green light to date.
LunsumioTM (mosunetuzumab), a humanized bispecific mAb, has received accelerated approval from the FDA this year. Indicated to treat a type of non-Hodgkin’s lymphoma (relapsed or refractory follicular lymphoma (FL), it presented an Objective Response Rate (ORR) of 80% in clinical trials, with 60% of patients presenting a Complete Response (CR) [11]. Patients affected by follicular lymphoma (FL) have very few treatment options when it comes to Biologics. The other treatment option for this condition is rituximab, which was approved in 1997 and was the first mAb for cancer patients. Its therapeutic indications include FL. In comparison with the new bispecific mosunetuzumab, rituximab has an ORR of around 50% and a CR of 6% [15]
Importantly, from 2015 to 2022, the FDA authorized only four bispecific antibodies, namely emicizumab (2017), amivantamab (2021), faricimab (2022), and mosunetuzumab (2022) [11][16][17][18].
ImjudoTM (tremelimumab) was approved for cancer this year, intravenously administered, indicated for unresectable hepatocellular carcinoma (uHCC) [7]. It is a mAb whose mechanism works by blocking CTLA4, thus stopping the interaction of ligands with the cytotoxic T-lymphocyte-associated antigen 4. The previous cancer Biologic indicated for uHCC to get the green light was TecentriqTM (atezolizumab)(2016). This Biologic is also a mAb but, in contrast to tremelimumab, it acts by blocking PD-L1 [1]. For uHCC, both drugs are indicated to be used in combination with other mAbs, namely atezolizumab + bevacizumab, and tremelimumab + durvalumab.
In clinical trials, tremelimumab combined with durvalumab, a PD-L1 blocker, demonstrated higher OS (16.43 months vs. control group 13.72 months) and also a better ORR (20.1 vs. 5.1, respectively) [19].
In another advancement by Janssen Biotech Inc., TecvayliTM (teclistamab), indicated for relapsed or refractory multiple myeloma (MM), was approved in 2022. Importantly, from 2015 to 2021, the FDA authorized five other Biologics for this disease, namely: DarzalexTM (daratumumab) and EmplicitiTM (elotuzumab), both in 2015, and Darzalex FasproTM (daratumumab and hyaluronidase), SarclisaTM (isatuximab), and the ADC BlenrepTM (belantamab mafodotin), all three in 2020 [1]. Of note, all the Biologics for MM hold Orphan Drug Status.
Belantamab mafodotin (approved in 2020) binds to the B-cell maturation antigen (BCMA), and therefore, has a similar mechanism of action to that of the novel teclistamab. However, the latter is the first bispecific mAb to treat MM. It binds to BCMA and also to CD3 receptors [8]. In clinical trials, teclistamab showed a good ORR, with 40% of the patients presenting a CR [20][21][22].
Intravenously administered, ElahereTM (mirvetuximab soravtansine) was the antibody-drug conjugate (ADC) of 2022 to be approved (fast-track process) by the FDA [23]. This ADC is a FRα-directed (folate receptor alfa) chimeric mAb that targets epithelial ovarian cancer, which has high expression of FRα. When internalized, ElahereTM releases its small molecule (DM4), a microtubule inhibitor, after cleavage of its disulfide linker, unleashing apoptotic cell death. The anti-tubulin agent DM4 is an analog of maytansine, which was last found, before 2022, almost one decade ago in another ADC KadcylaTM (rastuzumab emtansine) [14]. DM4 is genotoxic, it confers risk to pregnant women, and it is a potent CYP3A4 substrate. Patients treated with DM4 must be closely monitored [9]. From 2015 to 2021, nine ADCs were approved by the FDA [1] and ElahereTM is the tenth of this class.
Regarding efficacy, in a single-arm trial, ElahereTM demonstrated an ORR of 31.7% and a DOR of 6.9 months, but further research is still ongoing [23][24].

Ongoing Clinical Trials for the New Biologics for Cancer

There are trials ongoing for tebentafusp (phase 1b/2) to test this Biologic in metastatic cutaneous melanoma, but in combination with other Biologics (durvalumab and/or tremelimumab), and also tebentafusp alone in advanced non-uveal melanoma, with no results posted yet [25]. Regarding trials for nivolumab and relatlimab to potentially treat diseases other than its primary target, there are trials ongoing to test it in metastatic or unresectable chordoma and [26], a phase 2 trial to test it in advanced microsatellite stable (MSS) colorectal cancer [27], a phase ½ trial to test its effectiveness in liver cancer [28], and interestingly, just like KimmtrakTM (tebentafusp) mentioned earlier in this paper, whose therapeutic indication is metastatic uveal melanoma (MUM), the first treatment to date specifically for MUM, there is a phase 2 trial ongoing to test nivolumab and relatlimab for MUM [29]. A combination of mAbs such as OpdualagTM carries great potential for repurposing and exploiting new targets/diseases; unfortunately, there are no results posted yet regarding the ongoing trials mentioned.
Tremelimumab is being tested for bladder cancer, with a completion study date in 2026 [30]. It is currently only approved for adult patients, but ongoing studies were found to test tremelimumab in combination with durvalumab in pediatric patients with solid tumors and hematological malignancies [31], and a phase 1 study with a completion date in 2024 for metastatic melanoma [32].
Mirvetuximab soravtansine is being tested as a first-line treatment for triple-negative breast cancer [33], and in combination with pembrolizumab as a new option for endometrial cancer in a phase 2 study, expected to be completed in 2025 [34].
There are trials with mosunetuzumab for four other conditions: reduction of the tumor with mosunetuzumab in combination with polatuzumab vedotin for refractory, relapsed, or aggressive non-Hodgkin lymphoma in a phase 2 study [35]; a phase 1 study to test mosunetuzumab to treat B-cell lymphoma after replacement of patient’s stem cells by autologous stem cell transplant [36]; and a phase 1 study assessing the efficacy of mosunetuzumab in relapsed or refractory chronic lymphocytic leukemia (CLL) [37]. All of these three studies have a completion date expected in 2027. There is still a phase 1 study testing mosunetuzumab for systemic lupus erythematosus, with a completion date expected in 2024 [38]. None of these studies have posted results yet. Regarding teclistamab, ongoing trials were not found for a disease other than multiple myeloma.

2. Autoimmune Conditions

The second type of disease most targeted by the approved Biologics in 2022 is autoimmune conditions (Table 2).
Table 2. Biologics approved for autoimmune conditions by the Food and Drug Administration in 2022.
SpevigoTM (spesolimab) has been approved this year to treat generalized pustular psoriasis (GPP), a rare and autoinflammatory condition that can strike both children and adults, affecting more Asians than other population groups [43]. To date, there is no standard treatment specifically for GPP, therapeutic strategies being limited to the use of synthetic drugs and Biologics previously authorized for moderate and severe plaque psoriasis, which have a poor outcome in GPP. As other Biologics indicated to treat plaque psoriasis or psoriatic arthritis have distinct interleukin receptors as targets (i.e., IL-17R), spesolimab brings a new mechanism of action by binding to IL-36R (interleukin-36 receptor), thereby inhibiting IL-36 from binding to IL-36R [4], since GPP seems to have a singular mechanism in its pathogenesis involving the IL-36R [43]. Although further research is needed on this subject, current studies support the efficacy of anti-IL-36R therapy in GPP [43][44][45].
BriumviTM (ublituximab) (2022) is intravenously administered and it is indicated to treat relapsing forms of multiple sclerosis. Its mechanism of action is like that of OcrevusTM (ocrelizumab), the previous mAb for multiple sclerosis approved by the FDA, in 2017. These two drugs bind to CD-20 on B-cells, both pre-B cells and mature B cells, thereby unleashing cell lysis [42][46]. Prior to ocrelizumab, the FDA had only approved Zinbryta™ (daclizumab) (2016) [1], which acts by binding to a subunit of IL-2 receptors, namely CD-25. Between 2015 and 2022, only these three mAbs received the green light for this condition.
In trials, ublituximab has been demonstrated to be superior to an orally administered medication (teriflunomide) in the two endpoints evaluated. In the primary endpoint in trial I, the Annualized Relapse Rate (ARR) reported was 0.08 for ublituximab vs. 0.19 for teriflunomide, and in the same endpoint in trial II, it was 0.09 for ublituximab vs. 0.18 for teriflunomide. In the secondary endpoint in trial I, the average number of gadolinium-enhancing lesions was measured at 0.02 for ublituximab vs. 0.49 for teriflunomide 0.49, and in trial II it was 0.01 for ublituximab vs. 0.25 for teriflunomide, demonstrating lower rates and fewer lesions in the magnetic resonance imaging [47].
TzieldTM (teplizumab) binds to its target CD3 and patients with Stage 2 type 1 diabetes (T1D) can benefit from a delay in the onset of Stage 3. This is a first-in-class and unique treatment that can deactivate certain immune cells involved in T1D. The efficacy of teplizumab in delaying the onset of Stage 3 T1D has been demonstrated in trials. Indeed, the primary measure was time from randomization to the diagnosis of Stage 3 T1D. It was observed that 19.8 (45%) of the patients (of a total of 44) receiving teplizumab had a later diagnosis of Stage 3 TID than the placebo group [40][41][48]. Teplizumab is intravenously administered and it is one of the few Biologics authorized in 2022 for both adult and pediatric patients.
Another important advancement in autoimmune diseases this year is the first-in-class EnjaymoTM (sutimlimab), which is intravenously administered. It is indicated to decrease the need for red blood cells (RBCs) transfusion in cold agglutinin disease (CAD); CAD is a rare condition characterized by the destruction of RBCs in cold temperatures. Sutimlimab also brings a new mechanism of action by binding to the complement protein component 1, inhibiting the complement pathway [39][49]. In a clinical trial, more than half the patients positively responded to sutimlimab by increasing hemoglobin and no RBC transfusion was required after five weeks of treatment, and they reported decreased fatigue [50][51].

Ongoing Clinical Trials for the New Biologics for Autoimmune Conditions

Boehringer Ingelheim is conducting studies to test spesolimab in other conditions. There are trials ongoing to test the efficacy of spesolimab for palmoplantar pustulosis (PPP) in a phase IIa study, with results supporting its efficacy vs. the placebo, but there are still trials ongoing to keep testing for PPP [52][53]. In 2024, a phase 2 study is expected to be completed to test the efficacy of Spesolimab in hidradenitis suppurativa (HS) [54], ulcerative colitis (UC) [55], an improvement of the narrowing of the small bowel in Crohn’s disease patients [56], and there are also studies ongoing to test it in atopic dermatitis (AD) and other conditions whose mechanism is similar to those that can cause HC, UC, or AD [57][58].
Ublituximab is being tested in combination with umbralisib for proggressive CLL in a phase 2 trial, and in a phase 1 and 2 study testing tazemetostat in combination with umbrasilib and ublituximab to treat relapsed or refractory follicular lymphoma [59][60]; no results have been posted yet for either study. Regarding teplizumab and sutimlimab, ongoing trials were not found for diseases other than the primary authorized ones described in the Prescribing Information.

3. Aesthetic

DaxxifyTM (daxibotulinumtoxin A) was the Biologic for aesthetic purposes approved by the FDA in 2022 (Table 3) and it is administered by intramuscular injection. It is found in the literature as an advancement, considering past decades of the hegemony of BotoxTM (onabotulinumtoxin A) to treat glabellar lines. Daxibotulinumtoxin A shows promising results and greater internalization of the neurotoxin, and clinical trials have demonstrated significant differences in response rate and also a longer period of effect for this Biologic. Patients in this trial also showed a better response to this Biologic than to the placebo [61][62][63]. The mean duration of the effects of daxibotulinumtoxin A in clinical trials is around 24 weeks, while for onabotulinumtoxin A it is around 19 weeks [62].
Table 3. Botulinum Toxin A approved by the Food and Drug Administration in 2022.
The IGA-FWS (Investigator Global Assessment-Facial Wrinkle Severity) and Global Aesthetic Improvement Scale (GAIS) were used to assess the results. Participants in the trial using 40 U of daxibotulinumtoxin A obtained between a 1 and 2 point improvement in glabellar lines, on both scales, over those using 20 U of onabotulinumtoxin A [62][65].
Before 2022, JeuveauTM (prabotulinumtoxin A) was the last Biologic authorized for aesthetic purposes (2019) [1]. Prabotulinumtoxin A and onabotulinumtoxin A presented similar outcomes in a 3-month study evaluating their effect on crow’s feet. The main measure of efficacy for prabotulinumtoxin A vs. onabotulinumtoxin A was mean onset of action (3.81 days for prabotulinumtoxin A vs. 3.47 days for onabotulinumtoxin A) and time to peak effect (9.58 days for prabotulinumtoxin A vs. 11.11 days for onabotulinumtoxin A). The secondary measure was the duration of action (11.11 weeks for prabotulinumtoxin A vs. 11.22 weeks onabotulinumtoxin A) [66]. The literature is still lacking data comparing the novel daxibotulinumtoxin A with prabotulinumtoxin A for the treatment of glabellar lines.

4. Eye Disorders

There have been two important drug advancements for eye disorders in less than three years. In this regard, back in 2019, the single-chain fragment variable (scFv) BeovuTM (brolucizumab), which inhibits three isoforms of VEGF-A, received the green light from the FDA to treat neovascular (Wet) age-related macular degeneration (nAMD) [67]. Two years later, in January 2022, VabysmoTM (faricimab) (Table 4) was also approved for eye disorders such as nAMD and diabetic macular edema (DME). In the context of eye disorders, there is also ranibizumab, which was first approved in 2006 for nAMD, DME, and macular edema following retinal vein occlusion (RVO), and EyleaTM (aflibercept), authorized in 2011 for nMAD. In clinical trials, the main measure of which was a change in Best-Corrected Visual Acuity (BCVA), brolucizumab outperformed aflibercept in minor endpoints and was non-inferior in primary endpoints, and it showed a higher remission of retinal thickness when compared to ranibizumab [68].
Table 4. Biologic for eye disorders approved by the Food and Drug Administration in 2022.
In contrast to brolucizumab, faricimab is a bispecifc humanized antibody [2][18]. The small size of the immunoglobulin fragments mechanism found in brolucizumab and its drug delivery features are important characteristics for Biologics, and these are also seen as important characteristics in bispecific mAbs, such as faricimab, whose mechanism is to inhibit two pathways, enhancing the fight against many diseases. Faricimab exerts anti-vascular endothelial growth factor-A (VEGF-A) and anti- angiopoietin-2 (Ang-2) activity [69]. In clinical trials, faricimab demonstrated similar outcomes in the same measure (BCVA) and anatomic improvement when compared to brolucizumab. However, further research is required [70].

Ongoing Clinical Trials for Faricimab

Regarding the potential of faricimab to treat other conditions, in this year (2023), a phase 2 trial has begun for faricimab to test non-proliferative diabetic retinopathy, but no results have been posted yet [71]. This year, two phase 3 trials are expected to be completed to test faricimab in macular edema due to hemiretinal vein occlusion, retinal vein occlusion, and central retinal vein occlusion [72][73]; no results have been posted yet for those studies as well.

5. Enzymes and Proteins

Three out of the fifteen Biologics to get the green light in 2022 fall into the class of proteins and enzymes, as found in Table 5
Table 5. Proteins and enzymes approved by the Food and Drug Administration in 2022.
XenpozymeTM (olipudase alfa) was the first enzyme to be approved by the FDA in 2022. It is a replacement therapy indicated to treat a rare disease named acid sphingomyelinase deficiency (ASMD) (also known as Nieamann-Pick Disease) [74][75]. The deficiency of acid sphingomyelinase (ASM) leads to the accumulation of sphingomyelin and other lipids, which can cause involvement of the central nervous system (CNS), hepatosplenomegaly, and/or lung impairment. There are two types of ASMD, type A and type B. The former causes hepatosplenomegaly and CNS impairment, while type B leads to hepatosplenomegaly, and liver and lung impairment, and it may not present CNS disruption [78][79]. In clinical trials, olipudase alfa demonstrated improved clinical symptoms, including enhanced platelet counts, a reduction in liver and spleen volume, and a greater lung diffusing capacity, and it also cleared sphingomyelin from tissues [80][81].
Given the difficulty in managing neutropenia in some cancer treatments, RolvedonTM (eflapegrastim), which has been approved this year, is an important innovation. In this regard, Biologics for chemotherapy-induced neutropenia (CIN) started in 1991 with filgrastim, followed by pegfilgrastim in 2002. However, since then, the industry has struggled to develop a new Biologic other than biosimilars for CIN. Eflapegrastim has the addition of an Fc Fragment of a human IgG4 [76], which extends its half-life and increases its absorption by the bone marrow. In clinical trials, eflapegrastim demonstrated non-inferior efficacy in reducing neutropenia compared to pegfilgrastim at a reduced dose of G-CSF (Granulocyte-Colony Stimulating Factor); 3.6 mg and 6.0 mg, respectively, administered in all four cycles. Furthermore, the safety profiles of these two drugs are similar [82][83][84].
In 2022, nexoBridTM (anacaulase) was the only Biologic of topical administration approved with a distinct therapeutic indication: eschar removal in adults with full- or partial-thickness thermal burns. However, it still has significant limitations for the treatment of electrical and chemical burns, or burns to the face and genitalia [77]. Schar removal is a procedure that helps to better manage the wound and wound closure, and when eschar removal occurs in the first hours it can reduce bacterial growth and days of hospitalization [85]. Of note, no Biologic for this indication has been approved by the FDA in recent years.

Ongoing Clinical Trials for Eflapegrastim

Spectrum Pharmaceuticals Inc. is testing eflapegrastim for other conditions: pediatric participants with solid tumors or lymphoma and treated with myelosuppressive chemotherapy [86], to compare the effect of eflapegrastim on the duration of neutropenia in patients with early-stage breast cancer [87], but there are still trials to be carried out. No studies were found for anacaulase and olipudase alfa for diseases other than the primary ones described in the Prescribing Information.

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