Clinical Trials & Recent

advances in therapeutics
for management of
Autoimmune diseases

Dr.S.Viswanath
Postgraduate Pharmacology
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 • Currently available drugs in treating
Autoimmune diseases
Overview of • Landmark trials in Autoimmune
diseases
Presentation • Newer drugs and targets in treating
autoimmune diseases
• Summary

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The Timeline and Shift in Therapeutics of
Immunology

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First use of Cortisone
for Rheumatoid
arthritis- 1948

Rapamycin discovery from Muromonab-CD3 in 1986

Eastern Islands soil-1990s
 Biologics – TNF α inhibitors
Drugs Indications

Etanercept RA, JIA, PsA, Ps, AS, as

Infliximab (+) UC

Adalimumab (+)Hidradenitis suppurativa

Golimumab (+) UC

Certolizumab (+) CD
 TEMPO TRIAL( 2006)-
ETANERCEPT
Population: Patients with active Rheumatoid arthritis who had moderate to
severe disease activity.
Primary endpoint :Achieving a reduction in disease activity as measured
byACR20.ACR70, along with radiographic assessment of joint damage
progression.
Intervention: 25mg Etanercept s.c twice weekly /Oral Mtx (20mg/week)
/Combination of both.
Results: Combination therapy of methotrexate and Etanercept achieved
greater effectiveness ACR20(86%) ,ACR70(49%) with no radiographic
progression.
This underscored the potential additive clinical and radiographic
protection offered by the combination of Mtx & TNF inhibitors.
 TEAR TRIAL(2012)
Treatment of Early Aggressive Rheumatoid
Arthritis
Population: Patients with early rheumatoid arthritis who had moderate to
severe disease activity.
Intervention: Initial Combination therapy (Methotrexate, Etanercept, and/or
Prednisone) or Step-up therapy (starting with methotrexate alone and adding
other drugs as needed).
Primary endpoint :Achieving a reduction in disease activity as measured by
DAS28 score, along with radiographic assessment of joint damage
progression.
Results: Combination therapy of methotrexate and etanercept achieved
greater and faster DAS28 reductions and also showed less joint damage
progression.
 ASPIRE TRIAL(2006)-
INFLIXIMAB
Population: Patients with early Rheumatoid arthritis who received Mtx.
Intervention: Infliximab 3mg/kg /placebo along with Mtx.
Primary endpoint :Achieving remission as measured by DAS28, ACR20&70
along with radiographic assessment of joint damage progression.
Results: Combination therapy of methotrexate and Infliximab achieved
greater remission:
ACR20-(66% vs 54%)
ACR70-(37% vs 21%)
DAS 28- 33% vs 15%)
No radiographic progression-(59% vs 45%)
 Biologics targeting Interleukins
Target Drugs Indications
IL-1R Anakinra RA
Canakinumab CAPS-Cryopyrin associated
IL-1 beta
Autoinflammatory syndromes,
Gout
IL-1 alpha, Beta
(DECOY) Rilonacept Recurrent Pericarditis
IL-2R Daclizumab Multiple Sclerosis
IL-6R Tocilizumab RA, JIA
Sarilumab RA
IL-6 Siltuximab Multicentric Castleman’s Disease
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 MOBILITY TRIAL (2015)-
Sarilumab

Population: Patients with active RA with inadequate response to Mtx.

Intervention: 1:1:1- Sarilumab 150mg/Sarilumab 200mg /Placebo every
2 weeks along with Mtx.
Primary endpoint :Proportion of patients achieving ACR20

Results: Combination therapy of methotrexate and Sarilumab achieved

greater remission:
ACR20 at week 24-(58%vs 66% vs 33%)
 Biologics targeting Interleukins
Target Drugs Indications
IL-17 Secukinumab Ps, PsA, AS
IL-17R Brodalumab Psoriasis
IL-17A Ixekizumab Psoriasis
IL-23 Goselkumab Psoriasis

Tildrakizumab Psoriasis

Risankizumab Psoriasis
IL-12 & 23 Ustekinumab CD, Ps & PsA

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 PHOENIX TRIAL (2008)-
USTEKINUMAB
Population: Patients with Plaque Psoriasis.
Primary endpoint :Proportion of patients achieving PASI 75 at
week12
Intervention: Ustekinumab 45mg S.C/Ustekinumab 90mg S.C /Placebo
every 4weeks
Results: Response rates were higher in Ustekinumab group than placebo
PASI75 at week 12-(66%vs 75% vs 4%)
 MEASURE TRIAL-
SECUKINUMAB(2020)
Population: : Patients with Ankylosing spondylitis.
Intervention: 1:1:1- Secukinumab 150mg/Secukinumab 75mg/Placebo
every 2 weeks along with Mtx.
Primary endpoint :Proportion of patients achieving ASAS20 at week
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Results: Response rates were higher in Secukinumab group than
placebo : ASA20 at week 24-(61%vs 60% vs 28%)
 Biologics targeting B cells
Target Function Drugs Indications
CD-20 Present on B cells Rituximab RA, SLE, ITP, sclerosis, GVHD

Ocrelizumab Multiple Sclerosis

BlyS Development, survival Belimumab SLE
& stimulation of B cells

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 REFLEX TRIAL (2006)
Randomized Evaluation of Long-term Efficacy of
Rituximab in Rheumatoid Arthritis
Participants: Patients with active, long-standing RA who had not responded
adequately to TNF inhibitors.
Intervention: Receive either Rituximab in combination with Methotrexate or a
placebo alongside methotrexate. The Rituximab group received two infusions of
1,000 mg each, spaced two weeks apart.
Comparison & Outcome: American College of Rheumatology (ACR) 20
response rate at 24 weeks, indicating a 20% improvement in RA symptoms.
Results: 51% of patients receiving Rituximab achieved ACR20 (vs. 18% for
placebo), 27% achieved ACR50 (vs. 5% for placebo), and 12% achieved ACR70
(vs. 1% for placebo).
BLISS-LN TRIAL(2020): This landmark trial is pivotal as it
led to the first FDA-approved treatment specifically for Lupus nephritis

Population:
Adult patients aged 18 to 75 years who had active lupus nephritis with baseline
estimated Glomerular Filtration Rate (eGFR) of at least 30 mL/min/1.73 m²
Intervention: 448 participants were assigned to receive either intravenous
Belimumab (10 mg/kg) plus standard therapy (mycophenolate mofetil or
cyclophosphamide, with steroids) or a Placebo plus standard therapy over a 104-
week period​.
Primary endpoint :Primary Efficacy Renal Response (PERR), defined as achieving
an eGFR of ≥ 60 mL/min/1.73 m².
RESULTS: It met its primary endpoint, with 43% of patients receiving belimumab
achieving PERR, compared to 32% in the placebo group (p=0.0311).
 Biologics targeting T cells
Target Function Drugs Indications

CD-52 Present on T cells, B cells, Alemtuzumab Multiple Sclerosis

NK cells, & monocytes

CD-80 & 86 Present on APCs Abatacept RA, JIA, PsA

CD-28 Present on T cells
Inhibits T cell co-
stimulation

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 ATTAIN TRIAL(2008):
Abatacept Trial in Treatment of Anti-TNF
Inadequate Responders
Aim: Efficacy of Abatacept compared to placebo in terms of ACR20 response at 6
months.
Inclusion: Adult patients with moderate to severe rheumatoid arthritis (RA) who had
previously failed to respond to at least one tumor necrosis factor (TNF) inhibitor
Intervention: Participants were assigned to receive either Abatacept or placebo, both
combined with standard methotrexate therapy. The treatment was administered at
baseline and every four weeks thereafter for six months.
Results: 51% of patients receiving abatacept achieved an ACR20 response
compared to 29% in the placebo group (p < 0.001).
 Biologics targeting Integrins
Target Function Drugs Indications

α4 Leukocyte Natalizumab UC, CD, MS

trafficking during
α4β7 inflammation, Vedolizumab UC, CD
mainly in gut
Vedolizumab Targeting Integrin

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 GEMINI-1, 2 TRIALS-
VEDOLIZUMAB

Population : GEMINI 1: Adult patients with moderate-to-severe ulcerative colitis

(UC) who had inadequate response to corticosteroids, immunosuppressants.
GEMINI 2: Adult patients with moderate-to-severe Crohn’s disease (CD) who also
had an inadequate response to standard therapies.
Intervention: Vedolizumab 300mg vs Placebo -intravenous infusion at the baseline,
week 2, and week 6, followed by maintenance dosing every 8 weeks.
Primary endpoint: Clinical remission at week 6 for the induction phase and clinical
remission at week 52 for the maintenance phase.
Results: Vedolizumab showed significant Improvement in both trials in
induction as well as in maintenance therapy of IBD (GEMINI-I-31% vs 25%)
( GEMINI-II: 43% vs 30%)
Small Molecule Inhibitors – JAK Inhibitors
• JAK–STAT pathway: target to inhibit various cytokines
• 4 members: JAK1, JAK2, JAK3, and tyrosine kinase 2
• JAK-1 selective – minimize ADR risks of JAK 2 & 3

Drug Target Indications

Tofacitinib JAK 1 & 3 RA, PsA, UC

Baricitinib JAK 1 & 2 RA

Upadacitinib JAK 1 RA
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 SELECT-EARLY TRIAL-(2019)
(Upadacitinib)

Population: Patients with Moderate-to-severe Rheumatoid arthritis

(RA) who were Methotrexate (MTX)-naïve.
Intervention: 15 mg of Upadacitinib / 30 mg of Upadacitinib Once
Daily / weekly Methotrexate alone-24weeks
Primary endpoint :proportion of patients achieving ACR50 at week
12.
Results: Upadacitinib was significantly more effective than
methotrexate in achieving both the ACR50 response at week 12 .
ACR50 at week 12- (52% vs 56% vs 28%)
NEWER DRUGS & TARGETS
IN
AUTOIMMUNE DISEASES
TEPROTUMUMAB- First drug approved
for Thyroid related Eye disease

US-FDA approved in Jan 2020 for Thyroid related Ophthalmopathy.

• MOA: It is designed to target and block IGF-1R
• It prevents muscle and tissue expansion behind the eye to help reduce symptoms.

DOSAGE: Administered intravenously. The typical dosing regimen is:

Initial dose: 10 mg/kg on week 0
Subsequent doses: 20 mg/kg every 3 weeks for a total of 8 infusions over 21 weeks​.

ADVERSE EFFECTS:
Muscle spasms (25%);Nausea (17%);Alopecia (13%);Hyperglycemia (10%)
OPTIC TRIAL(2020)- TEPROTUMUMAB

• Phase 3 Trials
(OPTIC Trial):
• Demonstrated Consistent
reductions in proptosis
• Improvements in overall
disease activity and quality
of life​

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 A BAFF/APRIL Dual inhibitor -
Telitacicept
• APPROVAL: In March 2021, approved in China for the treatment active SLE.
• BAFF and APRIL are key factors in development and differentiation of B cells.
• BAFF and APRIL have two receptors: TACI (transmembrane activator and
calmodulin cyclin ligand interaction factor) and BCMA (B-cell maturation antigen).
• These receptors are usually expressed by B cell lineage
MOA:
• Telitacicept is a new full-human TACI-FC fusion protein prepared by using
recombinant DNA technology
• It can bind BAFF and APRIL, effectively blocking their binding to the receptor .
• The immature B cells can be prevented from continuing to develop further.
Telitacicept- Mechanism of action

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 Telitacicept
INDICATION: Treatment of B cell-mediated autoimmune diseases, such as Systemic
lupus erythematosus (SLE), Rheumatoid arthritis (RA) and Multiple sclerosis (MS).

For SLE: Doses of 80 mg, 160 mg, and 240 mg administered subcutaneously once a
week​
Adverse effects: Upper respiratory tract infections,UTI, Injection site reactions
Anifrolumab- First in Class molecule against
Type-1 IFN

• US-FDA approved for treatment of SLE, 2021.

Mechanism of Action
• It is a Humanized IgG1k monoclonal antibody that binds to subunit 1 of the type-1
IFN receptor (IFNAR1).
• IFN-α is the predominant type-1 IFN implicated in SLE pathogenesis.
• Anifrolumab antagonizes the receptor responsible for cellular signaling induced
by IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω.
Anifrolumab- Mechanism of action
 Anifrolumab

Indication: Treatment of Moderate to Severe Systemic lupus erythematosus in

adults . ​
Dosage: 300 mg as an intravenous infusion over 30 minutes every four weeks.
​Adverse effects:
•Increased risk of infections (e.g., upper respiratory infections)
•Infusion-related reactions (e.g., fever, chills)
•Potential increased risk of malignancies due to immunosuppression​
TULIP-1 & TULIP-2 TRIAL- Anifrolumab
(2019)
• Anifrolumab's efficacy and safety were evaluated in pivotal trials, notably the
TULIP-1 and TULIP-2 studies.
• These were phase 3, multicenter, double-blind, randomized, placebo-controlled trials
that included patients with moderate to severe SLE.
• IV Anifrolumab 150mg(TULIP-1) 300mg(TULIP-2) vs placebo every 4weeks for
48weeks:
• In TULIP-1, 40.6% of patients receiving Anifrolumab achieved a significant
reduction in disease activity (SLE Responder Index 4) compared to 23.3% on
placebo.
• In TULIP-2, 51.5% of patients treated with Anifrolumab met the same endpoint,
compared to 34.8% in the placebo group
Deucravacitinib- Selective TYK2 inhibitor

MOA: Inhibitor of tyrosine kinase 2 (TYK2), a member of the Janus kinase (JAK)
family. This selectivity helps reduce the risk of adverse effects seen with broader
JAK inhibitors.
Indication: Moderate to severe Plaque Psoriasis
Dosage: Adults with moderate to severe plaque psoriasis :6 mg taken orally once
daily.
Adverse effects: less than JAK inhibitors.
•Increased risk of serious infections.
•Malignancies: Potential risk, particularly in patients with a history of cancer.
•Elevated liver enzymes and triglycerides: Regular monitoring is advised due to
associated elevations
 Targetting IL-36

• SPESOLIMAB- Humanized IgG1 against IL-36R.

• APPROVED BY US-FDA IN September 2022
• 900mg single dose i.v infusion
IMSIDOLIMAB- IgG4 against IL-36R
• Indication: Generalised pustular psoriasis flares.
• Awaiting approval
• COMPLETED Phase 3 trial-GEMINI-1
• Used as iv infusion- 300mg/750mg single dose * 4 weeks
Whats new in IL-17 inhibition? NANOBODY?

SONELOKIMAB is a 40kDa humanized antibody

consisting of three VHH domains covalently linked
by flexible glycine-serine spacers.
Completed phase 2b trial: Psoriasis
It binds with high affinity to
• 2domains- IL-17A,IL-17F
• Central domain-human albumin-enrichment
of the drug at sites of inflammatory edema
Camelid antibody- Heavy chain only Antibody
LENABASUM-First in class Cannabinoid
analog
MOA:
• It is a CB2 agonist developed as an inflammation-resolving drug candidate
• Limited penetration into the central nervous system, to reduce psychoactive adverse
events .
• CB2 is mainly expressed on immune cells like dendritic cells and B cells.
• CB2 agonists increase expression of pro-resolving lipoxins and resolvins, while
decreasing production of inflammatory prostaglandins and leukotrienes,
cytokines,& chemokines.
• Overall, It facilitates the resolution of several inflammatory responses.

Indication: Under trials for Scleroderma, Cystic fibrosis,

Dermatomyositis, and lupus
Mechanism of action
Lenabasum

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 CD-19 CAR-T cell therapy
Fully human CD 19 CAR-T cell therapy was administered to 2 patients with
progressive Multiple sclerosis.(Phase 1)
Targetted approach against B cells
ICANS: Immune effector cell associated
Neurotoxicity Syndrome
Bispecific Antibody in Rheumatoid arthritis
 Other Emerging therapies
• Targeting Chemokine receptors- Quetmolimab-CX3CR1-phase 2-RA
• Targeting GM-CSF- Mavrilimumab-phase 2-spondyloarthritis
• Targeting Bruton tyrosine kinases- Evobrutinib and Fenebrutinib-phase 2 in
RA & SLE.
• Microbiome manipulation
• Vagal nerve stimulation
• Cells as therapies- T-reg cells, Tolerogenic Dendritic cells, Mesenchymal
stromal cells.

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 Summary

➢ Currently available drugs in treating Autoimmune Diseases

➢ Landmark clinical trials in Autoimmune Diseases

➢ Newer class of drugs in Autoimmune diseases

➢ Newer targets and Drugs in pipeline

 References
• Firestein & Kelley’s textbook of Rheumatology, 11th edition

• Hochberg textbook of Rheumatology, 8th edition,2023.

• Cai J, Gao D, Liu D and Liu Z (2023) Telitacicept for autoimmune

nephropathy. Front. Immunol. 14:1169084.doi: 10.3389/fimmu.2023.1169084

• Palanisamy Kanakaraj, Bridget A. Puffer,Simultaneous targeting of TNF and

Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model
of arthritis, mAbs, 4:5, 600-613, DOI: 10.4161/mabs.21227.