Corporate Overview
January 2020
This presentation contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as "may," "might," "will," "expect," "plan," "anticipate," "believe," "estimate," "intend," "future," "potential," "continue" and other similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. For example, statements Immunovant makes regarding our business strategy, our plans to develop and commercialize our product candidates, the safety and efficacy of our product candidates, our expectations regarding timing, the design and results of clinical trials of our product candidates, our plans and expected timing with respect to regulatory filings and approvals, the size and growth potential of the markets for our product candidates, and our ability to serve those markets, and our plans and expected timing with respect to regulatory filings and approvals are forward- looking. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. The product candidates that Immunovant develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all. In addition, promising interim results or other preliminary analyses do not in any way ensure that later or final results in a clinical trial or in related or similar clinical trials will replicate those interim results. In addition, clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release. In addition, such product candidates may not be beneficial to patients, or even if approved by regulatory authorities, successfully commercialized. The failure to meet expectations with respect to any of the foregoing matters may have a negative effect on Immunovant's stock price. All forward-looking statements are based on estimates and assumptions by Immunovant's management that, although Immunovant believes to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Immunovant expected. Such risks and uncertainties include, among others, the initiation and conduct of preclinical studies and clinical trials; the availability of data from clinical trials; the expectations for regulatory submissions and approvals; the continued development of Immunovant's product candidates and platforms; Immunovant's scientific approach and general development progress; Immunovant's ability to maintain or scale up manufacturing processes and transition such processes; and the availability and commercial potential of Immunovant's product candidates including the size of potentially addressable markets and degree of market acceptance. These statements are also subject to a number of material risks and uncertainties that are described in Immunovant's periodic and other reports filed with the Securities and Exchange Commission (SEC), including the risk factors detailed in Health Sciences Acquisitions Corporation's definitive proxy statement filed with the SEC on November 27, 2019. Any forward-looking statement speaks only as of the date on which it was made. Immunovant undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.
2
Immunovant
Our vision: Normal lives for patients with autoimmune diseases
Our asset: IMVT-1401, a novel, fully human monoclonal antibody inhibiting FcRn-mediated recycling of IgG
Our strategy for IMVT-1401:
- Be best-in-classin target indications where anti-FcRn mechanism has already established clinical proof-of-concept
- Be firstto study FcRn inhibition in target indications with clear biologic rationale and no known in-class competition
Our near-termvalue drivers: Four anticipated data readouts over the next 20 months
4
Immunovant Leadership
Management Team
Pete Salzmann, MD, MBA
Chief Executive Officer
Julia Butchko, PhD
Chief Development and Technology Officer
Brad Middlekauff, JD
General Counsel
Robert Zeldin, MD
Chief Medical Officer
Pamela Connealy, MBA
Chief Financial Officer
Board of Directors
• | • | Douglas Hughes |
Frank Torti, Chairperson | George Migausky | |
• | • | |
Myrtle Potter | Atul Pande | |
• | • | |
Andrew Fromkin | Pete Salzmann | |
• |
5
IMVT-1401: Program Highlights
IMVT-1401: A novel, fully human monoclonal antibody inhibiting FcRn
- Early evidence suggests that anti-FcRn agents could transform the treatment of autoimmune diseases mediated by pathogenic IgG antibodies
In Phase 1, IMVT-1401 generated compelling pharmacodynamic activity
- Clinically meaningful IgG reductions observed (78% IgG reduction at 680 mg dose level)
- No difference observed between intravenous and subcutaneous formulations at equivalent doses
IMVT-1401 has been well-tolerated to date
- No headaches reported in the highest dose multiple dose cohort tested
- No treatment-related serious adverse events (SAEs) or dose limiting toxicities reported
- No confirmed cases of anti-drug antibodies in any subject in multiple dose cohorts
IMVT-1401 was designed from inception for subcutaneous (SC) injection
- Requirement during development process
- Phase 1 data suggests every other week or less frequent dosing achievable for chronic use
6
IMVT-1401: A Pipeline in a Product
T a r g e t I n d i c a t i o n | P r e - | P h a s e | P h a s e | P h a s e | S t a t u s |
c l i n i c a l | 1 | 2 | 3 | ||
Myasthenia Gravis | ASCEND-MG | • Phase 2a open for |
(MG) | enrollment | |
• Phase 2a open for | ||
Graves' | ASCEND-GO | enrollment |
Ophthalmopathy (GO) | • Phase 2b open for | |
enrollment | ||
Warm Autoimmune | ASCEND-WAIHA | • IND cleared for |
Hemolytic Anemia | Phase 2 trial | |
(WAIHA) | initiation |
7
IMVT-1401: Multiple anticipated near-term value inflection points
MG
GO
WAIHA
- Phase 2a open for enrollment
Top-line results of Phase 2a study expected in 1H 2020 Pivotal Phase 3 study initiation expected in 2020
- Phase 2a open for enrollment
Initial results of Phase 2a study in Q1 2020 Phase 2b proof-of-concept study open for enrollment
Top-line results of Phase 2b study expected in early 2021
- IND cleared for Phase 2 trial initiation
Initial results of Phase 2a study expected in Q4 2020
Nasdaq Ticker: "IMVT"
Strong cash position expected to provide runway through four Phase 2 trials across three indications
8
Broad range of potential applications for anti-FcRn mechanism
IgG-mediated autoimmune diseases where FcRn mechanism may be relevant:
MG | Estimated prevalence (2017) | US | Europe | ||||
65,000 | 104,000 | ||||||
WAIHA | 42,000 | 66,000 | |||||
GO | 33,000 | 52,000 | |||||
ITP | 31,000 | 49,000 | |||||
PV | 28,000 | 45,000 | Total US = 242,000 | ||||
CIDP | 16,000 | 25,000 | |
BP | 8,000 | 13,000 | |
NMO | 7,000 | 12,000 | |
PF | 7,000 | 11,000 | |
GBS | 3,000 | 5,000 | |
PMN | 2,000 4,000 |
Total Europe = 386,000
Additional IgG-mediated autoimmune diseases
Note: List of diseases is illustrative only and does not represent our targeted indications (for more information, see Health Sciences | 9 |
Acquisitions Corporation's definitive proxy statement filed with the SEC on November 27, 2019). MG: Myasthenia Gravis; WAIHA: Warm |
Autoimmune Hemolytic Anemia; GO: Graves' Ophthalmopathy; ITP: Idiopathic Thrombocytopenic Purpura; PV: Pemphigus Vulgaris; CIDP:
Chronic Inflammatory Demyelinating Polyneuropathy; BP: Bullous Pemphigoid; NMO: Neuromyelitis Optica; PF: Pemphigus Foliaceus; GBS:
Guillain-Barré Syndrome; PMN: PLA2R+ Membranous Nephropathy
IMVT-1401
IgG antibodies implicated in certain autoimmune diseases
Antibodies in healthy individuals | Antibodies in autoimmune disease |
- Antibodies play an important role in immune defense against pathogens1
- Clearing bacteria, viruses, and other harmful organisms and substances
- Eliciting an immune response that leads to inflammation
- IgG antibody subclass accounts for ~75% of antibodies in the plasma of healthy people1
- In many autoimmune diseases, IgG antibodies develop that can recognize and bind to normal tissues2
- Targets may include cell-surface receptors or circulating proteins
- Result is a harmful immune response that damages critical tissues and organs
- Predisposing factors may include genetic susceptibility, environmental triggers, and factors not yet known3
IgG | IgE | IgD | IgA | IgM | |||||||
1. | Leusen J.H.W. The Role of IgG in Immune Responses. Molecular and Cellular Mechanisms of Antibody Activity, 2013 | 11 |
2. | Isabela S., et al. The role of autoantibodies in health and disease. Romanian Journal of Morphology and Embryology, 2016 | |
3. | Mariani S.M. Genes and autoimmune diseases - a complex inheritance. MedGenMed, 2004 |
IMVT-1401's mechanism shown to promote IgG degradation1
FcRn prolongs the | Inhibiting FcRn promotes |
half-life of IgG2 | IgG degradation2 |
- FcRn intercepts IgG, which would otherwise be degraded in lysosomes
- The FcRn-IgG complex is then recycled to the cell surface and free IgG is released back into circulation
- IMVT-1401binds to FcRn, thereby preventing it from recycling IgG antibodies back to circulation
- As a result, IgG is increasingly delivered to lysosomes for degradation
Blood (physiological pH) | Blood (physiological pH) | |||||
Endocytic | Endocytic | |||||
vesicle | vesicle | |||||
FcRn binds to | IgG dissociates at | IMVT-1401binds to | IMVT-1401remains | |||
FcRn in acidified | ||||||
IgG in acidified | physiological pH | endosome | bound at | |||
endosome | physiological pH | |||||
Acidified | Non-receptor bound | Non-receptor bound | ||||
proteins are degraded | Acidified | proteins are degraded | ||||
endosome | in lysosome | endosome | in lysosome | |||
FcRn-IgG complexes are | FcRn-IMVT-1401 complexes | |||||
sorted from unbound | are sorted from unbound | |||||
proteins | Lysosome | proteins | Lysosome | |||
Monocyte or endothelial cell | Monocyte or endothelial cell | |||||
Key: | IMVT-1401 | IgG | FcRn | Serum protein |
1. | Collins J. and Jones L., et al. IMVT-1401(RVT-1401), A Novel Anti-FcRn Monoclonal Antibody, Was Well Tolerated in Healthy Subjects | 12 |
and Reduced Serum IgG Following Subcutaneous or Intravenous Administration. Presented at American Academy of Neurology | ||
2. | Annual Conference, 2019. Program # P5.2-079 | |
Derry C., et al. FcRn: the neonatal Fc receptor comes of age. Nature Reviews Immunology, 2007 |
Phase 1 SAD/MAD study design
Single Ascending Dose SC | Single Ascending Dose IV | Multiple Ascending Dose SC | ||
Fixed 765 mg | N = 6:2 | |||||
Fixed 1530 mg | N = 6:2 | |||||
N = 6:2 | Fixed 765 mg | N = 6:2 | ||||
Fixed 500 mg | ||||||
Fixed weekly
680 mg dose N = 8:2 x 4
Fixed weekly
340 mg dose N = 8:2 x 4
Fixed 340 mg | N = 6:2 | Fixed | 340 mg | N = 6:2 |
5.0 mg/kg | N = 6:2 | Fixed 100 mg | N = 6:2 | |
1.5 mg/kg | N = 6:2 | 0.1 mg/kg | N = 4:0 |
Key
0.5 mg/kg | N = 3:0 | Canada |
Australia
Numbers presented as [subjects receiving IMVT-1401] : [subjects receiving placebo]
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IMVT-1401 produced clinically meaningful IgG reductions in Phase 1 study
Preliminary results from Phase 1 SAD/MAD cohorts
Single-dose administration produced | Repeat dosing at 680 mg SC resulted in |
a 78% IgG reduction | |
dose-dependent IgG reductions | |
without the need for IV induction | |
Mean total IgG reduction after single dose in healthy volunteers
Mean total IgG reduction after 4 weekly doses in healthy volunteers
from Baseline | 20% | ||||||||
0% | |||||||||
-20% | |||||||||
IgG Reduction | |||||||||
-40% | |||||||||
-60% | |||||||||
Serum | Placebo | 340 mg SC | |||||||
0.5 mg/kg SC | 500 mg SC | ||||||||
Percent | -80% | ||||||||
1.5 mg/kg SC | 765 mg SC | ||||||||
5.0 mg/kg SC | |||||||||
-100% | |||||||||
0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 | |
Nominal Day After First Dose |
20% | ||||||||
0% | ||||||||
-20% | ||||||||
-40% | ||||||||
-60% | ||||||||
Placebo | ||||||||
-80% | 340 mg SC | |||||||
680 mg SC | ||||||||
-100% | ||||||||
0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 |
Nominal Day After First Dose |
14
IMVT-1401 reduced levels of all four IgG subtypes
Preliminary results from Phase 1 MAD cohorts
IgG1 | ||||||||||
Serum IgG Reduction | 20% | |||||||||
0% | ||||||||||
from Baseline | -20% | |||||||||
-40% | ||||||||||
-60% | ||||||||||
-80% | ||||||||||
-100% | ||||||||||
Percent | ||||||||||
0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 | ||
Nominal Day After First Dose | ||||||||||
IgG3 |
Serum IgG Reduction from Baseline | 20% | ||||||||
0% | |||||||||
-20% | |||||||||
-40% | |||||||||
-60% | |||||||||
-80% | |||||||||
-100% | |||||||||
Percent | 0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 |
Nominal Day After First Dose | |||||||||
IgG2 | ||||||||
20% | ||||||||
0% | ||||||||
-20% | ||||||||
-40% | ||||||||
-60% | ||||||||
-80% | ||||||||
-100% | ||||||||
0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 |
Nominal Day After First Dose |
IgG4 | ||||||||
20% | ||||||||
0% | ||||||||
-20% | ||||||||
-40% | ||||||||
-60% | ||||||||
-80% | ||||||||
-100% | ||||||||
0 | 7 | 14 | 21 | 28 | 35 | 42 | 49 | 56 |
Nominal Day After First Dose |
15
Generally well-tolerated in Phase 1 study
Preliminary results from Phase 1 SAD/MAD cohorts
- 99 subjects dosed to date through SAD and MAD portions of Phase 1
- IMVT-1401:77 subjects
- Placebo: 22 subjects
- Most common AEs were mild erythema and swelling at injection site
- Injection site reactions were not dose or frequency related
- Occurred at similar incidence for drug and placebo treated subjects
- No headaches observed in 680 mg SC MAD cohort
- Albumin changes:
- Dose-dependent,reversible, and asymptomatic albumin reductions observed
- At day 28, mean albumin levels were 37.5 g/L in the 340 mg cohort, and 32.4 g/L in 680 mg cohort (normal range 36-51 g/L)
- 2 SAEs observed in two separate SAD cohorts, both ruled unrelated to treatment by study investigator (cancer, appendicitis)
- Treatment-emergentADA confirmed in 8% of IMVT-1401-treated subjects and 6% of placebo-treated subjects
- No subject in MAD cohorts has developed a confirmed ADA response to IMVT-1401
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Adverse events reported in Phase 1
Preliminary results from Phase 1 SAD/MAD cohorts
Single-Ascending Dose | Multiple-Ascending | |||||||||||||||
Dose | ||||||||||||||||
Intravenous Infusion | Subcutaneous Injection | Subcutaneous Injection | ||||||||||||||
0.1 | 100 | 340 | 765 | 1530 | Placebo | 0.5 | 1.5 | 5 | 340 | 500 | 765 | Placebo | 340 | 680 | Placebo | |
mg/kg | mg | mg | mg | mg | mg/kg | mg/kg | mg/kg | mg | mg | mg | mg | mg | ||||
n=4 | n=6 | n=6 | n=6 | n=6 | n=8 | n=3 | n=6 | n=6 | n=6 | n=6 | n=6 | n=10 | n=8 | n=8 | n=4 | |
MedDRA Preferred Term | ||||||||||||||||
Abdominal pain | 1 | 1 | ||||||||||||||
Abdominal pain upper | 2 | 1 | ||||||||||||||
Abnormal sensation in eye | 1 | 1 | ||||||||||||||
Back pain | 2 | 1 | 1 | 1 | ||||||||||||
Constipation | 1 | 1 | ||||||||||||||
Cough | 1 | 2 | ||||||||||||||
Diarrhea | 2 | |||||||||||||||
Dizziness | 1 | 1 | 1 | |||||||||||||
Dry skin | 1 | 1 | ||||||||||||||
Erythema | 1 | 1 | ||||||||||||||
Fatigue | 1 | 1 | 1 | 1 | 1 | 1 | 1 | |||||||||
Headache | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 4 | 1 | 1 | 2 | |||||
Injection site erythema | 5 | 1 | 5 | 6 | 7 | 8 | 7 | 4 | ||||||||
Injection site pain | 1 | 2 | 1 | |||||||||||||
Injection site swelling | 3 | 2 | 4 | 3 | 7 | 6 | 2 | |||||||||
Insomnia | 1 | 4 | ||||||||||||||
Myalgia | 1 | 1 | ||||||||||||||
Nasal congestion | 1 | 1 | 1 | 1 | ||||||||||||
Nausea | 1 | 1 | 1 | 1 | 1 | |||||||||||
Ocular hyperaemia | 2 | |||||||||||||||
Oropharyngeal pain | 1 | 1 | 2 | 1 | 1 | 1 | 2 | |||||||||
Pain in extremity | 1 | 1 | ||||||||||||||
Procedural complication | 1 | 1 | ||||||||||||||
Procedural dizziness | 2 | 1 | ||||||||||||||
Pyrexia | 1 | 1 | 1 | |||||||||||||
Rash | 2 | 2 | 2 | 1 | ||||||||||||
Rhinorrhea | 1 | 2 | ||||||||||||||
Sinusitis | 1 | 1 | ||||||||||||||
Somnolence | 1 | 1 | ||||||||||||||
Upper respiratory tract | ||||||||||||||||
infection | 1 | 1 | 1 | 3 | 1 | 1 | 1 | |||||||||
Vision blurred | 1 | 1 |
17
IMVT-1401 has been given as a SC injection
Subcutaneous Injection | Subcutaneous Infusion | Intravenous Infusion |
<10 seconds | 30-60 minutes | Potentially Hours |
18
IMVT-1401 designed from inception to be a potentially class-leading SC injection
• Fully human monoclonal antibody
• Generated from Ligand/OMT's OmniAb transgenic rat platform
- >400 antibody campaigns ongoing that use OmniAb technology1
- 12 clinical-stage antibodies in development1
- IgG1 backbone Fc-engineered to reduce effector function
- Optimized for SC delivery
- Current clinic formulation is 170 mg/mL
- Delivered by 27-gauge needle
IMVT-1401
1. Ligand 2019 Analyst Day presentation, presented March 12, 2019 | 19 |
IMVT-1401 has the potential to deliver a class-leading profile
IMVT-1401 attribute
Clinically meaningful
IgG reductions
SC injection
Simple dosing
schedule
Fully human antibody
Fc-engineered to reduce
effector function
Potential patient benefit
- 680 mg SC weekly: 78% reduction after four doses
- 340 mg SC weekly: 63% reduction after four doses
- Fast and minimally invasive
- No requirement for IV induction doses or lengthy SC infusions
- Provides option for at-home administration
- Fixed dosing, vs. weight-based, reduces potential for dose miscalculations
- Low risk of immunogenicity
- Low potential for unintended immune responses
20
IMVT-1401 and competitors' programs with subcutaneous (SC) injection or infusion
Company
Anti-FcRn candidate
SC administration regimen
IV induction dosing
SC dose
Mean IgG reduction observed
IMVT-1401
SC injection
N/A
340 mg SC weekly
680 mg SC weekly
63-78% after 4
doses
Efgartigimod (ARGX-113)
IV induction,
followed by SC
injection1
20 mg/kg IV x 2
doses1
300 mg SC
weekly1
"Approximately" 50% after two IV induction doses followed by
8 SC doses2
Rozanolixizumab
(UCB7665)
SC infusion
given over
30-60 minutes3,4
N/A
7mg/kg SC
weekly5
56% after 3
doses5
68% after 6
doses5
ABY-039 M281 ALXN1830 (SYNT001)
SC injection
N/A | ||
Not in clinic | Not in clinic | |
200 mg SC | with SC | with SC |
formulation | formulation | |
single dose6 |
~45%
Note: data as of 9/24/2019 and is not based on head-to-head comparison studies
1. | argenx, corporate presentation, August 2018 | 4. | UCB, ASH presentation, December 2017 | 21 |
2. | argenx, press release, issued June 14, 2018. Phase 1 data | 5. | UCB, press release, issued October 18, 2018. Phase 2 data | |
3. | Kiessling P., et al. The FcRn inhibitor rozanolixizumab reduces | 6. | Affibody, PEGS conference presentation, April 2019 | |
human serum IgG concentration: A randomized phase 1 study. | ||||
Science Translational Medicine, 2017 |
IMVT-1401 for Myasthenia Gravis
Myasthenia Gravis overview
- Rare autoimmune disorder affecting an estimated 65,000 people in the US1
- Characterized by weakness of voluntary muscles including ocular, facial, oropharyngeal, limb, and respiratory muscles1
- 15-20%of MG patients will experience at least one myasthenic crisis over their lifetimes, a potentially life-threatening acute complication2
- Disease caused by autoantibodies targeting the neuromuscular junction1
- ~93% of patients have an identified autoantibody1
- Anti-acetylcholinereceptor (AChR) antibodies (~85%)
- Anti-muscle-specifictyrosine kinase (MuSK) antibodies (~8%)
Normal Neuromuscular | Neuromuscular Junction | |
Junction | in Myasthenia Gravis | |
Receptors | ||||||
Acetylcholine | Blocked by | |||||
Nerve | Antibodies | |||||
Neuron | ||||||
ACh | ||||||
Receptor | ||||||
Muscle
Reduced Transmission | |||||
Normal Muscle Contraction | Impaired Muscle Contraction |
1. Meriggioli M.N. and Sanders D.B. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Review | 23 |
Clinical Immunology, 2012 | |
2. Sudulagunta S.R., et al. Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab. German Medical Science, 2016
Unmet need persists despite availability of treatment options
Current treatment paradigm1
1st Line | 2nd Line | 3rd Line | 4th Line | ||||||
• | Acetylcholinesterase | • | Immunosuppressive | • | IVIg | • Eculizumab | |||
inhibitors | agents | • | Plasma exchange | ||||||
• | Corticosteroids | • | Thymectomy | • | Immunoadsorption | ||||
• | Rituximab1 | ||||||||
Unmet need
- ~10% of MG patients refractory to current treatments, while 80% fail to achieve complete stable remission1
- Existing therapies associated with significant side effects
- Early line agents can lead to disease exacerbation and do not always prevent disease progression
- Treatment for more advanced disease often requires invasive and burdensome infusions
- Patients with anti-MuSK antibodies more likely to become refractory2
- ~50% of the refractory MG population, despite comprising <10% of the overall MG population
- Newest treatment option, eculizumab, only indicated for anti-AChR positive patients
1. | Rituximab is not approved by the FDA for myasthenia gravis | 24 |
2. | Mantegazza R. and Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment | |
strategies. Therapeutic Advances in Neurological Disorders, 2018
ASCEND-MG: Phase 2a study design
Screening
Key Inclusion Criteria:
- MGFA Class II-IVa
- QMG score ≥ 12 at screening
- Anti-AChRantibody positive
Up to 3 weeks
Treatment
IMVT-1401 680 mg
N = 7
IMVT-1401 340 mg
N = 7
Placebo
N = 7
6 weeks
Open label | Follow-up |
extension |
340 mg every other week
6 weeks | 6 weeks |
Primary Endpoints: | Secondary Endpoints: | Exploratory Endpoints: | ||
• | Safety & tolerability | • | IMVT-1401 pharmacokinetics | • Biomarkers (gene expression, |
• | Change from baseline levels | • | Change from baseline in | serum pro-inflammatory |
of anti-AChR antibodies, total | QMG, MG-ADL, quality of life | markers, receptor occupancy) | ||
IgG, and IgG by subclass | measures |
25
IMVT-1401 for
Graves' Ophthalmopathy
Graves' Ophthalmopathy overview
- Also called Graves' orbitopathy or thyroid eye disease (TED)
- 15,000-20,000patients with active GO in the United States per year
- Clinical features1:
- Proptosis
- Eye pain
- Double vision
- Light sensitivity
- Can be sight-threatening2
- Caused by autoantibodies that activate cell types present in tissues surrounding the eye2
- Close temporal and pathobiologic relationship with Graves' disease
Bahn, 2010
Figure 1. Patients with Graves' Ophthalmopathy
Panel A shows a 59-year-old woman with excess proptosis, moderate eyelid edema, and erythema with moderate eyelid retraction affecting all four eyelids. Conjunctival chemosis (edema) and erythema with bilateral edema of the caruncles, with prolapse of the right caruncle, are evident. Panel B shows a 40-year old woman with excess proptosis, minimal bilateral injection, and chemosis with slight erythema of the eyelids. She also had evidence, on slit-lamp examination, of moderate superior limbic keratoconjunctivitis.
1. | Davies T. and Burch H.B. Clinical features and diagnosis of Graves' orbitopathy (ophthalmopathy), UpToDate, 2018 | 27 |
2. | McAlinden C. An overview of thyroid eye disease. Eye and Vision, 2014 |
Anti-TSHR autoantibodies drive progression of GO and Graves' disease
Graves' ophthalmopathy | Graves' disease |
Orbital fibroblast | TSHR | Anti-TSHR |
antibody | ||
or adipocyte | ||
Inflammation and
proliferation
- Thyroid-stimulatinghormone receptor (TSHR) highly expressed on ocular fibroblasts and adipocytes1
- Activation leads to inflammation and proliferation
- Autoantibodies against insulin-like growth factor- 1 receptor (IGF-1R) also identified2
Thyrocyte | TSHR | Anti-TSHR |
antibody | ||
Thyroid hormone
production
- TSHR highly expressed on thyrocytes (cells that make up the thyroid gland)3
- Activation leads to increased production of thyroid hormone3
IMVT-1401 could address GO and Graves' disease caused by
any IgG autoantibody, whether against TSHR or IGF-1R
1. Smith T.J., et al. Role of IGF-1 pathway in the pathogenesis of Graves' orbitopathy. Best Practice & Research: Clinical Endocrinology & Metabolism, | 28 |
2013 |
- Liaboe C.A., et al. An Introductory Tutorial and Overview of Disease - Thyroid Eye Disease (TED), 2016
- Varewijck A.J., et al. Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy. Journal of Clinical Endocrinology & Metabolism, 2013
GO characterized by an active phase, followed by a static phase
Rundle's Curve describes natural history of disease1
Intensity
Inflammation
Severity
Desired outcome with early intervention in active phase
0-2 years (active phase) | 2+ years (static phase) | ||||||
• | Orbital tissue actively | • Inflammatory tissue replaced by fibrotic tissue | |||||
inflamed | • Steroids and immunosuppression no longer | ||||||
• | Steroids and other | effective | |||||
immunosuppressive | • Patients to be evaluated for surgery | ||||||
treatments can be effective | |||||||
1. Adapted from Hiromatsu Y., et al. Graves' ophthalmopathy: epidemiology and natural history. Internal Medicine, 2014 | 29 |
Limited treatment options for GO
Current treatment paradigm1
1st Line | 2nd Line | 3rd Line | Inactive disease | |||||
• Corticosteroids | • | Orbital radiotherapy | • | Rituximab2 | • Orbital surgery | |||
• | Immunosuppressive | |||||||
agents | ||||||||
Unmet need
- Currently no FDA-approved therapies for GO
- Corticosteroids are not effective in all patients, and approximately one-third of patients will relapse
- Sight-threateningdisease may occur in 3-5% of patients with Graves' disease3
- Medical emergency requiring immediate hospitalization and evaluation for surgery3
- Up to 20% of GO patients require surgical invervention3
1. | Bothun E.D., et al. Update on thyroid eye disease and management. Clinical Ophthalmology, 2009 | 30 |
2. | Rituximab is not approved by the FDA for Graves' ophthalmopathy | |
3. | Bartalena L., et al. Management of Graves' Ophthalmopathy: Reality and Perspectives. Endocrine Reviews, 2000 |
ASCEND-GO Phase 2 clinical program
ASCEND-GO1
- Phase 2a
- Trial ongoing in Canada
- Single arm, open label
- N=8
- 6 weeks of dosing
- 680 mg weekly x 2 doses
- 340 mg weekly x 4 doses
ASCEND-GO2
- Phase 2b
- Trial ongoing in USA and Europe
- Double masked, placebo controlled, randomized
- N=77
- 3 drug arms vs placebo
- 12 weeks of dosing
31
ASCEND-GO 1: Phase 2a study design
Screening | Treatment | Follow-up | ||||||||||||||||
Key Inclusion Criteria: | ||||||||||||||||||
• Moderate-to-severe | ||||||||||||||||||
active GO | IMVT-1401 680 mg/ | |||||||||||||||||
• Clinical activity score | 340 mg SC | |||||||||||||||||
(CAS) ≥4 | N = 8 | |||||||||||||||||
- Anti-TSHRantibody positive
3-6 weeks | 6 weeks | 12 weeks | ||
Primary Endpoints: | Secondary Endpoints: | Exploratory Endpoints: | ||
• Safety & tolerability | • | Change in proptosis | • | Biomarkers (gene expression, |
• Change from baseline levels | • | PK/PD | serum pro-inflammatory | |
of anti-TSHR antibodies, total | • | Anti-drug antibody levels | markers, receptor occupancy) | |
IgG, and IgG by subclasses | • | CT scans |
32
ASCEND-GO 2: Phase 2b study design
Screening
TreatmentFollow-up
Key Inclusion Criteria:
- Moderate-to-severeactive GO
- Clinical activity score
(CAS) ≥4 - Anti-TSHRantibody positive
3-6 weeks
Primary Endpoints:
- Proptosis responder rate
- Safety & tolerability
IMVT-1401 680 mg SC
N = 22
IMVT-1401 340 mg SC
N = 22
IMVT-1401 255 mg SC
N = 11
Placebo
N = 22
12 weeks
Secondary Endpoints:
• CAS responder rate
• Change from baseline levels of anti-TSHR antibodies, total IgG, and IgG by subclasses
8 weeks
Exploratory Endpoints:
- Biomarkers (gene expression, serum pro-inflammatory markers, receptor occupancy)
- CT scans
33
IMVT-1401 for Warm Autoimmune Hemolytic Anemia
Warm Autoimmune Hemolytic Anemia overview
Anti-red blood cell | Red blood | Anti-RBC autoantibodies | Antibody-coated RBCs undergo |
autoantibody | cells (RBCs) | bind to RBCs | extravascular hemolysis |
- Blood disorder marked by red blood cell destruction
- Estimated prevalence of 42,000 patients in US and 66,000 patients in EU1
- Presentation typically non-specific and occurs over several weeks to months
- Fatigue, weakness, skin pallor, shortness of breath
- Severe cases can be fatal2
1. Park S.H. Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances. | 35 |
Blood Research, 2016 | |
2. Roumier M., et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single-center experience with 60 patients. American Journal of Hematology, 2014
Limited options for treating WAIHA
Current treatment paradigm1,2
1st Line | 2nd Line | 3rd Line | 4th Line | ||||
• | Corticosteroids | • Immunosuppressive | • Rituximab3 | • Splenectomy | |||
• | RBC transfusion | agents | |||||
Unmet need
- Currently no FDA-approved therapies for WAIHA
- Only one-third of all patients maintain sustained disease control once steroids are discontinued
- Majority of patients will require either long-term steroid treatment or additional therapies1
- No clear guidelines on choice of treatment in patients failing treatment with corticosteroids
- RBC transfusions are indicated in patients who require immediate stabilization, despite the fact that autoantibodies present in WAIHA patients may react against RBCs in the transfusion product1,2
1. Salama A. Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review. | 36 |
Transfusion Medicine and Hemotherapy, 2015 |
- Park S.H. Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances. Blood Research, 2016
- Rituximab is not approved by the FDA for warm autoimmune hemolytic anemia
ASCEND-WAIHA: Phase 2 study design
Screening
Key Inclusion Criteria:
-
Primary or secondary
WAIHA - Direct Antiglobulin Test (DAT) positive
- Failed or intolerant to at least 1 prior treatment
- Stable on any current therapies
4 weeks
Primary Endpoints:
- Hemoglobin response rate*
- Safety & tolerability
TreatmentFollow-up
IMVT-1401 680 mg
N = 8
IMVT-1401 340 mg
N = 8
12 weeks | 8 weeks | |
Secondary Endpoints: | Exploratory Endpoints: | |
• | Change in hemoglobin, LDH, | • Biomarkers (gene |
bilirubin, & haptoglobin | expression, serum pro- | |
• | Time to response | inflammatory markers, |
• | QOL measures | receptor occupancy) |
- PK/PD
- Anti-drugantibody levels
* Defined as hemoglobin level ≥10 g/dL with at least a ≥2 g/dL increase from baseline | 37 |
Immunovant Recap
Our vision: Normal lives for patients with autoimmune diseases
Our asset: IMVT-1401, a novel, fully human monoclonal antibody inhibiting FcRn-mediated recycling of IgG
Our strategy for IMVT-1401:
- Be best-in-classin target indications where anti-FcRn mechanism has already established clinical proof-of-concept
- Be firstto study FcRn inhibition in target indications with clear biologic rationale and no known in-class competition
Our near-termvalue drivers: Four anticipated data readouts over the next 20 months
39
IMVT-1401: Multiple anticipated near-term value inflection points
MG
GO
WAIHA
- Phase 2a open for enrollment
Top-line results of Phase 2a study expected in 1H 2020 Pivotal Phase 3 study initiation expected in 2020
- Phase 2a open for enrollment
Initial results of Phase 2a study in Q1 2020 Phase 2b proof-of-concept study open for enrollment
Top-line results of Phase 2b study expected in early 2021
- IND cleared for Phase 2 trial initiation
Initial results of Phase 2a study expected in Q4 2020
Nasdaq Ticker: "IMVT"
Strong cash position expected to provide runway through four Phase 2 trials across three indications
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Immunovant Inc. published this content on 09 January 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 10 January 2020 08:17:02 UTC