Dr Tim Mitchell, CEO & Co-Founder Next-generation TYK2 ...€¦ · Licensed to China-based...
Transcript of Dr Tim Mitchell, CEO & Co-Founder Next-generation TYK2 ...€¦ · Licensed to China-based...
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Dr Tim Mitchell, CEO & Co-Founder
Next-generation TYK2/JAK1 Immunotherapeutics for
Autoimmune Diseases and Cancer (and Covid-19)
BioTrinity, April 2020
Specialists in Small Molecule Drug Development
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Psoriasis, RA, lupus, IBD, MS
T-ALL, ccRCC, immunotherapy
AML, ALL
Solid tumours
Anogenital
Prostate
Lung, colon,
Advancing our Pipeline
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AML: Acute Myeloid Leukaemia; RA: Rheumatoid Arthritis; ALL: Acute Lymphoblastic Leukaemia; IBD: Inflammatory Bowel Disease;
T-ALL: T-cell Acute Lymphoblastic Leukaemia; MS: Multiple Sclerosis; ccRCC – clear cell Renal (kidney) Cell Carcinoma; PARP - Poly ADP Ribose Polymerase;
ADP – Adenosine Di-Phosphate
• 100% focused on development of our proprietary TYK2/JAK1 inhibitors
Autoimmune
diseases
Cancer
Leukaemia
Monotherapy
Low dose gemcitabine
(LDG) combination
PARP inhibitor
combination
Immunotherapy combination
TYK2/JAK1
FLT3+Aurora
Chk1
SDC-1801
Licensed to China-based
specialty pharma
SDC-1802
SRA737
Clinical
Phase IITarget
Lead
optimisation
Candidate
selectionPreclinical
Clinical
Phase IPotential indications
Proprietary
Programmes
Partnered
Programmes
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TYK2/JAK Inhibitors are Emerging Targets of
Increasing Pharma Interest
• The TYK/JAK cell signalling family (TYK2, JAK1, JAK2, JAK3) is important
for maintaining healthy immune system
• Strong clinical validation (BMS, Pfizer) for TYK2 and TYK2/JAK1 in
psoriasis, but with room for improvement
• Late-stage clinical trials of TYK2 and TYK2/JAK1 inhibitors (BMS, Pfizer)
ongoing for lupus, UC, Crohn’s, vitiligo – readouts in 2020
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JAK Inhibition on Signalling of Key
Immunoregulatory Cytokines
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O’Shea J, et al. Immunity 2012;36(4);542-550
Therapeutic
opportunities
RA,
Resistance to I/O,
Viral/bacterial
pneumonia
Psoriasis, IBD, Lupus,
Resistance to I/O,
Viral/bacterial
pneumonia
Psoriasis, IBD, RA, LupusRA, respiratory failure
from viral infections
JAK2 and JAK3 inhibition associated with the FDA “black box” warnings for serious infections, lymphoma and thrombosis issued to
JAK1/JAK3 inhibitor Xeljanz (tofacitinib) and JAK1/JAK2 inhibitor Olumiant (baricitinib)
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We are Focused on Selective, Potent
TYK2/JAK1 Inhibitors
Significant clear opportunities available to Sareum
• No marketed products with selectivity for TYK2 – important for differentiation
• No TYK2 inhibitors in clinical trials for cancer – first-in-class opportunity
SDC-1801 and SDC-1802
• Potent & selective inhibitors of TYK2 and JAK1 kinases
• Oral twice-daily dosing in mice, potential for once-daily dosing in humans
• Favourable selectivity profile vs JAK2 and JAK3 kinases (cf tofacitinib, baricitinib,
ruxolitinib)
Development Strategy
• Internal focus on completing IND-enabling studies on SDC-1801 and SDC-1802
• Seek development partners for commercial licences at late-preclinical or early clinical stage
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SDC-1801: Targeting Autoimmune Diseases
• Good efficacy in disease models of psoriasis and rheumatoid arthritis
• Maximum tolerated dose not reached at 30x dose used in efficacy studies
• Dose-ranging studies underway
• Synthetic route developed for large-scale manufacturing for toxicology and clinical studies
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Rheumatoid arthritis model
SDC-1801 dosed orally (5, 10 & 20 mg/kg bid)
Well tolerated with pronounced, dose responsive effects on arthritic index and hind paw thickness
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SDC-1802: Targeting Multiple Cancers
• Good efficacy in immunotherapy disease models vs many cancers
• New preclinical data presented at AACR-NCI-EORTC (Oct 2019)
• Anti-tumour effects seen in models of kidney, colorectal & skin cancers and B-cell lymphoma
• Evidence that SDC-1802 induces anti-cancer activity through a novel immunotherapeutic mechanism
• Positive results seen when dosed orally, as a monotherapy and with chemotherapy
• Current focus on initiation of short-term toxicity and dose-ranging studies
• Initial formulation studies complete; now optimising manufacturing route
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SDC-1802 has no significant effect against pancreatic
tumour growth in immunodeficient mice
SDC-1802 gives significant reduction of pancreatic
tumour growth in immunocompetent mice
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TYK2/JAK1 and Covid-19
• Diseases such as Covid-19, SARS, MERS, influenza etc. can be fatal due to a “cytokine
storm” overreaction of the immune system
• Key cytokines elevated in Covid-19 ICU patients are reported to include:
• IL-2, IL-7, IL-10, G-CSF – all signal via JAK-family kinases
• Clinical trials of JAK-family inhibitors ruxolitinib, tofacitinib, baricitinib in Covid-19 patients are
in progress or planned
• Secondary bacterial infections induce IL-1β and GM-CSF
• GM-CSF reported to improve outcome in patients with pneumonia-associated ARDS
• IL-1β - GM-CSF pathway blocked by virally-induced IFNα and IFNγ
• TYK2/JAK1 inhibition blocks IFNα/γ signalling and thus restores GM-CSF levels
• GM-CSF signals via JAK2
• Suggests a TYK2/JAK1 inhibitor that does not inhibit JAK2 to be optimally beneficial
• Sareum’s SDC-1801/2 inhibit TYK2 and JAK1, but not JAK2
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Huang et al Lancet 2020; 395:497-506
Berg et al Eur Respir J 2017; 50:160193
Herold et al Am J Repir & Criti Care Med 2015; 189(5):609-11
IFN - Interferon; ARDS – Acute Respiratory Distress Syndrome
ICU – Intensive Care Unit; G-CSF – Granulocyte Colony Stimulating Factor
GM-CSF – Granular Macrophage Colony Stimulating Factor
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Licensing and Funding Opportunities
Tyrosine Kinase 2 / Janus Kinase 1 (TYK2/JAK1)
• Seeking co-development / licence partners for autoimmune and/or oncology applications
• Grant and other funding for Covid-19 applications
Checkpoint Kinase 1 (CHK1), FLT3+Aurora
• Demonstrates our ability to develop and commercialise clinical and preclinical candidates
• Potential for milestone and royalty payments
Funding
Psoriasis, RA, lupus, IBD, MS
T-ALL, ccRCC, immunotherapy
AML, ALL
Solid tumours
Anogenital
Prostate
Lung, colon,
Autoimmune
diseases
Cancer
Leukaemia
Monotherapy
Low dose gemcitabine
(LDG) combination
PARP inhibitor
combination
Immunotherapy combination
Lead
optimisation
Candidate
selection
TYK2/JAK1
FLT3+Aurora
Chk1
SDC-1801
Licensed to China-based
specialty pharma
SRA737
Clinical
Phase IITarget Preclinical
Clinical
Phase IPotential indications
SDC-1801