SD-101

an Investigational TLR9 Agonist

SD-101 is an investigational toll-like receptor 9 (TLR9) that has been studied in advanced cutaneous melanoma and head and neck squamous cell carcinoma in over 500 patients.

The safety and efficacy of SD-101 have not been established by health authorities. SD-101 is investigational and has not been approved in the US or globally.

SD-101

SD-101, an investigational agent in development, is a toll-like receptor 9 (TLR9) agonist which is believed to bind to the TLR9 receptors found on suppressive immune cells including myeloid-derived suppressor cells (MDSCs) and antigen-presenting immune cells. Toll-like receptors play a key role in the innate immune system and create a bridge to adaptive immunity.2 It is believed that activating TLR9 primes immune cells to promote anti-tumor T cell function.2,3

SD-101 has been tested in combination with pembrolizumab (Keytruda®) and other agents in over 500 patients enrolled in various Phase 1 and Phase 2 studies of melanoma, lymphoma, and head and neck squamous cell carcinoma. It is also currently being tested in the I-SPY2 Trial for patients with high-risk, Stage II/III breast cancer.

TLR9 agonists, such as SD-101, are not administered intravenously but by direct injection into the skin or tumors, making treatment of some solid tumors difficult. TriSalus will utilize its proprietary Pressure-Enabled Drug Delivery™ (PEDD™) approach for intravascular regional delivery of SD-101.

By infusing SD-101 via our technology, we now can administer it to visceral organs and directly to the site of disease. The goal of this approach is to enhance SD-101’s therapeutic index, increase anti-tumor immune activity intended to slow tumor progression and restore, enable, or improve responses to immunotherapies for treatment of liver metastases and pancreatic cancer.

TriSalus will initially evaluate SD-101 for the treatment of uveal melanoma liver metastases. We intend to develop additional programs looking at a combination of SD-101 and other immuno-oncology agents delivered with PEDD in a range of liver metastases and pancreatic cancer in which limited therapeutic options exist.

 

The safety and efficacy of SD-101 have not been established by health authorities. SD-101 is investigational and has not been approved in the US or globally.

Prior Clinical Trials of SD-101

 

Melanoma

SYNERGY-001/KEYNOTE-184 – Unresectable Stage IIIc/IV Metastatic Melanoma

More than half of patients will eventually progress despite treatment.5 As a result, there remains an unmet need for additional options for patients with resistant or refractory advanced melanoma.

A Phase 1b/2, multicenter, open-label trial was conducted to assess the combination of SD-101 and pembrolizumab, a PD-1 inhibitor, in patients with Stage IIIc/IV metastatic melanoma. Results in two patient cohorts of the study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. See results below. 

Melanoma – Cohort 1

The first cohort of 86 patients with advanced melanoma who were naïve to anti-PD-1/PD-L1 treatment and who received 2 mg dose of SD-101 plus 200 mg of pembrolizumab demonstrated an overall response rate (ORR) of 76% and a progression-free survival (PFS) rate at 18 months of 72%.6 By comparison, in a separate randomized, open-label, Phase 3 pembrolizumab monotherapy study in 834 anti-PD-1/PD-L1 treatment-naïve patients, pembrolizumab achieved an ORR rate of 34%.8

The safety and efficacy of SD-101 have not been established by health authorities. SD-101 is investigational and has not been approved in the US or globally.
Study Results Cohort 1

Best Overall Response for ITT Population by RECIST v1.16

Efficacy Table

 


 

Progression-free and Overall Survival Outcomes6

Efficacy-Table

 


 

Percent Change from Baseline by PD-L1 Status (2mg/Lesion)6

Efficacy-Table

 


 

Percent Change from Baseline Over Time in Target Lesions (2mg/Lesion)6

 


 

Response to SD-101 Plus Pembrolizumab in

Patients Naïve to Anti-PD 1/PD-L1 Therapy1

 


 

Response to Therapy in a Non-injection Lesion1

 


 

Drug Combination Inflamed Immunological Tumors6

 


 

Safety Summary6

 


 

Melanoma – Cohort 2

In the Phase 2 cohort expansion of the trial 61 metastatic melanoma patients who were resistant/refractory to anti-PD-1/PD-L1 therapy were evaluated. Patients who received SD-101 2 mg in combination with pembrolizumab had an ORR of 19.4%, and those who took SD-101 8 mg with pembrolizumab had an ORR of 13.3%.7 By comparison, in a separate Phase 2 study of pembrolizumab monotherapy in 540 advanced melanoma patients who were resistant/refractory to checkpoint inhibitors, pembrolizumab, achieved an ORR rate of 25%.9

The safety and efficacy of SD-101 have not been established by health authorities. SD-101 is investigational and has not been approved in the US or globally.
Study Results Cohort 2

Best Overall Response for ITT Population by RECIST v1.17

   

 


 

Percent Change from Baseline in Lesion(s)7

 


 

Organ-Specific Percent Change from Baseline in Target Lesions7

 

 


 

Safety Summary

 


 

Head and Neck Cancer

SYNERGY-001/KEYNOTE-184 in Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma

Historically, patients with recurrent inoperable or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have had a poor prognosis and limited second-line treatment options. 

A Phase 1b/2, multicenter, open-label trial was conducted to assess the combination of SD-101 and pembrolizumab, a PD-1 inhibitor in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who had no previous treatment. A Phase 2 cohort expansion of 50 treatment-naïve R/M HNSCC patients was conducted. Results were presented at the 2019 ASCO Annual Meeting. Overall, the results showed that patients who were treated with the combination of SD-101 and pembrolizumab achieved an ORR of 24%. Patients who received the SD-101 2 mg dose arm had an ORR of 22.2%, while those in the SD-101 8 mg dose arm had an ORR of 26.1%.11

The safety and efficacy of SD-101 have not been established by health authorities. SD-101 is investigational and has not been approved in the US or globally.
Study Results in HNSCC

Best Overall Response for ITT Population by RECIST10

 


 

Objective Response by PDL1 (CPS Score) and HPV Expression Status (P16 expression) (Pooled 8 mg and 2 mg/Injection)10

 


 

Tumors with Low IFNSignature at Baseline 10

 


 

Increase in Infiltration of Immune Cells10

 


 

Safety Summary

 


 

References:

  1. Ribas A., et al. Cancer Discov. 2018;8(10):1250-1257.
  2. Melisi, D., et al. Biomedicines. 2014;2(3):211‐228.
  3. Humbert, M., et al. Cancer Res. 2018;78(12):3280‐3292.
  4. Shirota, H., et al. Oncoimmunology. 2012;1(5):780782.
  5. KEYTRUDA® (pembrolizumab) for injection, for intravenous use [package insert]. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA. 2014. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf  Accessed on August 3, 2020.
  6. Milhem M., Long G.V., Hoimes C.J., et al. Phase 1b/2, Open Label, Multicenter, Study of the Combination of SD-101 and Pembrolizumab in Patients with Advanced Melanoma Who Are Naïve to Anti-PD-1/L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870). Study abstract 9534. American Society of Clinical Oncology (ASCO) annual meeting, 31 May-4 June, Chicago, USA.
  7. Amin A., Long G.V., Milhem M., et al. Phase 1b/2, Open Label, Multicenter Study of the Combination of SD-101 and Pembrolizumab in Patients with Advanced/Metastatic Melanoma Resistant to Anti-PD-1/PD-L1 Therapy (SYNERGY-001/KEYNOTE-184, NCT02521870). Study abstract 9555. American Society of Clinical Oncology (ASCO) annual meeting, 31 May-4 June, Chicago, USA.
  8. Robert C., et al. N Engl J Med. 2015;372(26):2521-2532.
  9. Ribas A, et al. Lancet Oncol. 2015;16:908-918.
  10. Cohen E., Nabell L., Ribas A., et al. Phase 1b/2, Open Label, Multicenter Study of Intratumoral SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (SYNERGY-001/KEYNOTE-184, NCT02521870). Study abstract 6039. American Society of Clinical Oncology (ASCO) annual meeting, 31 May-4 June, Chicago, USA.