A RETROspective Study of Combination Pyrimidine Nucleoside Therapy

A RETROspective Study of Combination Pyrimidine Nucleoside Therapy in Patients with Thymidine Kinase 2 (TK 2) Deficiency Joanne Quan, 1 Christina Domínguez-González, 2 Carmen Paradas, 3 Marcos Madruga-Garrido, 3 Andres Osorio Nascimento, 4 Francina Munell, 5 Hanna Mandel, 6 Tzipora Falik Zaccai, 6&7 Mira Ginzberg, 8 Galit Tal, 9 Caterina Garone, 10 Emanuele Barca, 11 Tristen Moors, 1 Michio Hirano, 11 1 Modis Therapeutics (a Wholly Owned Subsidiary of Zogenix, Inc), Oakland, CA, USA; 2 Hospital 12 de Octubre Instituto de Investigación, Madrid, Spain; 3 Hospital Universitario Virgen del Rocío, Sevilla, Spain; 4 Hospital Sant Joan de Déu, Barcelona, Spain; 5 Hospital Vall d'Hebron, Barcelona, Spain; 6 Western Galilee Medical Center, Israel; 7 Azrieli faculty of Medicine, Bar Ilan, Israel; 8 The Edith Wolfson Medical Center, Israel; 9 The Ruth Rappaport Children's Hospital Rambam Medical Center, Israel; 10 University of Cambridge, UK; 11 Columbia University Medical Center, New York, USA Modis would also like to acknowledge Myriam Ley Martos. Hospital Puerta del Mar. Cádiz and Javier Aguirre Rodríguez. Hospital Torrecárdenas. Almería Background TK 2 Deficiency (TK 2 d) q Ultra-rare autosomal-recessive mitochondrial DNA depletion/deletion syndrome caused by mutations in TK 2 gene q Clinically characterized by severe progressive proximal limb, bulbar, and axial muscle weakness which often causes respiratory failure and death q Subjects with untreated TK 2 d show progressive decline which is often fatal. No spontaneous recovery has been reported q Age at onset is prognostic for outcome: younger subjects have high mortality q There are no medicinal products indicated for treatment of TK 2 d. Treatment is limited to supportive care q TK 2 mutations impair the mitochondrial nucleotide salvage pathway required for synthesis of deoxyribonucleotide triphosphates (d. NTPs) Mechanism q Treatment with the pyrimidine nucleosides (deoxycytidine [d. C] and deoxythymidine [d. T]; ie, substrate enhancement therapy) aims to (a) maximize residual TK 2 activity to support mt. DNA replication and (b) increase the levels of the substrates phosphorylated by TK 1 and deoxycytidine kinase, thereby restoring the d. NTP pool available for mt. DNA synthesis Study MT-1621 -101 Subject Demographics in Study MT-1621 -101 q Study MT-1621 -101 (RETRO) is a retrospective, GCP-compliant, medical chart review study n Age of Onset ≤ 2 years 2 -12 years >12 years Median Age of Onset (Q 1, Q 3) Male Female Baseline Status Ambulatory Ventilator Support Yes Feeding Tube Yes 38 subjects 15 (40%) 14 (37%) 9 (24%) 2. 5 (1. 4, 11. 7) years 21 (55%) 17 (45%) q q q 16 (42%) 19 (50%) 8 (21%) of pyrimidine nucleosides administered as oral solution in patients with TK 2 d The study comprises records from 38 pediatric and adult TK 2 d patients The primary objective of RETRO is to describe the safety and tolerability of pyrimidine nucleosides in patients with TK 2 d The secondary objective is the assessment of efficacy (including survival) Patients were treated for a median of 71 weeks (range of 92 days-7 years) The survival analysis compared data to an untreated patient dataset extracted from published natural history studies and individual case reports The responder analysis included a within-patient responder analysis that assessed changes in the motor, respiratory, and feeding domains and compared these to the subject’s pretreatment baseline q Generated from 2 comprehensive natural history studies (Wang 2018, Garone 2018), 1 large case series (Domínguez-González, 2019) and systematic Pub. Med literature search through July 2019 q Search terms included thymidine kinase 2 deficiency, TK 2, thymidine kinase 2, TK 2 mitochondrial DNA maintenance defects q Dataset was curated to remove treated subjects, duplicates and to resolve discrepancies. q Data on age at loss of ambulation, age at loss of independent ventilation, and age at death were captured. FIGURE 1. Direct Adjusted Survival Curves Modeled from Treated and Untreated Data (Assuming Treatment from Time of Onset; Red = Untreated; Blue = Treated) Survival Probability Survival Analysis Untreated Patient Dataset Figure 1 A: ≤ 2 years at age of onset Figure 1 C: > 12 years at age of onset Time to Event (Years) q q Figure 1 B: >2 to ≤ 12 years at age of onset Time to Event (Years) No subjects treated with pyrimidine nucleosides in Study MT-1621 -101 died. Survival analysis compared treated subjects with untreated patient dataset that excluded subjects who died before age 1. 3 years (youngest age of treated patient) The statistical models applied utilized methods to correct for potential length biased sampling Comparing RETRO subjects to a dataset of all published untreated cases of TK 2 d (n=68), there was a statistically significant improvement in survival (p = 0. 0006), using the Cox regression model and age of onset as a strata variable Responder Analysis FIGURE 2. Responder Analysis – All Subjects Analysis Methods q Clinical included endpoints (eg, EK 2, HFMSE, 6 MWT), motor milestones (eg, walking), respiratory status, pulmonary function tests, and feeding tube status q Each subject was scored in the MOTOR, RESPIRATORY, and FEEDING domains according to predefined response thresholds q The last timepoint was compared with pretreatment baseline to determine the subject status: improved/remained stable/worsened Overall Response Analysis q In subjects administered pyrimidine nucleosides, most subjects (95%) either improved (68%) or remained stable (26%). A low percentage of subjects (5%) worsened (Figure 2) q In each age of onset category, the majority of subjects improved or remained stable during the study (Table 1) q As TK 2 d is a progressive disease, subjects who improved or remained stable may both be considered as demonstrating clinical benefit TABLE 1. MT-1621 -101 Response Analysis Age of Onset ≤ 2 Years 2 -12 Years Overall Response Improved 11 (73%) 11 (79%) Remained Stable 4 (27%) 3 (21%) Worsened 0% 0% Motor Domain Improved 12 (80%) 10 (71%) Remained Stable 3 (20%) 4 (29%) Worsened 0% 0% Respiratory Domain Improved 6 (40%) 4 (29%) Remained Stable 8 (53%) 10 (71%) Worsened 1 (7%) 0% Feeding Domain Improved 2 (13%) 1 (7%) Remained Stable 13 (87%) 13 (93%) Worsened 0% 0% >12 Years All Subjects 4 (44%) 3 (33%) 2 (22%) 26 (68%) 10 (26%) 2 (5%) 5 (56%) 3 (33%) 1 (11%) 27 (71%) 10 (26%) 1 (3%) 0% 7 (78%) 2 (22%) 10 (26%) 25 (66%) 3 (8%) 0% 9 (100%) 0% 3 (8%) 35 (92%) 0% Examples of Functional Improvement Ambulation: 3 subjects who had lost ambulation prior to treatment regained ambulation; 1 subjects who had never walked gained ambulation. Respiratory function: 1 subject receiving 24 hours/day of invasive mechanical ventilation prior to treatment discontinued all respiratory support following treatment. Feeding Support: 3 subjects had their feeding tubes removed, out of a total of 8 subjects on feeding tubes at study start SUMMARY Safety q Treatment with pyrimidine nucleosides significantly improved survival in subjects with TK 2 d q Greater than 90% of subjects experienced improvement in response or no further decline overall q A number of subjects regained milestones that were previously lost. These regained milestones included 4 subjects that gained ambulation, 1 subject discontinuing respiratory support, and 3 subjects had feeding tubes removed q Pyrimidine nucleosides were generally safe and well tolerated. No deaths occurred in TK 2 d subjects treated with pyrimidine nucleosides q Pyrimidine nucleosides may provide an effective treatment option for patients with TK 2 d q Modis Therapeutics is developing MT 1621, a GMP fixed dose combination of d. C/d. T for the treatment of TK 2 d q 36 subjects (95%) had at least one AE reported q Most AEs reported were considered not related to study drug (199 of 292) and were Grade 1 (186 of 292 events) q The most frequent AEs were diarrhea (63%, 24 of 38 subjects), increased blood creatine phosphokinase (18%, 7 subjects), increased alanine aminotransferase (16%, 6 subjects), pyrexia (16%, 6 subjects), increased aspartate aminotransferase (13%, 5 subjects) q Serious AEs (SAEs) were reported in 14 subjects (37%). The majority of SAEs were deemed related to TK 2 d and study drug; 2 patients experienced 3 events related to study drug alone (kidney stone, kidney stone removal, diarrhea). q Two subjects discontinued study drug due to AEs of increased GGT and increased liver enzymes. The elevations were reversible and did not meet criteria for drug-induced liver injury q There were no deaths in the study q Overall, study treatment was well tolerated References Wang J, Kim E, Dai H, et al (2018) Clinical and molecular spectrum of thymidine kinase 2 -related mt. DNA maintenance defect. Mol Genet Metab: 124(2): 124 -130. Garone C, Taylor RW, Nascimento A, et al (2018) Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet: 55(8): 515 -521. Domínguez-González C, Hernández-Laín A, Rivas E et al (2019) Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis: 14(1): 100.