Novartis RTH258 (Brolucizumab) Demonstrates Robust Visual Gains in Wet AMD Patients with a Majority on a 12-week Injection Interval

Source: Novartis

Tuesday, June 20, 2017 | Clinical Trials , AMD , Novartis


Novartis reported that RTH258 (brolucizumab) 6 mg met the primary and key secondary endpoints in two phase 3 studies, HAWK and HARRIER. RTH258 3 mg, evaluated in HAWK, also met these endpoints. These pivotal studies enrolled more than 1,800 patients with neovascular age-related macular degeneration (AMD) across 400 centers worldwide. The primary and key secondary efficacy endpoints were noninferiority of RTH258 to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48, and average mean change over the period of week 36-48, respectively.[3],[4] Both were met with highly significant P values. RTH258 was generally well tolerated with overall ocular and nonocular (systemic) adverse event rates comparable to aflibercept.[1],[2]

RTH258 demonstrated long-lasting efficacy versus aflibercept dosed every 8 weeks. A majority of patients, 57% (HAWK) and 52% (HARRIER), were maintained exclusively on a q12w (every 12 week) interval immediately following the loading phase through week 48.[1],[2]

"These results clearly and convincingly demonstrate RTH258 has the potential to reduce injection burden while providing excellent visual outcomes.  Given our legacy in developing medicines to preserve vision, we are pleased that RTH258 carries the promise of being the next major advancement for patients with nAMD" Vas Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis, said in a company news release. "Based on these robust data, we are looking forward to working with regulatory agencies to bring this pioneering treatment to patients."

Detailed analysis of the data is ongoing and will be presented at an upcoming medical congress. RTH258 is a highly innovative single chain antibody that enables much higher concentrations of antibody in the eye than approved therapies. Given the complexity of the formulation, Novartis has invested to ensure a competitive, low cost of goods formulation over the past 18 months to maximize the long term value of RTH258. Novartis expects to complete the pharmacokinetic study with the final manufacturing process to enable filing in 2018.

RTH258 has the potential to address the needs of patients with nAMD who would benefit from a long-lasting, efficacious treatment with a less frequent dosing regimen.[5]

About RTH258 (brolucizumab)
Designed specifically for the eye, RTH258 is the most clinically advanced, humanized single chain anti-body fragment in development. The proprietary innovative architecture results in a small molecule (26 kDa) with potent inhibition of, and high affinity to all VEGF-A isoforms.[6],[7] Potential benefits of the small size include better tissue penetration and rapid clearance from the systemic circulation.[6],[8],[9]

In preclinical studies,[6],[7],[8],[9] RTH258 inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction. Increased signalling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema[10]. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases.[11]

About HAWK and HARRIER

With more than 1,800 patients across 400 centers worldwide, HAWK and HARRIER are the first and only global head-to-head trials in patients with nAMD that prospectively demonstrate efficacy with a pre-specifed injection interval of 12 weeks.[1],[2] Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of RTH258.[3],[4]

The studies were designed to compare the efficacy and safety of intravitreal injections of RTH258 6 mg and 3 mg (HAWK only) versus aflibercept 2 mg in patients with nAMD.[3],[4] The primary efficacy objective of HAWK and HARRIER trials was to confirm that RTH258 is non-inferior to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to Week 48.[3],[4] Secondary endpoints include average mean change in BCVA from baseline over the period week 36-48, the proportion of patients on a q12w interval at week 48 and anatomical parameters.[3],[4]

In both protocols, patients were randomized to either RTH258 or aflibercept. Immediately following the 3-month loading phase, patients in the RTH258 arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label.[3],[4]

RTH258 6 mg met the primary and key secondary endpoints in two phase 3 studies, HAWK AND HARRIER. RTH258 3 mg, evaluated in HAWK, also met these endpoints. In both studies, these endpoints were met with highly significant p.[1],[2]

References

[1] Data on file.
[2] Data on file.
[3] ClinicalTrials.gov. Identifier NCT02307682. Available at https://clinicaltrials.gov/ct2/show/NCT02307682 (link is external). Accessed June 2017.
[4] ClinicalTrials.gov. Identifier NCT02434328. Available at https://clinicaltrials.gov/ct2/show/NCT02434328. Accessed June 2017 (link is external).
[5] Prenner JL, et al. Disease Burden in the Treatment of Age-Related Macular Degeneration: Findings From a Time-and-Motion Study. American Journal of Ophthalmology. 2015;160(4):725-731.e1.
[6] Escher D, Schmidt A, STeiner P, Maurer P, Weissgerber G. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract. Available at: http://www.euretina.org/nice2015/programme/free-papers-details.asp?id=4072&day=0 (link is external) (accessed 16 May 2017)
[7] Tietz J, Spohn G, Schmid G, et al. Affinity and Potency of RTH258 (ESBA1008), a Novel Inhibitor of Vascular Endothelial Growth Factor A for the Treatment of Retinal Disorders. IOVS. 2015; 56(7): 1501. http://iovs.arvojournals.org/article.aspx?articleid=2331210 (link is external).
[8] Nimz EL, Van't Land CW, Yanez JA, Chastain JE. Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. The Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 2016. Abstract 4996. http://www.arvo.org/webs/am2016/sectionpdf/RC/Session_443.pdf (link is external)
[9] Gaudreault J, Gunde T, Floyd HS, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. ARVO Annual meeting abstract. Invest Ophthalmol Vis Sci 2012;53:3025. http://iovs.arvojournals.org/article.aspx?articleid=2354604 (link is external)
[10] Qazi Y, et al. Mediators of ocular angiogenesis. J. Genet. 2009;88(4):495-515.
[11] Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol. 2007;55(6):413-415.


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