Novartis provides update on pegpleranib Phase III clinical trial program in patients with neovascular age-related macular degeneration (nAMD or wet AMD)

Two pivotal Phase III studies did not show additional improvement in best corrected visual acuity (BCVA) for pegpleranib and Lucentis (ranibizumab) combination treatment over standard of care Lucentis monotherapy[1],[2]

Recent Lucentis EU approval in new choroidal neovascularization (CNV) indication demonstrates Novartis’ strong commitment to innovate and grow Lucentis (ranibizumab) as standard of care in diseases of the retina – Lucentis is the only treatment available for a wide range of CNV conditions
Novartis continues to discover and develop next generation of treatment for neovascular age-related macular degeneration (nAMD) patients with RTH258

December 13, 2016

Novartis today announced initial topline results from two pivotal Phase III clinical studies evaluating the safety and efficacy of pegpleranib in combination with Lucentis^®(ranibizumab) for the treatment of neovascular age-related macular degeneration (nAMD). Studies OPH1002 and OPH1003, sponsored by Ophthotech Corporation, did not meet the primary endpoint of superiority for the pegpleranib and ranibizumab combination therapy, measured as best corrected visual acuity (BCVA) in terms of additional letter gains over ranibizumab monotherapy. At month 12, patients in the pegpleranib and ranibizumab combination treatment groups showed a 10.74 letter BCVA improvement in study OPH1002[1] and a 9.91 letter BCVA improvement in study OPH1003[2]. Patients treated with ranibizumab alone showed a 9.82 letter BCVA improvement in the OPH1002[1] study and a 10.36 letter BCVA improvement in the OPH1003[2] study.

“We are fully committed to innovate and grow Lucentis as standard of care in diseases of the retina and to continue our research in this area. The key message from the data is that the proven efficacy of Lucentis monotherapy was not improved by the addition of pegpleranib”, said Vasant Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis. “Together with Ophthotech we continue to analyze the data. We are confident that underlying data will provide further understanding and guidance on how best to help patients with this disease. Novartis continues researching new treatment options for patients with nAMD, and we are looking forward to the phase III results of our next generation treatment RTH258.”

Data from the OPH1002 and OPH1003 studies, including secondary and exploratory efficacy endpoints, will be presented at a future medical meeting.

About the OPH1002 and OPH1003 studies

The OPH1002 and OPH1003 studies are both randomized, double blind, Phase III clinical trial studies designed to evaluate the safety and efficacy of pegpleranib 1.5mg in combination with ranibizumab versus ranibizumab monotherapy in people with subfoveal neovascular age-related macular degeneration (nAMD)[1],[2]. A total of 1,248 patients over the age of 50 were enrolled across both studies (621 patients in the OPH1002 study and 627 patients in the OPH1003 study)[6] and were randomized to receive either pegpleranib in combination with ranibizumab or ranibizumab alone each month up to the 12 month primary endpoint of the study[1],[2].

The primary efficacy endpoint in both studies was defined as mean change in best corrected visual acuity (BCVA) from baseline at 12 months. A number of secondary and exploratory efficacy endpoints are currently being analyzed across both studies[1],[2].

About nAMD

Age-related macular degeneration (AMD) is a common and degenerative eye condition caused by damage to the macula[3], and is globally ranked as the third most common cause of blindness[7]. The disease is a leading cause of vision loss in people aged over 50 years[3] and impacts an estimated 20 to 25 million people worldwide[4]. It is the primary cause of blindness in industrialized countries[7]. Neovascular age-related macular degeneration (nAMD or wet AMD) occurs when abnormal blood vessels form underneath the macula and cause damage to the cells, particularly if they leak blood and fluid into the eye[8]. Without treatment, vision deteriorates within days[8].

About pegpleranib

Pegpleranib is a 32-mer pegylated DNA aptamer that selectively binds to PDGF-BB and PDGF-AB homo and hetero-dimers, respectively, thereby disrupting the interaction with their cognate tyrosine kinase receptors (PDGF-BB with PDGFR-alpha alpha, PDGFR -ßß and PDGFR-alpha ß; PDGF-AB with PDGFR-alpha alpha and PDGFR-alpha ß). These receptors are commonly expressed on cells of mesenchymal origin such as pericytes[9]-[13].. In a preclinical model, pegpleranib potently stripped neovascular pericytes from the underlying endothelial cells[14]. Pericyte stripping from a neovascular complex may leave the underlying endothelial cells in an unprotected and vulnerable state, thereby increasing their sensitivity to the effects of VEGF blockade[9]-[10],[12],[15]-[17]. Pegpleranib is currently being investigated in Phase III clinical trials for the treatment of neovascular age-related macular degeneration (nAMD or wet AMD)[1],[2],[5]

References
[1] ClinicalTrials.gov. Identifier NCT01944839. Available at https://clinicaltrials.gov/ct2/show/NCT01944839(link is external). Accessed October 2016.
[2] ClinicalTrials.gov. Identifier NCT01940900. Available at https://clinicaltrials.gov/ct2/show/NCT01940900(link is external). Accessed October 2016.
[3] National Eye Institute. Facts About Age-Related Macular Degeneration. Available at https://nei.nih.gov/health/maculardegen/armd_facts(link is external). Accessed October 2016.
[4] Chopdar et al. Age related macular degeneration. BMJ 2003; 326(7387): 485-488.
[5] ClinicalTrials.gov. Identifier: NCT01940887. Available at https://clinicaltrials.gov/ct2/show/NCT01940887(link is external). Accessed October 2016.
[6] Novartis data on file.
[7] World Health Organization. Priority eye diseases: Age-related macular degeneration. Available at http://www.who.int/blindness/causes/priority/en/index7.html(link is external). Accessed October 2016.
[8] NHS Choices. Macular Degeneration. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx(link is external). Accessed October 2016.
[9] Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998; 125:1591-1598.
[10] Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of antivascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006; 168: 2036-2053.
[11] Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008; 22:1276-1312.
[12] Hall AP. Review of the pericyte during angiogenesis and its role in cancer and diabetic retinopathy. Toxicol Pathol. 2006; 34:763-775.
[13] Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 2004; 15:197-204.
[14] Mitchell TS, Bradley J, Robinson GS, et al. RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis. 2008; 11:141-151.
[15] Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008; 8:592-603.
[16] Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004; 18:338-340.
[17] Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011; 473:298-307.