Impact case study database

Biologics are large biomolecular drugs, now ubiquitous in the treatment of human disease ranging from cancer to autoimmune disorders, comprising half of the top-ten blockbuster pharmaceuticals and grossing around USD30billion/year worldwide. Eighty per cent of these biologics are mAb. Researchers at Southampton have played a leading role in bringing two types of anti-CD20 mAb from lab to clinic to treat B cell disorders and inspiring the development of a new class of immunostimulatory mAb to treat cancer.

Clinical and commercial impact of ofatumumab (Arzerra)

Ofatumumab, marketed under the name Arzerra, was developed and patented by Glennie and colleagues in 2004 and licensed from Genmab to GSK in 2006. It was approved by the FDA in 2009 and the EU in 2011 for the most prevalent form of leukaemia, CLL, after Southampton researchers proved it was able to kill target cells resistant to similar drugs (covered in REF2014).

Globally, leukaemia accounts for some 300,000 new cases each year with 222,000 deaths, giving Ofatumumab a wide reach in its first approved indication. In 2016 it was approved by the FDA as a treatment for recurrent or progressive CLL [ 5.1] and for relapsed CLL in combination with Fludarabine and Cyclophosphamide [ 5.2]. Since August 2013 it has been assessed in 99 clinical trials [ 5.3], including in autoimmune conditions such as rheumatoid arthritis, which affects more than 400,000,000 patients worldwide, and multiple sclerosis (MS), which affects 2,100,000 patients worldwide. In MS, exciting phase 3 data (involving 1,882 patients), published in August 2019, was observed (ASCLEPIOS I and II trials), showing that ofatumumab reduced the annualised relapse rate over current treatment (teriflunomide) in patients with relapsing forms of MS [ 5.4].

Ofatumumab’s commercial impact since August 2013 has been highly significant, achieving sales revenues of more than GBP200,000,000, translating to GBP41,000,000 in royalties for Genmab [ 5.5]. GSK’s rights to its use in cancer were acquired by Novartis in August 2015 in a deal worth up to USD1billion (GBP6,500,000,000) [ 5.6].

Clinical and commercial impact of obinutuzumab (Gazyva)

The same programme of Southampton research was instrumental in the selection of a second anti-CD20 mAb, obinutuzumab (GA101, trade name Gazyva). The Head of Oncology at Roche Pharmaceutical Research and Early Development said: “The characterisation of type I and II CD20 mAb by the Southampton Lab and their clear demonstration of increased potency by type II reagents was an important factor in our decision to select GA101 for clinical development. Their pre-clinical work has now been validated in several phase 3 trials and has supported our expansion to new diseases such as lupus” [ 5.7].

Gazyva was the first type II anti-CD20 mAb to be humanised for clinical work. Capable of killing a significantly higher number of cancerous cells than its type I counterpart, and being less subject to internalisation, it was assessed in several multicentre phase III trials involving Southampton lead investigators (e.g. Professor Andrew Davies), head-to-head against rituximab in FL and CLL. Gazyva was shown to provide significantly better responses than rituximab in combination with chlorambucil in CLL and in previously untreated advanced FL patients. As a consequence of this phase III study, the drug was FDA-approved for CLL in November 2013 [ 5.8] and FL in November 2017 [ 5.9], changing frontline clinical treatment of these diseases. It was also approved as the first Non-Chemotherapy Combination Regimen for Treatment-Naïve Patients with CLL, alongside ibrutinib in 2019 [ 5.10].

Since August 2013 there have been 68 clinical trials assessing Gazyva [ 5.11] in multiple settings, from post-transplant lymphoproliferative disorder and renal disease, to lupus where the FDA granted Breakthrough Therapy Designation for adults with lupus nephritis based on data from the phase II Nobility study [ 5.12]. In adult patients with proliferative lupus nephritis, Gazyva, in combination with standard of care, demonstrated enhanced efficacy compared to placebo plus standard of care alone in achieving complete renal response at one year.

The commercial impact has again been highly significant. Sales of Gazyva have grown considerably year-on-year since its FDA approval in November 2013, reaching CHF632m (GBP515,000,000) in 2020 and giving a total of CHF2.2bn (GBP1,700,000,000) over the period. [ 5.13]

Clinical and commercial impact of work involving FcγRIIB mAbs

The added insight from the Southampton team also revealed a novel and unexpected mechanism of resistance for CD20 (and other) mAb through the inhibitory FcγRIIB. The pre-clinical work and partnership with BioInvent International led to the development and characterisation of new fully human FcγRIIB mAb and a first-in-human trial [ 5.14] assessing its safety and utility in B cell malignancies with promising safety and therapeutic profiles in patients.

Patents around this biology have been granted and licensed to BioInvent [ 5.15]. These approaches are also being explored in mantle cell lymphoma and in solid tumours in combination with checkpoint inhibitors such as anti-PD-1 including with a new FcγRIIB reagent (BI-1607) following pre-clinical evidence and mechanistic insight from Southampton. This work led to a deepened association with BioInvent, leading to GBP3,140,000 in funding since 2014. An example of the significant commercial impact arising from this clinical trial programme came in October 2020 when BioInvent and US-based CASI Pharmaceuticals announced an exclusive licensing agreement worth up to USD95m (GBP73,000,000) for the development and commercialisation of novel anti-FcγRIIB antibody, BI-1206, in mainland China, Taiwan, Hong Kong and Macau. [ 5.15]

Promising results from the phase 1/2a clinical trial of BI-1206, in combination with rituximab, for relapsed NHL were published in Blood in November 2020 [ 5.16]. In total 15 NHL patients were recruited to the Phase I trial, all of whom were late stage and had failed conventional treatments, including several lines of rituximab-containing therapies. Notably, of the 9 patients who completed the induction cycle, 6 patients showed either complete or partial responses several of which are still ongoing. Remarkably, two patients achieved a complete response, which continues to be sustained 12 and 24 months later. [ 5.14]

Clinical and commercial impact of the Southampton immunomodulatory antibody programme

Under its immunomodulatory antibody programme, Southampton has developed a range of novel immunostimulatory mAb (CD40, CD27, OX40, 4-1BB) and protein engineering approaches to boost their activity. This led to the discovery and patenting of several of these reagents, including a novel target CD27, immunostimulatory mAb which can promote anti-cancer immunity [ 5.17]. This intellectual property is licensed exclusively to Celldex Therapeutics, USA, who have undertaken several trials with a fully human mAb, varlilumab in combination with nivolumab/atezolizumab/ipililumab etc. in haematological and solid malignancies [ 5.18].