New indication and expansion into immuno-oncology
IND for prostate cancer approved
On 30 December 2015 the FDA approved the investigational new drug application (IND) for NBTXR3 to enter clinical trials for intermediate- and high-risk prostate cancer patients. As well as a potentially large new indication, this is Nanobiotix’s first trial to be conducted in the US. NBTXR3 is being investigated for a total of six indications including STS (Europe/Asia; Phase II/III; in partnership with PharmaEngine), liver cancers (Europe; HCC and metastases; Phase I/II), head and neck cancers (Europe; Phase I/II) and rectal cancer (pilot, run by PharmaEngine in Asia). The US trial will be a Phase I/II, open-label, non-randomised study with two treatment arms and will involve at least three US oncology centres. We expect the results to be reported around mid-2017.
We had already included this indication in our valuation, so make no changes on this announcement. Being the second leading cause of cancer death among men in the US, the indication represents a vast patient population of around 233k new cases and around 29k of deaths per year. We believe the latter is a good proxy for high-risk cases, which we use in our model. Based on this target patient market, and assuming 25% penetration of those patients who receive radiotherapy in the US and Europe, our calculated peak sales stand at €400m (we maintain our assumed price of €20k per patient). Assuming two years for the upcoming pilot trial and another three to four years for a pivotal study and regulatory filing, we estimate launch in 2021 (as previously included in our model).
New preclinical research in immuno-oncology
On 5 January 2016 Nanobiotix announced new plans to expand preclinical research into immuno-oncology. The underlying rationale is the observed effect of radiotherapy (RT) in amplifying the immune system’s response to the tumours it targets. Although this is a new area for the company, Nanobiotix will be able to use its lead product NBTXR3 as it is. The core idea behind this is a so-called immunogenic cell death (ICD) effect, which occurs after the RT. A combination regimen of RT enhanced with Nanobiotix’s NBTXR3 and used alongside immuno-oncology treatment theoretically should have a number of synergies:
■
NBTXR3 mechanistically enhances the effect of the RT without increasing the dose;
■
dual effect of standalone RT:
•
local effect: RT not only directly causes the death of cancerous cells in the specific location where it is targeted, but also changes surviving malignant cells so they become more ‘visible’ to the immune system; and
•
distant effect: due to ICD and other mechanisms, the immune system starts to recognise malignant cells and, if the cancer is spread, a distant anti-tumour effect has been also observed;
■
immunotherapy drugs enable the immune system to fight cancer and can be less effective in cases where a cancer has developed an immune-suppressive mechanism; RT can potentially counteract such mechanisms; and
■
such a multimodal treatment approach could have a greater therapeutic effect without worsening the safety profile or could even improve it if lower doses of RT or immunotherapy are required.
When RT is applied to a tumour locally, the resulting cancerous cell death activates different chain reactions that in turn amplify the immune system’s response to the tumour itself, which is also visible in distant locations away from the treatment field of RT. Several other mechanisms that are responsible for immunogenic potential of RT have also been described.1 For example, besides causing cell death, irradiation can alter malignant cells so they become more visible to the immune system. Such increased immunogenicity of a tumour (ie, whether a cancer is ‘visible’ to the immune system) can potentially enable a better control of the disease and has garnered significant attention in the research community over the past few decades.
More recently, the successful advance of immuno-oncology products has given the ICD effect a whole new perspective. Immuno-oncology drugs are meant to boost a patient’s immune system to fight the cancer, which implies the efficacy of such products depends on the status of a patient’s health and the cancer’s immunogenicity. A variety of different mechanisms have been described, which the cancer uses to shield itself from being noticed by the immune system. This in turn lessens immuno-oncology drugs’ efficacy. Therefore a combination of immuno-oncology treatments with RT looks like a natural fit. This has been investigated in numerous retrospective studies with prospective clinical data still very scarce, although with a number of trials already underway.
The RT dose is one of the key variables that causes uncertainty in modelling combination treatment trials. Some authors suggested that a low RT dose could be the reason why the ICD effect was sometimes not sufficient to observe a better control of cancer. It would follow that higher doses would be beneficial, which is not always possible. Therefore, due to its mechanistic ability (see our initiation of coverage) to enhance the RT without the need to increase the dose, Nanobiotix’s NBTXR3 seems like a natural evolution of a combination treatment. In preclinical trials Nanobiotix will investigate the potential of NBTXR3-enhanced RT in combination with existing immune-oncology products. Although specific oncology products are not disclosed, in our view, some obvious examples would be anti-PD-1/PD-L1, anti-CTLA4 or CAR T-cell therapies.
To date, RT alongside treatment with ipilimumab (Yervoy, Bristol-Myers Squibb; anti-CTLA4; approved for melanoma by the FDA in 2011) is one of the most-researched combinations in this area. Due to ipilimumab’s established clinical use, there have been numerous case studies and retrospective trials published, so this direction can provide some learning points and insights that can be leveraged to expand in other indications.
Early-stage R&D partnerships with companies involved in immuno-oncology seem plausible to us due to the win-win situation enabled by multiple synergistic interactions. Although we see the scientific rationale as sound, it is still the first step and we do not include any immune-oncology projects in our model at this stage. We will revisit this opportunity once Nanobiotix announces more details or, possibly, a new clinical project. Nevertheless, we can see potential for this project to progress rapidly should a partner emerge even before the project enters clinical trials.
