A business case assessment for a novel mAb product
An investment company asks you, as its consultant, to advise on whether it should invest £10 million for a 25% share of a company with a monoclonal antibody (mAb) product that binds to and neutralises a cytokine that is clearly linked with causation of severe asthma. This mAb has not yet been tested in humans, but it has been extensively tested in non-clinical studies (toxicology, safety pharmacology, efficacy pharmacology, etc.). How would you assess the products, and how would your advice vary according to features of that assessment? You may make reasonable assumptions about the properties of the mAb, which should be stated.
Monoclonal antibodies (mAbs) are an increasingly important area of development and are utilised in many disease areas (Liu, 2014). The first FDA approved mAb product was used to prevent organ rejection in patients requiring kidney transplants. This product was mouse derived therefore posed an immunogenicity risk. This murine mAb has been followed by the development of chimeric mAbs, made up from both mouse and human regions. More recently, the use of B-lymphocyte cDNA libraries and phage display technology have allowed for the production of totally human mAbs (Singh et al., 2018). This was demonstrated by adalimumab, a mAb directed against tumour necrosis factor-α (TNF-α) and licenced for the treatment of rheumatoid arthritis. The improved immunogenic profile of humanised mAbs means that most modern mAbs under development are fully-humanised (Santos et al., 2018). The development of humanised mAbs can been seen in figure 1.
All mAbs have the same basic structure and are made up from a heavy and light chain. They have a Fab and Fc region and antigen binding sites at the terminal of each ‘arm’, termed the complimentary determining region (CDR). The Fc region is found at the base of the molecule and binds to proteins, immune molecules, and cell receptors, including the FcRn on endothelial reticular membranes. The binding specificity of the mAb is determined by the CDR structure (Moorthy et al., 2015). Figure 2 shows the typical structure of a mAb.
Humira alone generated some $20b of revenue worldwide in 2018, due to decrease to $13b by 2024 because of biosimilar competition following patent loss (Statista, 2020). The 2018 sales represent under a fifth of total revenues from biologics that year (Statista, 2019) which clearly shows the high marketability of biologics and the huge potential for generating revenues if an efficacious product can be developed, even after loss of exclusivity.
Severe asthma as a disease area
Asthma is a chronic disease and affects over 300m people worldwide, this figure is predicted to grow to over 400m by 2025 (Peters et al., 2006). The prevalence of asthma in the USA and EU is quite similar at 8% for adults and 8-9% for children. Asthma can present with different intensities and is defined by the level of treatment required for control (Chen et al., 2018), such as the need high dose inhaled or oral glucocorticoids and the frequency of exacerbations (Chung et al., 2013). For patients with severe asthma the consequences are serious and may be life-threatening. There is no consensus over the prevalence of severe asthma, estimates are from 2-38% (Hekking et al., 2015). This wide range is thought, at least in part, to be due to hospitalisations for individuals with uncontrolled asthma, opposed to those who would truly be classed as severe (Vianello et al., 2016). Recent ERS/ATS guidelines have cleared up a few diagnostic complications and define severe asthmatics as, those who “require high doses of controller medications” (Chung et al., 2013). Despite severe asthma accounting for only a relatively small number of individuals, it is a significant factor in global disease burden (Chen et al., 2018). Severe uncontrolled asthma has a disproportionate impact on healthcare resources and patients suffering from severe asthma and poor asthma control have significant unmet needs (Bahadori et al., 2009).
The emergence of biologics in this disease area has led to a considerable improvement in severe asthma control however, most of these new products only treat allergic and eosinophilic asthma (Canonica et al., 2016) Furthermore of these targeted patients, up to 30% of them have not seen improvements in spite of meeting all eligibility criteria which highlights the difficulties in addressing this disease area. High patient variability and lack of clarity over causal mechanisms for severe asthma (Caminati et al., 2016) are thought be at the root of this issue. Further difficulties in development of drugs for severe asthma surround the lack of reliable biomarkers that are predictive of a clinically significant improvement (Humbert, Busse and Hanania, 2018). High eosinophil count has been linked to disease severity (Kerkhof et al., 2018), but again, there is high variability between patients (Mathur et al., 2016). For example, mepolizumab shows a reduction of blood eosinophils but lung function and FeNO values do not always correlate (Ojanguren, Chaboillez and Lemiere, 2018).
Quality-of-Life (QoL) measures can be used as outcome parameters but these appear to be more relevant for allergic asthmatics, opposed to severe asthmatics (Chen et al., 2018). Furthermore, benefits to QoL are subjective and are impacted by a range of factors such as the length of time the patient has had the disease and the patient’s lifestyle, activity level and age (Caminati et al., 2016).
Severe asthma is a chronic condition and as such, any treatment will be long-term. Therefore, the safety of biologic drugs is of paramount importance Cardiovascular concerns such as those that relating to omalizumab must be totally avoided (Iribarren et al., 2017).
Cytokines linked to Asthma
Current Ab products for asthma target IgE, IL-4 or IL-5. While these products have shown varying degrees of efficacy, the biologics have not been compared trials. While there is some advice to guide selection, it is unclear whether some patients will respond better to one medication than another (Bleecker et al., 2018).
For the purposes of this assignment, as assumption is made that the proposed mAb product is novel and targets a cytokine that has not previously been addressed, IL-17.
IL-17 has been shown to be a potent inflammatory inducer and elevated levels of IL-17 can be considered to be a causal factor in the development of severe asthma (Roussel et al., 2010). It promotes airway eosinophilia (Zhao, Yang and Gao, 2011) and contributes to the structural alterations of the airways seen in asthmatics (Al-Muhsen et al., 2013). It has further been linked to neutrophilic asthma and appears to have a role in treating asthma for patients who have become steroid resistant (Chesné et al., 2014). Figure 3 summaries the evidence to support a role for IL-17.
Assessment of the product
Biologics are associated with a wide range of adverse effects and drug development fall-out is commonly due to safety failures or an inability to demonstrate efficacy. Many products have been withdrawn or discontinued for these same reasons. For example, Biciromab. By comparison Imciromab was withdrawn by its manufactures based on production costs alone and the impact that had on its profitability (Lefranc et al. 2009).
For the purposes of the assignment, the proposed mAb drug candidate will be referred to a CmAb (Candidate mAb). It is assumed that any differences between cynomolgus IL-17 and human IL-17 are very small, if any exist at all and that the mAb in question displays a comparable inhibitory effect against both types of cytokine. As such, findings from the non-clinical stage of development should be indicative of the drug properties in patients. It is further assumed that IL-17 as a target has been validated and that CmAb has bene optimised for engagement of this antigen. Furthermore, it is assumed that preclinical testing done thus far has shown no alarming results that warrant further significant development of CmAb as a therapeutic product.
Affinity, Specificity and Penetration
mAb mode of action centres around an Antibody-Antigen (Ab-Ag) interactions. This is most often measured by the equilibrium dissociation constant (Wang et al., 2017). As the mechanism of action of mAbs is due to its binding to a ligand, in-vitro binding assays can be used a surrogate measure of likely efficacy and an assessment of mAb candidate molecules.
CmAb must recognise and readily bind to the cytokine IL-17. The higher this binding affinity, the more potent the product is and the more efficacious it is likely to be (Bee et al., 2013). Additionally, mAbs with higher affinities will have a reduced cost of goods (COG) as a smaller volume will be needed to have the desired therapeutic effect (Shukla et al., 2017). Functional cell-based assays can be used as a proof of concept for CmAb and its potency (Tada et al., 2014).
Target specificity is one of the most critical key features of a mAb product. Tissue cross-reactivity (TCR) studies are used to determine any off-target binding from the investigational product as well as, identifying unexpected areas of on-target binding (Leach et al., 2010). If CmAb demonstrates exclusive on-target biding and that this on-target binding is in the expected tissues and areas, it strengthens its proposition as a viable therapeutic product.
CmAb must be able to penetrate tissues quickly and effectively. If the product is unable to enter cells, it can aggregate and will lead to a reduction in efficacy and increase in the rate of catabolism and can lead to immunogenicity problems (Shire, 2009). Furthermore, interactions if mAb products with immune components can lead to a number of problematic effects such as “antibody-dependent cellular cytotoxicity (ADCC)”, “complement-dependent cytotoxicity (CDC)”, and “antibody-dependent cell-mediated phagocytosis (ADCP)” (Wang et al., 2017). Therefore, the interaction between CmAb and the human immune system must be characterised.
The potential for a mAb product to be a good drug is determined by its half-life. It must stay in the circulation, unchanged for sufficient time in order to act on the target, before being safely eliminated. The longer the half-life, the less often it will need to be administered, which has impacts on both cost and convivence to the patient and in the case of a chronic disease such as severe asthma, this is crucial. The structure of the molecule is critical to its half-life, scFv (single chain variable fragment) lack the Fc domain and so are unable to interact with and bind to the FcRn region on membranes (Tabrizi, Tseng and Roskos, 2006). As a result, these molecules have significantly reduced half-life, as quick as 30 hours, these low molecular weight molecules are also able to be renally eliminated from the body (Roskos, Davis and Schwab, 2004). If CmAb half-life is too low, the product must be modified by making additions to the Fc domain or the addition of polyethylene glycol (PEGylation) on the Fab fragments (Keizer et al., 2010).
The assumed structure of CmAb as a complete antibody should mean that it has a relatively long half-life but, this must be determined in order to ensure it will stay active in the patients for 8 weeks, allowing for bi-monthly administration of CmAb, in line with other competitor products.
Immunogenicity and Toxicology
Toxicity of mAbs is usually due to the inhibition or enhancement of target cell activity for example, immunomodulatory mAbs can activate or suppress the immune system however, toxicity can also occur due to on-target binding in undesired tissues (Brennan et al., 2010). For example, cardiotoxicity with use of trastuzumab (Bria et al., 2008). As such, the prevalence of these toxicities is inherently linked to the presence of the target antigen and its expression in normal body tissues and under normal body functions. It is therefore necessary to determine and define the potential areas of toxicity that are likely to occur with the use of any mAb product. The Fc region can be modified in order to alter antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) which both have on off- and on-target toxicities. IL-17 is thought to be overexpressed in severe asthmatics (Chesné et al., 2014) and so, this should reduce the chance of CmAb-associated toxicities however, this must be carefully monitored throughout clinical development.
While the use of NHPs should represent a comparative disease model, transgenic models can also be used to determine potential toxicity. CmAb must show low systemic toxicity and low toxicity in body organs to be considered for further development. No changes in bodyweight, haematology, neurobiology, cardiovascular & respiratory function, or pathology can been seen.
Bridging or immuno- assays determine the potential of anti-drug-antibody production and are significant in this case as patients are suffering from chronic diseases. if ADAs are detected, this will be a significant problem for the development of CmAb. ADA response can reduce efficacy and induce adverse events (Gorovits et al., 2018). For example, the ADA response of anti‐TNF mAbs leads to a total loss of efficacy (Prado, Bendtzen and Andrade, 2017) ADAs can also impact on clearance and therefore, half-life, as demonstrated in mAb products including, infliximab (Moots et al., 2017).
Immunosuppression can result from the chronic administration of anti-inflammatory mAbs which reduce T- and B- cell activity, if this is observed it can increase the risk of opportunistic infection (Rychly and DiPiro, 2005). Non-clinical testing in NHPs should show that this is not a likely outcome from chronic administration of CmAb (Brennan et al., 2010)., As this is not a guarantee of immunogenic effects prior to First Time in Human dosing (FTIH), this again is something that will require close monitoring through drug development.
Allergic Responses and CRS
Aside from the adverse effects previously discussed mAbs have been shown to cause allergic reactions, due to interactions of attached carbohydrate molecules such as occurs with cetuximab (Chung et al., 2008). The occurrence of allergic reactions is problematic for asthmatics and needs to be eliminated as a possibility if CmAb is to progress through development.
Cytokine release syndrome (CRS) is a severe immune reaction that occurs in response to immunotherapy where there is an elevation in inflammatory cytokines (Catapano and Papadopoulos, 2013). While this is usually a concern for immune-based therapies it is still a concern and its risk must be determined. In-vitro cytokine release assays must show that CmAb does not cause the release of cytokines.
Manufacture and CMC
Development of a manufacturing process for a protein requires the consideration of many different factors including purification and scalability of techniques and materials (Shukla et al., 2017).
Cellular impurities can be immunogenic (Sharma, 2007) or carcinogenic (WHO, 1998), particularly when originating from microbial systems (del Val et al., 2012). Lack of aseptic conditions can lead to the introduction of pathogens and endotoxins, which can severely impact on patient health (Shepherd, Wilson and Smith, 2003). It is therefore critical that the manufacturing process is robust, controlled and verified.
When scaling production, changes to the mAb structure must be minimised as the chance of protein aggregation and fragmentation can impact on efficacy and immunogenicity (Rosenberg, 2006). The production method must maintain material and processes within acceptable ranges when production is scaled up for the development of CmAb as a marketable product (Kelley, 2009).
Product Characteristics Review
Assuming that CmAb showed no concerning results with any of the non-clinical testing it is reasonable to assume that it has a good safety and efficacy profile. Provided it has a half-life is around 8 weeks it would also fit with the dosing schedule of other, similar mAB products on the market for (severe) asthma and if it can be formulated as an at-home subcutaneous auto-injecting pen, it will improve its marketability and acceptable by purchasers and prescribers alike.
Assuming the manufacture process can be safeguarded and scaled appropriately, there does not appear to be any areas of concern that would impact on an assessment for investment.
If CmAb has an uncertain safety or efficacy profile, it will need to be reformulated and as such, an assessment over its acceptability as an investment cannot be made.
Despite decades of advances in drug product manufacturing, pharmaceutical process development and approval is still extremely lengthy, highly expensive and uncertain (Paul et al., 2010). When considering the successful clinical development of a biologic agent, the overall success rate is estimated at 31% (Jayasundara, Keystone and Parker, 2012). Figure 4 shows a graph of the projected market size of pharmaceuticals until 2024 which demonstrates the huge potential for drug that are able to make it past these developmental (and funding) hurdles.
When looking at similar products in the same therapeutic areas, we can compare revenues generated from the 2018 company annual reports. Novartis’s Xolair product generated $1,039m in global net sales in 2018 and is clearly the market leader (Novartis, 2018). Global sales of GSK’s Nucala generated £563m in 2018, up 64% AER. US sales represented £341m alone (GSK, 2018). AstraZeneca’s Fasenra has a global market share of 20% and sales of $297m in its first full year (AstraZeneca, 2019). Data on Teva’s Cinqair (reslizumab) and AstraZeneca’s Tezepelumab product were not publicly available
Fasenra has had an application to widen its therapeutic indications to include Eosinophilic granulomatosis with polyangiitis and hyper-eosinophilic syndrome both of which are eligible for orphan drug designation (AstraZeneca, 2018). While GSK have looked to expand Nucala’s use in children with severe eosinophilic asthma (GSK, 2018) and these areas are likely to be possible targets for CmAB.
The value of the product can be calculated for CmAb based on figures for the total market size estimated from AstaZeneca’s 20% of the global market share (AstraZeneca, 2018) for Fasenra indicating a total market size of $1.485b.
Assuming, due to competition in the therapeutic area, the market share of CmAb amount to only 5% that would generate $74.25 million of revenue annually. US patent lengths are statutory and are granted for 20 years (FDA, 2018). Revenues can only be generated following drug development and marketisation, which can typically take 8 years (Stewart, Allison and Johnson, 2001).
To be conservative, we will assume a ten-year programme of development before CmAb is able to be placed on the market. This therefore represents $742.5m in total revenues during the initial patent period. This figure is only indicative as unforeseen costs, risks and time to development can impact these calculations considerably. Additionally, post-approval marketing costs must also be accounted for and may represent a significant proportion of generated revenue.
Capitalised costs of the biologic drug development programme are estimated as being $427m (Towse, Mestre-Ferrandiz and Sussex, 2012). Although $211.6m of this is attributed to preclinical phase leaving $215.6m as the expected capitalised costs from Phase I through to completion of Phase III.
Notwithstanding the outlined caveats, a £10m investment (assumed to be $13m at a normalised late-January 2019 rate) in the developing company for 25% equity will generate an overall return on investment of $118.73m after the end of the initial 20-year patent, representing an annualised, year-on-year profit of $5.94m.
A core assumption must be made that the intellectual property of CmAb can be protected and patented. If this is not possible, this does not represent a viable business opportunity.
Profitability calculations are made under a conservative 5% market share, for an estimated 10 years of possible sales, assuming a longer than usual development period. This market share is likely to grow as the drug establishes itself on the market, especially due to its unique targeting of IL-17. If market share were to be, for example just 2% more (at 7%) the total return on investment stands at $193m. Further indications can be sought for CmAb as has been the case with competitor products to extend the patent life and open up greater potential sales areas, especially with the exploration of disease areas eligible for orphan drug designation.
Additionally, global trends indicate growing asthma prevalence. Up to 100 million additional diagnoses are anticipated over the next decade (Ferkol and Schraufnagel, 2014). As such, the patient population is growing. Furthermore, NCIE guidelines are encouraging patients to transition from traditional, metred-dose inhalers to powdered-dose inhalers as a result on environmental concerns (NICE, 2019). These PDIs have demonstrably lower efficacy, especially in younger populations (Miyahara et al., 2008) and provide an interest potential area for wider adoption of biologic therapies for uncontrolled asthma.
If the proposed investment was just in CmAb, it would represent a worthwhile business proposition however, as the investment is in the originating company, the potential to benefit from further drug development is a strong additive reason to proceed. Due to the 25% equity stake, any potential development, legal or liability problems to the investing company can be mitigated reducing the overall risk of this investment.
It is therefore the recommendation if this report to invest £10m for a 25% stake in the originator company for this new mAb product, targeted against a cytokine with clear causation in severe asthma.
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