• Darren Wogman

A target product profile (TPP) for ATL-104. Use in Oral Mucositis (OM). Darren Wogman MSc

Updated: May 25, 2021

An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London


1 Product details

1.1 Brand name

N/A


1.2 Trade Name/ INN

N/A


1.3 Product Type

Topical epithelial mitogen (Otte et al., 2001) and possible nuclear factor of activated T cells (NFAT) activator (Fortin et al., 2001)


1.4 Disease Area

HPV sub-population in Head and Neck Cancer


1.5 Target Indication

ATL-104 is intended to decrease the incidence and duration of oral mucositis (OM) in patients with head and neck cancer (HNC) receiving cytotoxic therapy who score >= Grade 3 on WHO OM rating scale. The rationale underlying ATL-104 is that it can regenerate the GI tract post-cytotoxic cancer therapy. Current non-analgesic treatment (Palifermin) requires IV administration proving clear advantage to a swillable/swallowable administration. It is simpler to administer and should not be systemically available (Hunter et al., 2009), reducing the chance of adverse effects.


1.6 Product Vision

ATL-104 will become the first-line preventative treatment for OM. In order to be a success, the substance must not be costly to manufacture and for end-user purchase. As ATL-104 is a recombinant plant lectin produced in yeast cells (Hunter et al., 2009), this should not be costly to produce.


Most marketed products are covering agents, analgesic, anti-microbial or antihistamine in nature, except for the IV administered palifermin growth factor (Beaven and Shea, 2007). The ease of use, self-administration and efficacy of ATL-104 makes this product highly attractive to patients and healthcare providers and accounts for significant potential of market acceptance.


As it requires no specialist administration, can be taken in advance of commencement of cytotoxic cancer therapy, in the patient's own home aiding convenience and reducing the burden on healthcare professionals. Required visits to treatment centres and overall cost of treating and providing palliative care to these patients is therefore significantly reduced.


1.7 Formulation

ATL-104 is formulated into an oromucosal solution, oral rinse. It should not require any specific or novel dosing device, aiding its adoption by healthcare providers and purchasers.


1.8 Manufacture

The mouthwash is produced by making a suspension of the ATL-104 protein in sterile water and necessary excipients to ensure stability in accordance with British Pharmacopia methods for production of liquid formulations. If possible, this should be done with a suitable salt of the ATL-104 protein.


1.9 Background

In healthy individuals, there is a high turnover of mucosal epithelial cells. However, in patients receiving cytotoxic cancer therapy, epithelial turnover is significantly reduced as a result of cellular DNA damage and downstream inflammatory and protective processes (Sultani et al., 2012), thought to involve mucosal mast cell degranulation mediated by T-cell action (Yong, 1997) which leads to mucosa breakdown and the development of OM.


ATL-104 is a recombinant form of phytohemagglutinin-L (PHA-L), produced in yeast cells. PHA-L has proven mitogenic effects on the oral cavity and GI tract in animal models (Linderoth et al., 2005). Use of ATL-104 has been shown in clinal trials to “substantially [reduce] the median duration of severe oral mucositis” (Hunter et al., 2009).

Oral rinses can be incorporated into normal oral hygiene regimens already in place for these patients and therefore increase treatment adherence in individuals on several medication and treatment regimens. Patients are likely to already be brushing their teeth 2-4 times a day, in line with guidelines for OM prevention (UKOMiC, 2019) and the inclusion of an oral rinse in this process is not considered burdensome.


1.10 Mode of action

PHAs have been shown to induce proliferation, MAPK activation and c-fos mRNA expression (Otte et al., 2001). They contribute to GI mucosa growth and regeneration by selectively binding to specific carbohydrate molecules of GI epithelial cell brush borders. It is thought that this causes reversible (Linderoth et al., 2005) growth and an increase in cell length and mitotic activity (Pusztai et al., 1990).


The increase in mitotic activity replaces damaged cells in the mucosa, restoring function and integrity to the tissue while reducing ulceration and other symptoms of OM.


1.11 Dosing and Administration

15ml of mouthwash at 50mg/ml concentration. Given twice a day for 6 days at the start of each chemo-/radio- therapy cycle. It is expected that there will be use covering at least a 6 month period.


All other dosing and administration should be as per the IB.


Comparisons with other mitotic inducers, namely the IV administered palifermin (human growth factor) indicate that the drug should not be administered within a day either side of myelotoxic chemotherapy however, it is unclear if this is as a direct result of the administration route or a pharmacodynamic/kinetic effect (Dailymed.nlm.nih.gov, 2018). No additional dosing considerations are provided in the literature.


1.12 Safety



1.12.1 Contraindications

No contraindications have been established


1.12.2 Adverse Events

ATL-104 is assessed to be safe and well-tolerated.


ATl-104 acts locally and is not readily absorbed in the gut, reducing systemic exposure and the chance of developing adverse effects.


No evidence shows that ATL-104 may be an irritant. No effects were seen from the safety pharmacology battery. No significant haematology, biochemistry or urinalysis changes are attributable to the drug.


1113 adverse events were recorded for 62/63 individuals, with 143 (14%) being serious. Of these, 346 events were determined to be related to the treatment. Most adverse effects reported were mild or moderate and the prevalence of these was the same across all treatment groups and placebo. Where adverse effects were reported, these were generally GI distress symptoms and likely to be a result of concurrent treatment. 15% of reported events were thought to be related to the treatment. It is therefore unlikely that additional adverse effects will occur that are related to the specific treatment in future.


Adverse effects reporting for palifermin (skin rash and increase in cataract incidence) are likely due to as a result of this drugs mode of action and warrant no concern for ATL-104.


1.12.3 Overdose

No data are available regarding overdosage and preclinical data highlights lack of systemic exposure to warrant any concern in this area.


1.12.4 Abuse/Potential dependency

No data are available regarding abuse potential and preclinical data highlights lack of systemic exposure and impact on CNS and neurological systems to warrant any concern in this area.


1.12.5 Effects on ability to drive

Not relevant. No data are available regarding effects of ability to drive and preclinical data highlights lack of systemic exposure to warrant any concern in this area.


1.12.6 Drug Interactions

As a protein therapeutic, the risk of drug interactions is low. Pre-clinical studies failed to identify any likely interactions. Due to local action and lack of systemic exposure it is unlikely that ATL-104 will cause any drug interactions in Cytochrome P450 enzymes or protein transporters.


However, there are suggestions that it can impact on absorption in the GI tract for a few days post-administration, although this is thought to resolve with time.


Palifermin is indicated in an interaction with heparin. While it is suggested this results from concurrent IV administration of both drugs, it is something that should be considered and on balance of being cautious, should be avoided.


1.12.7 Stability

ATL-104 is shown to be stable under normal conditions as per the IB.

1.12.8 Storage

ATL-104 should be stored under the conditions outlined in the IB


1.13 Efficacy

Animal Models:

The treatment has been shown to stimulate mitosis and regeneration of the GI tract of rats after administration of cytotoxic, chemo-therapy drugs (Linderoth et al., 2005). Preclinical studies also indication a change in GI mass of the dog, indicating the growth of this tissue and likely efficacy.

Clinical Trials:

Primary endpoint: The incidence of maximum severity and duration rating scale assessments.

Secondary endpoint: Area under the curve (AUC) of the mucositis score.

Number of additionally required hospitalisations related to OM.


The extent and severity of OM was assessed by the standard rating scales from the World Health Organization (WHO) and Western Consortium for Cancer Nursing Research (WCCNR).

A reduced duration of mucositis was observed in patients treated with ATL-104 when compared to the control.


Median duration of symptoms of 2 & 3.5 days, depending on dosage provided for active groups compared to 10.5 days in placebo group. Statistical analysis using the Wilcoxon two test showed a statistical difference un median duration to the placebo group (p <0.001).


When severity and duration were assessed via AUC, the average score reduced by 18-25% compared to the control. Improvements seen with the WCCNR Scale were in line with these.


These efficacy results are comparable with those seen in palifermin clinical study (Hunter et al., 2009).


1.14 IP Strategy

Initial patent granted for use of plant lectins (EP97927282) has since been challenged and revoked (EPO.org, 2019). IP will then be sought for ATL-104 specifically as it is a recombinant product and able to be protected.


1.15 Upsides

Once this product is successfully commercialised for its use in the HPV sub-group of HNC, this product can be re-indicated for use in other orphan-eligible patients suffering from high OM incidence, which is thought to affect up to 75% of all cancer patients that require some form of cytotoxic therapy and more in paediatric cases (Miller, Donald and Hagemann, 2012). This clearly represents a significant number of potential users and benefit.

2 Competitive Analysis

2.1 Prevalence/Market size/Projections

The market size for an effective OM treatment in HNC patients in America, Europe and Japan was estimated in 2010 at being $1.5b annually (Redington Inc, 2010) while South Korea’s Enzychem Lifesciences Corp estimate $2.6b in sales can be generated from the production of a successful OM therapy.


This has undoubtably grown as the patient population has increased and unmet need has not been addressed.


2.2 Competitive Environment

Alternative Therapies

Amifostine Amifostine has been indicated for use in HNC patients suffering from xerostomia (Santini, 2001) however, a systemic review performed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) found no clinical improvement for tis use in treating OM (Nicolatou-Galitis et al., 2012). Amifostine is thought to act as a chemoprotectant via its action as an anti-ROS free radical scavenger as well as roles in inducing cellular hypoxia, DNA protection and repair (Kouvaris, Kouloulias and Vlahos, 2007).


Extensive systematic reviews by Cochrane Institute have shown only 3 treatments with demonstrable, albeit uncertain, efficacy in reducing OM severity (Clarkson et al., 2010, Worthington et al., 2011).


Palifermin

Palifermin is a keratinocyte growth factor and has a similar mode of action to ATL-104, in that it induces mitosis, although this is through the activation of other cellular processes. It is indicated for use in treating OM in hematopoietic stem‐cell transplantation (HSCT). IV palifermin administration has shown efficacy and is used to prevent OM. However, due to the cost and inconvenience of requirement attendance at a specialist treatment centre, it is not often used in patients who might otherwise benefit from it (Negrin and Toljanic, 2019). It has also not been indicated for use in HNC patients and has since been withdrawn from the European market (EMA, 2016).


The palifermin product, Kepivance has a “[potential to stimulate tumour] growth and [has not been indicated for use in any non-hematologic cancers.].” Adverse reactions are seen in over 20% of users and include “rash, fever, elevated serum amylase (Grade 3/4), pruritus, erythema, and [oedema]”. Concurrent use of Heparin has been shown to increase systemic drug exposure. Clinical trials highlighted the following adverse effects: “rash, erythema, oedema, pruritus..dysesthesia, tongue discoloration, tongue thickening, alteration of taste, pain, arthralgias, and dysesthesia” (Dailymed.nlm.nih.gov, 2018).


Cryotherapy

Cryotherapy has also been shown to reduce the severity of OM symptoms if used during chemotherapy infusion. The rationale behind this is that sucking ice chips results in vasoconstriction and therefore reduced blood circulation in the mouth, thus limiting the exposure of this area to chemotherapeutic agents. As these agents tend to have a half-life of ~20 minutes, Cryotherapy taken for up to 45 minutes prior to and immediately following chemotherapy infusion lowers the incidence of OM when compared to ‘good oral hygiene practices’ (Rocke et al., 1993).


Photobiomodulation (PBM)

PBM or, Low Level Laser Therapy (LLLT) has been shown, in some cases to reduce OM intensity. It is thought to work by interacting with mitochondrial cytochrome c oxidase (CcO) (Karu, 2010) reducing oxidative stress and causing an increase in ATP production and cellular metabolism. Literature suggests a cascade of downstream metabolic effects including the release of growth factors and reducing in inflammatory markers. It has been shown to improve wound repair and promote tissue growth, proliferation and remodelling (Hawkins and Abrahamse, 2005). MASCC/ISOO clinical practice guidelines highlight the use of PBM for HNC patients and those having hematopoietic stem cell transplant therapy (Lalla et al., 2014).

The application of PDM therapy requires costly specialist equipment, patient visits to specialist treatment centres and specific training for those administering the treatment. While this is a promising area for development, there are significant impracticabilities for its use for widespread populations of OM patients.


Promising therapies under development

While not exhaustive, the following constitutes the state of development in several drugs being produced and marketed for treatment of OM and may inform potential future competition in the market.


Brilacidin Oral Rinse

A Brilacidin Oral Rinse is currently undergoing clinical trials to determine efficacy in OM and does appear to be yielding positive results (Clinicaltrials.gov, 2019a). Its mode of action is thought to be through the inhibition of Phosphodiesterase 4 (PDE4) (Kumar et al., 2013). It has been designated with fast track status by the FDA. Innovation Pharmaceuticals Inc have applied for authorisation to move into Phase III trials with this product (Innovation Pharmaceuticals Inc, 2019).


Mosedipimod capsule

Mosedipimod is currently undergoing Phase II clinical trials to determine if its immunomodulation function can reduce OM severity (Clinicaltrials.gov, 2019b). Its mode of action is thought to be that of a cytokine and immune cell stimulator. It has been granted Orphan status for neutropenia (NIH - National Cancer Institute, n.d.).


Dusquetide

Dusquetide is an Innate Defence Regulator thought to treat OM by treating the innate immune dysfunction that underlies OM (Kudrimoti et al., 2016). It is formulated as IV administration and is currently recruiting for Phase III trials, having been granted Fast Track status by the FDA (Clinicaltrials.gov, 2019c).


Samital oral rinse Samital is a blend of botanical extracts that are thought to protect the mucosal tissue and increase the proliferation of fibroblastic cells (Pawar et al., 2012) and has demonstrated in Phase II trials to significantly reduce the severity of OM in HNC patients (Clinicaltrials.gov, 2018a). The specific mode of action is multi-faceted. A mucosal tissue barrier is formed, maintaining capillary integrity. Inflammatory cytokine production is blocked through the inhibition of NF-kB. Prostaglandin and leukotriene production are also inhibited. Tumour necrosis factor alpha and other inflammatory cytokines are also inhibited (NIH - National Cancer Institute, n.d.). While highly promising this drug is yet to move into Phase III trials.


Avasopasem manganese

Avasopasem manganese has received Breakthrough Therapy and Fast Track designations from the FDA and is currently recruiting for Phase III trials to determine efficacy in treating OM in HNC patients (Clinicaltrials.gov, 2018b). This drug is a dismutase mimetic that works in away like superoxide dismutase enzymes preventing damage to off-target tissues following radiotherapy. It is also thought that the reaction of superoxide into hydrogen peroxide may increase efficacy of stereotactic body radiation therapy (SBRT) on the treatment and targeting on cancerous cells (Galera Therapeutics Inc, 2019).


Rebamipide

Rebamipide is a mucosa protectant used in Asia, primarily of the treatment of peptic ulcers, gastritis and Behçet’s Disease (Matsuda et al., 2003) it is thought to work in several ways including induction of prostagladins, up-regulation of growth facts, induction of mucus secretion and inhibition of inflammatory cytokine release (Yasuda et al., 2011). The literature suggests the use of this as an oral rinse following small scale studies (Akagi et al., 2019) although, it has not been approved for use by FDA and is not indicated for the treatment of OM.


2.3 Comparator(s)

There are no other PHA-based products on the market nor, in development.


3 Commercialisation strategy


Orphan drug designations will be sought from the FDA and EMA in HPV related HNC indications. ATL-104 will be developed and taken through Phase III clinical trials. The drug will be further developed for commercialisation and launched onto the American and European markets. Following the products’ establishment in these markets, marketing authorisation will be sought from the PMDA and the relevant clinical data imported and where necessary additional clinical trials be carried out.


3.1 Customer Insight Opportunities

The Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO), UK Oral Management in Cancer Care Group (UKOMiC), The Oral Cancer Foundation.


3.2 Main User Groups

Healthcare professionals and practitioners who are able to prescribe medication to HNC patients.


3.3 User Needs

Users will expect greater efficacy in OM reduction from ATL-104 when compared ot current treatments. These are rather limited as it stands sand ATL-104 should therefore meet this need as the mouthwash product has demonstrated efficacy in clinical trials (Hunter et al., 2009).


As OM has been demonstrated to result in treatment delays, complications and early withdrawal of cancer treatments for patients (Oronsky et al., 2018), users will expect greater adherence from patients to these chemo-/radio- therapy programmes. This will result in an increase of successful treatment outcomes for HNC patients and lower their overall treatment burden as a result of fewer hospitalisations and the ability for this product to be administered at home, without the need for clinician involvement in a treatment centre.


3.4 Target Patients

Adult HPV-related HNC patients diagnosed with OM.

3.5 Patient unmet needs

There is significant unmet need not least with regards to the economic impact, but patients suffering from severe OM may require tube feeding, are much more susceptible to infection, and are significantly more likely to require further hospitalisation as a result. Patients with OM experience severe pain and debilitation and are experience significantly higher discontinuation rates for their cancer treatment (Lalla et al., 2014). Patients who discontinue treatment will clearly experience higher mortality.


ATL-104 treatment can reduce the severity of OM and allow patients to continue to self-feed and require fewer hospital admissions. Increasingly the likelihood of cancer treatment adherence and continuation at therapeutically efficacious dose ranges, ultimately improving survivability outcomes (Hunter et al., 2009).


There is no other compelling treatment for OM currently on the market that reduces OM severity in this way. The only alternative is PBM therapy which is impractical and costly to implement. ATL-104 mouthwash can be self-administered at home and is likely to have high adherence as a result.


3.6 Target Purchasers

Local health trusts and authorities, global health authorities and private healthcare providers with a requirement for drugs to treat OM.


3.7 Purchaser Needs

Purchasers will require demonstrable efficacy improvements when compared to available treatments and standards of care of good oral hygiene and PBM therapy. Efficacy for ATL-104 has been demonstrated in clinical trials (Hunter et al., 2009). As treatment of OM reduces the need for tube feeding, opioid analgesics and overall hospital admissions, the use of ATL-104 will result in significant cost savings for managing mucositis and HNC patient care (Hunter et al., 2009).


There will be an increase in successful treatment outcomes as a result of higher rates of cancer therapy adherence due to the treatment of OM.


Purchasers will expect the ATL-104 to be easy to store and maintain a long shelf-life. In order to meet this expectation, the product will be formulated to be as stable as possible. This can be achieved through lyophilization (Telikepalli et al., 2015) and reconstitution with appropriate buffered vehicles and stabilisers at the point of drug dispensing.


Purchasers will also expect that ATL-104 can be produced at a cost low enough to make use of the drug viable. Estimations of cost for GMP manufacture of the product from manufacturing CROs has shown that ATL-104 may be manufactured for a relatively low price.


3.8 Wider Impact

3.8.1 Social Impact


OM has been suggested to affect nearly all HNC patients (Trotti et al., 2003). With a median treatment cost increase of $18-$25k per patient where increased hospitalisations represented up to $14,000 of these (Nonzee et al., 2008). Further costs include the treatment of infections as a result of the disrupted mucosa and tube feeding as a result of ulcerated oral cavity (Yokota et al., 2014). OM is a significant cause of cancer treatment discontinuation, alteration or delay (Sonis et al., 2004). This clearly has an important impact on overall survivability outcomes for those undergoing cancer treatment as well as the economic burden placed on healthcare providers, users and systems. A chemotherapy cycle is thought to cost $4k without mucositis and over $9k per cycle with mucositis as a result of increased hospitalisations and further costs would be incurred as a result of pain management and tube feeding (Elting et al., 2007).


Around the world, HNC accounts for around 700k new cases each year (Drake, 2017). There are currently no FDA-approved drugs for the prevention of OM in HNC patients who receive chemo-/radio- therapy. Greater adherence to cancer treatment and the reduction in associated costs from treating OM and its complications will relieve a significant financial burden at all levels and will have a profound social impact in all markets where HPV-related HNC patients are treated.


3.8.2 Medical Impact

There has been little advancement in the treatment of OM. Where treatments are in place, they require clinician administration and often are administered during delivery of cancer care. OM causes significant secondary health complications of infection notwithstanding the requirement of tube feeding and in ability to take drugs orally.


ATL-104 is expected to work locally, by directly interacting with the oral mucosa, promoting its repair and regeneration. As this product is formulated in a swallowable mouthwash, it can be self-administered by patients in their home. Due to its local action, it should not reach the systemic circulation and is therefore unlikely to have adverse effects above and beyond mild GI interactions which, might otherwise further complicate cancer care.


Once ATL-104 has been successfully commercialised for its use in the HPV sub-group of HNC patients, the product could be further developed for other orphan cancer patient indications that suffer from OM for example pharynx, larynx, nasopharynx and hypopharynx HNCs which would all qualify for orphan designation from both the EMA and FDA as they affect less than 1 in 50,000 patients and affect less than 2000,000 patients in the US (ASHA.org, n.d.).


3.9 Development Plan

We plan to apply for orphan drug designation approval with the EMA and FDA. We will also seek parallel shared advice (PSA) from both agencies as per the SOPP 8001.6 guidance (FDA.gov, 2019) in order to ensure that approval requirements will be met expeditiously.


Clinical development work will be conducted both within the UK (an EU state at the time of writing) and the USA to ease this process and ensure sufficient patient recruitment. This parallel application will accelerate the process of introducing the product into other markets should the company wish to in the future. Additional benefits of the FDA Orphan Drug programme include 50% tax credits for trials, improved approval times and patent exclusivity for up to seven years (Cheung et al., 2004).


In order to achieve these plans the following will be required:


6-month repeat-dose toxicity in Sprague-Dawley rats

9-month repeat-dose toxicity in Beagle dogs 104-week carcinogenicity study in Sprague-Dawley rats 26-week carcinogenicity study in transgenic mouse 23-week reproductive toxicology study in Sprague–Dawley Rats (Wolfe, 2010)

Immunogenicity assessment (FDA.gov, 1997)

Pivotal Phase III study in marketable formulation of ATL-104


3.10 Delivery System

N/A

4 Estimated Cost of Development


Further development costs estimated to be around £52.5m made up from £50m estimated for Phase III trial and follow-up as well as the following preclinical studies:


Repeated-dose toxicity testing needs to be carried for 6 months in rodent (156 Sprague – Dawley rats) and 9 months in a non-rodent species (32 beagle dogs) with a cost estimate of $350k and $550k respectively (Wolfe, 2010). As ATL-104 is a gene product, the production of anti-drug antibodies against ATL-104 should be determined during these dose toxicity studies but could cost $200k if carried out as a standalone study (Wolfe, 2010).


Carcinogenicity studies must be carried for this patient population. This is a 104-week study in many rodents, for example 480 Sprague-Dawley rats and has an estimated cost of $1m as well as an additional test in transgenic mice which has an estimated cost of $650k (Wolfe, 2010).


As reproductive toxicology has not yet been carried out, this also needs to be done and are estimated to cost anywhere between $425,000 (Wolfe, 2010).


As ATL-104 is a biologic, it will require immunogenicity testing (FDA.gov, 1997). This is estimated at $250k and will involve 48 Sprague – Dawley Rats being assessed over a 8 week period (Wolfe, 2010)


4.1 Success Estimate

The FDA’s cliniclatrials.gov page shows a total of 13 withdrawn, 20 terminated and 2 suspended studies for indications of OM. A further 39 studies have an unknown status. 156 studies have been completed although, most of these do not have data available to see in order to determine if these have been successful in their aims. Of these 156, only 38 of them are Phase III studies. Just 7 Phase III studies are currently recruiting, one of which is for PBM therapy (clinicaltrials.gov., n.d.)


Systematic reviews have found only 3 treatments to benefit OM. One of these, palifermin has already been withdrawn from the market and cryotherapy and PBM being the others, leaves a clear gap in the market for a treatment like ATL-104. In the case of palifermin, withdrawal was a commercial decision. With orphan designation and appropriate pricing, this drug is likely to be a successfully marketed product once it has received approval from the regulatory agencies.


A recent review found the success of drug moving from Phase III to marketing approval ranges from around 50% - 75% depending on the indication, with an overall approval rate of 59% (Wong, Siah and Lo, 2018). Success estimates of orphan drugs are higher and estimates for biologic drugs are also considered to be greater than small molecule entities (Fagnan et al., 2014), this is likely to be due to myriad reasons and complications. Efficacy at Phase III and appropriate pricing and marketing strategies should ensure success of ATL-104.


4.2 Current Cost of treatment

The cost for treating OM has been estimated to be ~$25k per patient (Nonzee et al., 2008, this excludes secondary costs of prolonged or discontinued cancer care and treatments of secondary infections.


4.3 Pricing Strategy

The most comparable drug, palifermin was priced at $8k for a 6-day course. This correlated to an unclear OM reduction, with some studies showing no benefit at all compared to placebo (Blijlevens et al., 2012) and ultimately was not accepted by the market and withdrawn for commercial reasons.


The demonstrated efficacy and narrow indication of ATL-104 as a treatment of OM in HPV-related HNC patients should mean it is better positioned for up-take by the market. Its orphan designation further supports pricing at an attractive position. Potential use for off-label usage should also be borne in mind when considering the marketability of this drug and potential post-approval market penetration.


OM has been shown to significantly impair global health status and disutility in both the EQ-5D-3L and EORTC QLQ-C30 models (Hagiwara et al., 2017). Additionally, the ability to continue with cancer treatment means that ultimate QALY outcomes for these patients are considerable. Orphan drugs are typically reimbursed at £100k-£300k per QALY under NICE guidelines. Provided these drugs have a net NHS budget impact of less than £20m per year, within their first three years there should not be any further commercial discussion regarding their use (NICE, 2017).


On the basis that a typical 6-month course of chemotherapy consists of up to 8 cycles of treatment (CancerResearchUK.org, n.d.), the pricing of ATL-104 is suggested to be £20,000 per treatment. This should bring it to £160,000 for one course of chemotherapy which is well within the range for orphan drug reimbursements and will therefore strongly position it for broad uptake by users, payers and prescribers. This price will also ensure economic interests of the developing company are secured even with the narrow indication and limited patient population. Furthermore, potential off-label uses represent additional revenue streams following successful marketing authorisation.


If orphan designation cannot be secured, the pricing strategy will have to be entirely re-worked and a suggested price of £6,000 for a 6-day treatment will be suggested. This should improve its market acceptance compared to palifermin and the use of the drug should be supported by its improved efficacy.


References

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ASHA.org. (n.d.). Head and Neck Cancer: Incidence and Prevalence. [online] Available at: https://www.asha.org/PRPSpecificTopic.aspx?folderid=8589943346&section=Incidence_and_Prevalence [Accessed 25 Nov. 2019].


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Clinicaltrials.gov. (2018b). A Study to Investigate the Effects of GC4419 on Radiation Induced Oral Mucositis in Patients With Head/Neck Cancer - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03689712 [Accessed 17 Nov. 2019].


Clinicaltrials.gov. (2019a). Study of the Effects of Brilacidin Oral Rinse on Radiation-induced Oral Mucositis in Patients With Head and Neck Cancer - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/study/NCT02324335 [Accessed 16 Nov. 2019].


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Clinicaltrials.gov. (2019c). DOM-INNATE: Study of SGX942 for the Treatment of Oral Mucositis in Patients With Concomitant Chemoradiation Therapy for Head and Neck Cancer - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03237325 [Accessed 17 Nov. 2019].


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An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London

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