Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

The present Industry Update covers the period 16 July–15 August 2011, with information sourced from company press releases, media newswires, regulatory agencies and relevant patent offices. The restructuring announced by Merck was not unexpected but its adverse effects will be keenly felt by employees, particularly in the USA. The approval of Pradaxa™ in Europe is welcome and likely to provide a significant clinical benefit. Reports of Phase III clinical studies were few in number, however some exciting early stage research was reported, most notably in relation to the potential development of broad-spectrum antiviral therapeutics.

Business development

Business restructuring

Merck

On 29 July, Merck‘s announcement of US$2 billion in profits for the second quarter was accompanied by the news that the company plans to shed a further 12,000–13,000 jobs, in order to decrease its annual cost base by another $1.5 billion [201]. The new restructuring would add to cuts related to the Schering–Plough merger, bringing overall savings to more than $4.5 billion. The impact will be felt hardest in the USA, where 35–40% of the cuts are anticipated. Headcount will be reduced at headquarters, in administrative functions, via consolidation of office facilities and from the ongoing sale and closure of manufacturing plants. The company plans to continue hiring in some markets, especially emerging markets that Merck has targeted for growth as drug sales stagnate in the USA and Europe. Merck‘s strategy of operating more flexibly from a lower cost base reflects the generally difficult environment faced by the large pharma companies. In the present case, sales are like to take a significant hit on the back of the loss of exclusivity on Merck‘s blockbuster allergy and asthma drug Singulair™. Merck CEO Kenneth Frazier had previously indicated that investment in R&D would be protected; however, Merck also announced plans to close down the RNA interference research facility it obtained 5 years ago through its $1.1 billion acquisition of Sirna Therapeutics; the closure will result in the loss of 50 positions [202]. Despite the investment, RNAi-based drugs have not seen significant progression into Merck‘s pipeline, and the company has highlighted the difficult challenges associated with effective delivery of such drugs. Merck‘s decision comes less than 1 year after Roche ended a high-profile collaboration with Alnylam Pharmaceuticals, a global leader in RNAi [203], and Novartis chose not to exercise a $100 million option to broadly license Alnylam‘s RNAi trigger IP [204]. At the present time, no RNAi-based drugs have received marketing approval.

Acquisitions & mergers

Bristol-Myers Squibb & Amira Pharmaceuticals

On 21 July, Bristol-Myers Squibb Company and Amira Pharmaceuticals, Inc., announced they had signed a definitive agreement under which Bristol-Myers Squibb will acquire privately held Amira Pharmaceuticals, a small-molecule pharmaceutical company focused on the discovery and early development of new drugs to treat inflammatory and fibrotic diseases [205,206]. Under the terms of the agreement, Bristol-Myers Squibb will acquire all of Amira Pharmaceuticals‘ issued and outstanding shares of capital stock and stock equivalents in an all-cash transaction for a purchase price of $325 million upfront and potential additional milestone payments totaling $150 million. Bristol-Myers Squibb will secure Amira Pharmaceuticals‘ fibrosis program, including the lead asset AM152, an orally available lysophosphatidic acid 1 receptor antagonist. AM152 has completed Phase I clinical studies and is now poised for Phase IIa proof-of-confidence studies for the treatment of idiopathic pulmonary fibrosis and systemic sclerosis, or scleroderma. Bristol-Myers Squibb will also obtain Amira Pharmaceuticals‘ preclinical autotaxin program, which may be useful in the treatment of neuropathic pain and cancer metastases. Bristol-Myers Squibb plans to retain Amira Pharmaceuticals‘ scientists, who work on both of these programs and will remain located in San Diego, CA USA.

Licensing & collaboration agreements

Merck & Roche

On 20 July, Merck announced that it had signed a new nonexclusive agreement with Roche for the global promotion, upon appropriate marketing approvals, of Victrelis™ (boceprevir) as part of a triple-combination therapy regimen with peg-IFN-α and ribavirin (peg/riba) [207]. Under the terms of the agreement, Roche and Merck will work together in global markets, including Europe, Asia and Latin America, to educate physicians and patients about hepatitis C virus. The companies previously announced an agreement to promote Victrelis in the USA and collaborate to explore new treatment regimens for patients with chronic hepatitis C virus.

Vaxxas

On 3 August, the University of Queensland start-up company Vaxxas Pty Ltd announced plans to develop its Nanopatch™ vaccine-delivery technology with a $16.4 million investment from a syndicate of Australian and international venture capital funds [208,209]. The Nanopatch vaccine-delivery technology originated from the research of Professor Mark Kendall at the Australian Institute for Bioengineering and Nanotechnology. Smaller than a stamp and working via the skin, investors believe the Nanopatch will have a very significant impact on the way vaccines are delivered in the future. Potential benefits include reductions in cost and refrigeration requirements relative to syringe-delivered vaccines, as well as improved convenience and elimination of the discomfort associated with conventional needle-based administration.

Acceleron & Celgene

On 3 August, Acceleron Pharma, Inc. and Celgene Corporation announced they had entered into a joint development and commercialization agreement for ACE-536 for the treatment of anemia [210]. The companies already have a collaboration around sotatercept (ACE-011) entered in 2008. Under the new agreement, the two companies will collaborate to develop both actives and potentially others for treating anemia across a wide range of indications. Celgene and Acceleron will jointly develop, manufacture and commercialize ACE-536, a novel protein therapeutic that inhibits members of the TGF-β superfamily involved in erythropoiesis. Additionally, Celgene will have an option to future Acceleron programs developed for anemia. Celgene will make an upfront payment to Acceleron of $25 million. Under the terms of the agreement, Acceleron will be responsible for conducting the Phase I and initial Phase II clinical trials and Celgene will conduct the subsequent Phase II and Phase III clinical studies. Acceleron will manufacture ACE-536 for the Phase I and Phase II clinical trials and Celgene will have responsibility for the manufacture of Phase III and commercial supplies. Acceleron will pay a share of the development expenses through to the end of 2012 and Celgene will be responsible for development costs thereafter. Acceleron is eligible to receive development, regulatory and commercial milestone payments of up to $217 million for the ACE-536 program. The companies will co-promote the products in North America. Acceleron will receive tiered double-digit royalties on worldwide net sales.

Array BioPharma & Genentech

On 9 August, Array BioPharma announced an oncology agreement with Genentech, a member of the Roche Group, for the development of each company‘s small-molecule Checkpoint kinase 1 (ChK-1) program [211]. The programs include Genentech‘s compound GDC-0425 (RG7602), currently in Phase I, and Array‘s compound ARRY-575, which is being prepared for an investigational new drug application to initiate a Phase I trial in cancer patients. Under the terms of the agreement, Genentech is responsible for all clinical development and commercialization activities. Array will receive an upfront payment of $28 million and is eligible to receive clinical and commercial milestone payments up to $685 million, and up to double-digit royalties on sales of any resulting drugs. ChK-1 is a protein kinase that regulates the tumor cell‘s response to DNA damage often caused by treatment with chemotherapy. In response to DNA damage, ChK-1 blocks cell-cycle progression in order to allow for repair of damaged DNA, thereby limiting the efficacy of chemotherapeutic agents. Inhibiting ChK-1 in combination with chemotherapy can enhance tumor cell death by preventing these cells from recovering from DNA damage. Both GDC-0425 and ARRY-575 are highly selective, oral ChK-1 inhibitors designed to enhance the efficacy of some chemotherapeutic agents.

Regulatory news & approvals

Product approvals

Brilinta™ (ticagrelor)

On 20 July, AstraZeneca announced that the US FDA has approved Brilinta tablets to reduce the rate of myocardial infarction (MI) and cardiovascular death in adult patients with acute coronary syndrome [212]. A new oral antiplatelet medicine, Brilinta, is an allosteric antagonist of ADP receptors of subtype P2Y12, a protein found mainly on the surface of blood platelets and thus an important regulator in blood clotting. Brilinta has been shown to reduce the rate of a combined end point of cardiovascular death, MI or stroke compared with clopidogrel. The difference between treatments was driven by cardiovascular death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention, Brilinta reduced the rate of stent thrombosis. The US FDA approval is based upon data from the landmark PLATO study, a superiority trial that compared treatment with Brilinta to clopidogrel in 18,624 acute coronary syndrome patients worldwide. AstraZeneca received EU approval for ticagrelor under the trade names Brillique™ and Possia™ in December 2010.

Orencia^® (abatacept)

On 29 July, Bristol-Myers Squibb Company announced that the US FDA had approved a subcutaneous formulation of Orencia for the treatment of adults with moderate to severe rheumatoid arthritis (RA) [213]. Orencia is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately-to-severely active RA. Orencia may be used as monotherapy or concomitantly with disease-modifying anti-rheumatic drugs other than tumor necrosis factor (TNF) antagonists. Orencia should not be administered concomitantly with TNF antagonists and is not recommended for concomitant use with other biologic RA therapy, such as anakinra. Orencia is the first biologic for the treatment of RA available both as a self-injectable (subcutaneous) and an intravenous infusion formulation. Approval was based on the successful results of the Phase III ACQUIRE study, a randomized, double-blind, double-dummy, multinational registrational trial involving 1457 patients. The primary end point of ACQUIRE was to determine non-inferiority of Orencia subcutaneous plus methotrexate (MTX) to Orencia IV plus MTX at 6 months.

RoActemra™ (tocilizumab)

On 3 August, Roche announced today that the EC had approved the use of RoActemra for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids [214]. RoActemra (known as Actemra outside Europe) is a humanized monoclonal antibody that can be given alone or in combination with MTX. sJIA is the rarest form of juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA). The disease affects about 10–20% of children with JIA, with the peak age of onset between 18 months and 2 years, although the disease can persist into adulthood. sJIA has an estimated 2–4% overall mortality rate and accounts for almost two-thirds of all deaths among children with arthritis. Symptoms range from joint inflammation accompanied by intermittent fever, skin rash, anaemia, enlargement of the liver or spleen and inflammation of the lining of the heart and/or lungs. In the most severe cases of sJIA, up to two-thirds of children experience chronic arthritis, and approximately half of children will develop significant joint disabilities. RoActemra is currently used for the treatment of adult RA in people who have either responded to, or who were intolerant to, previous therapy with one or more DMARDs or TNF inhibitors. It is the only licensed biologic treatment to target the IL-6 pathway, which plays a pivotal role in sJIA pathogenesis. Approval was based on positive data obtained from the Phase III TENDER study which assessed the short term safety and efficacy of RoActemra versus placebo, in reducing signs and symptoms in patients (aged 2–17 years) with active sJIA. The results showed that 85% (64 out of 75) of children with sJIA receiving RoActemra experienced a 30% improvement in the signs and symptoms of sJIA and an absence of fever after 12 weeks of therapy, compared with 24% (nine out of 37) of children receiving placebo (p < 0.0001).

Pradaxa^® (dabigatranetexilate)

On 4 August, Boehringer Ingelheim announced the approval by the EC of their oral blood thinner Pradaxa for the prevention of strokes in people with atrial fibrillation (AF), the most common sustained heart rhythm disorder [215]. One in four adults over the age of 40 develop AF in their lifetime, resulting in 4.5 million people suffering from AF in Europe alone. AF patients have a five-times increase in risk of suffering a stroke, resulting in 3 million people worldwide having AF-related strokes each year. Thus, millions of patients across Europe could benefit from Pradaxa, seen by some as the most significant advance in blood thinning treatments approved for stroke prevention for over 50 years. During this time, the standard of care to prevent patients with AF from strokes has been vitamin K antagonists such as warfarin. Whilst effective, they have numerous limitations resulting in only half of eligible patients receiving warfarin and fewer than half of these patients being controlled within the desired therapeutic range. The approval of Pradaxa for stroke prevention in AF patients is based on results from the RE-LY clinical trial, one of the largest studies ever conducted in AF that included over 18,000 patients. Pradaxa, like warfarin, is a direct thrombin inhibitor but unlike warfarin, it provides effective, predictable and consistent anticoagulation with a low potential for drug–drug interactions. These benefits, together with the effective absence of drug–food interactions, minimize the need for routine coagulation monitoring or dose adjustment.

Clinical trials

Edurant™

On 19 July, Janssen Therapeutics presented 96-week findings from two pivotal Phase III clinical trials, known as ECHO and THRIVE, comparing the efficacy, safety and virology profile of its non-nucleoside reverse transcriptase inhibitor (NNRTI) Edurant (rilpivirine) versus the NNRTI efavirenz (EFV), in antiretroviral treatment-naive, HIV-1-infected adults [216]. The findings were presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome, Italy. Pooled ECHO and THRIVE results for Edurant and EFV, each administered once daily with a nucleoside/nucleotide background regimen showed that 78% of patients in both the Edurant arm (n = 686) and the EFV arm (n = 682) reached an undetectable viral load at 96 weeks. These data demonstrated non-inferiority (12% margin) of Edurant to EFV in lowering viral load in this population at 96 weeks, consistent with the 48-week primary analysis. Patients taking Edurant had a virologic failure rate of 14% compared with 8% experienced by patients taking EFV, of which 3 and 2% occurred in the second year of treatment, respectively. Upon virologic failure, the emergence of resistance and cross-resistance to the NNRTI class was higher in the Edurant arm compared with the EFV arm. Adverse events (AEs) leading to discontinuation in the Edurant arm were 4% compared with 9% in the EFV arm and there were no new safety concerns with either NNRTI between 48 and 96 weeks. The most common AEs of interest (all grades) reported in the Edurant arm versus the EFV arm at week 96 included dizziness (8 vs 27%), abnormal dreams/nightmares (8 vs 13%) and rash (4 vs 15%). The incidence of Grade 2–4 AEs at least possibly related to treatment over at least 96 weeks was 17% in the Edurant arm versus 33% in the EFV arm.

Extended-release carbidopa–levodopa capsule (IPX066)

On 15 August, GlaxoSmithKline and Impax Pharmaceuticals announced top-line results of the ASCEND-PD Phase III clinical study of IPX066 versus carbidopa–levodopa plus entacapone (CLE), in patients with advanced Parkinson‘s disease (PD) [217]. IPX066 is an investigational extended-release capsule formulation of carbidopa–levodopa, intended to maintain consistent plasma concentration of levodopa for a longer duration versus immediate-release levodopa. The primary end point of the double-blind crossover study was the percentage of ‘off time‘ (OT) during waking hours as measured by patient diary. OT is the functional state when patients‘ medication effect has worn off and there is a return of the motor symptoms (dyskinesia) of PD. Patients entered the study with a baseline OT of 36.1% (5.9 h) and at the end of the randomized IPX066 treatment phase patients had an OT of 24.0% (3.8 h) compared with 32.5% (5.2 h) for CLE (p < 0.0001). This represents a 33.5% decrease in OT for IPX066 from baseline versus a 10% decrease for CLE. The ASCEND-PD study comprised a randomized, double-blind two-treatment, 2-week crossover study of IPX066 and CLE, and is the one of three Phase III studies of IPX066. Study subjects taking a stable dose of CLE were converted to IPX066 over a 6-week period, then randomized to one of the two treatments (IPX066 or CLE) for 2 weeks and then crossed over to the other treatment for an additional 2 weeks after a 1-week washout with IPX066. The study enrolled 110 subjects, with 91 subjects entering the randomized comparative phase of the study. A total of 84 subjects completed the randomized double-blind comparative phase of the study. Top-line results of the pivotal phase III studies ADVANCE-PD (in advanced PD) and APEX-PD (in early PD) were reported earlier this year [218,219].

Intellectual property

Silence therapeutics

On 3 August, Silence Therapeutics plc announced that the USPTO had issued the company a notice of allowance on a patent application involving the central technology involved in AtuPLEX™ [220]. AtuPLEX is a drug-delivery platform that enables the functional delivery of siRNA molecules to targeted diseased tissues and cells, while increasing their bioavailability and intracellular uptake [101]. This patent is directed to AtuFect, a key specific proprietary lipid that serves as the basis for the AtuPLEX delivery system. The AtuPLEX delivery technology is used in a number of Silence‘s partnered and internal RNAi therapeutic candidates. The patent also provides key layers of protection for several RNAi therapeutics in the pipeline including Silence‘s lead RNAi therapeutic candidate, Atu027. Results from an interim Phase I clinical study involving Atu027 were presented by Silence Therapeutics at the American Society of Clinical Oncology‘s annual meeting. Promising anti-tumor activity was observed, and in addition the treatment was well tolerated with no observed dose-limiting toxicities or evidence of cytokine activation. Positive pharmacokinetic data showed dose-dependent increases in both siRNA and lipid levels, suggesting no evidence of drug accumulation during repeat treatment.

POZEN

On 8 August, POZEN Inc. announced that the US District Court for the Eastern District of Texas had issued a favorable verdict in the litigation between POZEN and several generic pharmaceutical companies, which had filed Abbreviated New Drug Applications seeking approval from the US FDA to market generic copies of Treximet^®[221]. Treximet is used for the treatment of migraines and contains sumatriptan, a selective 5-HT1 receptor subtype agonist, and the sodium salt of naproxen, an NSAID. Treximet is marketed by GlaxoSmithKline, POZEN‘s exclusive US licensee. The District Court ruled US Patent No. 6060499 [102] (the ‘499 patent) and 6586458 [103] (the ‘458 patent) to be valid, enforceable and infringed by Par Pharmaceutical, Inc. (Par), Alphapharm Pty Ltd. (Alphapharm), and Dr Reddy‘s Laboratories, Inc. (DRL). A third US Patent No. 7332183 [104] (the ‘183 patent) covering the Treximet formulation was held to be valid, enforceable and infringed by Par and DRL. The ‘183 patent was not asserted against Alphapharm. Teva Pharmaceuticals, USA, Inc., another defendant in the litigation, entered into a settlement agreement with the company in April 2010 under which it was dismissed from the litigation, but agreed to be bound by the outcome. The District Court also ordered that defendants‘ ANDAs not be approved by the US FDA until, with respect to Par and DRL, at least the expiration of the ‘183 patent on 2 February 2025, and with respect to Alphapharm, the expiration of the ‘499 and ‘458 patents on 14 August 2017. Each of the above dates may be extended by 6 months if the US FDA grants GlaxoSmithKline‘s petition for pediatric exclusivity.

Echo Therapeutics

On 8 August, Echo Therapeutics, Inc., a company developing the Symphony™ non-invasive, wireless, transdermal continuous glucose-monitoring system and the Prelude™ SkinPrep System for transdermal drug delivery, announced the receipt of notices of issuance for two patents covering its Symphony transdermal continuous glucose-monitoring system and notices of registration for the trademarks Prelude and Symphony [222]. Echo Therapeutics received notice that its patent application entitled, ‘System and method for continuous non-invasive glucose monitoring‘ will issue as US Patent No. 7963917 [105]. As a result of a patent term adjustment that is expected to add nearly 4 years to the term of the patent, it is expected to expire in 2025. Echo Therapeutics also received notice that its patent application entitled ‘Transdermal analyte for monitoring systems and methods for analyte detection‘ was issued as South Africa Patent No. 2009/06959 and will expire in 2028.

MAP Pharmaceuticals

On 11 August, MAP Pharmaceuticals, Inc. announced that the PTO had issued to the Company US Patent No. 7,994,197 entitled ‘Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side-effect profile‘ [223]. The patent, which expires in 2028, results from the Company‘s discovery that dihydroergotamine (DHE) can be administered to achieve pharmacokinetic profiles that result in both rapid efficacy and minimal side effects [106]. Levadex^®, which contains the company‘s proprietary formulation of DHE, is an orally inhaled investigational drug for the potential acute treatment of migraine in adults. Timothy S Nelson, President and CEO of MAP Pharmaceuticals commented, “we have designed Levadex to overcome the limitations of currently available migraine therapies by combining our novel formulation capabilities with our proprietary TEMPO^® inhaler, and to target an optimal pharmacokinetic profile for rapid relief of migraine while minimizing side effects”. The issuance of this patent follows the recent company announcement that the Levadex NDA has been accepted for filing by the US FDA. In accordance with the company‘s collaboration agreement with Allergan, Inc., the US FDA‘s acceptance for filing of the NDA triggers a $20 million milestone payment to MAP Pharmaceuticals.

Pfizer

On 15 August, Pfizer announced that it had been successful in its patent infringement action against Teva Pharmaceutical USA Inc. [224]. As a result, Teva are prevented from receiving approval for a generic form of Viagra^® until October 2019. Amy Schulman, executive vice president and general counsel for Pfizer commented, “we are pleased that the court recognized the validity and enforceability of our Viagra patent for the treatment of erectile dysfunction. Protecting the intellectual property rights of our innovative core is critical, and Friday‘s court decision acknowledges Teva‘s clear violation of our patent rights”. Viagra was originally used to treat high blood pressure and the patent was initially set to expire in 2012; however, 10 years ago Pfizer were granted a second patent for the drug‘s use in treating impotence. Teva questioned the validity of this second patent; however, the Virginia federal court judge ruled that Teva‘s proposed generic equivalent of Viagra would infringe the 2012 patent. This is a much-needed drug for Pfizer as it faces difficult times ahead when it loses the exclusive rights to sell Lipitor, its top-selling cholesterol drug, in November 2011 [225].

Journal publications

Biomimetic VEGF nanostructures promote ischemic tissue repair

On 1 August, a study led by researchers at Northwestern University was published in the online issue of the Proceedings of the National Academy of Sciences that reported the development of novel synthetic nanostructures that promote the growth of new blood vessels by mimicking VEGF [1]. The demand for novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide, is considerable. The present study, also reported in the News feature of this issue [2], presents the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage and treadmill endurance compared with control. A key advantage of this biomimetic approach is the enhanced residence time of the nanofibers within treated tissues relative to VEGF itself, the consequent relative improvement in therapeutic efficacy and the proportionately lower cost of production of the synthetic peptide.

Broad-spectrum antiviral therapeutics

On 10 August, MIT News reported on a development by researchers at MIT‘s Lincoln Laboratory wherein drugs have been designed to selectively target virus-infected cells while leaving uninfected cells unharmed [226]. A detailed description of the novel methodology, as well as results from in vitro and animal studies was published on 27 July in the journal PLoS One[3]. The researchers tested the drug against 15 viruses and found it was effective against all of them. Examples included the H1N1 influenza virus, a stomach virus, a polio virus and viruses associated with dengue fever and several other types of hemorrhagic fever. The drug works by targeting a type of RNA produced only in cells that have been infected by viruses, and because the technology is so broad-spectrum, it could potentially be used to combat outbreaks of new viruses. The new therapeutic agents are referred to as double-stranded RNA-activated caspase oligomerizers(DRACOs). Viral replication involves the creation of long double-stranded RNA, which is not otherwise found in human or other animal cells. As part of their natural defenses against viral infection, human cells have proteins that latch onto dsRNA, setting off a cascade of reactions that inhibits the replication process. However, many viruses circumvent this defense mechanism by blocking one of the steps further down the cascade. The researchers at MIT recognized the opportunity to combine a dsRNA-binding protein with another protein that induces cell apoptosis. Therefore, when one end of the DRACO binds to dsRNA, it signals the other end of the DRACO to initiate apoptosis. Each DRACO also includes a ‘delivery tag,‘ taken from naturally occurring proteins, that allows it to cross cell membranes and enter any human or animal cell. However, if no dsRNA is present, DRACO leaves the cell unharmed. Most of the tests reported in this study were conducted in human and animal cells cultured in the lab. However, the researchers also tested DRACO in mice infected with the H1N1 influenza virus and observed excellent efficacy; the tests also showed that the DRACO itself is not toxic to mice. The researchers are now testing DRACO against more viruses in mice and hope in the future to successfully progress the technology in human trials.

Financial & competing interests disclosure

Gareth Rees is employed by Genesis Oral Biosciences and has, in the past, received compensation from GlaxoSmithKline in respect of consultancy and scientific writing services. Gareth Rees is a named inventor on four patents assigned to GlaxoSmithKline, and owns shares in the company. Alex Latham is an intern at Genesis Oral Bioscience. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.