Therapeutic Delivery: Industry Update Covering October 2018

Abstract

This industry update covers the period from 1 to 31 October 2018 and is based on information sourced from company press releases, scientific literature, patents and various news websites. With the expiry in Europe of AbbVie's (IL, USA) principal patent on Humira this month, the first biosimilar versions of the drug have been launched. AstraZeneca (Cambridge, UK) announced that is has out-licensed two none core drugs to Grunenthal (Aachen, German), while Pfizer (NY, USA) announced the creation of a new company, set up in collaboration with Bain Capital (MA, USA) to exploit Pfizer's clinical and preclinical assets in the neuroscience field. In digital health, 23andMe (CA, USA) announced that the US FDA has authorized marketing of one of its consumer genetic tests, that assesses the genetic factors that affect drug metabolization, hence the safety and efficacy of some drugs. Novartis (Basel, Switzerland) continued to grow its activities in digital health with the creation of the Novartis Biome, an incubator and support program for early-stage companies in this area. Novartis also announced that it has filed applications in the EU and USA for the approval of siponimod, a drug targeting secondary progressive multiple sclerosis and Roche (Basel, Switzerland) gained FDA approval for an antiviral treatment for influenza. Janssen (Beerse, Belgium) announced it had won a label extension for its blood glucose-lowering drug, Invokana^®, for the reduction of cardiovascular events in diabetes. Roche presented data at ECTRIMS, a major annual conference on multiple sclerosis (MS), held in Berlin, Germany this month (10–12 October 2018), showing the potential benefits of administering its drug, Ocrevus, earlier in the treatment pathway for MS compared with other standard treatment. At the same event, Celgene (NJ, USA) presented results from a survey that showed MS patients’ concern around brain atrophy and cognitive loss in MS, highlighting that the disease has a neurodegenerative as well as an inflammatory component. Novartis also presented a significant amount of data supporting its marketed drugs as well as its development pipeline in the disease. This month, presentation of data from two studies at the American Academy of Ophthalmology annual meeting (27–30 October 2018, Chicago, IL, USA) further supporting the potential of eye scans in the early detection of Alzheimer's. A paper by a research team at the University of Rochester (NY, USA) demonstrated the feasibility of a new mechanism to transport drugs across the blood–brain barrier, which could help development more effective CNS drugs.

Keywords:

• biosimilar
• central nervous system
• digital health
• influenza
• multiple sclerosis

Acquisitions, licensing deals & other commercial news

First Humira biosimilars launched in EU market

Five biosimilar variants of AbbVie's (IL, USA) Humira^® (adalimumab) have already been approved by the EMA over the past 18 months but with the expiry on 15 October of AbbVie's European patent EP97906572.9 (human antibodies that bind human TNF-α), these can now start to be launched on the market [1]. Announcements for the launch of Hulio^® (Mylan/Fujifilm Kyowa Kirin Biologics [Tokyo, Japan]); Imraldi^® (Biogen [MA, USA]/Samsung Bioepis [Incheon, Korea]) and Amgevita^® (Amgen [CA, USA]) were made around the patent expiry date, and a few days earlier an announcement by Sandoz (Holzkirchen, Germany), that it had reached an agreement to license AbbVie's intellectual property relating to the drug also cleared the way for its launch of Hyrimoz^®, meaning that four biosimilars are due to enter the market. Boehringer Ingelheim (Ingelheim am Rhein, Germany) also won approval for its variant, back in October 2017, but is understood to be still involved in patent litigation with Abbvie, so is not yet free to launch.

The EU accounts for around $4.4B of Humira's total global annual sales of $18B (up to 30 June 2018) and so provides a good market opportunity, even considering the number of entrants.

In UK, the National Health Service (NHS) is anticipating that it can save up to £150 M from a current annual adalimumab bill of more than £400 M through the adoption of biosimilars [2]. NHS England has issued guidance suggesting that 90% of new patients started on the best value medicine within 3 months of a biosimilar launch and that 80% of existing patients should be switched to the best value project within 12 months of launch. According to NHS Improvement, the organization that oversees NHS Trusts in England, savings of £324 M were achieved by switching from using ten ‘expensive’ medicines to ‘better value and equally effective’ alternatives, mainly generic and biosimilar medicines, against a target of £250 M so it has a good track record in drug switching.

However, there are some challenges in switching adalimumab users compared with other biologics such as infliximab and rituximab. Unlike the latter two, which are clinician administered, adalimumab is commonly self-administered using an automated injection pen and the devices provided with the approved biosimilars have slightly different operating steps that might cause confusion in switching. Also, formulation differences might affect levels of pain leading to patient dissatisfaction and as the molecules are not identical, there is the possibility of immunogenicity when switching that might increase clinician resistance to change medication for existing patients.

In USA, by far the largest market for Humira, AbbVie has patent protection until 2023 and has already reached agreement with several adalimumab manufacturers to launch around that date. This presumably reduces the risk of any further patent litigation that might threaten AbbVie's current monopoly before that date.

There are now around 50 biosimilar approved in the Europe, but as of July 2018, only 12 have been approved in USA with a similar number currently under review by the US FDA.

AstraZeneca & Grünenthal announce agreement on rights to Nexium^® & Vimovo^®

AstraZeneca (Cambridge, UK) announced that it has divested the rights to two of its market drugs to Grünenthal (Aachen, Germany) [3]. The deal covers the European prescription rights for Nexium^® (esomeprazole), a proton pump inhibitor used to reduce stomach acid in patients with gastrointestinal reflux conditions and ulcers, and Vimovo^® (naproxen/esomeprazole), a modified-release fixed-dose combination of naproxen, a pain-relieving nonsteroidal anti-inflammatory drug and esomeprazole, for the treatment of inflammatory diseases, including osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in patients at risk of developing stomach ulcers through the use of nonsteroidal anti-inflammatory drugs administered as monotherapy.

The divestment reflects AstraZeneca's intent to concentrate its business on oncology, cardiovascular, renal and metabolism and respiratory indications, as well as an opportunity for Grünenthal to expand its portfolio in its core market of innovative pain management and related therapies.

Grünenthal will make an upfront payment of around $800 M on completion of the deal, with the potential of additional milestone payments and royalties of around $100 M. European sales of the drugs are currently around $150 M annually.

AstraZeneca will retain the rights and continue to commercialize Nexium in all markets outside Europe. They will also continue to manufacture and supply Nexium to Grünenthal under a long-term supply agreement.

Bain Capital & Pfizer create a new CNS company, Cerevel Therapeutics

Pfizer (NY, USA) and Bain Capital (MA, USA) announced the creation of a new biopharmaceutical company focusing on the development of new drugs to central nervous system (CNS) disorders [4]. Pfizer is transferring several precommercial neuroscience assets to the new company, including three clinical-stage compounds and several preclinical compounds targeting a wide range of CNS disorders including Parkinson's disease, Alzheimer's disease, epilepsy, schizophrenia and addiction. Funds controlled by Bain will initially contribute £350 M to the business with more funding available later if required. The most advanced compounds are a D1 partial agonist that is planned to enter a Phase III study in 2019 and a selective GABA 2/3 agonist initially targeting epilepsy and ready to enter Phase II studies.

The new company will be based in the Boston area and Pfizer will assist in recruiting a team of dedicated scientists and executives with appropriate expertise in neuroscience.

Executives from Pfizer and Bain will serve on Cerevel Therapeutics's board of directors and Pfizer will retain a 25% holding in the business.

Earlier in the year, Pfizer announced a decision to exit neuroscience but the formation of Cerevel ensures continued development of drugs in its portfolio, as well as, an upside if they are successfully commercialized by the new business. The partnership with Bain also allows it to offset some of the risk in developing CNS treatments, an area of high unmet need, but also high failure rate.

Digital health

FDA authorizes 23andMe's consumer genetic variant test for assessment of genetics factors on drug metabolization

23andMe (CA, USA) announced that it has gained FDA authorization via the de novo classification process for a test to detect 33 variants for multiple genes that impact the ability to metabolize certain medications [5]. The test is conducted on a saliva sample collected by the consumer and submitted for analysis.

23andMe has had a challenging past with the FDA as it progresses its ambition to provide genetic testing and interpretation direct to individual consumers. In 2013, the FDA sent a warning letter advising the company it was marketing its Saliva Collection Kit and Personal Genome Service without appropriate clearance or approval. 23andMe had previously submitted a 510k notification for the test but subsequently had failed to address the agency's concerns about analytical and clinical validation of the tests. The FDA expressed concern about potential health consequences that might result from false positive or false negative diagnoses for some of the indications being tested, which could result in unnecessary intervention or failure to react to a risk. The letter requested corrective action to address the concerns and, to comply, the company only provided ancestry reports and raw data to customers purchasing the service.

For the latest clearance, the FDA determined it to be class II but also confirmed that premarket notification is required for this type of test, unlike for the recessive gene tests that the company had previously gained authorization for. Based on their genetic data, the test allows prediction of predisposition to fast or slow metabolization, which when supported by appropriate clinical evidence, may determine whether someone will have reduced treatment efficacy or an increased chance of side effects from certain medications. To support safe use of the test, the FDA has defined six special controls that need to be implemented including a label stating that the consumer should not use the test results to stop or change any medication without seeking medical advice [6].

So, while the FDA is eager to speed up the approval and use of new medical technology, it recognizes the need to minimize risk. For consumer tests, three main areas of risk exist; the accuracy of the test (particularly in terms of false positive or false negative diagnoses), how the user might interpret the results and how they might act upon the results.

23andMe noted that this approval is part of its ambition to provide all the types of genetic health information to customers that it offered before receiving the FDA warning letter in 2013.

Novartis launches digital health innovation lab: the Novartis Biome

Novartis (Basel, Switzerland) continued its commitment to embracing digital health in its business with an announcement of the creation of the Novartis Biome [7]. This initiative includes a digital health innovation lab located in San Francisco that provides workspace, mentorship and resources typically offered in start-up incubators. Additionally, the Biome offers access to Novartis’ clinical datasets gathered in validation studies that can be used by partnering companies to help shape and design their proof-of-concept studies. Another benefit for start-ups is that they are not automatically required to give Novartis equity in their business in order to participate.

The aim of the Biome is to accelerate the uptake of digital technologies within Novartis in a more systematic way than through specific deals as well as supporting their use more widely in healthcare.

Over the past few years, Novartis has announced several digital deals and initiatives, including connected inhaler deals with Qualcomm (CA, USA) and Propeller Health (WI, USA) and a digital therapeutic deal with Pear Therapeutics (MA, USA) in schizophrenia and multiple sclerosis (MS).

Novo Nordisk announces key digital health partnerships & planned launch of a connected diabetes pen

Novo Nordisk (Bagsværd, Denmark) announced a plan to launch two connected diabetes injection devices (pens) enabling wireless sharing of insulin dosing data with other systems and devices [8]. This is aligned with Novo Nordisk's strategy of developing the means to integrate its products with digital platforms already being used by people with diabetes to manage their disease better. Building upon existing work with IBM Watson Health (NY, USA) and Glooko (Göteborg, Sweden), the company also announced new partnerships with Dexcom (CA, USA), Glooko and Roche that advance the approach. The ability to integrate seamlessly delivery devices such as pens and pumps with blood sugar monitors and diabetes management systems has the potential to improve patient convenience and opens the way to more automated management of the disease and the reduction risk due to use error. Novo plans to launch the durable (reusable) devices, NovoPen^® 6 and NovoPen Echo^® Plus, in key markets from early 2019. It also intends to add connectivity to its disposable, prefilled injection pens later in 2019. Disposable devices are more commonly used in key markets such as Europe, due to greater convenience and ease of use, but the cost of electronics required for connectivity has been an issue if they are disposed of with each device.

Phillips-Medisize announces availability of next-generation Connected Health Platform

Phillips-Medisize (WI, USA), an end-to-end provider of innovation, development and manufacturing solutions to the pharmaceutical and medical device industries, announced the rollout of its third-generation Connected Health Platform, a cloud-based, scalable and secure medical device data system for pharmaceutical companies and drug delivery device providers [9]. The platform is based on InterSystems (MA, USA) HealthShare, a healthcare informatics platform used to create unified, community-wide health records; the two companies also announcing a collaboration this month to support the development of the Phillips-Medisize platform [10].

Phillips-Medisize was the first company to develop an FDA-approved combination-connected medicine solution to support patients and develop a deeper understanding of how they take their medication. The device and connected solution were launched in collaboration with Bayer (Leverkusen, Germany), as the Betaconnect system for use with Betaseron, a drug used in the management of MS.

Electronic health records seek to consolidate the patient information on patient health to improve the healthcare management. Although they routinely capture data on the diagnosis and treatment of disease such as hospital tests, clinical consultations and prescriptions, they currently don't directly capture drug usage data, which given high levels of nonadherence can result in a poor understanding of treatment efficacy.

Solutions such as the Philips-Medisize platform create the opportunity for comprehensive healthcare data collection and management. Analysis of the data can then provide insights that support the development of improved therapeutic delivery.

Regulatory news

Novartis announces FDA & EMA filing acceptance of siponimod, a new treatment for MS

Novartis announced that both the FDA and the EMA had accepted its filings in USA and EU respectively for approval of siponimod (BAF312) for the treatment of secondary primary multiple sclerosis (SPMS) [11]. If approved, the drug would be the first orally administered disease-modifying therapy (DMT) with the potential to delay progression and expand possibilities for SPMS patients.

Siponimod belongs to the same class of drug as Gilenya™ (fingolimod), which is already marketed by Novartis. It binds and acts as a selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor that is present on the surface of lymphocytes, a type of immune cell synthetized in the bone marrow and found in the blood and in lymph tissue. Although lymphocytes are an important part of the body's immune system, in MS, they attack nerve cells in the brain and spinal cord, triggering the disease. The binding increases lymphocyte retention in the lymph glands, reducing their concentration in the CNS and, thus, reducing the risk of nerve damage. Compared with Gilenya, the binding appears to be more selective to S1P1 and S1P5 receptor subtypes and also has a shorter circulation half-life, which reduces side effects including lymphopenia and cardiovascular complications. In addition, its ability to enter the brain and selectivity target S1P5, as well as S1P1, which are expressed in neurons and glia cells, which means that the drug may also exhibit a neuroprotective effect in addition to lowering lymphocyte activity. Glia includes oligodendrocytes that are important in the production of myelin that sheaths neurons and astrocytes. Animal studies have shown that siponimod also induces long-term release of neurotrophic BDNF in the midbrain of EAE mice. BDNF is a protein that works to support neuronal survival and new nerve cell growth and differentiation, and hence, plays a key role in synaptic plasticity and cognition. This is supported by clinical data obtained by Novartis in which measurements using Symbol Digit Modalities Test (SDMT), a standard cognitive test on patients treated with siponimod showed a significant improvement in cognitive processing speed from baseline to month 24, compared with placebo.

The FDA and EMA applications are for siponimod as a treatment only for SPMSand Novartis says it has no plans to evaluate it further with relapsing-remitting disease, a form of MS that is already well treated by a range of MS drugs including Gilenya.

FDA approval for Xofluza™ (baloxavir marboxil) as a novel antiviral for the treatment of influenza

The FDA announced its approval of Xofluza™ (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu), the first antiviral flu treatment with a novel mechanism of action approved in the USA in nearly 20 years [12]. The treatment is indicated for people 12 years of age or older who have presented with flu symptoms for no more than 48 h.

The safety and efficacy of the drug was assessed in two clinical trials involving 1832 participants who were randomized to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 h of experiencing flu symptoms. In both trials, the Xofluza arm showed a more rapid alleviation of symptoms compared with placebo and equivalent performance compared with the other antiviral.

The FDA noted that antivirals are not a substitute for annual vaccines but can form part of a treatment program in which it is important to have different antiviral options to overcome viral resistance to treatment.

Xofluza was discovered by Shionogi & Co., Ltd (Osaka, Japan) and then developed and commercialized globally in collaboration with the Roche. Roche hold the global rights to the drug outside Japan and Taiwan, where they are retained by Shionogi.

Johnson & Johnson wins US approval for first-in-class diabetes drug

Janssen Pharmaceutical Companies of Johnson & Johnson (Beerse, Belgium) announced that it had gained FDA approval for its drug Invokana^® (canagliflozin) to reduce the risk of major adverse cardiovascular events in adults with Type 2 diabetes (T2D) [13]. Invokana is a sodium glucose cotransporter 2 (SGLT2) inhibitor that was previously approved in 2013 for the improvement of glycemic control in T2D when taken in conjunction with diet and exercise. But this new approval is based on further data that showed a 14% decrease in the combined risk of heart attack, stroke and cardiovascular death, compared with placebo in studies involving more than 10,000 adults with T2D and established cardiovascular disease or risk factors. Cardiovascular complications are common and a significant cause of death for people with diabetes. This approval makes it the only oral T2D treatment indicated to reduce the risk of heart attack, stroke or cardiovascular death. Eli Lilly (IN, USA), Merck's (NJ, USA) Jardiance^®, another SGLT2 inhibitor, gained a label extension for cardiovascular death back in 2015 but failed to show a reduction in stroke and heart attack. However, Invokana also has a downside in that the data showed an increase in the risk of lower limb amputation. AstraZeneca is gathering data for its approved SGLT2 inhibitor, Farxiga^®, which it hopes will allow it to make similar claims around reduction of cardiovascular disease and risk factors.

ECTRIMS 2018

ECTRIMS, the annual congress of the European Committee for Treatment and Research in MS was held in Berlin, Germany this year (10–12 October 2018) and attended by nearly 12,000 MS neurologists, researchers and pharmaceutical industry representatives. There were around 120 podium and nearly 1000 poster presentations given over 3 days. In the following sections are some of the industry updates from the event.

Early initiation of OCREVUS in MS treatment show reduction in disability progression compared with standard treatment

Roche (Basel, Switzerland) presented clinical data at the conference that show early initiation of treatment with Ocrevus™ (ocrelizumab) reduces disability progression over 5 years in relapsing and primary progressive MS [14]. In the open-label extension of two ongoing clinical trials, people with relapsing MS (RMS) who had continuous Ocrevus treatment over 5 years had better outcomes in brain atrophy and confirmed disability progression than patients who switched to Ocrevus after the first 2 years of IFN-β-1α treatment. Additionally, people with RMS, switched to Ocrevus from IFNβ-1α after the controlled trial period, showed a rapid reduction in annualized relapse rate, as well as nearly a complete absence of T1 gadolinium-enhancing lesions, both of which are associated with effective disease suppression.

There has been considerable debate recently about the value of administering DMT earlier in the development of MS. It is common for patients to start on safer but less effective DMT treatments, such as interferons, and then only progress to newer and potentially more effective DMTs when the earlier medications cease to be effective as the disease progresses. The rationale for this has been driven by concerns about safety, as at least some of the more effective treatments present higher risks, especially when used for longer periods of time. But some of the newer treatments that have already entered the market, such as Ocrevus, or will in near future, such as siponimod, mentioned previously in this Industry News, may also improve safety as well as effectiveness. They then need to address concerns over cost–effectiveness against existing medications that have or will be coming off patent, so data such as these published by Roche will help the argument for their earlier use if they can be shown to delay progression over existing treatment pathways.

Survey results presented at ECTRIMS reveal MS patients’ concerns on cognitive decline & brain atrophy

Although a decline in physical disability is generally considered to be the biggest issue in the progression of MS, results of a patient survey presented by Celgene (NJ, USA) at the conference showed that patients are also concerned about cognitive issues as well as the impact of brain atrophy associated with the disease [15]. Although the progression of MS is commonly seen to be associated with the development of lesions in the brain and spinal cord, there is increasing evidence that brain atrophy is also a major driver of disease activity and is associated with irreversible neurological and cognitive impairment as well as neuropsychiatric symptoms. Yet, despite this, 63% of respondents said they had not discussed atrophy with their MS specialist and only 20% of respondents were satisfied with the information provided to them on how to prevent brain atrophy.

Some research studies have also shown that atrophy correlates better with disability and cognitive impairment than measurements of lesions, and it, therefore, might be a good biomarker for disease progression. MS is primarily seen as an inflammatory disease, but the presence of atrophy demonstrates that it also has a neurodegenerative component that might also be a good target for future drug development as current DMTs mainly focus on inflammation.

A total of 1337 people with MS or responding on their behalf participated in the survey that was self-administered online in March 2018.

Novartis provides an update on its MS drug portfolio

Novartis presented 33 different abstracts at the conference covering both developmental and marketed drug portfolios in MS [16]. These included new data suggesting the level of neurofilaments, protein fragments in the blood, is elevated in MS patients when damage to neurons occurs and can form the basis of a predictive biomarker for physical disability progression in patients with relapsing remitting MS, when collected at several points over 12 months. The company also presented long-term safety of siponimod in SPMS and baseline data from two parallel Phase III trials that are now fully enrolled and being conducted to evaluate efficacy and safety of the drug in patients with RMS in comparison with an existing drug teriflunomide.

Science

Study points to new method to deliver drugs to the brain

A challenge in developing treatments for CNS disorders is the difficulty in getting drugs across the blood–brain barrier and into the brain. Recent research [17] published by a group at University of Rochester Medical Center (NY, USA) suggested that the glymphatic system, which removes waste from the brain in a similar way that the lymphatic system operates in the rest of the body, might provide a viable route of administration. In an animal study, antibodies were directly introduced into the cerebral spinal fluid (CSF). Hypertonic saline was used to remove CSF from the brain by osmosis and then new CSF, carrying the antibodies, was then delivered to the brain by the glymphatic system. Uptake of the antibodies in the brain could then be observed by imaging. The researchers suggest that the method could be used to deliver small molecules, such as viral vectors for gene therapy, as well as antibodies.

Financial & competing interests disclosure

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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