Therapeutic Delivery: Industry Update Covering January 2019

Abstract

This Industry Update covers the period from 1 to 31 January 2019 and is based on information sourced from company press releases, scientific literature, patents and various news websites. Bristol-Myers Squibb (NY, USA) and Celgene (NJ, USA) announced a merger to create one of the largest oncology-focused pharmaceutical businesses. Also, with a focus on oncology, Lilly (IN, USA) announced it is acquiring Loxo Oncology (CT, USA). Alphabet’s life sciences business, Verily (CA, USA), announced it had raised new funds to invest in new business opportunities and acquisitions. Talee Bio (PA, USA) and Agenus (MA, USA) announced that they had won grants to support their work in cystic fibrosis and vaccine development, respectively. Biogen (MA, USA) established two new collaborations aimed at expanding its neuroscience pipeline and Voyager Therapeutics (MA, USA) and Neurocrine Biosciences (CA, USA) agreed a collaboration to develop and commercialize gene therapy treatments also in neuroscience. In digital health, Proteus Digital Health (CA, USA) continued the development of digital pill technology, with the initiation of a study in oncology and Otsuka (Tokyo, Japan) agreed a collaboration with Click Therapeutics (NY, USA) to develop digital therapies to treat major depressive disorder. This month also finally saw the approval of Mylan’s (PA, USA) generic version of GSK’s (Brentford, UK) blockbuster inhaled drug, ADVAIR. Several developments in novel drug delivery methods were reported including the use of microneedles to deliver contraceptives, inhaled delivery of mRNA and a study supporting the use of peptoids to deliver gene therapies into cells. A publication from the Salk Institute (CA, USA) suggested a cellular mechanism might be important in reducing the risk of cancer, and a study by a team at Washington University (MO, USA) supported the possibility of gene therapy to treat neuropathy.

Keywords:

• digital medicine
• gene therapy
• microneedle
• nanotechnology
• neurology
• oncology
• peptoid
• respiratory

Acquisitions, licensing deals & other commercial news

Bristol-Myers Squibb to acquire Celgene

In one of the largest pharmaceutical deals ever, Bristol-Myers Squibb (BMS; NY, USA) announced that it is to acquire Celgene (NJ, USA) in an agreed takeover that values the latter at up to US$90 billion and which will create one of the largest global oncology drug businesses with additional portfolios in immunology, inflammation and cardiovascular disease [1]. Celgene shareholders are being paid with a combination of BMS stock, cash and Contingent Value Rights that will pay out on the achievement of certain milestones in Celgene’s developmental pipeline.

Most notably, the deal gives BMS access to two CAR-T engineered cell treatments for cancer in Celgene’s near-term pipeline, bb2121, which it has been developing in collaboration with Bluebird Bio (MA, USA) for multiple myeloma and JCAR017 for the treatment of relapsed diffuse large B-cell lymphoma – which it acquired via a $9 billion buyout of Juno Therapeutics (WA, USA) in 2018. The deal should also allow BMS to develop novel therapeutics, as well as pursuing immuno-oncology combinations, such as the potential of treating some cancers with both CAR-T and checkpoint inhibitors. This could be critical for BMS in defending its Opdivo checkpoint inhibitor business from the threat from Merck and Co (NJ, USA) and its drug Keytruda.

BMS and Celgene expect to complete the transaction in the third quarter of 2019, following regulatory clearance.

Verily announces $1 billion investment round to fund growth & innovation

Verily, an Alphabet company (CA, USA), today announced a $1 billion investment round to allow it to expand its business activities relating to its life sciences portfolio [2]. The funds will be used to expand its commercial collaborations, seek new business opportunities and target acquisitions. Its current activities include:

• A collaboration with Biogen (MA, USA) and Brigham and Women’s Hospital (BWH; MA, USA) to develop a better understanding of the causes of multiple sclerosis and why the disease progresses differently among those diagnosed with it. It is anticipated that this understudying research will support the development on new treatments [3].

• A collaboration with Sanofi (Paris, France) and Sensile (Hägendorf, Switzerland) to develop a connected, prefilled pump insulin delivery in the treatment of diabetes [4]. The aim of the partnership is to develop an easier to use device that can address Type II as well as Type I diabetes.

• A joint venture with GSK (Brentford, UK), Galvani Bioelectronics to develop bioelectronic medicines based on implantable electronic devices that can complement of replace existing drug therapies in therapeutic areas that include inflammatory, metabolic and endocrine disorders such Type II diabetes, where efficacy in animal models has already been established [5].

• A collaboration with Alcon to develop a contacts lens to monitor blood sugar levels noninvasively for the treatment of diabetes. This work was recently terminated as it was found the measurements of blood sugar in the eye did not correlate well with those in the blood [6].

The funding round was led by Silver Lake (London, England) with Ontario Teachers’ Pension Plan (Toronto, Canada) and other global investment companies involved.

Vectura provides financial update

Vectura (Chippenham, England UK), a specialty pharmaceutical company focusing on treatments using inhaled drugs provided a preclose trading update ahead of its financial year results [7]. It announced increased sales of its marketed drugs flutiform used in the treatment of asthma and Ultibro used in the treatment of chronic obstructive pulmonary disease as well as providing an update on its developmental pipeline which includes both dry powder and nebulized drugs. It is still awaiting US approval of its generic version of GSK’s Advair, VR315, following a rejection by the US FDA requiring a further clinical study to address with the aim to resubmit in 2020. It also announced a new deal with its existing VR315 partner, Hikma Pharmaceuticals (London, USA), to develop generic versions of GSKs newer drug portfolio delivered by the Ellipta inhaler.

Agenus awarded grant to enable QS-21 innovations

Agenus Inc., (MA, USA), announced an award for a grant of approximately $1 million by the Bill and Melinda Gates Foundation (WA, USA) to develop a plant cell culture-based manufacturing process for an adjuvant, QS-21 Stimulon^®, which is a key component in several vaccines targeting infectious and endemic diseases [8]. At present, QS-21 is manufactured from the Quillaja saponaria tree, exclusively sourced from a particular area in Chile, causing concerns about sustainability of product availability and the environment. The grant will support a partnership with Phyton Biotech (Ahrensburg, Germany) which has experience in the development and application of environmental solutions for the production of high-value chemical from plants (phytochemicals). Phyton Biotech will use its Plant Cell Fermentation (PCF^®) technology, to demonstrate a feasible model for the consistent, large-scale commercial production of high purity QS-21 directly from plant cell cultures, at an acceptable commercial cost.

QS-21 is currently used as an adjuvant in GSK’s Shingrix that is in commercial production for vaccination against shingles as well as several other vaccines in clinical development.

Talee Bio receives grant award from the Cystic Fibrosis Foundation to advance development of gene therapy product candidates

In another grant announcement, Talee Bio (PA, USA), has been awarded $4.5 million from the Cystic Fibrosis Foundation to support preclinical development of two therapy product candidates, TL-101 and TL-102. TL-101 utilizes a recombinant adeno-associated virus (AAV)-based gene therapy and TL-102 a lentivirus-based as viral vectors to deliver the therapy by inhalation [9].

Talee Bio was founded by researchers from the University of Iowa (IA, USA) and the Children’s Hospital of Philadelphia (PA, USA) and Militia Hill Ventures, a Philadelphia based venture capital firm, with support from Emily’s Entourage (PA, USA), a not for profit organization that raises money and awareness to support finding a cure for rare mutations of cystic fibrosis.

The funds will be used to expedite the development of both gene therapy candidates for all people with cystic fibrosis, particularly for whom no viable treatment options for the underlying cause of the disease, exist.

Lilly announces agreement to acquire Loxo Oncology

Eli Lilly and Company (Lilly; IN, USA) announced it had agreed to acquire Loxo Oncology, Inc. (CT, USA) for approximately $8 billion [10]. Loxo focuses on the development and commercialization of highly selective medicines for patients with genomically defined cancers, that arise from a single DNA change. It has one drug, larotrectinib (VITRAKVI), recently approved by the FDA for use by adult and pediatric patients with solid tumors driven by a gene mutation known as TRK fusion and co-marketed with Bayer (Leverkusen, Germany), as well as three others drug in clinical development and several other preclinical assets.

The acquisition of Loxo is the largest in a series of transactions made by Lilly to broaden its portfolio of commercial and developing cancer treatments.

Neurocrine & voyager therapeutics announces collaboration to develop & commercialize gene therapy treatments

Neurocrine (CA, USA) and Voyager Therapeutics (MA, USA) announced a new collaboration to develop and commercialize Voyager’s gene therapy technology in Parkinson’s disease, Friedrich’s ataxia and two other programs still to be agreed [11].

One of the therapies, VY-AADC, is an investigational gene therapy product being developed, to introduce AADC gene directly into cells, enabling them to produce the enzyme AADC, required to produce dopamine from levodopa. In Parkinson’s disease, cells in the sustantia nigra, that normally support dopamine production in the brain, start to die resulting in a dopamine deficit. In the early stages of Parkinson’s disease, administration of oral levodopa is an effective treatment to address this deficit, but as the disease progresses, it becomes ineffective and causes sides effects such as dyskinesia. The approach being pursued by Voyager is to use VY-AADC to genetically modify cells in the putamen region of the brain which are unaffected by the development of Parkinson’s disease, to produce AADC. If successful, this approach would then allow levodopa treatment to remain effective for a longer period.

Friedrich’s ataxia patients have mutations of the FXN gene resulting in a reduction in the production of frataxin protein causing degeneration of sensory pathways and other symptoms. In a single treatment, VY-FXN01 seeks to slow the progression of disease by restoration of FXN protein levels to at least 50% of normal in relevant neurons and cardiac myocytes.

Under the agreement, Neurocrine has agreed to fund clinical studies for VY-AADC and VY-FXN01 as well as development of two further programs. It will gain marketing rights for the products when approved and pay milestone and royalty fees to Voyager.

Biogen announces two new development focused on new treatments in neurology

This month, Biogen (MA, USA) announced two new agreements aimed at developing new treatments for neurological disorders.

It signed an agreement with Skyhawk Therapeutics (MA, USA) to leverage the latter’s technology around RNA splicing modifiers in the discovery of innovative small molecule treatments for patients with spinal muscular atrophy, multiple sclerosis and other neurological diseases [12]. Biogen gains an option to license therapies and then take responsibility for the development and potential commercialization for therapeutic entities arising from the collaboration. Skyhawk received an upfront payment from Biogen and may receive further development milestone payments and royalties on commercial sales.

Many neurological diseases are caused by a process called exon skipping, which during a process called mRNA splicing results in important regions in the final mRNA sequence being missed. Skyhawk’s SkySTAR technology platform combines information from computational, kinetic, & structural models of RNA to identify molecules that can bind to specific regions on the mRNA molecule to avoid irregular mRNA splicing.

The second collaboration, with C4 Therapeutics (MA, CA) targets removal proteins from cells that cause disease [13]. It utilizes C4 Therapeutics’ protein degradation platform to discover and develop potential new treatments for neurological conditions, including Alzheimer’s disease and Parkinson’s disease. As for the deal with Skyhawk, Biogen is making an upfront payment and will then take suitable candidates for development and potential commercialization, making further milestones payments as the programs progress and royalty payments on any drug commercialized.

Digital Health

Proteus Digital Health launches digital oncology medicines to improve patient outcomes

Proteus Digital Health (CA, USA) announced a partnership with the University of Minnesota and Fairview Health Services (MN, USA) to bring digital medicine to the treatment of cancer [14].

Seven patients with stage 3 or 4 colorectal cancer have been provided with the digital treatment in a study that began in September 2018. They take the chemotherapy drug, capecitabine, packaged in a capsule with the Proteus digital pill. The latter sends a signal via a patch worn by the patient to a smartphone that can then share the data with a healthcare professional. This provides the ability to monitor adherence remotely allowing healthcare staff to intervene more easily when issues arise, improving support and reducing the need for hospital visits.

Fairview Health Services, a nonprofit, integrated health system providing a broad range of healthcare services in the Minneapolis-St. Paul metropolitan area and in greater Minnesota, anticipates that the improved level of treatment management associated with the ability to monitor patients better remotely will help it improve services and reduce costs. They have struck a deal with Proteus in which it only pays for the digital pill if adherence levels exceed agreed thresholds of approximately 80%.

The Proteus pill was approved by the FDA in 2014 as a medical device via the 510k route as a ‘Ingestible Event Marker’. Its use with Abilify, a drug marketed by Otsuka (Tokyo, Japan) for the treatment of schizophrenia and bipolar disorder was approved in 2017 although it is understood that this treatment has yet to be used outside clinical trials. Unlike Abilify where the digital pill was embedded in the active medication, requiring specific regulatory approval as a drug–device combination product via the New Drug Application (NDA) approval route, the oncology treatment requires no further approval as the active drug and digital pill are co-packaged in a capsule.

Although it remains to be seen if technology such as the Proteus Digital Pill can demonstrate sufficient value in improving outcomes to justify its cost in a wide range of applications, pioneering studies such as that being undertaken in colorectal cancer will allow valuable data to be collected that provide better understanding of the impact of nonadherence on outcomes and may eventually pave the way for more personalized medicines where treatment can be adapted based upon data gather remotely outside the clinic.

Otsuka to work with Click Therapeutics to develop digital therapies for major depressive disorder

Otsuka America (CA, USA) announced a collaboration with Click Therapeutics (NU, USA), to create a new digital therapeutic to treat major depressive disorder [15].

The goal of the partnership is to utilize the principles of cognitive therapy to develop a regulated medical app that can be used either with or without prescription drugs. Click brings to the collaboration expertise in software development, and Otsuka experience in the development and commercialization capabilities in the field of psychiatric disorders. As mentioned above, Otsuka already has experience in developing and commercializing digital health technologies from its work with Proteus.

Regulatory news

First generic of ADVAIR DISKUS^® is approved in the USA

Mylan Pharmaceuticals (PA, USA) announced that the US FDA has approved Wixela™, its generic version of GSK’s ADVAIR (fluticasone propionate and salmeterol inhalation powder) [16]. The approval follows two previous rejections by the FDA, the last back in 2018 that cited only minor issues that have now been addressed. Mylan has not been alone in struggling to gain approval, Hikma and Sandoz (Holzkirchen, Austria) both received complete response letters from the agency that they are still addressing. Teva Pharmaceutical Industries (Petah Tikva, Israel) won approval in 2017 for a liquid form of the same drug combination delivered in a metered dose inhaler, although it is not directly substitutional for ADVAIR. ADVAIR had sales in the USA of approximately £1.6 billion in 2017, down from £2.8 billion in 2013 and, based on 25-year sales from 1992 to 2017, it is the fourth bestselling drug in the USA. The market for ADVAIR has diminished in part due to pricing pressures but also as a result of the arrival of newer therapies in an increasingly competitive market. As a result, analysts estimate that Mylan will make less than $200 million from Wixela in the USA in 2019.

Science

Research published that supports the development of a long-acting contraceptive designed to be self-administered via microneedle patch

Research published in the journal Nature Biomedical Engineering, support the possibility of developing a long-acting contraceptive based upon a microneedle device that can be self administered [17]. Current long-acting contraceptives require implanted devices or patches that need to be worn on the skin continuously. This new approach could allow an effective long-term contraceptive to be delivered by the application of a microneedle patch by the user for 5 s, once per month. The research led by a postdoctoral student, Wei Li, at Georgia Tech (GA, USA), describes the development of a device which incorporates tiny molded air bubbles into the top of the microneedle structure that the drug-containing microneedles to break free from the patch’s backing material, when the latter is removed. The needles then remain embedded in the skin so they can continue to elute drug over a period of a few weeks before the needles decay and are bio-absorbed. The needles are fabricated from biopolymers selected to ensure appropriate mechanical stability during the drug-delivery period and biodegradability so they can be absorbed and eliminated from the body. Tests carried out on rats did not attempt to stop pregnancy but showed levels of hormone released from the needles circulating in the blood could be sufficiently high enough to stop pregnancy in humans. Although the results are encouraging, the researchers emphasized that much work still needs to be done before a human version could be developed and approved as a contraceptive. A Phase I clinical trial of an influenza vaccination using rapidly dissolving microneedles previously conducted by the team in collaboration with Emory University (GA, USA), showed efficacy and that they did not cause pain. Tests on efficacy, as well tolerability of the proposed contraceptive device, for example not causing rash where the patch is applied, would need to be studied in a program of clinical trials before the product could be approached and marketed.

There has been growing interest in the use of microneedles to deliver drugs for a range of applications. Georgia Tech has been a leader in this field and several companies including 3M (MN, USA), Corium International (CA, USA) and Zosano Pharmaceutical (CA, USA) are also developing the technology in several therapeutic areas.

Researchers develop an inhalable form of mRNA that could be used to treat lung disease

ScienceDaily reported that researchers from Massachusetts Institute of Technology (MIT; MA, USA) have developed an inhalable form of mRNA that could potentially be administered directly to the lungs to treat diseases such as cystic fibrosis [18].

Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins including therapeutic proteins, holding promise in the treatment of a variety of diseases. Unlike DNA gene therapy, mRNA does not modify the genome in host cells and so can be used to produce a therapeutic protein that is only needed temporarily. However, a major obstacle to this approach has been finding safe and efficient ways to deliver mRNA molecules to the target cells. mRNA introduced systemically into the body can be easily broken down so normally needs to be transported in a nanoparticle protective carrier, such as a polymer, and utilizes viral vectors to transport the mRNA into target cells.

A concern with some carriers is that they do not break down in the body so accumulation could lead to side effects, especially in sensitive organs such as the lung. In the current study, the researchers used poly(β-amino ester)s (PBAEs), mixed with mRNA molecules to form spheres, approximately 150 nanometers in diameter, that were suspended in a liquid and delivered using a nebulizer, as a mist to mice. The mRNA molecules used encoded a bioluminescent protein, luciferase and 24 h after administration, lung cells in the host mice were found to have produced the bioluminescent protein. Following administration, the protein level gradually fell over time as the mRNA was cleared, but by giving repeated doses, steady levels of the protein could be achieved as would be required for continuous dosing of a therapeutic.

The study was partially funded by TranslateBio (MA, USA), a company developing mRNA therapeutics, and which is already testing an inhalable form of mRNA in a Phase I/II clinical trial in patients with cystic fibrosis and which provided an update this month on its mRNA programs [19]. Funding for the work also came from UK-based EPSRC and a grant from the National Cancer Institute (MD, USA). The research was published in the journal Advanced Materials [20].

Nanoscale peptoid-based drug-delivery method

A team led by Yuehe Lin, a professor in Washington State University’s School of Mechanical and Materials Engineering (WA, USA), and Chunlong Chen, a senior scientist at the Department of Energy’s Pacific Northwest National Laboratory (PNNL; WA, USA), have developed a method of delivering drugs into cells using nanoparticles, without the toxic effects commonly associated with nanotechnology delivery [21]. The team used flower-shaped nanoparticles, approximately 150 nanometers, made up of layers of peptoids. Peptoids have a similar structure to peptides, but with the side chains connected to the nitrogen atoms in the oligomer backbone rather than the carbon atoms.

Ease of synthesis and biocompatibility has made peptoids attractive targets as biologic scaffolds and drug-delivery vehicles. The lower toxicity associated with the nanoparticles developed in the current work is attributed to the crystalline structure and fluorination of structures.

To test the approach, the team added fluorescent probes to the peptoids so they could observe them entering the cells, where they can release their drug cargo, before being expelled from the cell. At present, the approach has only been tested with model drug molecules, but the researchers plan to conduct further studies using therapeutic medicines.

Autophagy, cellular recycling process associated with cell survival may in fact stop initiation of cancer

Research published in Nature and reported in ScienceDaily [22] suggests that a cellular process normally associated with cancer cell survival might promote cell death and stop initiation of cancer.

Researchers at the Salk Institute (CA, USA) led by Jan Karlseder and Reuben Shaw, were exploring the linkages between telomeres, the repeating nucleotide sequences at each end of a chromosome, that protect it from deterioration or fusion with neighboring chromosomes. Each time a cell replicates, the length of the telomere region reduces, until eventually it ceases to be protective, resulting in a risk of mutation and potentially cancer. Molecular signals then normally instruct the cell to stop replicating, a process known as senescence. However, in some situations, genetic or epigenetic factors, allow cells to proliferate beyond this limit until they eventually reach a stage of extreme telomere dysfunction known as ‘crisis’, at which point, biological mechanisms, including programmed cell death by apoptosis and autophagy, are triggered. To proliferate, cancers cells must shield themselves from these processes. Importantly, autophagy can both inhibit cancer as it is a method for cell death, but also promote cancer as it can allow cells to utilize cellular components from the process in order to survive the hostile conditions associated with cell crisis. So, the factors that determine whether autophagy promotes or inhibits cancer are of great research interest.

In the current research, Karlseder and a postdoctoral fellow in his group, Joe Nassour, disabled the growth-limiting genes of cells, enabling the cells to replicate uncontrollably, until their telomeres were sufficiently shortened to putting them into crisis. They then investigated the relative importance of apoptosis and autophagy for the death of cells in crisis compared with that for normal cells. For normal cells, both mechanisms were responsible for the death of normal cells, but for cells in crisis, autophagy was found to be by far the more dominant process. The researchers found that when they inhibited autophagy in the crisis cells, cells rapidly proliferated. This was a surprising observation with potentially significant implications in the development of cancer therapies. Without autophagy, cells that lose inhibiting mechanisms, such as tumor-suppressing genes, can advance into crisis and then replicate uncontrollably. Inhibition of autophagy has been seen to be a mechanism to treat cancer, but the current research has shown, that in at least some conditions, it may result in the opposite effect and some approaches to cancer treatment consequently will need to be reassessed.

Research supports the potential of developing gene therapy treatments for peripheral neuropathy & other nerve diseases

Scientists from Washington University School of Medicine (MO, USA) have published research in the Journal of Experimental Medicine that supports potential for gene therapy to prevent the loss of peripheral nerves in multiple conditions [23,24].

When a nerve axon is damaged by drugs or by injury, a protein, SARM1, is liberated which triggers it to self-destruct. In the current research, a mutated and inactive version of the SARM1 protein that blocks axon destruction was delivered to cells using an adeno-associated virus-mediated expression. Nerve axons were found to be still intact more than 10 days after nerve transection, suggesting that mutated from of SARM 1 suppressed the action of normal SARM1 proteins that have become activated in mice with nerve injuries. The work suggests that a therapeutic approach could feasibly be developed to prevent the loss of peripheral nerves in multiple conditions. The researchers specially mentioned peripheral neuropathy that can arise from chemotherapy for cancer treatment or poorly controlled diabetes but suggested the approach may have wider utility in the treatment of neurological diseases that result in axion degradation. However, previous research has suggested that SARM1 suppression is ineffective in amyotrophic lateral sclerosis so further work is required to better understand the various mechanisms that cause nerve destruction.

Having highlighted the potential importance of SARM1 inhibition and the ability to deliver treatments via gene therapy, the Washington University team are studying other possible ways to block SARM1, including small molecules for drug development.

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.