Industry Update Covering January 2021

Keywords:

• COVID-19
• drug delivery
• medical device
• mRNA
• nanoparticle
• vaccine

COVID-19 therapeutic update

A smart device for delivery of COVID-19 vaccines

A team from Swansea University (Swansea, UK) has received a grant to develop a smart microneedle vaccine device that can both deliver vaccine and also assess its efficacy by measuring the body’s inflammatory response [1]. Although the research is targeting COVID-19, it is envisaged the technology can provide a platform to treat other infectious diseases.

Intradermal delivery has long been recognized as an effective delivery route for vaccines and other therapeutic agents; Sanofi Pasteur (Paris, France) has US FDA approval for a flu vaccine delivered by this route using a prefilled syringe with a microneedle. It is argued that the epidermis can elicit a strong immune response and that injection into this region is less painful than for conventional subcutaneous or intramuscular injections. Microneedle arrays such as the one being developed by the team in Swansea enable a device to be applied as a patch, with multiple needles increasing the delivery rate of a therapeutic or vaccine. This approach could also allow self-administration of a vaccine that could accelerate the roll out of the vaccine program. However, progress in developing microneedle patches has been slow due to challenges in developing technology and fabrication methods that enable high volume manufacture at low cost. Concerns also remain around their safety and efficacy [2].

The Swansea team claim their device, once developed, would be first smart vaccine device that will both deliver and measure the efficacy of a COVID vaccine. They argue that the approach would enable more efficient vaccine trials to conducted and would also allow those vaccinated to know when they have achieved immunity.

Janssen reports topline efficacy data for its Phase III study for a single-dose COVID-19 vaccine

Johnson & Johnson’s (Beerse, Belgium) announced topline data for an investigational single-dose COVID-19 vaccine being developed by its pharmaceuticals division, Janssen Pharmaceutical Companies (Beerse, Belgium) [3]. The analysis came from 43,783 participants with a total of 468 symptomatic cases of COVID-19 with study end points at 14 and 28 days after vaccination. Across all the regions studied, USA, Central and South America and in South Africa, the vaccine was on average, found to be 85% effective in preventing severe disease. For the vaccinated cohort, onset of protection was observed from day 14 and continued to increase during the study with no cases of severe disease reported after day 49. The safety profile was good, with serious fever occurring in less than 0.2% of those treated. Serious adverse events were lower in the treated arm compared with those who received placebo.

The vaccine uses a human adenovirus that has been modified to incorporate a gene for making the spike protein of the SARS-CoV-2 virus. When the adenovirus enters a host cell, the spike protein is created, triggering an immune response that then provides protection again SARS-CoV-2 virus.

The fact that the vaccine achieved a good level of protection with a single injection is seen as a significant advantage over other vaccines approved to date that require two injections several weeks apart to achieve protection.

The vaccine candidate utilizes Janssen’s proprietary AdVac^® platform, which has already been used develop and manufacture an Ebola vaccine regimen that has been approved in Europe and is being used in other vaccine developments against Zika, RSV, and HIV. To develop the vaccine, Janssen entered a collaboration with Beth Israel Deaconess Medical Center (MA, USA) in March 2020.

Janssen stated it intends to file for US Emergency Use Authorization in the coming weeks and expects to have product ready for immediate shipment on a not-for-profit basis following authorization.

Novavax report results for its COVID-19 vaccine, NVX-CoV2373

Novavax (MD, USA) also announced interim results for a study testing the safety and efficacy of its NVX-CoV2373 vaccine against COVID-19 [4]. In a study that enrolled more than 15,000 participants between 18 and 84 years of age, 62 COVID-19 cases were observed with 56 in the placebo group versus six cases observed in treated group, resulting in an estimated 89.3% vaccine efficacy. Importantly, given increasing concern around new variants of the virus that are more transmissive, and which might be resistant to earlier vaccines, it was encouraging that around 50% of the confirmed COVID cases in the study involved the UK variant of the virus. This suggests there was good exposure in the study to this variant and that immunization against it was effective. Based on this study and other studies running in the USA and Mexico, Novavax claim that this was the first vaccine study to demonstrate clinical efficacy against the new UK and South Africa variants of COVID-19.

Unlike the other COVID-19 vaccines approved to date, NVX-CoV2373 introduces the spike protein directly into the host rather than replying upon the host’s own cells to create the protein. To do this, the vaccine utilizes the company’s recombinant nanoparticle technology to create an antigen derived from the coronavirus spike protein. A proprietary adjuvant is used in the vaccine formulation to enhance the host immune response after injection.

Based on these results, Novavax announced that it has started a rolling submission to the The Medicines and Healthcare products Regulatory Agency (MHRA), the UK’s regulatory authority for medicines approvals.

Lilly reports study results for neutralizing antibody bamlanivimab (LY-CoV555) that suggest it can reduce risk of COVID for care home residents by up to 80%

Although a lot of the focus on treatments for COVID-19 has been on vaccines, there is still a need to identify medicines that can reduce the severity of the disease for those already infected. In many cases, this has involved looking at opportunities for repurposing existing approved drugs, but this month, Eli Lilly and Company (IN, USA) announced results of a study to assess the effectiveness of its drug bamlanivimab (LY-CoV555) in reducing risk of contracting symptomatic COVID-19 among residents and staff of long-term care facilities [5]. The study involved 965 participants who had tested negative, and 132 who has tested positive for SARS-CoV-2 virus at baseline and were then randomized to receive either 4200 mg of bamlanivimab or placebo. After an 8-week follow-up, there was a significantly lower frequency of symptomatic COVID-19 (the primary end point) in the bamlanivimab treatment arm versus in the placebo arm, suggesting that the drug was effective in reducing preventing infection by the virus as well as potentially treating those in the early stages of infection.

Unlike a vaccine that aims to stimulate the body’s own immune response to a virus, bamlanivimab is a monoclonal antibody that directly targets the virus and aims to neutralize it. As a result, it may be effective in preventing serious disease in those already infected by SARS-CoV-2 virus, but compared with vaccines it is unlikely to be cost effective in the prevention of the disease. The data outlined in the press release is from a larger study, BLAZE-2 that aims to enroll around 5000 patients to assess the efficacy and safety of the drug in the treatment of COVID-19. The drug was developed in collaboration with Canadian biotechnology company AbCellera (Vancouver, Canada) specifically for the treatment of COVID-19 and although not approved, is authorized for emergency use by the FDA for the treatment of mild to moderate COVID-19 in high-risk patients for as lower dosage form (700 mg), delivered by infusion.

Acquisitions, licensing deals & other commercial news

Sanofi to acquire Kymab

Sanofi (Paris, France) announced it is to buy Kymab (Cambridge, UK) for an upfront payment of approximately US$1.1 billion with a further $350 million contingent on achievement of specified milestones [6]. Kymab is a clinical-stage biopharmaceutical company focusing on the development of fully human monoclonal antibodies for the treatment of immune-mediated diseases and in immuno-oncology. Its lead compound, KY1005, targets T-cell immune dysregulation in patients with immune-mediated conditions and in a Phase IIa study in 2020 reported positive results in the treatment moderate to severe atopic dermatitis. Other drugs in its pipeline include KY1044, in clinical development for the treatment of cancer either as monotherapy or in combination with anti-PD-L1 therapeutics and KY1043 an immune checkpoint inhibitor in preclinical development, also for the treatment of cancer. It has partnerships with Novo Nordisk (Bagsværd, Denmark), Sosei Heptares (Cambridge, UK) and a collaboration with Bill & Melinda Gates Foundation (WA, USA) focused on the identification of new vaccines and therapeutic antibodies to a range of infectious diseases.

As well as adding KY1005 to its pipeline, the acquisition will also provide Sanofi with access to new antibody technologies and research capabilities. It is anticipated that the purchase will conclude during the first half of 2021.

Gilead & Vir Biotechnology to collaborate on treatments for chronic hepatitis B

Gilead Sciences, Inc. (CA, USA) and Vir Biotechnology (CA, USA) announced a collaboration to evaluate therapeutic combination treatment approaches that might provide a functional cure for chronic hepatitis B virus (HBV) [7]. They plan to initiate a multi-arm Phase II study to investigate combinations of their developmental drugs, selgantolimod, VIR-2218 as well as a commercially sourced PD-1 antagonist as a potential treatment pathway for the disease.

Although current antiviral therapies for HBV can suppress the virus, they rarely achieve complete clearance and thus require continuous treatment. VIR-2218 is an investigational drug being developed by Vir and currently in Phase II studies in combination with pegylated IFNα-2a, an approved immunomodulatory agent. It is a subcutaneously administered siRNA that targets HBV, with the objective of stimulating an effective immune response and direct antiviral activity against HBV. Studies have shown that it can reduce levels of hepatitis B surface antigen, a protein associated with HBV. Selgantolimod is an investigational drug being developed by Gilead that induces cytokines in human peripheral blood mononuclear cells that activate an antiviral function by multiple immune mediators that can target HBV. It is administered orally. PD-1 antagonists inhibit PD-1 that downregulates T-cell function, thus increasing immune response. They have been approved for cancer treatment, but it has been suggested that they could have a role in the treatment of HBV by reinvigorating dysfunctional T cells that are observed in patients with the chronic disease. The rationale for a combination approach being pursued by Gilead and Vir is that a curative treatment requires a reduction of the levels of circulating viral proteins together with stimulation of the immune system to generate new T cells that can then bring the infection under control.

Vir is clinical-stage immunology company focused on the use immunologic approaches to treat and prevent serious infectious diseases including HBV. Gilead has a long-established presence in the treatment of hepatitis including Vemlidy, a drug approved for the treatment of HBV in Europe and the USA.

Merck acquires mRNA contract development & manufacturing organization AmpTec

Merck (Darmstadt, Germany) announced that it has acquired AmpTec (Hamburg, Germany), a contract development and manufacturing organization with capability in mRNA technology [8]. Although Merck is best known as a pharmaceutical company, it has diversified activities in lifesciences and the supply for performance materials including in diagnostics, electronic displays and gene editing. The acquisition of AmpTec complements its existing capability in the manufacture of lipids that are commonly used as carriers for the delivery of mRNA therapies. AmpTec also has a diagnostics business that focusing the manufacture of RNAs and DNAs for in vitro diagnostics, which adds to Merck’s current activities in the production of raw material for the sector. The value of the acquisition transaction was not disclosed.

Novartis invests in Credence for injectable delivery scale-up

Credence MedSystems (CA, USA), a developer of drug-delivery systems, announced a strategic investment in the company by Novartis (Basel, Switzerland) [9]. The undisclosed investment will support development and scaling of Credence’s innovative drug-delivery systems, focusing initially on its Companion^® Safety Syringe System. The syringe system is designed to prevent reuse and incorporates proprietary automated needle retraction technology. An attraction of the system is that compared with a conventual syringes, it does not require any additional user steps to ensure needle safety after use. The Novartis investment follows news of a collaboration with Schott, a leading provider of primary drug packaging solutions to the pharmaceutical industry, that will see the two companies collaborate to incorporate Credence’s safety needle into SCHOTT’s pre-fillable syriQ^® glass and SCHOTT TOPPAC^® polymer syringes. Prefilled syringes are used by pharmaceutical companies to provide ready to use systems for injectable drug delivery, reducing drug preparation and delivery errors. Integrated needle safety is increasingly being used to avoid needle stick injuries during and after use in both initial and at-home settings.

Amneal to acquire substantially all of Kashiv Specialty Pharmaceuticals

Amneal Pharmaceuticals (NJ, USA) announced that it is to acquire 98% of Kashiv Speciality, a subsidiary of Kashiv Biosciences (NJ, USA) for approximately $70 m upfront plus an additional $8 million in contingent payments upon the achievement of certain regulatory milestones as well as royalties on future sales [10]. The deal gives Amneal ownership of four publicly disclosed drug-delivery platforms; a gastric retention technology in the form of a swellable pill, an osmotic oral drug-delivery system that provides delayed drug release and formulation technologies to improve drug solubility and sustained drug release. Kashiv Speciality has focused on using these technologies to develop new dosage forms of existing genetic drugs using the FDA 505 (B) (2) approval route. This allows the new form of the drug to utilize existing safety data from the original innovator product but also improve its performance using new formulation or device technology.

Regulatory news

ViiV Healthcare announces FDA approval of Cabenuva

ViiV Healthcare (NC, USA), a company majority owned by GlaxoSmithKline plc (Brentford, UK) announced that it had gained FDA approval for Cabenuva for the treatment of HIV-1 infection in adults [11].

The treatment consists of two co-packaged injectable drugs: cabotegravir, which was developed by ViiV, and rilpivirine, an approved drug developed by Janssen. Dosing is monthly rather than the daily treatment for other approved treatments. In pivotal studies for the new drug, 90% of patients preferred it to their existing treatment, presumably driven by the convenience of less frequent dosing even though this requires two injections per month rather than a daily tablet.

ViiV Healthcare is a specialist HIV company established in 2009 by GlaxoSmithKline and Pfizer (NY, USA), with Shionogi (Osaka, Japan) becoming a partner in 2012.

Updates on clinical research

Lyndra Therapeutics announces first subjects dosed in Phase I clinical trial of once-weekly rosuvastatin extended-release capsule, LYN-047

Lyndra Therapeutics (MA, USA) announced initiation of a Phase I study to evaluate safety, tolerability and pharmacokinetics of a once-weekly formulation of rosuvastatin, a drug used to treat dyslipidemia, a disease arising from abnormal levels of cholesterol or lipids in the blood [12]. Rosuvastatin, is normally administered as a daily pill, but this can result in poor adherence, which can be at least partially addressed by moving to less frequent dosing.

Lyndra has been working on an extended-release oral capsule designed to provide consistent drug levels for a week or more. The approach uses extrusion technology to incorporate active drug into polymer rods, which are then assembled into flexible star-shaped structures, or stellates that can then be folded into a conventional pill capsule. Once swallowed, the capsule disintegrates in the stomach and the stellate expands. It is then retained in the gut for an extended period during which the drug is released at a constant rate. After a period of time, the structure disintegrates, passes through the lower GI tract and excreted. In the Phase I study, to be run in Australia, 16 participants will receive a 140 mg capsule (equivalent to seven 20 mg daily capsule) in two administrations 1 week apart.

In total, Lynda has eight compounds in preclinical or clinical development, in a mixture of partners and owned programs. Its lead program, for extended-release risperidone, is in Phase II.

Glaukos’ glaucoma implant matches eye drops in 24-month analysis

Glaukos Corporation (CA, USA) announced results from 24-month interim analysis of a 36-month study initiated to assess the safety and efficacy of travoprost delivered from it iDose^® TR sustained-release ocular implant for the treatment of glaucoma [13]. The 154-subject, multicenter, double-blind, randomized, study compared effectiveness of two different travoprost release rates from the implant to a comparator, timolol applied topically to the eye twice daily. The primary efficacy end point is noninferiority in reduction of intraocular pressure of the implant treatment compared with the eyedrops. Topically glaucoma treatments are known to have adherence issues and it is hoped that iDose^® device can provide an alternative dosage regimen that could result in better outcomes. Although the results showed little overall difference between the treated and control groups, around 20% of participants showed average intraocular pressure reductions from baseline of at least 40%, respectively, versus 13% in the timolol control arm suggesting the treatment is more effective than eyedrops for at least some glaucoma patients. The study showed favorable safety for the implant.

Glaukos Corporation is an ophthalmic medical technology and pharmaceutical company focused on novel therapies for the treatment of glaucoma, corneal disorders and retinal diseases.

Biohaven provides a clinical update on Alzheimer’s drug

Biohaven (CT, USA) announced disappointing results for a Phase II/III trial for an investigational drug, troriluzole targeting symptomatic treatment of mild-to-moderate Alzheimer’s disease (AD) [14]. The topline results failed to show any benefit of the drug over placebo measured using cognitive assessments or change in hippocampal volume as assessed by MRI. However, analysis of a subgroup including only moderate AD patients, suggested that there might be potential benefit. Further analysis will continue, and full results are expected in the coming months and will be presented at a major conference.

Glutamatergic dysfunction is associated with neurodegeneration as well as with psychiatric conditions including schizophrenia, bipolar disorder and major depressive disorder. Glutamate is an important neurotransmitter but excessive production results in cell stress and death. Troriluzole is a prodrug of riluzole, which is FDA approved for amyotrophic lateral sclerosis and has been tested in clinical trials for several neurodegenerative diseases including Parkinson’s disease, Huntington’s disease and AD. Troriluzole reduces side affects associated with riluzole, potentially allowing larger doses to be administered.

It was also announced this month that an FDA decision on the approval for aducanumab another AD treatment being developed by Biogen (MA, USA) and Eisai (Tokyo, Japan) has been delayed by 3 months with Prescription Drug User Fee Act action date now 7 June 2021 [15].

Collaborations

New collaboration to investigate new treatments for schizophrenia

The University of Oxford announced a new collaboration a partnership between its Department of Psychiatry, the Earlham Institute (Norwich, UK), Biogen and Boehringer Ingelheim (Ingelheim am Rhein, Germany) to investigate a new drug target for the treatment of schizophrenia [16]. The collaboration will investigate which proteins are selectively produced by the kalirin gene in the human brain. Kalirin is associated with multiple neurological disorders as evidenced by genome sequencing, postmortems and clinical studies. But it has also been shown to create schizophrenia-like symptoms in kalirin knockout mice. The Earlham Institute, a center of excellence in genomics and computational biology, will lead on the bioinformatic analysis of the publicly available data for schizophrenia as well as the sequencing of protein data generated at the University of Oxford. For Biogen and Boehringer Ingelheim, it is hoped that a better understanding of the microbiological processes associated with the disease will enable the development of new and improved treatments for schizophrenia. The project is the first to be funded by the Psychiatry Consortium, an international £4 million collaboration between several global pharmaceutical companies, and charities, led by the UK’s Medicines Discovery Catapult, that supports high-value drug discovery projects in this area of unmet patient need.

Science & novel technologies

Nanoparticle drug delivery technique shows promise for treating pancreatic cancer

Researchers from the Kansas City Veterans Affairs Medical Center (MO, USA) and North Dakota State University (ND, USA) have developed an approach that uses nanoparticle to target the delivery drugs in the treatment pancreatic cancer [17]. Treatment by infusion of the drug gemcitabine is the current standard of care, but the drug rapidly degrades in systemic circulation, has toxic side effects, and can suffer from loss of efficacy due to tumor resistance. Consequently, the drug offers only a small improvement in patient survival time. Extracellular receptor kinase inhibitors (ERKi) provide another treatment pathway that potentially complements gemcitabine by targeting the ERK1/2 activity that gives rise to tumor resistance, but again have limitation due to toxicity, poor solubility and rapid clearance.

The current research exploits the fact that pH inside tumor cells is lower than the pH elsewhere in the body, a property that can be used to target therapeutic delivery. pH-responsive nanoparticles were manufactured from polyethylene glycol-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. These structures are stable at normal in vivo pH but degrade at lower pH enabling release of a drug payload. The approach was tested using nanoparticles loaded with gemcitabine and ERKi to target cancer cells cultured in the laboratory. It was found that addition of ERKi significantly increased sensitivity of the cancer cells to gemcitabine and performance was significantly improved to that unencapsulated therapy using the same drug combination.

Although further work is required before the approach could be taken into clinical testing and commercialization, the researchers believe they have identified a simple, yet efficient approach to target drug delivery for pancreatic cancer as well as potentially for other cancer types. The work was published in Molecular Pharmaceutics [18].

Nanoparticle drug-delivery system

Nucleic acid-based therapeutics, including siRNA have the potential to treat neurodegenerative diseases such as Parkinson’s disease and AD, but a key challenge is ensuring that these entities can enter the brain safely and efficaciously. Disruption of the blood–brain barrier (BBB) after trauma brain injury (TBI) has been used as an approach, but this only provides a limited timeframe for treatment. Researchers at Brigham and Women’s Hospital and Boston Children’s Hospital (MA, USA) have developed a new approach that uses nanoparticles to increase the efficiency of transfer and could be uses as the basis of delivery of therapeutic agents on an on-going basis. The team used nanoparticles formed from poly(lactic-co-glycolic acid), or PLGA, which is biodegradable and biocompatible polymer that has already been approved by the FDA for use in several applications. They engineered the surface properties of the nanoparticles to maximize their penetration across the BBB in healthy mice and showed they could encapsulate anti-tau siRNA in the nanoparticles and deliver it in therapeutically significant quantities to the brain. Tau is expressed after TBI and is also associated with neurodegenerative processes and suppression is seen to be a potential treatment pathway. With this in mind, the team then went on to demonstrate the ability to reduce the expression of tau by 50%, in TBI mice by transfer of anti-tau siRNA using the nanoparticles, irrespective of the treatment being administered during or outside the period that the BBB was temporality disrupted by TBI. Attempts to deliver the anti-tau siRNA across the BBB using a conventional drug-delivery approach failed to show an effect. The researchers are now looking at other targets in addition to tau and believe that their approach should help other teams developing neurodegenerative treatments to test efficacy [19,20].

Application of quantum computing to drug discovery

Cambridge Quantum Computing (CQC; Cambridge, UK) and Roche (Basel, Switzerland), announced a collaboration focusing on the use of quantum computing to support early-stage drug discovery and development [21]. Quantum computing had been growing in interest over the past 10 years, as it has the potential to dramatically increase computational speed in areas such as modeling and simulation. This benefit comes about because quantum computers perform calculations based on the probability of a state whereas classical computers carry out logical operations using defined states (the 0s and 1s in a binary system). Furthermore, the information in each unit in a quantum computer (a qubit) can be influenced by the other qubits in the system which means there is an exponential increase in the information density in the system as the number of qubits are increased. In contract in classical computer there is only a linear increase in information density as the information units (bits) are increased. So, for example, IBM has estimated that modeling a penicillin molecule on a classical computer would take 10⁸⁶ bits, which is more than the total number of atoms in the observable universe. But the same model on a quantum computer may only require 286 qubits. There are challenges to be overcome; for example, there is a high error rate in a quantum computer, but if this can be addressed then the technology has enormous potential in modeling and simulation. In a recent report [22], BCG (MA, USA), a consulting group, presented a roadmap for the use of quantum computing in drugs discovery starting with computer-aided drug discovery, which uses computing alongside wet chemistry testing to identify targets, through to full in silico drug discovery and design, which is probably 20 years away from being realized. The collaboration between CQC and Roche focuses on the application of noisy-intermediate-scale-quantum algorithms for early-stage drug discovery and development, particularly in Alzheimer’s disease where it can complement Roche's existing efforts in discovering and developing new treatments for the disease.

Summary

This Industry Update covers the period from 1 January through to 31 January 2021 and is based on information sourced from company press releases, scientific literature, patents and various news websites. This month saw an award of a grant to a team from Swansea University (Swansea, UK) for the development of a smart device that can both deliver and monitor the effectiveness of a COVID vaccine. There were also positive updates from Janssen, the pharmaceutical division of Johnson and Johnson and Novavax on their COVID-19 vaccines and Eli Lilly announced results that suggested that bamlanivimab, a neutralizing antibody might reduce risks from COVID-19 to patients in care homes. Sanofi announced that it is to acquire Kymab to expand its pipeline and development capabilities in fully human monoclonal antibodies for the treatment of immune-mediated diseases and in immuno-oncology. Gilead and Vir Biotechnology announced a collaboration to develop combination therapies that aim to cure chronic hepatitis B and Merck announced it is to expand its capabilities in mRNA technology through the acquisition of AmpTec. Novartis made a strategic investment in Credence, a developer of innovative, needle safe, drug delivery systems. Amneal announced that it is to acquire the majority of Kashiv Speciality, giving it access to several novel drug delivery platforms. Viiv Healthcare announced approval of a new treatment of HIV-1 infection in adults that require much less frequent dosing than current therapies, and Lynda Therapeutics announced initiated of a Phase I clinical trial to test the safety and efficacy of its controlled release technology in the treatment of abnormal levels of cholesterol. Glaukos published a 24-month interim analysis for its study looking at the efficacy of an ocular impact to treat glaucoma. Biohaven announced that its Phase II/III trial for an investigational drug, troriluzole failed to demonstrate benefit in the treatment of Alzheimer’s disease. A new collaboration to explore new treatment approaches for Schizophrenia was announced in the UK as the first project supported by the Psychiatry Consortium. Research into the development of two nanoparticle drug-delivery systems was published and Roche and CQC announced a collaboration to apply quantum computing to support early-stage drug discovery and 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.