Industry Update: The Latest Developments in the Field of Therapeutic Delivery, March 2020

Keywords:

• cell therapies
• clinical trials
• COVID-19
• drug delivery
• gene therapy
• mergers and acquisitions
• oligonucleotides
• product approvals
• rare diseases
• targeted therapeutics

Business news

Acquisitions, mergers, licensing

Gilead Sciences & Forty Seven

The strategic focus in oncology being pursued by Gilead Sciences (CA, USA) is further supported by its announcement of an agreement to acquire the clinical stage, immuno-oncology company Forty Seven (CA, USA). Through the acquisition, Gilead will gain the potential first-in-class CD47-blocking investigational monoclonal antibody magrolimab [1]. CD47 is a transmembrane protein present on cell surfaces that signals to inhibit destruction of the cell by macrophages, a ‘don't eat me’ signal and its occurrence on normal cells prevents unwanted auto-immune attacks. Cancer cells, including those of Hodgkin's lymphoma, ovarian cancer, gastric cancer and lung cancer, can over express CD47 and so mask the other cell surface signals that would normally identify tumor cells as foreign and trigger a macrophage attack. It is also associated with the triggering of the adaptive immune system, including T cells, to invoke a long-term immune system defense against the cancer [2,3]. Magrolimab is currently in a clinical trial for the treatment of high-risk myelodysplastic syndrome, untreated acute myeloid leukaemia, B-cell non-Hodgkin lymphoma and certain solid tumors. Two additional Forty Seven assets ready for clinical testing are also being advanced and will form part of the acquisition; an anti-cKIT antibody with potential utility in stem cell transplantation conditioning and an anti-SIRPα antibody with immuno-oncology and transplantation conditioning potential. The acquisition is expected to close during the second quarter of 2020 [1].

Lilly & Sitryx

An exclusive global licensing and research agreement has been struck between Eli Lilly (IN, USA) and Sitryx (Oxford, UK) to study up to four novel preclinical targets identified by Sitryx (including Sitryx's current two lead projects), that could result in potential new therapies for autoimmune diseases. Research at Sitryx is focused on the regulation of cell metabolism in order to identify disease-modifying agents in immuno-oncology and inflammation. The founding academic researchers at Sitryx have made significant discoveries in the understanding, across a broad field of immunology, particularly of how critical the energetic status of immune cells is to how they behave. The 5-year research collaboration will make Sitryx responsible for drug discovery and Lilly responsible for clinical development and commercialization [4].

Moleculin Biotech & University of Texas Medical Branch at Galveston (UTMB)

Moleculin Biotech (TX, USA) have entered into an agreement with the University of Texas Medical Branch at Galveston (UTMB, TX, USA) covering research on the portfolio of molecular inhibitors held by Moleculin, notably the 2-deoxy-D-glucose prodrug WP122 for potential antiviral properties, including action against coronavirus [5]. The therapeutic utility of 2-deoxy-D-glucose to impact glycolysis and glycosylation and affect progression of viral infection at a cellular metabolism level is impaired by its poor cell penetration and short half-life. WP1122, the diacetyl ester of 2-deoxy-D-glucose, through its greater lipophilicity has increased cellular uptake and the time-dependent deacetylation to the active form, results in an increased parent drug half-life [6]. Under the agreement, Moleculin will supply compounds including WP1122 along with technical support to UTMB, who will test them in various viral disease models, including COVID-19.

Collaborations

AstraZeneca & Silence Therapeutics

A new modality, small interfering RNA (siRNA), has been added to the drug-discovery capabilities at AstraZeneca (Cambridge, UK) through their newly announced collaboration with Silence Therapeutics (London, UK). The collaboration will utilize the technology developed by Silence to inhibit liver-expressed gene targets. Additionally, the companies will work together to seek to extend the technology and to achieve targeted delivery of siRNA molecules to other tissues (heart, kidney and lung), in pursuit of novel potential therapies for cardiovascular, renal, metabolic and respiratory diseases. The two companies will collaborate during the discovery phase where AstraZeneca will identify gene targets and Silence will design siRNA molecules against those targets and make materials for toxicology as well as Phase I clinical studies. AstraZeneca will lead the clinical development and commercialization, with Silence having an option for codevelopment of two selected programs starting from Phase II [7].

Sanofi Pasteur & Translate Bio

Translate Bio (KY, USA), with expertise in messenger RNA (mRNA) therapeutics, and Sanofi Pasteur (Paris, France), the vaccines global business unit of Sanofi, have announced the development of their existing agreement around mRNA vaccines for infectious diseases, to collaborate on the development of a novel mRNA vaccine for COVID-19 [8]. The discovery, design and manufacture of the mRNA vaccine candidates to elicit antigen production, that generate an immune response against the SARS-CoV-2 virus, will be undertaken by Translate Bio. Sanofi will provide the collaboration with its expertise in vaccine development, to advance potential vaccine candidates into and throughout the clinic.

Forge Therapeutics & Roche

As part of the approaches to manage antibiotic resistance, which can affect the utility of entire existing classes of drugs, the development of new classes of antibiotics is critical. Novel agents that act against previously unaddressed targets within bacteria will help advance the introduction of therapies that will circumvent current resistance pathways evolved by bacteria. Forge Therapeutics (CA, USA) has developed a series of lead compounds that kill bacteria by inhibiting the enzyme known as LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which is essential to the key biosynthetic step in the maintenance of the outermost membrane of the bacterial cell. It is unique to Gram-negative organisms [9], such as Pseudomonas aeruginosa, which can cause the most serious hospital-acquired infections in patients with chronic lung diseases, especially in those with weakened immune systems. LpxC inhibitors have in fact been in development for over a decade [10], though none have made it beyond early phase trials. This failure is likely associated with the fact that these earlier candidates were mostly based on a hydroxamic acid pharmacophore. This active group appears to be responsible for poor selectivity of the bacterial enzyme, low oral bioavailability and rapid metabolism, resulting in utility-limiting pharmacokinetic properties [11]. The novel antibiotics Forge have identified do not utilize a hydroxamic acid group to enable binding to and inhibition of LpxC. Roche (Basel, Switzerland) have now entered into a research collaboration and option agreement with Forge Therapeutics to license FG-LpxC LUNG, an LpxC inhibitory compound currently at the preclinical stage, which is to be evaluated as a treatment for serious Gram-negative pulmonary infections. Under the option agreement, Forge will continue the development with funding from Roche and on exercise of the option Roche will assume further development activity [12].

CytomX & Astellas

CytomX Therapeutics (CA, USA) and Astellas Pharma (Tokyo, Japan) have announced their collaboration to advance novel T-cell targeting, bispecific, therapeutic antibodies for the treatment of cancer [13]. These new therapies will be based on the Probody^® technology antibodies created by CytomX, which behave, as the name suggests, as antibody prodrugs. The inactive Probody is activated by protease enzymes within the tumor, releasing the antibody which can then bind to the target site within the tumor and exert its therapeutic effect. This selective mode of action may improve both the safety and efficacy of the Probody-delivered antibody relative to a conventional agent [14]. The bispecific nature of the Probody platform candidates that the collaboration will advance resides in their construction, which allows them to bind to CD3 on T-cells and to specific antigens on the tumor (e.g., EGFR), such that they direct the cytotoxic T cells to the tumor as well as having direct antibody pharmacological effect on tumor cell viability [15]. CytomX already has five Probody immunotherapeutic products in clinical trials (Phase I and Phase II), including those partnered with Bristol Myers Squibb (NJ, USA) and with AbbVie (IL, USA).

Dragonfly Therapeutics & Merck

Somewhat analogous to the T-cell engaging technology from CytomX that was just described, the TriNKET (Tri-Specific NK cell Engagement Therapies) from Dragonfly Therapeutics (MA, USA) target and engage with the immune system's natural killer (NK) cells and link them to tumor cells through surface proteins, thus enhancing the effectiveness of NK cells against cancers. This enhanced recognition of cancers by NK cells also improves the way NK cells interact with other immune system cells, activating T-cells and B cells (including production of antibodies against the tumor cells by this class of immune system cells) [16]. An existing strategic collaboration between Dragonfly and Merck (NJ, USA) has just been expanded beyond oncology to cover additional new targets in immunology and infectious disease. In addition to upfront cash and agreement on milestone payments as the collaborative work advances, the deal includes an equity investment by Merck in Dragonfly [17].

Pfizer & BioNTech

A codevelopment and distribution agreement for a potential COVID-19 vaccine has been announced between Pfizer (NY, USA) and BioNTech (Mainz, Germany). The initial vaccine candidate, BNT162, is an mRNA-based product which encodes for SARS-CoV-2 antigens, that on administration will activate T cells and B cells to potentially generate immunity to the virus and prevent COVID-19 [18]. The vaccine presumably delivers the mRNA within the lipid nanoparticle vaccine technology developed by BioNTech, as is the case for an investigational mRNA-based influenza vaccine the two companies began collaborating in 2018 [19–21]. Human clinical trials are expected to initiate in April.

Orionis Biosciences & Novartis

The early stage, drug discovery company Orionis Biosciences (MA, USA and Ghent, Belgium) has announced a collaboration with Novartis (Basel, Switzerland) for the partners to pursue small molecule drug discovery based around the Allo-Glue^™ platform developed by Orionis. The research will be across therapeutics areas [22]. The Allo-Glue platform can undertake drug ligand interaction studies and characterize drug-protein interactions in living cells on a very large scale, as well as claim up to around 20,000 gene levels, which is equivalent to the complexity of the entire human genome. This includes allosteric activity, where small molecule interaction with a protein modulates how that protein can engage with a second protein as part of a cellular process, hence the name of the platform technology [23]. The partners envisage that the platform could deliver innovative small molecule drug candidates with industry leading efficiencies, in terms of selectivity and specificity, for target and at a scale and speed not achievable by existing approaches.

Vir Biotechnology & Alnylam Pharmaceuticals

In an expansion of an existing agreement on the development of infectious disease therapeutics based on RNA interference (RNAi), Vir Biotechnology (CA, USA) and Alnylam Pharmaceuticals (MA, USA) have announced inclusion of the development of treatments for COVID-19 in their collaboration. RNAi silences messenger RNA, which when it is derived from an infecting organism results in the disabling of its replication. Small interfering RNAs (siRNAs) that target coronavirus RNAs, selected from a library developed by Alnylam based on SARS-CoV-2 and SARS-CoV (the infectious agent in SARS) genomes, will be developed utilizing the lung delivered siRNA conjugate technology also from Alnylam. Lead candidates from Alnylam will be evaluated by Vir for antiviral activity, who will select a candidate for clinical development. Development and commercialization will then be led by Vir with Alnylam, once proof of concept is established, Alnylam will be able to either share all profits and losses associated with the program, or take development and commercialization milestone payments along with sales royalties. Alnylam have two RNAi products currently approved and marketed, which include patisiran (Onpattro^®) for the treatment of polyneuropathy associated with the rare genetic disease transthyretin-mediated amyloidosis and givosiran (Givlaar^®) used to treat acute hepatic porphyria [24].

Other business news

Regeneron Pharmaceuticals novel COVID-19 antibody program

Regeneron Pharmaceuticals (NY, USA) has announced it will develop a virus-neutralizing antibody cocktail to treat or act as a pre-exposure prophylactic for the SARS-CoV-2 infection. Antibodies generated from their humanized mouse platform and isolated from human subjects who have recovered from the infection, will be screened to select lead candidates to create the cocktail. Combining multiple antibodies that target different components of the virus structure may be effective against variants in the virus pool. Using its established approaches to rapid cell line creation for antibody production, Regeneron expect to have material available to initiate clinical trials at the beginning of the summer [25]. The company has also announced a collaboration with Sanofi to start a Phase II/III trial investigating the potential benefit of the IL-6 inhibitor sarilumab (Kevzara^®), currently approved for treatment of rheumatoid arthritis, as treatment for the inflammatory lung complications seen in critically ill COVID-19 patients. The US part of the adaptive design trial will begin in New York, a major site of the disease outbreak in the USA and will assess the safety and efficacy of adding sarilumab (high dose vs low dose vs placebo) to the standard of care. The Phase III part of the trial will explore long-term outcomes against multiple disease measures (including death, requirement for use of ventilator and need for supplemental oxygen) [26].

Icosapent ethyl (Vascepa^®, Amarin) patent litigation ruling favors generics

Commercially successful medicines invariably attract the attention of generic companies that are eager to be early to market, once intellectual property barriers to market entry come down. The US District Court for the District of Nevada has ruled in favor of generic companies who had filed an abbreviated new drug application (ANDAs) for icosapent ethyl capsules, currently marketed by innovator Amarin (Dublin, Ireland/NJ, USA) as Vascepa^®, and are subject to current in-force and pending patents. Icosapent ethyl (ethyl eicosapentaenoic acid) is an ester of a fish oil derived omega-3 fatty acid, which is metabolised and is the biologically active form. Manufacturing of highly purified eicosapentaenoic acid from fish oils is a key and challenging step in producing the product. It is approved in the USA for the treatment of severe hypertriglyceridemia or as an adjunct to maximize statin therapy in patients with elevated triglyceride levels, cardiovascular disease (or risk factors for cardiovascular disease) and has become very commercially successful. Amarin will appeal the ruling in order to protect its franchise, even though there are no generic products currently approved and protection in other territories of at least 8 years is in place [27].

Recombinant polyclonal antibody therapy against COVID-19 (GigaGen) enters development

GigaGen (CA, USA) has announced that it now has a recombinant polyclonal antibody product, the recombinant anti-coronavirus hyperimmune gamma globulin termed as rCIG, in development for the treatment of COVID-19. This therapeutic protein is a combination of antibodies based on those present in recovered COVID-19 patients and includes high concentrations of specific antibodies that interfere with viral replication. The recombinant generation approach to producing the antibody mix avoids the risk of a discontinuous supply associated with purely plasma-derived polyclonal antibodies (requires a flow of plasma donors). It also assures more consistent lot-to-lot product attributes, along with significantly higher potency than plasma-derived polyclonal products. However, at the time of writing the development was at a very early stage, with GigaGen currently recruiting subjects who had contracted and recovered from COVID-19 to donate blood to help initiate the development of the recombinant polyclonal [28].

Lead vaccine candidate for prevention of COVID-19 infection identified by Johnson & Johnson

Based on the work it started in January, Johnson and Johnson (NJ, USA) has announced that it has selected a lead vaccine candidate to progress into testing against COVID-19. The Biomedical Advanced Research and Development Authority (BARDA), a part of the US Department of Health and Human Services, is supporting this work at Johnson and Johnson and is committing more than $1 billion (USD) to enable vaccine research, development and the required clinical testing on the route to commercialization. Human clinical studies should start no later than this September and if studies are favorable, during early 2021 the vaccine may be available for emergency use. Manufacturing capacity at Johnson and Johnson is to be expanded, with a goal of providing a global supply greater than one billion doses of the vaccine. The expansion will include new US vaccine manufacturing capabilities and growth of the company's vaccine manufacturing capacity in other countries. Planning of production at risk is in hand to be ready for early availability, subsequent to regulatory approval [29].

Merck collaboration with the Walter & Elizabeth Hall Institute of Medical Research discovers novel anti-malaria agents

Merck and the Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia) have been engaged in collaborative research on the discovery of antimalarial agents that act at multiple stages in the lifecycle of the causative parasites (Plasmodium falciparum) and the partners have just published some of their findings [30]. Two parasite aspartic protease enzymes, critical to its ability to get into and out of red blood cells and production of the parasite proteins essential to replication, termed plasmepsin IX and plasmepsin X, are inhibited by the novel class of agents discovered in the work. Optimizing relevant aspartic protease inhibitors held in a library at the Swiss Tropical and Public Health Institute (Basel, Switzerland), led to the investigational compound WM382. The activity of this compound in animal models of malaria, including the lack of cross resistance to existing classes of anti-malarial compounds and the potential for a high barrier to resistance development, due to the dual enzyme inhibitory action of WM382, is described in the published work [31]. It is important to note that WM382 is an indicator of potential for new anti-malarial therapeutics and may not represent a potential drug in its own right. It may need further optimization to manage, as there are unknown human metabolism and pharmacokinetic challenges, which may also impact on whether dose and dosing frequency for the compound are amenable to development, especially as part of a combination therapy. Additionally, selectivity for the parasite enzymes with low affinity for human aspartyl proteases, such as renin, presenilin, β-secretase and cathepsin will be important for appropriate safety and tolerability of an antiplasmepsin drug candidate [32].

Effect of the COVID-19 pandemic on industry R&D activities

The ability to conduct research and development and bring new treatments to patients is being affected by the COVID-19 pandemic. Although very many companies are likely affected, a number have already formally announced an impact of the spread of COVID-19 on their ability to conduct key R&D activities, especially with delays in starting up and progressing clinical trials, the rescheduling of activities with regulatory authorities and delayed product launches including, among many others, Intercept Pharmaceuticals (NY, USA), Eli Lilly, bluebird bio (MA, USA), Moderna (MA, USA), Vertex (MA, USA), Pfizer and Bristol Myers Squibb [33–39]. The further effect of the pandemic on the advancement of new medicines will be watched anxiously both by clinicians and patients.

Product approvals & other regulatory news

Idecabtagene vicleucel injection (Bristol Myers Squibb/bluebird bio)

Based on Phase II trial data, a biologics license application has been submitted to the US FDA by partners Bristol Myers Squibb and bluebird bio for a cell therapy product to help patients with relapsed and refractory multiple melanoma. The target patient group includes those who have already been through three prior therapies and have disease progression during or within 60 days of their last treatment. The drug, termed idecabtagene vicleucel, also known as ide-cel and bb2121, is a CAR T-cell therapy that targets the B-cell maturation antigen (BCMA), a protein expressed on multiple myeloma cancer cells. It is a fusion protein that is constructed from a murine extracellular single chain variable fragment, specific for BCMA, which is attached to a human CD8α component fused to the CD137 4-1BB and CD3-^ζ chain signalling domains of T-cells. On binding of idecabtagene vicleucel to BCMA on multiple myeloma cells, T-cell proliferation with subsequent cytokine secretion and killing of BCMA-expressing cells occurs, offering a unique mode of therapy for patients with difficult to treat diseases, where prior treatment has been unsuccessful [40].

Onasemnogene abeparvovec injection (Zolgensma^®, AveXis)

During March, Novartis-owned AveXis (Basel, Switzerland) had two favorable pieces of regulatory news in respect of its unique gene therapy product onasemnogene abeparvovec. The first was a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP). Conditional marketing authorization was recommended for use of the product in the treatment of the rare, disabling and life threatening neuromuscular disease spinal muscular atrophy (SMA) in patients (babies and young children) with a bi-allelic mutation of the SMN1 gene, who have been diagnosed with SMA type 1. This is the more common form of the disease which can have effects before birth and shows rapid progression. The approval also included the treatment of patients with the SMN1 gene mutation and up to three copies of the SMN2 gene [41]. The Japanese regulatory authority, the Ministry of Health and Labour and Welfare also approved the gene therapy for treatment of SMA in a defined patient group, which included those under two years of age and those who are presymptomatic [42]. The drug is given as a one-off intravenous infusion to provide replacement of the faulty genetic material, which is delivered via an adeno-associated 9 viral vector into the patients' cells where it incorporates and restores normal function, stalling disease progression.

Ozanimod capsules (Zeposia^®, Bristol Myers Squibb)

Ozanimod (Zeposia^®, Bristol Myers Squibb) is an orally-administered sphingosine-1-phosphate (S1P) receptor modulator, a class of drugs with potential in immune-inflammation conditions that work by binding to S1P. This results in the reduction of lymphocyte egress from lymph nodes, thereby decreasing lymphocyte numbers in the peripheral circulation or the CNS, and potentially impairing their contribution to autoimmune diseases. It became part of the Bristol Myers Squibb portfolio through the company's acquisition of Celgene in 2019. The FDA has approved ozanimod for the treatment of relapsing forms of multiple sclerosis in adults, including relapsing remitting, active secondary progressive and clinically isolated syndrome forms of the disease. Different to other S1P receptor modulator drugs already approved, there is no requirement in the approved ozanimod labeling for patients to undergo any genetic testing for the CYP2C9 genotype, or to be subject to observation for bradycardia at the first dose when initiating therapy [43]. The CHMP recommended to the European Commission, its positive opinion of the drug in the treatment of adults with relapsing and/or remitting multiple sclerosis and having active disease [44]. The clinical data on which the approvals were based were Phase III, active-controlled studies where the comparator drug was standard-of-care IFB-β-1a. Ozanimod showed a reduction in disease activity based on relapse rate and reduction in existing and new or enlarging brain lesions. In the light of the impact of COVID-19 on healthcare systems, Bristol Myers Squibb has decided to delay the commercialization of ozanimod until the environment is amenable to launch.

Adenovirus type 5 vector novel coronavirus vaccine (CanSino Biologics)

CanSino Biologics (Tianjin, China) has announced that it has been given regulatory approval to initiate dosing in a Phase I trial in China, with its novel coronavirus vaccine for prevention of COVID-19. The vaccine employs a genetically modified replication-defective adenovirus 5 viral vector to generate an immune response to the SARS-CoV-2 spike protein. It was developed in partnership with the Beijing Institute of Biotechnology (Beijing, China), with the demonstrated delivery platform in an approved adenovirus 5 platform Ebola vaccine, jointly developed by the same partners [45].

Osilodrostat tablets (Isturisa^®, Recordati)

Cushing's disease is a rare but serious condition caused by excess production of cortisol associated with a tumor of the pituitary gland, which secretes excess adrenocorticotropic hormone and in turn stimulates the over production of cortisol by the adrenal glands. It is marked by weight gain (especially above the waist but with thin arms) and fat accumulation between the shoulder blades, a round and red full face sometimes with acne, hypertension, fatigue and muscle weakness, depression and anxiety. Mortality in sufferers is fourfold that in the healthy population. Current treatment includes surgery and possibly radiotherapy to remove the tumor, but it can re-occur. Removal of the adrenal glands may also be required in some cases and there are some drug treatments that can be used with varying degrees of success to reduce the action of cortisol. However, effective treatments for patients where pituitary surgery is not possible or has been undertaken but has not been completely effective are desired. Recordati (Milan, Italy) have announced that their cortisol synthesis inhibitor therapy for such patients has now been approved by the US FDA. Osilodrostat tablets (Isturia^®) are the first and only 11-β-hydroxylase inhibitors to be available for the treatment of Cushing's disease. The enzyme 11-β-hydroxylase facilitates the final step in the synthesis of cortisol in the adrenal glands, and its inhibition by osilodrostat in clinical studies was associated with normalization of cortisol levels in a significant number of treated subjects, along with an acceptable safety profile. It is expected that osilodrostat tablets will be available commercially in the second or third quarter of this year [46].

Bimatoprost implant (Durysta^™, Allergan)

The Bimatoprost implant represents an innovative approach to providing treatment for glaucoma for patients challenged by the need to administer prostaglandin analogue or β-blocker eye drops on a daily basis, avoiding the risk of missed doses due to forgetfulness or lack of disease cues to motivate adherence to therapy. Eye drops also have the difficulty with installation for elderly subjects, typical of glaucoma patients due to dexterity, hand steadiness and grip strength requirements for using these products. As Durysta^™ (Allergan, Dublin, Ireland), bimatoprost implant has been approved by the FDA on the basis of two 20 month duration Phase III trials, with timolol eye drops being used as a comparator drug [47].

The biodegradable implant contains 10 mcg of the prostaglandin analogue bimatoprost in a poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (D,L-lactide) and polyethylene glycol delivery system, a technology based on the Novadur^™ technology developed by Allergan [48] and has already been employed in the marketed dexamethasone ocular implant product Ozurdex^® (Allergan). The tiny rod shaped implant (it will pass through a 28 gauge needle) is placed into the anterior chamber of the eye using a specially designed, single use, preloaded applicator. It settles within the inferior iridocorneal angle (where it can be monitored by gonioscopy) and slowly releases the contained drug for localized action, producing a higher concentration in the target tissue of the iris-ciliary body and lower concentrations in other ocular tissues (associated with side effects), than are achieved by the topical use of bimatoprost eye drops already marketed for glaucoma treatment. As biodegradation of the carrier polymer initiates, the implant swells to about twice its original size within a day after insertion but then gradually diminishes in size as the drug is released in a zero-order fashion. Drug liberation occurs over 90 days in an in vitro test, with complete release of bimatoprost, based on the analysis of recovered implants from treated animals, in about 80 days [49,50]. In human clinical studies intraocular pressure was controlled for up to 1 year post dosing in 40% of subjects studied, and in 28% of subjects studied for up to 2 years [50].

Empagliflozin tablets (Jardiance^®, Boehringer Ingelheim/Lilly)

Although now established as part of the therapy of Type 2 diabetes, the sodium glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance^®, Boehringer Ingelheim Pharmaceuticals, CT, USA/Eli Lilly, IN, USA) has also been investigated, administered at a lower dose than that used in the therapy of Type 2 diabetes, as a potential therapy and as an adjunct to insulin in the treatment of Type 1 diabetes. Following on from the outcome of a US FDA Endocrinologic and Metabolic Drugs Advisory Committee in November 2019, which strongly recommended against approval of the partner companies' supplemental New Drug Application (sNDA) for the medicine in this indication [51], the regulator has issued a complete response letter indicating that it is unable to approve the application in its current form. A spokesperson for Boehringer Ingelheim affirmed a commitment to continuing studies of therapies for diabetes (Phase III trials of empagliflozin in diabetic chronic kidney disease and in heart failure are ongoing) but what this means for the future of the SGLT2 inhibitor in Type 1 disease is not clear [52].

Durvalumab injection (Imfinzi^®, AstraZeneca)

AstraZeneca has announced that its PD-L1, immuno-oncology therapy, durvalumab injection (Imfinzi^®) has received US FDA approval as the first-line therapy for the treatment of extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab inhibits the interaction of PD-L1 with PD-1 to overcome a tumor's capability to evade the immune system and enable its ability to recognize and attack the cancer. SCLC is an aggressive and fast progressing disease that represents about 15% of diagnosed cases of lung cancer. About two thirds of those patients have the extensive-stage disease, where the cancer has progressed widely through the lungs or to other parts of the body. It is a devastating diagnosis, as only 6% of patents survive to 5 years after a diagnosis. Durvalumab was studied as an addition to the standard of care chemotherapy and reduced the risk of death and increased median overall survival time relative to standard of care alone, thus bringing a valuable new medicine as an option for patients with ES-SCLC. Durvalumab is already approved in some countries for the treatment of other forms of lung cancer, advanced bladder cancer and it is in ongoing trials for a range of other cancers [53].

Clinical Trials

Phase III trial of favipiravir tablets (Avigan^®, Fujifilm) for treatment of COVID-19 infection underway in Japan

The start of a Phase III trial in Japan to evaluate favipiravir (Avigan^®) tablets (Fujifilm, Tokyo, Japan) as a treatment for COVID-19 has been announced. Favipiravir is an inhibitor of RNA-dependent RNA polymerase, an enzyme key to viral replication that is not employed in human cells [54]. Favipravir was developed originally as a treatment for influenza, approved by the Japanese regulatory authority and with the product already manufactured and stockpiled by the Japanese government. The intent was to only make it available for the treatment of influenza in an outbreak caused by a novel or re-emergent strain when other treatments were found not to be effective. The drug has never been made available through hospital and pharmacies in Japan to date and is not approved in markets outside Japan [55]. The fact that it has possible broad antiviral activity has triggered the move to investigate it for COVID-19 and Fujifilm has begun to increase production of favipiravir tablets with partners in Japan and in other countries. The company has indicated its intention to work with the government to be in a position to supply favipiravir in Japan and in other countries for trials against COVID-19 [54].

Favorable Phase IIa trial outcomes in NASH for AKR-001 (Akero Therapeutics)

Akero Therapeutics (CA, USA) has announced favorable Phase IIa clinical trial results for its treatment of a non-alcoholic steatohepatitis (NASH), AKR-001. Weekly dosing of 28–70 mg led to absolute reduction in liver fat of 12–14% at 12 weeks of treatment relative to the placebo and 75–85% of patients were eligible for the end of study biopsy, meaning they had a relative reduction of 30% or greater [56]. AKR-001 is a fusion protein based on fibroblast growth factor 21 (FGF21), a native hormone that acts across many organ systems including the liver and has a physiological role in maintaining metabolic balance and reducing cellular stress. FGF21 itself has too short a half-life (just a few hours) to be useful in therapy alone. The engineered FGF21 represented by AKR-001 has a half-life of 3–4 days, has a balanced potency at the target receptors FGFR1c, 2c and 3c (affecting lipolysis/lipogenesis, key to liver fat reduction), low affinity for FGF4 (associated with proliferation of hepatocytes) and a high affinity for the FGF coreceptor β-klotho, which is essential for effective FGF receptor binding, and hence potency and efficacy [57]. NASH represents a significant unmet medical need with currently no approved therapies.

Evinacumab (Regeneron Pharmaceuticals) demonstrates positive Phase III trial outcomes

The rare genetic disease, homozygous familial hypercholesterolemia (HoFC) is marked by very high levels of low-density lipoprotein cholesterol (LDL-C) leading to early onset atherosclerosis, including the risk of cardiac events in teenage sufferers. Those with the disease usually show poor response to current therapies, including statins and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), meaning there is a significant unmet need for new, more effective therapies to help patients with this disorder. At the American College of Cardiology Annual Scientific Session/World Congress of Cardiology meeting (IL, USA) in late March, Regeneron Pharmaceuticals presented detailed Phase III results of the use of their angiopoietin-like 3 (ANGPTL3) blocker evinacumab, a fully human monoclonal antibody and its effectiveness in controlling elevated cholesterol levels in HoFC subjects. The blocking of ANGPTL3 is a novel cholesterol lowering mechanism, inhibiting its interference with triglyceride metabolism. In HoFC patients already on statins and with the majority on PCSK9 inhibitors, treatment with evinacumab on top of that existing cholesterol-lowering medication resulted in LDL-C being reduced by more than half the level measured at the start of therapy, in over half of the subjects treated and attaining levels in the typical healthy adult range. The ability to have such an effect on potentially life-threatening cholesterol levels in these patients represents a significant step forward in managing this inherited disease. Regeneron is planning to start submitting for regulatory approvals for evinacumab for this indication in mid-2020 and trials in other difficult-to-treat elevated cholesterol diseases are ongoing [58].

Rapid viral load reduction following single injection of investigational HIV-1 capsid inhibitor GS-6207 in Phase I study (Gilead Sciences)

In a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI) (MA, USA), Gilead Sciences shared early phase trial data on its investigational HIV-1 capsid inhibitor GS-6207. In a Phase I study, healthy volunteers dosed with an oral tablet formulation demonstrated pharmacokinetics of GS-6207 that were supportive of once-weekly dosing in both fasted and fed states. In a second Phase I study in subjects with HIV, a subcutaneous injection formulation demonstrated rapid reductions in viral load with antiviral activity being sustained through to 10 days. The novel mode of action and disruption of the capsid (the protein shell that surrounds the genetic material and associated enzymes within the virus) is potentially effective in inhibiting viral replication, and the long half-life could enable GS-6207 to contribute to a new long-acting treatment regimen [59].

Promising trial data supports continued evaluation of vesatolimod (Gilead Sciences) as part curative regimens in antiretroviral-free therapy of HIV-1 infection

In a further announcement at the CROI meeting, Gilead Sciences updated Phase Ib trials of its Toll-like receptor 7 (TLR7) agonist vesatolimod, which is being explored as part of an HIV cure research program. It was administered to HIV positive subjects and added on to existing antiretroviral therapy, which was stopped at a point in the study to investigate viral rebound. Enhanced immune function, modestly increased time to viral rebound and reduced levels of intact HIV DNA were found with the investigational compound. The improvements in immune function resulting in a reduction in viral reservoir and increased time to rebound, are important when considering the drug as having value, as part of combination antiviral therapy, though the observed effects were considered modest. Animal model data on the possible role of vesatolimod as part of combination treatment with broadly neutralizing antibodies with or without an experimental vaccine, to achieve viral remission without antiretroviral therapy was also presented [60].

Favorable Phase III trial data for long-acting two-drug injectable HIV treatment (rilpivirine with cabotegravir, Janssen Pharmaceutical Companies)

The Janssen Pharmaceutical Companies of Johnson and Johnson (Cork, Ireland) also presented at CROI, announcing positive (non-inferiority to standard-of-care oral therapy with triple fixed-dose combination abacavir/dolutegravir/lamivudine tablets) results of a Phase III trial for monthly dosing over 96 weeks with the intramuscular injection of a nanoparticle fixed dose combination of rilpivirine and cabotegravir, as well as patient satisfaction and preference for the injectable formulation. They also described positive outcomes at 48 weeks for a trial of the same nanoparticle formulation dosed every 2 months compared with it given monthly. Again, there was patient preference over daily oral therapy and the less frequent dosing regime was non inferior to monthly dosing, thus potentially offering convenient alternate options to existing treatments [61,62].

Decreased cough frequency for sufferers of refractory or unexplained chronic cough in Phase III trial of gefapixant (Merck)

Gefaxipant (Merck, USA) is an investigational selective purinoceptor 3 (P2X3) antagonist. The P2X receptor family are a group of ion channels that are activated by adenosine triphosphate and excessive activation of P2X3 in the airways and lungs is possibly associated with infection or injury and may cause chronic cough. It is believed that up to 10% of adults may suffer from chronic cough. In a Phase III trial treatment of patients with unexplained or refractory cough that had persisted for 1 year, a significant reduction in cough frequency over 24 h was seen for dosing at evaluation points of 12 and 24 weeks, using the high dose in the study. A lower dose investigated was not effective. Currently, no approved therapies for chronic cough are available and these findings may open a way for Merck (NJ, USA) to seek regulatory approval for gefapixant, although they have only indicated an intent so far to continue trials and to present detailed clinical findings at a future conference [63].

Durability of response up to five years post-dosing & benefit in older patients demonstrated for gene therapy onasemnogene abeparvovec (Zolgensma^®, AveXis)

The progress of onasemnogene abeparvovec (Zolgensma^®, AveXis) through key global regulatory approvals was noted earlier in this article, and during this month AveXis also announced new clinical data on the gene therapy. The therapeutic benefit of the one-time dose was found to be sustained over an observation period of up 5 years post treatment in children with SMA type 1, a significant outcome in a progressive disease that can lead to the need for ventilator support or even death in the majority of sufferers by the age of 2 years [64]. AveXis also announced the improvement in patients with Type 2 disease (where the disease is not as aggressive as in Type 1 and sufferers can survive beyond adolescence, but with 30% not surviving beyond 25 years). In patients between 2 and 5 years treated with onasemnogene abeparvovec, there were increases in signals indicating, relative to historical controls, a slowing of disease progression in 92 % of subjects treated. AveXis also announced that they had provided new clinical data to the FDA around the safety of intravenous and intrathecally administered drug, in response to an earlier clinical hold imposed by the regulator, and advising of no cases of sensory neuronopathy across 355 patients treated [65].

Serious medical problems in heart failure successfully addressed through use of vericiguat (Merck/Bayer)

Development partners Merck and Bayer (Berlin, Germany) announced that their orally administered, soluble, guanylate cyclase stimulator vericiguat administered on top of existing heart failure therapies, significantly reduced the risk of hospitalization due to heart failure or cardiovascular death in patients that had worsening chronic heart failure with reduced ejection fraction. There is a need to provide improved therapies for this potentially life-limiting disease (20% of those diagnosed die within 2 years), which represents about half the patients with heart failure. To open a pathway to regulatory approval, the companies indicated that they plan to begin discussing the trial findings with regulatory authorities [66].

Significant cholesterol reductions seen in Phase III trial of bempedoic acid (Nexletol^™) & Phase II trial of bempedoic acid/ezetimibe (Nexlizet^™) (Esperion)

Esperion (MI, USA) presented new analyses of Phase III and Phase II clinical trial data for its novel cholesterol lowering drug bempedoic acid (Nexletol^™) and a fixed combination product of bempedoic acid with ezetimibe (Nexlizet^™). Bempedoic acid is a liver-targeted prodrug, by enzymatic activation specific to hepatic tissue involving acyl-CoA synthase, with the active form generated being an inhibitor of ATP citrate lyase. This enzyme is part of the cascade associated with cholesterol synthesis but is upstream of the enzyme that is the target of statins HMG CoA reductase, which is not restricted to the liver (extrahepatic activity of statins may be associated with adverse events). In the clinical study results announced, there was significant LDL-C and high sensitivity C-reactive protein lowering by bempedoic acid relative to the placebo in diabetic patients, without loss of glycaemic control. It also significantly lowered high sensitivity C-reactive protein in non-diabetics, whether they were on statins or not. The fixed combination was also highly effective at cholesterol lowering in diabetic patients. Bempedoic acid was approved earlier this year as an add on to statins for patients whose hypercholesterolaemia is insufficiently controlled [67].

Worsening of heart failure reduced regardless of background therapy by dapagliflozin (Farxiga, AstraZeneca)

Although, as the earlier paragraph on empagliflozin indicates, SGLT2 inhibitors may have broader potential than in just Type 2 diabetes and AstraZeneca has now presented new data from a study of its SGLT2 inhibitor dapagliflozin, in treatment of heart failure with reduced ejection fraction, a trial that is being conducted in patients without diabetes as well as in those with diabetics. This is a very interesting advance for what started as a purely antidiabetic drug, should the indication be approved (it is currently in late stages of regulatory review at the FDA). Dapagliflozin therapy reduced the incidence of worsening heart failure or cardiovascular death (primary composite trial end point) relative to the placebo, regardless of the use of other background heart failure medication. The FDA is expected to announce its decision on the application for approval of the new indication during the second quarter of the year [68].

The rare genetic disease indolent systemic mastocytosis improved by treatment with avapritinib tablets (Ayvakit^™, Blueprint Medicines)

The rare disease, systemic mastocytosis is a consequent to the D816V mutation of the KIT gene and results in uncontrolled mast cell activity. Symptoms including rash, pruritis, fatigue, bone pain and brain fog are chronic and severe, are debilitating and affect sufferers' lives significantly, especially as their occurrence can be unpredictable, but when present they can persist irrespective of treatment using existing therapies. Whist a minority of sufferers have the advanced, aggressive form of the disease, the majority of patients have the indolent (smouldering) form of the disease. Blueprint Medicines (MA, USA) is pursuing the development of its oral KIT and PDGFRA mutant kinase inhibitor, avapritinib (Ayvakit^™) for treating patients across a range of forms of systemic mastocytosis (using doses lower than those for which this drug is currently approved as treatment of gastrointestinal stromal tumors) and it has now announced data from an ongoing Phase II trial in patients with the indolent form of the disease. Improvements in biomarkers (declines in serum tryptase level, bone narrow mast cell count and KIT D816V allele burden) were found and patient-reported symptom improvements, along with improved quality of life were attained in patients given avapritinib compared with those given the placebo. Blueprint also has been granted Breakthrough Therapy Designation from the FDA for avapritinib in the treatment of advanced systemic mastocytosis [69].

First participant dosed in Phase I study of an mRNA vaccine against COVID-19 novel coronavirus (Moderna)

Moderna has announced that the first subjects in a Phase I trial were dosed with its lipid nanoparticle formulation mRNA vaccine, mRNA-1273, against SARS-CoV-2, which codes for the full virus surface Spike protein. The vaccine is being dosed on a two-dose schedule 28 days apart, and the trial is exploring the three dose levels, 25, 100 and 250 μg of mRNA, with the trial intending to evaluate safety, reactogenicity, immunogenicity and following up subjects for up to 12 months post second vaccination. The development speed is remarkable, from finalizing the genetic sequence of the virus on 13 January 2020 to shipping of first clinical batch of vaccine on 24 February 2020. Moderna is preparing its manufacturing capabilities in preparation for a scale up should safety and efficacy be found in the early trials [70].

Summary

As the global COVID-19 pandemic advanced during March 2020, there was much associated activity in the industry that was manifested in news releases. Whilst there was disruption to clinical trials, regulatory activities and new product launches the industry reported a very significant extent of discovery and development effort towards prevention and treatment of the coronavirus disease. This included novel, modality vaccine candidates at various stages from Sanofi/Translate Bio, Pfizer/BioNTech, Vir/Alnylam, Johnson & Johnson, CanSino Biologics and Moderna, antibodies for prophylaxis and treatment being advanced by Regeneron and GigaGen and small molecule antivirals from Moleculin/UTMB and Fujifilm. Despite the apparent dominance of COVID-19 activity, there was plenty of other therapeutic delivery news including a long acting antiglaucoma ocular implant from Allergan, gene therapy product approvals for AveXis and a CAR T cell therapy regulatory submission by Bristol Myers Squibb. Additionally, novel therapeutic target therapeutics and drug targeting in immunology, immuno-oncology metabolic and rare diseases featured in the industry news as strongly as ever.

Financial and competing interests disclosure

The author is a former employee, and is a current shareholder, of Bristol-Myers Squibb, which has active research programs and marketed medicines in some of the therapeutic areas covered in this article. The author has 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.