Industry Update Covering November 2018

Summary

November 2018, the period covered by this article, showed strong activity in mergers/acquisitions and collaborations, including the announcement of a deal for the global manufacture of a micellar nanoparticulate formulation of paclitaxel. The month also brought positive clinical trial news in therapeutic areas such as pancreatic cancer using CAR-T therapies and asthma. In regulatory news, the US FDA issued a warning highlighting concerns about the serious complications that can occur when using unapproved painkillers with implantable drug pumps and approval was announced for an oral film formulation to treat Lennox-Gastaut syndrome. November also saw patents being issued on novel therapeutic delivery methods for ocular delivery and the use of proprietary vitamin A-micellar delivery vehicle. Information sources used in compiling this update included company press releases and other news websites.

Keywords:

• competitor intelligence
• emerging technologies
• personalized delivery

Business news

Acquisitions, mergers, licensing

Zymeworks & BeiGene announce a collaboration & licensing deal

The Vancouver-based biopharmaceutical company, Zymeworks (Canada) and BeiGene (Beijing, China) announced that they have entered into a strategic collaboration for the clinical development and commercialization of Zymeworks’ investigational HER2-targeted bispecific antibodies, ZW25 and ZW49. Under the terms of the agreement disclosed, Zymeworks also granted BeiGene a license to its’ proprietary Azymetric™ and EFECT™ platforms with a view to developing and commercializing up to three other antibodies using these proprietary platforms.

ZW25, Zymeworks’s lead candidate is currently in Phase I clinical trials and has orphan drug status for both gastric and ovarian cancers. It is a bispecific antibody and is based on Zymeworks’ Azymetric™ platform, which simultaneously binds two nonoverlapping epitopes of HER2 [1].

Generex acquires Olaregen Therapeutix

Generex Biotechnology (FL, USA) has announced the intention to acquire of 51% of the New York-based Olaregen Therapeutix. With the proposed acquisition will come the commercialization of its wound-healing product Excellagen^®. Excellagen is a 510K US FDA-cleared medical device based on a flowable dermal matrix for the treatment of a variety of wound types. It is anticipated that Excellagen will act as a platform technology for the delivery of a wide range of therapeutics including peptides, antimicrobials and small molecule drugs. Generex Biotechnology made an initial up-front payment of an $400,000 and the companies expected to have closed the transaction by the end of the quarter.

Commenting on the acquisition, Anthony J Dolisi, CEO of Olaregen, stated: “We are proud to be joining the Generex family of companies with this new venture. This is an exciting time for the team at Olaregen, which was established with the primary purpose of commercializing Excellagen, a proprietary, patented, advanced wound-healing product that has been FDA cleared based on excellent clinical results and has a 17-year patent protection. The Generex family of companies provides a unique opportunity to execute our commercial launch strategy to deliver product through surgical centers, department of defense, operating rooms, VA system, wound care centers, as well as podiatrists’ offices on the front line in the diagnosis and treatment of patients with wounds and ulcers resulting from diabetes and cardiovascular complications” [2].

Baxter to manufacture Oasmia’s Apealea^®

Oasmia Pharmaceutical AB (Uppsala, Sweden) disclosed a new agreement with Baxter Oncology GmbH (Halle, Germany) for global commercial manufacturing of its micellar nanoparticulate paclitaxel formulation, Apealea. The financial details of the agreement were not disclosed but it was revealed it is a 5-year contract with Baxter BioPharma Solutions for global commercial manufacturing of Apealea. In announcing the agreement, it was disclosed that technology and know-how had already been transferred to Baxter and manufacturing is planned to commence shortly.

Apealea is based on Oasmia’s patented excipient platform XR-17, which forms micellar nanoparticles with paclitaxel. Oasmia also announced on 22 November 2018 that it had received notification of approval in the European Union for treatment of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer in combination with carboplatin in first relapse [3,4].

Tetra Biopharma announce joint venture with Altus

The Ontarian-based biopharmaceutical company, Tetra Biopharma (Canada), which specializes in cannabinoid-based drug discovery and development, announced a nonbinding agreement to discuss the formation of a joint venture with Quebec-based Altus Formulation (Canada). The aim of the proposed agreement would be to explore opportunities for the use of Altus’ propriety patented platforms: Intellitab™ an abuse deterrent technology, Flexitab™ a sustained-release tablet technology and SmartCelle™ a nano-technology with a view to enhance the solubility of their cannabinoid products. No further details of the agreement were disclosed [5].

Entos to use precision Nanosystems’ NanoAssemblr™ platform

Vancouver-based companies Precision Nanosystems (Canada) and Entos Pharmaceuticals (Alberta, Canada) announced on 13 November 2018 that they had entered into a license and supply agreement that allows for the GMP manufacturing of Entos’ lead (undisclosed) candidate using Precision Nanosystems GMP capabilities and their proprietary NanoAssemblr™. Nanosystems’ formulation technology approach provides a seamless path from experimental studies through to manufacture of clinical supplies. In particular, low volume prototype formulations can be scaled-up using the NanoAssemblr family, which provides a combination of microfluidic mixing and manufacturing of nanoparticles. Entos Pharmaceuticals employ a proprietary drug formulation technology Fusogenix which delivers a wide range of therapeutics, gene therapy, mRNA, miRNA, RNAi and CRISPR directly into the cytosol of target cells [6].

Collaborations

Insulet joins with Samsung for smartphone controlled insulin pump

Insulet Corporation (MA, USA) announced a collaboration with Samsung Electronics America Inc. (NJ, USA) to allow for the development of a control app for their FDA-cleared Omnipod DASH™ Insulin Management System. If approved, the combination of the system and a personal Samsung’s Galaxy smartphone will be the first device providing consumers the ability to securely control their insulin pump therapy using such an app.

Discussing the proposed collaboration, David Rhew, Chief Medical Officer and VP/GM for Enterprise Healthcare, Samsung Electronics America stated: “By integrating Samsung smartphones with drug delivery medical devices like Insulet’s Omnipod System, we have demonstrated that consumer-based digital health technologies can not only monitor and track one’s condition, but they can enable patient control of medical treatments” [7].

Enable enters into two strategic alliances

Cincinnati-based drug delivery company Enable Injections, Inc. (USA) announced in November that they had entered two strategic alliances with a view to developing new methods of facilitating delivery of larger volume drugs in a home environment. These agreements are with Apellis Pharmaceuticals (KY, USA) and UCB (GA, USA).

Enable’s large volume wearable drug delivery device, Enable Smart enFuse™, can facilitate subcutaneous administration of large 5 ml to 50 ml doses and will be used in clinical trials to delivery Apellis’ immunotherapeutic product candidates. A key advantage of Enable’s technology is that it can be used with any standard container closure system and can be programmed to mix lyophilized solutions [8].

Other business news

Aerogen announce significant investment

Aerogen, the Galway (Ireland)-based aerosol-drug-delivery company, disclosed on 4 November 2019 that Temasek (Singapore) had acquired a minority stake in the company. The financial details of the investment were not disclosed but, commenting on the deal John Power, founder and CEO of Aerogen, reported “We are excited to realize the growth opportunities this collaboration will bring. Temasek, our partner of choice, has deep global and sector expertise, which will accelerate our market penetration” [9].

Product approvals & other regulatory news

FDA issues warning on pain drugs for implantable pumps

On 14 November 2019, the FDA issued a Safety Communication urging that patients, caregivers, compounders, pharmacists and healthcare providers are made aware of risks associated with the intrathecal administration of pain medications that have not been approved for this route of administration to allow them to make informed treatment decisions.

Among the reasons given by the FDA for issuing this communication are the numerous medical device reports describing adverse events with implanted pumps received by the FDA. According to the press release, these reports describe pump failures and dosing errors. Serious adverse reactions reported in patients described in these reports include pain, opioid withdrawal, fever, vomiting, muscle spasm, cognitive changes, weakness and cardiac and respiratory distress [10].

Approval for Genentech’s Actemra

Genentech (CA, USA), a member of the Roche Group, announced on 26 November 2019 that the FDA had approved its single-dose, prefilled autoinjector ACTPen™ which delivers 162 mg/0.9 ml of tocilizumab (Actemra^®). Approval is indicated for an additional formulation for adult with rheumatoid arthritis who have previously had an inadequate response to one or more disease-modifying anti-rheumatic drugs, and also for adult with giant cell arteritis. The company expected the ACTPen™ to be commercially available in January 2019 [11].

Aquestive’s oral film formulation for Lennox-Gastaut syndrome approved

Aquestive Therapeutics (NJ, USA) received approval from the FDA for its SYMPAZAN™ (clobazam) oral film. SYMPAZAN has been approved by the FDA as the first (and only) oral film indicated to treat seizures associated with Lennox-Gastaut syndrome (LGS).

LGS is severe form of epilepsy which typically manifests during infancy or early childhood. Children with LGS can experience several different types of seizures the most commonly of which are atonic, tonic and atypical absence seizures. Cognitive development dysfunction and general developmental milestone delays can also factors in children with LGS.

The SYMPAZAN formulation is based on Aquestive’s proprietary PharmFilm^® technology – which can be used for buccal, sublingual and lingual drug delivery [12,13].

Intellipharmaceutics’ generic Effexor XR approved

On 27 November 2019, Intellipharmaceutics International Inc. (Toronto, Canada) announced that the FDA had approved the company’s abbreviated new drug application for venlafaxine hydrochloride extended release capsules in the 37.5, 75 and 150 mg strengths. This product is a generic version of the branded product Effexor^® XR – sold in USA by Wyeth Pharmaceuticals, LLC (NJ, USA). This newly approved product is based on Intellipharmaceutics proprietary and patented extended release matrix technology; Hypermatrix™ [14].

Clinical trials

Exicure updates on clinical trials

As part of reporting their third quarter results Exicure, Inc. (IL, USA) – a company that employs proprietary 3D, spherical nucleic acid (SNA™) technology to facilitate gene regulatory and immunotherapeutic drug delivery announced the completion of two Phase I trials and the commencement of a Phase Ib/II trial.

The company has reported the completion of a Phase I clinical trial for AST-008, results indicated the desired highly potent immune system activation was achieved without serious adverse events or dose-limiting toxicity.

Additionally, the company reported that it had completed patient dosing in the Phase I clinical trial of XCUR17 – top-line results were expected by the end of 2018.

The company also announced that the FDA opened an investigational new drug (IND) application for the Phase Ib/II trial for Exicure’s AST-008. AST-008 is a Toll-like receptor 9 (TLR9) agonist drug candidate designed for immuno-oncology applications. The company expected patient dosing to commence before the end of 2018 [15].

TriSalus announces positive clinical data for their drug-delivery technology

On 7 November 2019, Trisalus Life Sciences (CO, USA) reported positive Phase Ib results of a trial that involved the use of its proprietary pressure-enabled drug-delivery (PEDD) technology to administer a concentrated dose of anti-carcinoembryonic antigen (CEA) chimeric antigen receptor (CAR-T) cells precisely at the site of a solid tumor. In the trial, five patients (four with pancreatic and one with colorectal stage IV adenocarcinoma) each received three hepatic artery infusions of Sorrento Therapeutics (CA, USA) autologous anti-CEA CAR-T cells – the therapeutics were delivered employing Trisalus’ PEDD.

PEDD has been designed as an interventional medical device to create a favorable pressure gradient that can penetrate the solid tumor microenvironment and increase drug concentration in the tumor without increasing systemic toxicity [16].

Kala to file a new drug application for an AMPPLIFY-enabled product

As part of the reporting of its 2018 third quarter financial results, Kala Pharmaceuticals (MA, USA) announced that it had filed a new drug application (NDA) with the FDA for KPI-121 0.25% for the treatment of dry eye disease. KPI-121 employs Kala’s AMPPLIFY mucus-penetrating particle (MPP) drug delivery technology to enhance penetration of the active, loteprednol etabonate, into target tissue of the eye. According to Kala, their MPPs are selectively sized nanoparticles and have noncovalent proprietary coatings which facilitate distribution of drug encapsulated particles across mucosal surfaces and enhance uptake which can improve efficiency and decrease the necessary dose [17].

Clearside Biomedical Phase III failure

Clearside Biomedical Inc. (GA, USA) announced on 5 November 2019 that its Phase III sapphire clinical trial failed to meet its primary end point. The trial was to investigate XIPERE™ used in combination with EYLEA^® (aflibercept) an intravitreal anti-VEGF agent. The trial compared this combination to intravitreal Eylea monotherapy, for the treatment of retinal vein occlusion. The primary end point established for the trial was a comparison of the proportion of patients in the combination treatment arm versus the intravitreal Eylea-alone control arm, who reported improvements in ‘best corrected visual acuity’ from baseline of at least 15 letters on the Early Treatment Diabetic Retinopathy Study scale, the evaluation was carried out 8 weeks after initial treatment. Following the analysis of the 8-week data, the company has decided to discontinue the clinical development of combination therapy for the treatment of retinal vein occlusion [18].

XIPERE is a proprietary suspension of a corticosteroid, triamcinolone acetonide, specifically formulated for administration to the back of the eye via suprachoroidal injection into the space located between the choroid and the outer protective layer of the eye.

Clearside also announced in November that they had submitted an NDA for XIPERE for the treatment of macular edema associated with uveitis [19].

Eyenovia updates on clinical programs

In a series of press releases in November 2018, the New York-based Eyenovia Inc. (USA) reported on clinical developments for their pipeline of microdose therapeutics using their proprietary piezo-print technology for the treatment of ophthalmic diseases and conditions.

On 26 November 2018, the company announced that it had initiated the Phase III study for pharmacologic mydriasis. The study will investigate the safety and efficacy of the Eyenovia’s first-in-class fixed-combination phenylephrine 2.5% – tropicamide 1% ophthalmic solution, administered as a microdose using the company’s proprietary OpteJet™ dispenser. Top-line results from this Phase III study are expected by Q2 2019 [20].

Also, on 28 November 2018, the company reported on the full trial results for its Phase II PG21 study. The results were published in the November issue of Clinical Ophthalmology Journal [21]. The primary aim of the study was to demonstrate the effect of Eyenovia’s microdosing on intraocular pressure lowering – for treating conditions such as glaucoma.

Discussing the outcome of the trial Sean Ianchulev, Eyenovia’s chief executive officer and chief medical officer, commented: “in addition to our two previous Phase II studies in mydriasis, we believe that PG21 further demonstrates that microdosing is well tolerated, easily delivered and therapeutically effective without the waste, discomfort and ocular overdosing associated with legacy eyedropper delivery” [22].

Pulmatrix announces positive Phase I results

Pulmatrix Inc. (MA, USA) announced positive results from its first in-man trial of its inhaled dry powder iSPERSE™ formulation of itranconazole for the treatment of asthma patients with allergic bronchopulmonary aspergillosis. Announcing this positive result, the company said it planned to proceed to Phase II studies by the end of 2018. Pulmatrix’s product candidates are based on its proprietary iSPERSE™ technology: a dry powder delivery platform, which is aiming to maximize therapeutic delivery to the lungs.

Commenting on the outcome of the trial, Jim Roach, MD, chief medical officer remarked: “with the Phase I study results now firmly in hand, we remain very enthusiastic about the potential for pulmazole to address the significant limitations associated with oral itraconazole, and more importantly, to address the significant unmet medical need that patients with asthma and allergic bronchopulmonary aspergillosis currently face. We believe that these results strongly support the further advancement of pulmazole into Phase II” [23].

IntelGenx announce clinical progress with two products

In two separate announcements in November 2018, Quebec-based company IntelGenx (Canada) announced the commencement of dosing in a Phase IIa study for their and the acceptance by the FDA of a resubmission of an NDA for the oral film formulation RIZAPORT^® for the treatment of migraine.

The Phase IIa study announced on 28 November 2018 aims to enroll up to 70 subjects with mild-to-moderate Alzheimer’s disease in a randomized, double-blind, placebo controlled Phase IIa proof of concept study for Montelukast Versafilm™. It is anticipated that IntelGenx’s Montelukast buccal film formulation will demonstrate enhanced bioavailability compared with the existing tablet formulations [24].

Additionally, IntelGenx reported in November that the FDA had accepted its resubmission of the NDA for RIZAPORT for the treatment of acute migraines in adults. The FDA has indicated it has assigned a Prescription Drug User Fee Act (PDUFA) goal date of 1 April 2019 for the completion of the review of the NDA. RIZAPORT is a proprietary oral soluble film formulation for the delivery of rizatriptan benzoate [25].

Lyndra reports positive clinical data

Lyndra Therapeutics (MA, USA) reported positive early clinical data for a proof of concept, prototype study with a formulation containing 50 mg of memantine hydrochloride. Lyndra Therapeutics aims to create a drug delivery platform technology that can offer the opportunity to offer once weekly dosing regimens for therapeutics that currently require once-a-day dosing. Lyndra’s drug-delivery platform is based on intellectual property licensed from the Massachusetts Institute of Technology (MA, USA) which describes methods for producing delivery vehicles that can increase residence time in the GI tract, US20170266112A1 [26].

Early stage research

Self-implantable, double-layered micro-drug-reservoirs for efficient & controlled ocular drug delivery

A report in Nature Communications [27] on research by Than et al. discusses a novel ocular delivery approach that consists of an eye patch equipped with an array of detachable microneedles with the ability to penetrate the ocular surface and act as implantable micro-reservoirs for controlled drug delivery. Proof-of-concept preclinical data presented in the report indicated that the technology had the ability to deliver an anti-angiogenic monoclonal antibody (DC101). Additionally, this preclinical work also indicated that a quick release of an anti-inflammatory compound (diclofenac) followed by a sustained release of DC101 provided synergistic therapeutic outcome in a corneal neovascularization disease model.

Cyclodextrin-enhanced delivery of sumatriptan

Researchers from Poznań and Krakow in Poland reported in a Nature Communications article that the formation of inclusion complexes of sumatriptan and β-cyclodextrin and 2-hydroxylpropylo-β-cyclodextrin significantly modifies its dissolution properties. The formation of these complexes has been found to enhance permeability of the active through artificial biological membranes that approximate a gastrointestinal model. In vivo models used indicated an enhanced pharmacological activity in terms of migraine pain and attendant symptoms [28].

Bacterial-mediated delivery of RNAi effector molecules

Researchers from Charité Universitätsmedizin Berlin (Germany), Institute of Pathology and the Laboratory of Experimental Pathology Berlin, Germany, have described, in a publication in Nature Communications, bacterial delivery of shRNAs directed against HPV16-E7-specific mRNA to oral squamous carcinoma cells. The delivery of RNAi effector molecules employing transkingdom RNAi technology is discussed as an alternative to other delivery techniques. The authors claim that this is the first time that tkRNAi technology has been shown to be a successful treatment for oral squamous carcinoma cells; efficiently delivering RNAi effectors to the oral squamous carcinoma cells [29].

Noninvasive delivery strategies for biologics

Researchers from the University of North Carolina at Chapel Hill, (NC, USA), Biologics Drug Product Development, Sanofi Research and Development (MA, USA) and Harvard University (MA, USA) have presented a very thorough review article in Nature Reviews Drug Discovery volume on noninvasive delivery strategies for biologics. This timely review covers noninvasive delivery options including subcutaneous, transdermal, oral, inhalation, nasal and buccal routes of delivery and includes therapeutics including proteins, peptides and other biopharmaceuticals [30].

Ultrasound used to release actives in the brain

Scientists from Stanford University (CA, USA) have reported the use of ultrasound to release drug from nanoparticulate carriers injected into the blood stream. Using an in vivo rat model and a fast acting anesthetic as a proof of concept molecule, the researchers showed that using this release mechanism, pharmacologically active amounts of the drug could be released in specific small areas of the rats’ brains targeted by a beam of focused ultrasound. In the study, the ultrasound intensity was typically 1/10th to 1/100th of the intensity used in clinical procedures. Each of the nanoparticles encapsulated both drug molecules and a droplet of perfluorocarbon. Discussing the possible applications of this technology, one of the authors' Airan stated: “We hope to use this technology to noninvasively predict the results of excising or inactivating a particular small volume of brain tissue in patients slated for neurosurgery” [31].

Novel platform for 3D printing of personalized medicine

The Hebrew University (Jerusalem, Israel) has disclosed their novel technology enabling the 3D printing of drug capsules with controlled release capabilities. The capsules produced with this methodology are based on 3D printing of hydrogel matrices. In addition to the ability to select release profiles via this technique, there is also the possibility to tailor accurately dosage levels and even drug combinations for individual patients [32].

Magnetic nanosprings for cancer therapies

A team of scientists from Korea University (Seoul, South Korea) and the Far Eastern Federal University (Vladivostok, Russia) reported that they had developed cobalt and cobalt–iron nanosprings that could potentially be used as targeted drug delivery agents for cancer therapeutics. The paper reported that the research group studied the magnetic properties of these unusual structures that appear to be a nanowire with a diameter of approximately 50 nM and consists of a chain of approximately 200 atoms. They have chiral characteristics that appear to be modified in different magnetic fields and it is possible that they might act as transportation capsules for therapeutics, however research in this area is at a very early stage [33].

Harpoon announces early preclinical data

San Francisco-based immune-oncology company Harpoon Therapeutics Inc. (USA) presented early preclinical data at the 2018 Society for Immunotherapy of Cancer annual meeting in Washington, DC, held 9–11 November 2018. Harpoon’s technology platform is a novel antibody-derived platform; TriTAC™ (Tri-specific T cell-Activating Construct) designed for destruction of solid tumors. Data presented supported the company’s decision to develop a new Protease-activated Tri-specific T cell Activating Construct (‘ProTriTAC’) platform. Therapeutics designed using this platform will be administered as an inactive pro-drug and then activated at the desired site by tumor-associated proteases. It is anticipated that Harpoon’s lead therapeutic candidate may enter clinical trials in 2019 [34].

Patents

Lens drug delivery system granted to OcuMedic

OcuMedic Inc, the New Jersey-based company (USA) that specializes in ocular delivery announced on 5 November 2018 that it had received notice from the European Patent Office that it had been granted a patent titled ‘Contact Drug Delivery System’. This patent covers the company’s intellectual property for timed released ocular delivery of drugs through prescription, soft contact lenses. The broad claims allow for extended wear contacts that can potentially deliver a wide variety of drugs for the treatment of conditions such as glaucoma and dry eye. The lenses can also potentially provide controlled release of anti-inflammatory, antibiotic and pain-reducing drugs that could find application for postoperative care for procedures such as cataract and LASIK surgery [35].

Oasmia granted a patent for its nanotechnology platform

Oasmia Pharmaceutical AB (Uppsala, Sweden) announced on 20 November 2018 that it had received notification of allowance of patent from the United States Patent Trademark Office related to its nanotechnology platform XR17. XR17 is an excipient based on vitamin A that can be used for drug delivery applications. It forms micelles that are between 20 and 60 nM in size and can form these micelles hydrophilic actives. This platform is used in Oasmia’s lead drug candidate OAS-19 [36].

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.