2014 Feb;5(2):113-8. doi: 10.4155/tde.14.2.
Industry Update: The latest developments in therapeutic delivery.
Abstract
The present industry update covers the period 1 November-30 November 2013, with information sourced from company press releases, regulatory and patent agencies as well as the scientific literature. The reuse of already approved medical products and techniques is not new to drug development – but is also becoming increasingly common in drug delivery. Proof points include recent announcements such as Unilife´s at-home delivery platform partnered with MedImmune, Liquidia´s particle-by-design PRINT technology launch, or Actinium Pharmaceuticals versatile antibody-based radiopharmaceutical delivery platform that allows the combination of specific antibodies with various therapeutic isotopes. Examples for convergence in delivery is the combination of drugs with therapeutic implantables and interventional devices such as Ariste Medical´s use of drug eluting polymer for devices made with polytetrafluoroethylene, Bard´s Lutonix drug-coated percutaneous transluminal angioplasty dilatation catheter and Micell technologies´ eluting absorbable polymer coronary stent system. Another synergistic approach is to mimic nature as demonstrated by the University of Lincoln´s use of cell-penetrating peptides to deliver ‘bulky’ biologics to target sites. Finally we report on cases to positively influence unfavorable pharmacokinetics through formulation for example Civitas Therapeutics´ respiratory delivery platform for the rapid l-dopa delivery and relief from debilitating motor fluctuations in Parkinson´s disease or Aphios Corporation´s oral delivery of cannabinoids with biodegradable polymer nanoparticles for faster and less variable drug uptake in pain management.
- PMID:
24483189
[PubMed – in process]
Business development
Financing
Midatech LtdMidatech Ltd. (Abingdon, UK), manufacturing biocompatible gold nanoparticles (GNP), announced on 5 November the raising of GB£10 million investment led by Ippon Capital SA (Geneva, Switzerland), which itself committed £7.6 million. According to Midatech, this will allow further progress towards commercialization of its development programs for diabetes and cancer through partnering and licensing agreements. There are further plans to license out the GNP technology for diagnostics, imaging and nonmedical fields such as cosmetics and electronics to create additional revenues. The diabetes portfolio is partnered through MidaSol Therapeutics LP, a strategic joint venture formed with the film drug-delivery technology-centered MonoSol Rx. Products include GLP-1-linked GNPs for the treatment of Type 2 diabetes mellitus and, MidaForm™ insulin PharmFilm®, which uses insulin-linked GNPs (MidaForm insulin) formulated into PharmFilm, for the delivery of insulin through the inside of a patient‘s cheek. Phase IIa clinical studies with this drug in diabetes patients are expected to report results in the second half of 2014. Further MidaSol recently announced its first research collaboration with a major US pharmaceutical company to evaluate the application of GNP and PharmaFilm technologies with certain molecules in its partner‘s diabetes portfolio [101].
LiquidiaLiquidia Technologies launched a new company, called Envisia Therapeutics, on 13 November with US$25 million in Series A funding led by Canaan Partners, New Enterprise Associates, Pappas Ventures, Morningside Ventures and Wakefield Group. It is aimed to develop an extended-release glaucoma treatment that could last for several months after one injection. Envisia Therapeutics uses Liquidia‘s PRINT platform to design particles at the micro- and nano-scale that use a polymeric delivery system to prolong the release of a drug over time. Its lead product ENV515 delivers a prostaglandin analog to compartments in the eye over a long period of time, potentially giving glaucoma patients a reason to comply with a treatment regimen. The PRINT platform is used for other areas such as vaccines and inhaled drugs as well with particles uniquely tailored for each application in size, shape and chemistry [102].
Licensing & collaboration agreements
BioTimeBioTime (CA, USA), a hydrogel technology manufacturer for drug delivery, signed an exclusive sublicense agreement 19 November with Jade Therapeutics (UT, USA) to allow the use of the hydrogel in its own sustained-release treatments for the eye. Jade addresses corneal healing following damage to the eye from disease or injury, delivering recombinant human growth hormone to activate cells involved in the tissue-building process. To enable delivery to the eye over a period of about a week to treat persistent corneal epithelial defects the product will be improved in its this drug-releasing capacity with BioTime‘s HyStem hydrogel technology to deliver the hormones within a web of molecules that mimics the human extracellular matrix [103].
Aquavit Pharmaceuticals, Inc.Aquavit Pharmaceuticals, Inc. (NY, USA) announced on 5 November that it has further extended its personalized drug-delivery platform by signing a binding preliminary agreement with Korean Huons Co, Ltd. This gives Aquavit the worldwide, perpetual and unlimited license for global commercialization, and the two companies will be investing up to $20 million to further develop, GMP manufacture, and market the technology. Aquavit‘s portfolio includes microneedle technology (Aquagold® fine touch), desktop robotics for formulations, and proprietary and personalized compounds and admixtures [104].
Development & manufacturing agreements
Catalent Pharma SolutionsCatalent Pharma Solutions (NJ, USA) announced on 8 November the launch of its new ‘FormProRx‘ web tool at the forthcoming 2013 American Association of Pharmaceutical Scientists Annual Meeting and Exposition. This web-based application has been developed to assist drug-development teams seeking to determine the optimal finished dose suited to their product based on product requirements, target indications and molecule properties and to assess multiple oral drug-delivery technologies in order to establish which may be the most appropriate for their molecule. Users can gain access to a customized report for their active pharmaceutical ingredient characteristics and product requirements across 24 dimensions under the categories ‘solubility and permeability,‘ ‘physiochemical properties‘, ‘potent handling‘ and ‘active pharmaceutical ingredient processing‘ [105].
UnilifeInjectable drug-delivery specialist Unilife (PA, USA) partnered with AstraZeneca‘s MedImmune (MD, USA) on 12 November to use its wearable devices with MedImmune‘s line of large molecules, a market estimated by the company to exceed $8 billion in 10 years time. The agreement allows MedImmune to customize Unilife‘s devices for molecules in its pipeline. With its “peel, stick and click” steps of use, the device gives patients an at-home delivery platform for drugs that normally require intravenous injection. Unilife already has a similar agreement with Sanofi (Paris, France) for the use of its self-retracting automatic injectors [106].
Regulatory news & approvals
Product approval
BardBard, Inc. (NJ, USA) announced on 25 November that its Lutonix® technology centre submitted the final module of the premarket approval application to the US FDA for the Lutonix Drug-Coated percutaneous transluminal angioplasty dilatation catheter (DCB). The Lutonix DCB is being clinically evaluated in the global, multicenter LEVANT 2 randomized clinical trial to compare the safety and efficacy of its DCB to standard angioplasty balloons for the treatment of peripheral arterial disease in superficial femoral and popliteal arteries. Drug-coated balloons may allow physicians to treat diseased arteries without having to leave a permanent implant behind. Today no such device is approved for use in the USA and Lutonix DCB, currently only available in Europe and several other countries worldwide, is limited to investigational use in the USA under an IDE from the FDA [107].
PfizerPfizer Inc. (NY, USA) announced on 4 November that the FDA has approved a prior approval supplement for EMBEDA® (morphine sulfate and naltrexone hydrochloride) extended release capsules CII. This included an update to the EMBEDA manufacturing process that addressed the prespecified stability requirement that led to the voluntary recall of EMBEDA from the market in March 2011. Pfizer anticipates product availability in the second quarter of 2014 [108].
Clinical trials
Micell TechnologiesMicell Technologies Inc. (NC, USA), announced on 21 November published results of a comprehensive analysis of optical coherence tomography following MiStent Sirolimus eluting absorbable polymer coronary stent system (MiStent SES®) implantation. The rapidly absorbable coating of the MiStent SES is intended to precisely and consistently control drug elution and limit polymer exposure duration, thereby reducing the safety risks associated with current commercially available drug-eluting stent technologies. Using an approved drug (sirolimus) and polymer, Micell‘s patented supercritical fluid technology allows a rigorously controlled drug/polymer coating to be applied to a bare-metal stent. The MiStent SES leverages the benefits of the Eurocor (CE marked) Genius® MAGIC cobalt chromium coronary stent system, which has demonstrated excellent deliverability, conformability and flexibility. Evaluations of vascular healing taken at multiple time points (4, 6, 8 and 18 months postimplantation) demonstrated excellent vessel healing with a low rate of neoatherosclerosis compared with previously reported results with other drug-eluting stents. High rates of stent coverage in early follow-up, with further improvement at 18 months‘ follow-up, low stent strut malposition at all-time points and neointimal hyperplasia thickness, area and volume that remained static from eight to 18 months without evidence of late restenosis were observed [1,109].
Actinium PharmaceuticalsActinium Pharmaceuticals (NY, USA) met with the FDA on 20 November and is planning to roll out a Phase III pivotal trial of its targeted immunotherapeutic cancer treatment using a radioisotope delivery platform with the primary endpoint of complete remission lasting 6 months. The FDA communicated those positive results from the single study of Iomab-B would put the drug on the path to approval and in the Phase I/II trial 100% of the leukemia and myelodysplastic syndrome patients achieved this. Actinium‘s delivery platform is a targeted form of radiotherapy that couples antibodies with radioactive isotopes such as iodine 131 and carries them directly to tumors while mitigating the radiation effects on healthy cells. In patients over 55, there are currently no FDA-approved treatments for acute myeloid leukemia and no standard of care, according to the company. Actinium also has an antibody based α-emitters development candidate, actimab-A, in early trials [110].
Bio-Path HoldingsBio-Path Holdings, Inc. (TX, USA), developing a liposomal delivery technology for nucleic acid cancer drugs, announced on 7 November a poster presentation at the 55th Annual Meeting of the American Society of Hematology in New Orleans on results from the ongoing Phase I trial evaluating the company‘s lead compound liposomal Grb-2 antisense oligonucleotides in hematological cancers. Bio-Path‘s drug-delivery technology involves microscopic-sized liposome particles that distribute nucleic acid drugs systemically and safely throughout the human body, via simple intravenous infusion. The delivery technology is applied to single stranded (antisense) nucleic acid compounds and the company is currently focused on developing liposomal antisense drug candidates. BP-100–1.01 is a neutral-charge; liposome-incorporated antisense drug substance designed to inhibit the adaptor protein (Grb-2) expression, which is essential to cancer cell signaling and hence should interrupt its vital signaling function and have a therapeutic application in cancer [111].
InVivo TherapeuticsInVivo Therapeutics Holdings Corp. (MA, USA), a biomaterials company with technologies for drug delivery with a focus on treatment of spinal cord injuries, confirmed on 15 November that the clinical trial of a degradable polymer scaffold designed to promote healing following acute spinal cord injury, will be ready to enroll patients in the first quarter of 2014. The company has signed confidentiality agreements with more than ten qualified sites considering participation in the human safety study. Most work on the InVivo hydrogel product development programs has been temporarily suspended due to the company‘s focus on the scaffold manufacturing initiative for the pending trials as well as a review of its portfolio [112].
Patents
OramedIsrael‘s Oramed (Jerusalem, Israel) won a patent on 19 November from the EU for its oral insulin pill, giving the company access to the diabetes market estimated to be worth approximately $14 billion by 2017, according to analysts. The patent covers Oramed‘s process for the oral administration of proteins. The company‘s main insulin pill is currently in Phase II trials for Type 2 diabetes, and its oral exanatide capsule, also for Type 2, is in early clinical stages [113].
AphiosAphios Corporation (MA, USA) announced on 4 November that it received notification of allowance for a US Patent entitled “Nanoencapsulated Δ-9-tetrahydrocannabinol” for the oral delivery of cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) in biodegradable polymer nanoparticles. The patented technology will be utilized in the manufacturing of APH-0812 for pain and cachexia in AIDS and cancer patients, and APH-1305 for multiple sclerosis and other CNS disorders. The nanotech formulation of Δ9-THC will also have applicability in several other chronic diseases such as obesity, smoking cessation and schizophrenia according to the company. In the currently marketed oral formulation, synthetic Δ9-THC (Dronabinol®) is dissolved in sesame seed oil and is commercially available as an oral capsule (Marinol®). Oral administration causes slow, variable Δ9-THC uptake and requires drug administration several times a day because of first pass metabolism. For the novel patented formulation, pharmaceutical grade Δ9-THC and other cannabinoids from Cannabis sativa are manufactured following cGMP utilizing Aphios‘ patented SFS-CXP manufacturing technology platform. Alternatively, the nanoformulation will be utilized to deliver Δ9-THC and other cannabinoids from a subcutaneously implanted depot[114].
Ariste MedicalAriste Medical, Inc. (TN, USA), announced on 7 November that a second patent has been issued by the US Patent and Trademark Office relating to its drug-eluting polymer for devices made with polytetrafluoroethylene (PTFE) and expanded PTFE. The novel coating is capable of incorporating multiple pharmaceutical agents, helping to preserve the function of a wide variety of implantable medical devices. Ariste is developing a drug-eluting surgical mesh for hernia repair, as well as a drug-eluting vascular graft for the prevention of restenosis-induced graft failure in hemodialysis patients. The second patent provides additional protection over the method of drug delivery. Ariste has completed preclinical models demonstrating proof-of-concept using expanded PTFE grafts coated with antibiotics and has achieved significant reductions in bacterial colonization. Ariste believes that its technology will help prevent mesh failure due to infection in the hernia repair setting. In addition, Ariste is pursuing a Series A to fund development of the drug eluting mesh for hernia repair. In 2012, Ariste raised $1.275 million in seed capital [115].
Civitas therapeuticsCivitas therapeutics, Inc.(MA, USA), a biopharmaceutical company with a lead program in Parkinson‘s disease that leverages the ARCUS® respiratory delivery platform, announced on 8 November that the US Patent and Trademark office has issued US Patent 8,545,878 entitled “Capsules containing high doses of levodopa for pulmonary use” which covers the pharmaceutical composition of Civitas‘ lead program, CVT-301, an inhaled formulation of l-dopa being developed for the rapid and reliable relief from debilitating motor fluctuations (OFF episodes) associated with Parkinson‘s disease. The reliability of other oral l-dopa formulations is significantly compromised by delayed and unpredictable absorption and excessive variability in circulating plasma drug concentrations inherent to the oral delivery route. CVT-301 leverages the ARCUS® platform to optimally deliver a precise dose to the deep lung for rapid and predictable l-dopa absorption. A Phase I study in healthy volunteers showed that CVT-301 rapidly achieved target l-dopa plasma levels with a pharmacokinetic profile supportive of its therapeutic potential. The recently completed Phase IIa double blind, placebo controlled, dose finding study (CVT-301–002) recapitulated the pharmacokinetic profile in patients, produced rapid and durable improvement in motor function when administered to patients in the OFF state, and was generally safe and well tolerated at all doses tested. These clinical studies have been funded in part by grants from The Michael J Fox Foundation for Parkinson‘s Research [115].
Publications
Nottingham UniversityA team of researchers from Nottingham University (Nottingham, UK) published on 13 November the use of a bone-healing polymer to achieve delivery of cancer drugs to tumors in the brain after surgery. Many brain cancer relapses occur as a result of leftover tumor cells in the brain after surgery. By using a polymer made up of two different microparticles, LGA and PEG, the scientists found a way to safely deliver chemotherapy and neutralize the remaining cells. A surgeon would use the polymer to line the cavity left after the removal of a tumor. Upon reaching body temperature, the paste solidifies and, when preloaded with cancer drugs, gradually releases them after the surgery is complete. The scientists showed this using solution-based tests as well as a 3D model before a trial in a mouse brain with the cancer drug etoposide[116].
University of LincolnResearchers at University of Lincoln (Lincoln, UK) reported on 13 November results from the development of a safe way to deliver biologics directly to tumors and other target sites by using cell-penetrating peptides (CPPs). Large molecules, which can include proteins, nucleic acids, sugars and other complex compounds, present a challenge for delivery and CPPs are known to facilitate the delivery of therapeutic biologics into target cells. As CPPs are highly toxic the researchers are looking for ways to render them nontoxic but still able to selectively pass through cell membranes in cancer cells [117].
University of IowaA group from the University of Iowa (IO, USA) published on 13 November on a patch that delivers DNA-loaded nanoparticles for bone regeneration avoiding painful, repeated injections. In animal tests delivery of genetic material that codes for the PDGF-B stimulating cell production, regrew enough bone to cover skull wounds. The patch itself is composed of a collagen scaffold loaded with synthetically created plasmids with the DNA. The scientists hope to continue the studies by creating a similar method to spur blood vessel growth in the bone, leading to even more fully realized bone regeneration [2,118].
University of California Los AngelesResearchers at UCLA´s Jonsson Comprehensive Cancer Center (CA, USA) have developed nanoparticles capable of clearing a path for drugs to pass through to a tumor as reported on 20 November. They focused on tumors associated with pancreatic cancer, a notoriously difficult cancer to treat, which are surrounded by structural elements called stroma blocking standard chemotherapy drugs from reaching the cancer cells. Using a dual-wave method of two different nanoparticles, injected quickly one after the other, the first wave of nanoparticles carries a signaling pathway inhibitor that removes these stroma ‘gates‘, and the second wave carries the cancer drug, which then can easier access the tumor. Tests in mice are promising. The US Public Health Service and the National Cancer Institute funded the study [119].
Financial & competing interests disclosureO Steinbach is an employee of Royal Philips Electronics North America Corporation. 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.
References
| 1 . | Attizzani GF, Bezerra HG, Ormiston J et al. Serial assessment by optical coherence tomography of early and late vascular responses after implantation of an absorbable-coating Sirolimus-Eluting stent (from the first-in-human DESSOLVE I trial). Am. J. Cardiol.112(10),1557–1564 (2013). [CrossRef] [Medline] |
| 2 . | Elangovan S, D‘Mello SR, Hong L et al. The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor.Biomaterials35(2),737–747 (2014). [CrossRef] [Medline] [CAS] |
▪ Websites
| 101 . | Midatech Raises £10 Million to advance gold-nanoparticle technology for diabetes and cancer treatment. http://midatechgroup.com/midatech-raises-10-million-to-advance-gold-nanoparticle-technology-for-diabetes-and-cancer-treatment |
| 102 . | ENVISIA therapeutics debuts with $25 million series a financing. www.envisiatherapeutics.com/wp-content/uploads/2013/11/Envisia-Launch-Release.pdf |
| 103 . | BioTime signs exclusive agreement with Jade therapeutics for ophthalmic drug delivery applications of HyStem® technology. www.jadetherapeutics.com/News.html |
| 104 . | Aquavit pharmaceuticals adds new advanced drug delivery technology to product portfolio. www.prnewswire.com/news-releases/aquavit-pharmaceuticals-adds-new-advanced-drug-delivery-technology-to-product-portfolio-230663001.html |
| 105 . | New interactive web tool helps innovators match formulations to drug delivery technologies. http://germany.catalent.com/index.php/news-events/news/New-Interactive-Web-Tool-Helps-Innovators-Match-Formulations-to-Drug-Delivery-Technologies |
| 106 . | Unilife announces supply agreement with MedImmune for wearable injectable drug delivery devices. http://ir.unilife.com/releasedetail.cfm?releaseid=806151 |
| 107 . | Bard submits final PMA module to the FDA for the Lutonix drug-coated balloon. http://investorrelations.crbard.com/phoenix.zhtml?c=91501&p=irol-newsArticle&ID=1879892&highlight= |
| 108 . | Pfizer receives FDA approval for a prior approval supplement for EMBEDA® (morphine sulfate and naltrexone hydrochloride) extended release capsules CII.www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_fda_approval_for_a_prior_approval_supplement_for_embeda_morphine_sulfate_and_naltrexone_hydrochloride_extended_release_capsules_cii |
| 109 . | Paper published in American Journal of Cardiology demonstrates favorable vascular healing following MiStent SES implantation.www.micell.com/businessdevelopment/Micell%20AJC%20OCT%20Data%20PR_11_21–13%20Final.pdf |
| 110 . | Actinium announces plans for IOMAB™-B Phase III pivotal trial following meeting with US FDA. www.actiniumpharmaceuticals.com/2013%20Release%20Final.pdf |
| 111 . | Data from Bio-Path Holdings Phase I Clinical trial in hematological cancers to be presented at American Society of Hematology Annual Meeting.www.biopathholdings.com/pdf/BPTH_PR_Presentation_at_ASH_Annual_Meeting_001.pdf |
| 112 . | InVivo Therapeutics lead program on track. www.invivotherapeutics.com/2013/11/invivo-therapeutics-lead-program-on-track |
| 113 . | Oramed receives patent in the EU for the oral delivery of insulin. www.oramed.com |
| 114 . | Aphios granted US patent for oral delivery of cannabinoids such as Δ9-THC in nanoparticles. www.aphios.com/news-and-current-events/press-releases-and-news/235-aphios-granted-united-states-patent-for-oral-delivery-of-cannabinoids-such-as-9-thc-in-nanoparticles.html |
| 115 . | Ariste medical receives issued US patent and raises seed capital. www.aristemedical.com/news/?p=24 |
| 116 . | Drug-releasing material targets post-surgery tumour tissue. www.theengineer.co.uk/medical-and-healthcare/news/drug-releasing-material-targets-post-surgery-tumour-tissue/1017469.article |
| 117 . | Tackling a large challenge for new modes of drug delivery. www.lincoln.ac.uk/news/2013/11/802.asp |
| 118 . | A bio patch that can regrow bone. http://now.uiowa.edu/2013/10/bio-patch-can-regrow-bone |
| 119 . | Nanotech researchers‘ two-step method shows promise in fighting pancreatic cancer. www.newsroom.ucla.edu/portal/ucla/ucla-nanotechnology-researchers-249350.aspx |
Affiliations
Oliver C Steinbach
Philips Healthcare, Clinical Science & Research Programs, Philips Healthcare – Clinical Research Board, 3000 Minuteman Road, Andover, MA 01810, USA.oliver.steinbach@philips.com
