Industry Update: The latest developments in therapeutic delivery

Business development

Reports on the injectable & nanotechnology drug-delivery market

Various reports published by MarketsandMarkets in April addressed the global drug-delivery market: injectables divided in to two major segments, devices and formulation, were valued at US$22.5 billion in 2012 and are expected to reach $43.3 billion by 2017 [201]. The same publisher predicts gains in the nanotechnology drug-delivery market through 2016, with 74% growth worldwide and approximately 85% growth in the USA. Despite remaining safety concerns regarding nanomedicines, a global nanotechnology boom is expected with its relatively low R&D cost as compared with its ability to improve the delivery of particular drugs [202]. Next to the Profiles of Start-ups and Emerging Companies report in early stage drug-delivery technologies [203], and the Global Transfection Technologies Market Report (2012–2017) with applications spanning gene therapy and delivery of therapeutics [204], MarketsandMarkets published on the Drug Delivery Technology Market predicted to be worth $224.2 billion by 2017 [205].

Financing

Entrega

Boston startup Entrega (MA, USA) is developing a novel needle-free drug-delivery capsule option for large-molecule drugs that normally require intravenous injections to treat diseases, such as Parkinson’s, cancer and arthritis. Entrega is creating a capsule that releases tiny, drug-coated wafers in the small intestine that attach themselves to the intestine’s internal lining and release drugs like miniature versions of a dermal patch, according to a report in The Boston Globe on 2 April 2013 [1].

Ambrx

Antibodies as a drug-delivery technology are gathering a lot of interest in the pharmaceutical arena. On 9 April 2013, Ambrx (CA, USA) received $15 million from Japanese drugmaker Astellas Pharma (Tokyo, Japan) up front to license the company’s technology on antibody–drug conjugates (ADC) for further development, and another $285 million as Ambrx reaches milestones in research, development, regulation and sales specifically for cancer treatment. ADCs are mimicking human antibodies allowing drugs to more efficiently and safely reach their targets, for example, in cancer treatments a toxic drug payload and tumor-specific targeting of receptors. Ambrx’s lead drug candidate for growth deficiency, ARX201, has completed Phase II trials. Other licensees of the ADC technology are Merck, Eli Lilly and Bristol-Myers Squibb (CA, USA) [206].

Novaliq

On 15 April 2013, Novaliq’s (Heidelberg, Germany) drug-delivery platform that helps poorly soluble drugs dissolve more easily in eye drops received $18.1 million in its fifth round of financing, bringing the total amount raised to $35.2 million, which has come exclusively from entrepreneur Dietmar Hopp’s dievini Hopp Biotech Holding. This recent investment will advance its lead product CyclaSol, the company’s clear liquid eye drop based on the delivery technology semifluorinated alkanes, into clinical Phase I trials by the first quarter of 2014. Dry eye syndrome is a disorder of the tear film and affects an estimated 25–30 million people over the age of 40 in the USA and more than 300 million worldwide [207].

Auris Medical

Auris Medical (Basel, Switzerland) announced on 17 April 2013 a $50.6 million financing round from Sofinnova Ventures and Sofinnova Partners for its novel drug to treat inner-ear problems via an injection into the middle-ear cavity. This will help to pursue Phase III clinical trials into the second half of this year with AM-101 treatment for acute tinnitus and AM-111 treatment for acute inner-ear hearing loss. Both are administered via intratympanic injection or injection into the eardrum [208].

Licensing & collaboration agreements

Santaris Pharma

Santaris Pharma A/S (Hoersholm, Denmark), a privately held biopharmaceutical company focused on developing medicines targeted to disease-related mRNAs and miRNAs, has announced a worldwide strategic alliance with Bristol-Myers Squibb to discover and develop novel medicines using Santaris Pharma’s proprietary Locked Nucleic Acid Drug Platform. Under the terms of the agreement, Santaris Pharma will receive an upfront payment of $10 million, up to $90 million in potential milestone payments per product and funding of on-going discovery and research activities. In addition, Santaris Pharma will be eligible to receive royalties on the worldwide sales of all medicines arising from the alliance [209].

scPharmaceuticals

scPharmaceuticals (MA, USA), is succeeding SpringLeaf Therapeutics, which failed to produce a wearable subcutaneous pump system. According to a report in the Boston Globe on 3 April 2013, SpringLeaf ceased to exist last month without conducting a single clinical trial of its subcutaneous pump, despite collecting $20 million from investors. scPharmaceuticals, which will continue work on a wearable pump of its own, the SenseCore Minipump, uses some of SpringLeaf’s technology with the Swiss Sensile Medical Holding to develop a wearable battery-operated minipump for patients with heart failure that delivers drugs with a small needle under the skin. The drug is a novel formulation of the diuretic furosemide, which is currently used only in tablet or intravenous form. scPharma expects to submit a new drug application by early 2015 [2].

Development & manufacturing agreements

BIND Therapeutics

AstraZeneca (London, UK) and BIND Therapeutics (MA, USA) announced on 23 April 2013 that they have entered into a strategic collaboration to develop and commercialize Accurin™, a targeted and programmable cancer nanomedicine from BIND’s Medicinal Nanoengineering^® platform, based on a molecularly targeted kinase inhibitor developed and owned by AstraZeneca. The collaboration gives AstraZeneca exclusive rights to the development and commercialization of the nanomedicine, while BIND will lead manufacturing. BIND could receive upfront and pre-approval milestone payments totaling $69 million, and more than $130 million in regulatory and sales milestones and other payments as well as tiered single- to double-digit royalties on future sales [210].

GlaxoSmithKline

GlaxoSmithKline (GSK) and A*STAR’s Institute of Chemical and Engineering Sciences (ICES; Singapore), have signed a 5-year strategic agreement to develop new evidence-based formulations that are reformulated to provide additional patient benefit specifically for emerging markets. This extends ICES long-term relationship with GSK since 2003 and builds on ICES’ strengths and expertise in synthesis, formulation and process development, as well as GSK’s vast experience in drug candidate selection, optimization and product development in novel formulations [211].

Regulatory news & approvals

Product approval

Becton, Dickinson & Company

BD Medical (NJ, USA), a segment of Becton, Dickinson and Company, announced on 11 April 2013 the commercial launch of a new passive needle guard technology, BD UltraSafe PLUS™, a Passive Needle Guard that has received 510(k) clearance as an anti-needlestick safety device. This product, in addition to offering needlestick safety in an easy-to-use one-handed device, is enhanced with ergonomic features designed to facilitate comfort and support for healthcare providers and patients. In addition, this safety device is designed to meet increasingly complex biotechnology drug requirements, including higher viscosity [212].

A.P. Pharma

The US FDA issued A.P. Pharma (CA, USA) a rejection letter on 1 April 2013 detailing problems with its sustained-delivery treatment for chemotherapy-induced nausea and vomiting. The company submitted a new drug application to the agency in September 2012 for its delayed-onset injectable treatment, APF530, which makes use of a delivery system that significantly extends the active life of the antagonist granisetron and the polymer-based Biochronomer™ delivery platform allowing for only one injection every 5 days rather than once or twice per day. But the FDA responded with a letter to A.P., requesting several changes be made to the drug, including the quality of materials at the manufacturing level, the need for further studies regarding the syringe system and the classification of Phase III trials with regard to chemotherapy type. To address these concerns, A.P. will push its projected launch of the drug to the first half of 2014, rather than the original projection of early 2013 [213].

Biogen Idec

Biogen Idec’s recently approved Tecfidera™, an oral treatment for multiple sclerosis (MS), is entering pharmacies on 3 April 2013, filling the need for a safe and effective option for patients with the disease [214]. Tecfidera, formerly BG-12, is the third oral MS treatment approved, and analysts expect it to dominate the reported $12 billion market, creating a potential revenue of up to $3 billion a year. For patients with MS, one of the most common causes of neurological disabilities in young adults, Tecfidera is a welcome alternative to frequent injections. Tecfidera targets MS differently than other products, and while its exact mechanism of action is unknown, it has been demonstrated to activate the Nrf2 pathway showing better results and fewer side effects than other oral treatments in the past.

TissueGen

TissueGen (TX, USA), a developer of drug-delivering polymer fibers, released its broad-range mesh technology Elute™ to the market as announced on 10 April 2013. TissueGen’s biodegradable polymer mesh delivery system has two mechanisms of release: the actual blend of polymers enables precise control of the time of degradation of the material in the body and the porosity of the material to control drug release [215]. TissueGen recently partnered with Biomedical Structures (RI, USA), in developing and manufacturing Elute, which is available in several different devices so far, including cardiovascular stents, urethral stents and a growth-hormone-laden suture material [216].

Delcath

Delcath Systems’ (NY, USA) cancer drug-delivery device got a 16 to 0 vote with no abstentions by the FDA´s Oncologic Drugs Advisory Committee that the associated risks likely outweigh any benefit and narrowed the label of the device, indicating its use only for metastatic melanoma that arises in the eye [216]. The Melblez™ device, a catheter-based system designed to deliver the chemotherapeutic melphalan directly to the liver, requires further testing and Delcath is now considering a new filter for the system, requiring a new trial process. Currently, there are no FDA-approved drugs for the treatment of metastatic ocular melanoma [3].

Clinical trials

Perosphere Inc.

Perosphere Inc. (NY, USA) and Daiichi Sankyo Company Ltd (Tokyo, Japan), announced on 25 April 2013 that they have entered into a clinical trial agreement under which Daiichi Sankyo will support and co-sponsor a Phase I clinical study testing the safety, tolerability and effectiveness of PER977, a novel oral once-daily anticoagulant, to reverse the anticoagulant activity of edoxaban, Daiichi Sankyo’s investigational oral, once-daily, direct factor Xa-inhibitor. This is a synthetic, small, new molecular entity being developed by Perosphere that has been reported in preclinical studies to directly bind to heparins as well as circulating direct factor Xa- and IIa-inhibitors and therefore has the potential to reverse their anticoagulant effect [217].

Civitas

Civitas Therapeutics announced on 19 April 2013 successful Phase II trial results for its inhaled Parkinson’s drug CVT-301, the novel delivery of which promises to make the disease more manageable for patients on an everyday basis, the company says [218]. Using its ARCUS™ delivery platform, a method that incorporates a dry powder and a dose-controlled, self-administered inhaler, the new CVT-301 introduces the Parkinson’s drug levodopa, or l-dopa, into the lungs, where it is rapidly absorbed into the bloodstream and crosses the blood–brain barrier. Civitas is a spinout of Alkermes, which licensed the ARCUS™ technology from MIT Advanced Inhalation Research startup. Very similar research at Northeastern University was communicated on 22 April 2013 to have developed a treatment for Parkinson’s disease via delivery through the nose using GDNF. The protein acts directly on the motor area of the brain, the substantia nigra, preventing the degeneration and death of the neurons there [219].

Patents

Reexamination Certificate for Locked Nucleic Acid patent

SantarisPharma A/S (Hoersholm, Denmark), a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced that the USPTO issued an Inter Partes Reexamination Certificate for US Patent No. 6770748 on 1 April 2013. The certificate, which follows a decision by the USPTO to dismiss an appeal that had been filed by Isis Pharmaceuticals during the proceeding, confirms the patentability of original, amended and new claims added by Santaris during the proceeding. The ‘748 patent is a continuation-in-part of US Patent No. 6268490 (the ‘Imanishi Patent). The ‘Imanishi patent was previously subject to an ex parte reexamination request also brought by Isis, which ended with the USPTO issuing an Ex Parte Reexamination Certificate on 6 December 2011, confirming the patentability of all the original claims. The Imanishi and ‘748 patents claim rights to the Locked Nucleic Acid or Bicyclic Nucleic Acid chemical structure used for developing antisense molecules [101].

Publications

Opening blood–brain barrier

According to the study published on 24 April 2013, researchers at Harvard and Boston University have developed a surgical technique to deliver drugs across the blood–brain barrier by creating a direct pathway through the nose. To prevent infection or leakage of cerebral fluid, the researchers grafted a nasal mucosal patch over the opening, which is permanent and water-tight, but allows therapeutic agents to enter the brain. By using this novel endoscopic method, which surgeons use to remove brain tumors through the nose without facial incisions, the method worked successfully in rat models [4].

Nanotechnology drug delivery

Researchers at Cornell University presented at the American Chemical Society meeting in New Orleans on 7 April 2013 on a prototype of a combination drug-delivery and diagnostic inorganic, silica-based nanoparticle. The dye-infused particles called ‘Cornell dots’ (C-dots) received early 2011 FDA approval for clinical trials. Originally developed for diagnostics the Cornell team has created a vehicle capable of holding cancer drugs by drilling a hole into the C-dots, which are less than 10 nm in diameter. The C-dots come with favorable pharmacokinetics: rather than circulating in the human body and entering the liver, as larger particles do, the C-dots remain in the body for less than 6 h and are excreted in the patient’s urine [5].

A group from University of San Diego reported on 10 April 2013 during the 245th ACS National Meeting and Exposition in New Orleans, Louisiana, on self-propelled ‘microrockets’ that could enhance drug delivery for cancer. Joseph Wang and his team have created a micromotor that uses material in its surrounding environment, such as stomach acid. The research team is looking to extend the microrockets’ release time and make them more specifically compatible with certain drugs [6].

Finally, German researchers published on 26 April 2013 the use of the highly stable structure of a uniquely shaped human immune protein as a model for high-concentration vaccine delivery. The protein C4BP acts as a countermeasure against bacteria in the blood under normal conditions. One of many such immune proteins, C4BP has eight ‘arms’, or chains – seven α chains and one β chain – held together by a central ‘body’ called the oligomerization domain, which is named due to its structure the ‘spider protein’. The central body of a synthetic version of the molecule keeps the protein together and active despite the harsh environment of the bloodstream and can be used as a platform for drugs, essentially replacing any number of the seven α chains with new treatments [7].