Industry Update: The Latest Developments in Therapeutic Delivery

The present industry update covers the period 1–3 January 2014, with information sourced from mainly company press releases, regulatory and patent agencies. This month an upbeat report predicted a growth in the global nanomedicine market of 12.3% compound annual growth rate and an expected value of US$177.60 billion in 2019. There was positive news on the clinical trials front for Progenics, Celsion, Endo Pharmaceuticals, Alkermes, Cynapsus and Oramed. Adamis announced this month that it had completed the acquisition of 3M’s Taper Dry Powder Inhaler technology. In regulatory news it was announced that Indian authorities have recommended that each new drug-delivery system, including modified release dosage form, should be treated as a new drug and subjected to the requirement of complete studies as a new drug.

Industry forecasts

Global market for nanomedicine expected to grow at 12.3% compound annual growth rate to reach US$177.60 billion in 2019

According to a new market report published by Transparency Market Research in January “Nanomedicine market (neurology, cardiovascular, anti-inflammatory, anti-infective, and oncology applications) – global industry analysis, size, share, growth, trends and forecast, 2013–2019” the market for nanomedicine was valued at US$78.54 billion in 2012 and is expected to reach a value of $177.60 billion in 2019, growing at a compound annual growth rate of 12.3% from 2013–2019.

North America dominated the market in 2012 and is expected to maintain its market position until 2019. However, the Asia–Pacific market is estimated to grow at a faster pace (compound annual growth rate of 14.6% from 2013–2019). Europe is also expected to grow at a relatively higher rate compared with North America, owing to constantly improving regulatory framework and the presence of an extensive product pipeline portfolio [1].

Business development

Impax & Durect sign a $63 million agreement to develop& commercialize Durect’s ELADUR^® pain patch

Durect Corporation (CA, USA) announced on 7 January they had entered into an agreement granting Impax (CA, USA) the exclusive worldwide rights to develop and commercialize ELADUR^®, Durect’s investigational transdermal bupivacaine patch for the treatment of pain associated with post-herpetic neuralgia.

ELADUR is an investigational transdermal drug patch intended to deliver bupivacaine for up to 3 days from a single application. Durect has previously announced positive results for ELADUR from a 60 patient Phase IIa clinical trial of patients suffering from post-herpetic neuralgia [2].

Elixir medical announces first commercial implant of the DESolve^® novolimus eluting coronary scaffold system in Europe

Elixir Medical (CA, USA) announced on 15 January that the first commercial implant of Elixir Medical’s CE Mark-approved DESolve Novolimus Eluting Coronary Scaffold was performed in Germany by Professor Dr med. Holger Nef, Head of the Cardiac Catheterization Laboratory, University Hospital Giessen, Germany.

Elixir’s DESolve scaffold for coronary artery disease is fully bioresorbable. It consists of a proprietary poly-l lactide-based polymer and incorporates the novel antiproliferative drug, Novolimus.

The DESolve Nx pivotal trial enrolled 126 patients at 13 centers in Europe, Brazil and New Zealand. 1-year safety and efficacy results for the DESolve Novolimus Eluting Coronary Scaffold System had previously been announced at the Transcatheter Therapeutics 2013 scientific conference in San Francisco in October 2013.

At the one year time point, the DESolve Nx trial demonstrated a low Major Adverse Cardiac Events rate of 5.69% with no definite scaffold thrombosis. Results using multislice coherence tomography, a noninvasive imaging modality to visualize coronary arteries and the manifestations of coronary artery disease, demonstrated that the lumen area measurements of treated vessels at 1 year were maintained to the results that were observed at 6 months using other imaging modalities [3].

NanoViricides raises $20 Million

NanoViricides (CT, USA) announced on 24 January that it has raised approximately $20 Million in a registered direct offering. The company estimate that this funding will enable them to complete Phase I and II human clinical studies of their injectable FluCide drug candidate and also through initial human clinical trials of DengueCide.

DengueCide has received Orphan Drug designation by the US FDA as well as the European Medical Agency

With this raise, the company now has approximately $40 Million which the company plans to use to facilitate clinical trials for FluCide and DengueCide, the company stated that it will also be able to expedite development of its four other drug candidates, Oral FluCide, HerpeCide™, HIVCide™, and EKCCide™ into the FDA approval process [4].

Adamis Pharmaceuticals announces completion of acquisition of 3M Technology

Adamis Pharmaceuticals (CA,USA) announced on 7 January that it had it made a final payment of $7 million to fully acquire from 3M Company and 3M Innovative Properties Company certain intellectual property and assets relating to 3M’s Taper Dry Powder Inhaler technology under development for the treatment of asthma and chronic obstructive pulmonary disease. Adamis intends to utilize the assets to develop a dry powder inhaler device for the treatment of asthma and chronic obstructive pulmonary disease to deliver the same active ingredients as GlaxoSmithKline’s Advair Diskus^®. The intellectual property includes patents, patent applications and other intellectual property relating to the Taper assets [5].

Collaborations

Scholar Rock to collaborate with J&J Innovation

Scholar Rock (MA, USA) announced on 8 January that it has entered into a collaborative agreement with J&J Innovation (London, UK) to discover and develop novel biologics for the treatment of autoimmune diseases and cancer. The aim of this partnership is to target growth factor signaling in the immune system microenvironment with proprietary niche activators. Scholar Rock’s technology is designed to take a new approach by targeting TGF-β1 niche activators locally

The research collaboration will focus on the discovery and development of novel biologics, called niche activators, to target TGF-β1 in the immune system microenvironment and offer a potential new therapeutic approach for autoimmune diseases and cancer immunotherapies. Immunologists from the J&J Innovation Centre and Janssen Biotech will work with Scholar Rock to therapeutically target the TGF-β1 activation mechanism by applying Scholar Rock’s proprietary technology platform.

Under the agreement, Janssen Biotech, Inc. obtains a worldwide exclusive option to license, develop and commercialize biologic therapeutics resulting from the alliance with Scholar Rock. Scholar Rock will receive research support, and is eligible to receive option payments, preclinical, clinical and regulatory milestone payments [6].

Regulatory news & approvals

India to treat applications with novel drug-delivery systems as new drugs

A 6 January report in the Indian portal pharmabiz.com has reported that following consultation the Indian regulatory authorities have recommended that each new drug-delivery system including modified release dosage form whether a copy of a studied and approved drug or another one should be treated as a new drug and accordingly subjected to the requirement of complete studies as a new drug. The Indian Health Ministry will soon amend Rule 122 (E) of the drugs and cosmetics rules, 1945 to include new drug-delivery systems including modified release dosage forms of drug formulation as new drug [7].

NDA accepted for novel ready-to-use injection device rheumatoid arthritis

MedacPharma (IL, USA) announced on the 28 January that the FDA had accepted its New Drug Application for its lead product candidate, MPI-2505, a subcutaneous injectable methotrexate in a ready-to-use injection device. Proposed indications include rheumatoid arthritis, poly-articular-course juvenile rheumatoid arthritis and psoriasis.

The subcutaneous mode of delivery of MPI-2505, with a wide range of dosing options, has been designed to improve bioavailability and overcome tolerability issues associated with oral methotrexate therapies [8].

Salix announces acceptance of NDA filing for budesonide foam in patients with distal ulcerative colitis

Salix Pharmaceuticals (NC, USA) announced on 30 January that the FDA has accepted for filing a NDA for Budesonide 2 mg Rectal Foam for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The FDA has issued an action date of 15 September 2014 under the Prescription Drug User Fee Act.

Budesonide is a high potency corticosteroid that was developed to minimize the systemic adverse consequences of classic corticosteroids, such as hydrocortisone, which have higher levels of systemic absorption. Clinical trials suggest that the budesonide foam formulation demonstrates improved reach (or spread) and rapid distribution of budesonide to the sigmoid colon and the rectum, without the difficulties and inconvenience associated with retention of enema formulations. These trials also suggest that the foam provides more immediate and targeted therapy for distal ulcerative colitis than is available with oral therapies. The oral foam formulation for rectal administration was designed to improve both the patient’s ability to retain the drug in the rectum following administration as well as distribution of the active drug to the rectum and sigmoid colon, Salix licensed this budesonide foam product from Dr Falk Pharma (Bourne End, UK) [9].

Avanir submits an NDA for novel sumatriptan product

Avanir Pharmaceuticals, Inc. (CA, USA) announced on 30 January that it had submitted a NDA to the FDA for approval of AVP-825, Breath Powered™ investigational drug-device combination product for the acute treatment of migraine.

AVP-825 is an investigational drug-device combination product consisting of low-dose sumatriptan powder delivered intranasally utilizing a novel Breath Powered delivery technology. If approved, AVP-825 would be the first fast-acting, dry-powder intranasal form of sumatriptan for the treatment of migraine.

The Breath Powered delivery technology is activated by user’s breath to propel medications deep into the nasal cavity where it is claimed, absorption is more efficient and consistent than through most other routes. As the user exhales into the device it automatically closes the soft palate and seals off the nasal cavity completely. Through a sealing nosepiece placed into the nostril, the exhaled breath carries medication from the device directly into one side of the nose. As the medication is delivered, the air flows around to the opposite side of the nasal cavity and exits through the other nostril. Closure of the soft palate helps prevent swallowing or inhalation of sumatriptan powder into the lungs [10].

Clinical trials

Endoscience & BioDelivery Sciences announce positive top-line results from the Phase III clinical trial of BEMA buprenorphine in opioid naive patients with chronic pain

Endoscience Pharmaceuticals Inc. (PA, USA) and BioDelivery Sciences International (NC, USA) announced positive top-line results from their Phase III clinical trial of BioErodible MucoAdhesive (BEMA) Buprenorphine in opioid naive patients with chronic pain on 23 January. The proprietary BEMA delivery technology is a BEMA, which adheres to the cheek and dissolves after 15–30 min, thus, preventing opioid abuse. The trial successfully met its primary efficacy endpoint in demonstrating that BEMA Buprenorphine resulted in significantly (p < 0.005) improved chronic pain relief compared with placebo. Additional secondary endpoints were supportive of the efficacy of BEMA Buprenorphine compared with placebo. Following on from this trial is a further one in opioid-experienced patients, with preliminary results expected in mid-2014.

These positive results have triggered a $10 million milestone payment from Endoscience Pharmaceuticals to Biodelivery Sciences International and a second similar milestone payment will be triggered related to the completion of the opioid experienced study and if successful, the potential for an NDA submission by late 2014 [11].

Alkermesprovides update with its late-stage CNS pipeline

Alkermes plc (Dublin, Ireland) provided clinical trial updates on two of its late-stage product candidates in its proprietary CNS pipeline January. The company unveiled aripiprazolelauroxil two-month, a new product candidate addition to its portfolio of atypical antipsychotics for the treatment of schizophrenia. If approved, aripiprazolelauroxil two-month would be the first and only long-acting atypical antipsychotic medication dosed every two months. This new two-month product candidate is designed to provide physicians and patients with a longer dosing option than the once-monthly formulation of aripiprazolelauroxil, which is currently completing the Phase III. Aripiprazolelauroxil utilizes the LinkeRx technology. In addition, Alkermes provided details regarding its pivotal Phase III program for ALKS 5461, a Fast Track-designated new medicine being evaluated for the treatment of major depressive disorder in patients who have had an inadequate response to standard therapies. The Phase III trials for ALKS 5461 is expected to begin in the first quarter of 2014.

The pivotal clinical program is expected to include three core Phase III efficacy studies and to enrol a total of approximately 1500 patients with major depressive disorder who have had an inadequate response to standard therapies. The pivotal program will also evaluate remission as a secondary endpoint, following the recently reported remission data from the Phase II study of ALKS 5461, in which 35–50% of patients in the study achieved remission, as evaluated by Montgomery-Asberg Depression Scale scores, across the two stages of the study. In addition to the three core efficacy studies, the pivotal program will also include studies to evaluate the long-term safety, pharmacokinetic profile, titration schedule and human abuse liability of ALKS 5461. The first study to commence in the ALKS 5461 pivotal program will be a study to evaluate onset of clinical effect, safety and tolerability [12].

Positive results announced in Phase IIa clinical trials for novel oral insulin product

Oramed the Israeli-based drug delivery company announced positive Phase IIa clinical trial results for its ORMD - 0801 oral insulin capsule for the treatment of Type 2 diabetes on 30 January. Oramed’s CEO Nadav Kidron stated: “Following on the results from this Type 2 diabetes study we are gearing up to start a multi-center Phase IIb study later this year. We are also excited about the potential of this drug for Type 1 diabetes and plan to initiate a Phase IIa FDA study for this indication in the near term” [13].

Progenics Pharmaceuticals presents Phase II Trial of PSMA antibody drug conjugatein prostate cancer patients

Progenics Pharmaceuticals (NY, USA) presented a poster entitled “A Phase II trial of prostate specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration resistant prostate cancer (mCRPC)” at the American Society of Clinical Oncology’s 2014 Genitourinary Cancers Symposium in San Francisco, CA, USA on 30 January. The Phase II trial assessed the antitumor activity and tolerability of its antibody drug conjugate, PSMA antibody drug conjugate, in patients with metastatic castrate resistant prostate cancer. The PSMA ADC comprises a fully human monoclonal antibody selectively targeting PSMA linked to a chemotherapeutic drug. Using technology licensed from Seattle Genetics, Inc. (WA, USA) the PSMA antibody is linked to monomethylauristatin E, a compound that inhibits cell proliferation by disrupting the cellular ‘backbone’ required for replication. The resultant antibody-drug conjugate attaches to the PSMA protein on the surface of prostate cancer cells and is designed to internalize into the cancer cell, release active anticancer drug, and destroy the malignant cell [14].

Celsion reports Phase III results for ThermoDox^®

Celsion Corporation (NJ, USA) reported initial overall survival data from its post-hoc ana-lysis of results from its Phase III HEAT Study of ThermoDox^®. ThermoDox is Celsion’s proprietary heat-activated liposomal encapsulation of doxorubicin in combination with radio frequency ablation. This ana-lysis followed the announcement on 31 January 2013, that the HEAT Study did not meet its primary endpoint, progression-free survival. As provided for in the HEAT Study’s Special Protocol Assessment agreement with the FDA, Celsion was required to continue to follow patients for overall survival, the secondary endpoint of the Study. Data from four quarterly reviews of overall survival have been evaluated since the announcement of top line progression-free survival data.

Data from the updated HEAT Study ana-lysis suggests that ThermoDox may significantly improve overall survival, compared with control, in patients whose lesions undergo radio frequency ablation treatment for 45 min or more. These findings apply to patients with single hepatocellular carcinoma lesions (64.4% of the HEAT Study population) from both size cohorts of the HEAT Study (3–5 cm and 5–7 cm) and represent a subgroup of 285 patients (41% of the patients in the HEAT Study) [15].

Cynapsus report early stage clinical trial results for its Parkinson’s disease sublingual treatment

On 13 January Cynapsus Therapeutics Inc. (Toronto, Canada) announced positive top line data from its recently completed healthy volunteer pilot crossover trial comparing its fast acting APL-130277, a sublingual thin film strip formulation of apomorphine, to a commercially available injectable formulation of apomorphine.

Apomorphine, a potent dopamine agonist, is the only drug approved specifically for the treatment of acute motor fluctuations/hypomobility (freezing or ‘OFF’ episodes) in patients with advanced Parkinson’s disease. Presently, apomorphine is administered by intermittent subcutaneous injection usually via a prefilled injection pen or by continuous infusion pump.

The key findings can be summarised as follows:

• Sublingual delivery of apomorphine with APL-130277 was better tolerated than the subcutaneous injection in the studied doses;

• The pharmacokinetics profile of APL-130277 was proportional between doses and exposures above the minimum expected efficacious level were similar to or longer than seen following subcutaneous injection;

• APL-130277 achieved apomorphine mean T_max of 31 and 40 min for the 10 mg and 15 mg formulations, respectively. The subcutaneous injection achieved apomorphine T_max of 27 and 24 min for the 2 mg and 3 mg formulations, respectively;

• The mean time to reaching a plasma concentration of apomorphine associated with therapeutic benefit of ‘Time to ON’ was 10–13 min for the two doses of APL-130277 versus 4–5 min for the subcutaneous injection. The times achieved are reflective of patients’ expectations for a rapid return to ‘ON’; and

• APL-130277 was safe and well-tolerated in CTH103 as in previous clinical studies (i.e., CTH101 and CTH102). There were fewer adverse events and the adverse events were less intense for subjects exposed to the 10 mg and 15 mg strips versus the subcutaneous 2 mg and 3 mg injections. The adverse events for the 3 mg injection dose were dose-limiting and escalation of the subcutaneous injection to a higher dose as a comparator could not be pursued [16].

Early stage development

Roche reports new method for efficiently transporting antibodies across the blood–brain barrier

Roche reported on 8 January of published results on the Roche-designed Brain Shuttle technology that efficiently transfers investigational antibodies from the blood through the blood–brain barrier into the brain in preclinical models. Roche Pharma Early Research and Development scientists reported that such enhanced transfer of antibodies through the blood–brain barrier was associated with a marked improvement in amyloid reduction in the brain of a mouse model of Alzheimer’s disease.

The study published showed that the Roche Brain Shuttle acts by engaging the natural transferrin receptor in a specific mode that triggers a process called receptor-mediated transcytosis to transport molecules into the brain [17].

Antibiotic ‘smart bomb’ can target specific strains of bacteria

An article on the ScienceDaily website on 30 January reports that researchers from North Carolina State University have developed an antibiotic “smart bomb” that can identify specific strains of bacteria and sever their DNA, eliminating the infection. The technique claims to offer a potential approach to treat infections by multi-drug resistant bacteria.

The approach works by taking advantage of a part of an immune system present in many bacteria called the CRISPR-Cas system. The CRISPR-Cas system protects bacteria from invaders such as viruses by creating small strands of RNA called CRISPR RNAs, which match DNA sequences specific to a given invader. When those CRISPR RNAs find a match, they unleash Cas proteins that cut the DNA [18].

On-demand vaccines possible with engineered nanoparticles

Recent work from University of Washington engineers was reported on 7 January in an online article on ScienceDaily. The team carried out preclinical evaluation with nanoparticles synthesized using an engineered protein that both mimics the effect of an infection and binds to calcium phosphate. Preclinical data reported indicated that after 8 months, mice that were challenged made threefold the number of protective ‘killer’ T cells compared with mice that had received the protein but not the calcium phosphate nanoparticles. The nanoparticles appear to work by ferrying the protein to the lymph nodes where they have a higher chance of meeting dendritic cells. The article claims that this novel process could cut costs by not having to rely on refrigeration, and vaccines could be produced with rudimentary equipment in more precise, targeted numbers. It is also claimed that the vaccines could be manufactured and delivered using a disposable patch rather than via injection [19].

Patents

Oramed receives patent allowance in Israel and Australia for Platform Technology in oral delivery of proteins

Oramed Pharmaceuticals Inc. (Jerusalem, Israel) announced on 2 January that it has received Notices of Allowance from the Israel and Australian Patent Offices. The patent entitled, “Methods and Compositions for Oral Administrations of Proteins” covers a core concept of the company’s technology for the oral delivery of drugs and vaccines currently delivered via injection. The patent has also been approved in Japan, China, Russia, and New Zealand [20].

Lpath announces issuance of patent supporting its iSONEP™ program.

Lpath, Inc. (CA, USA), which develops bioactive lipid-targeted therapeutics, announced on 22 January that it received official notification from the US Patent and Trademark Office that the company has been issued a patent supporting its iSONEP™ program. The newly issued US patent, No. 8614103, is entitled, “Compositions and Methods for Treating Ocular Conditions.” It claims methods of using monoclonal antibodies (including iSONEP) that bind sphingosine-1-phosphate in the treatment of a wide variety of ocular conditions, including wet age-related macular degeneration [21].

Financial & competing interests disclosure

E Harris is a partner in Innovation21 Ltd, providing consultancy, advisory and evaluation services to pharmaceutical/biotechnology companies and government funded agencies. 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.