Drug Delivery Report

Joanne  Pearson,  Business Analyst
PharmaVentures Ltd, Magdalen Centre, Oxford Science  Park, Oxford OX4 4GA, UK

Introduction

The approval of Exubera®  (inhaled PEGylated insulin) for the treatment of diabetes  highlights the vogue for, and potential  for, commercial success in reformulating existing therapies  for pulmonary delivery. This article will focus on the proprietary mechanisms  utilised by specialist biotechnology  companies  for the pulmonary delivery of reformulated insulin. In doing this, it also profiles three speciality drug-delivery companies  with pulmonary delivery expertise - Nektar Therapeutics, Aradigm
and Alkermes  - and the partnering approach they have taken in commercialising their technologies. A range of pulmonary therapies  are in clinical development, targeting profitable but competitive disease areas, and these  are outlined in the three profiles. In the next decade  we will see the launch of more drugs delivered via the pulmonary route  (for non-respiratory indications) and it will be intriguing to ascertain what market share they can capture in competition with established  therapies.
In January 2006,  Exubera was approved  for the treatment of types 1 and 2 diabetes  mellitus, both in the US and in Europe. In type 1 diabetes  (insulin-dependent diabetes),  Exubera is indicated for use in combination with longer acting insulin, while for type 2 diabetes  it can be used alone, as an alternative to rapid-acting  insulin injections/oral antidiabetics,  or in combination  with these therapies. Sales of diabetes-related drugs exceeded  US$12 B in 2004 (Bernstein Research), with worldwide revenues expected  to rise annually by 12%  through to 2011; this exceeds the expected  industry-wide sales growth  rate of 6%. The approval of Exubera was greeted with mixed reactions from analysts. Would this product  be Pfizer's next blockbuster  with potential  peak annual sales of US$1.5 B (Lehman market analysis), or more of a gimmick that  would not supplant  or even complement injectable insulin as the gold-standard treatment for diabetes?

Profile: Nektar Therapeutics

Co-developed by Pfizer and sanofi-aventis (then Aventis),  recombinant human  insulin (later named Exubera) was originally supplied to Nektar Therapeutics (then Inhale Therapeutic Systems) in November 1996 to be developed  with its proprietary deep-lung delivery system and formulation  technology.  Nektar developed  a non-invasive, dry powder  form of this insulin for use in its inhaler device. sanofi-aventis transferred the sole rights for Exubera to Pfizer in January 2006.
For successful drug delivery across the lung surface, there is a dual requirement for the active compound to be in an inhalable formulation  and be accompanied by a
device capable of delivering that  formulation.  For Exubera, the optimal size of particles for absorption is 1-3 µm.
In a 1-µm aerosol particle there are 300 million insulin molecules stabilised with glass formers. This formulation is used in conjunction  with Nektar's pulmonary inhaler. The inhaler injects compressed air at the speed of sound through the dry powder,  converting the insulin into an aerosol cloud. The inhalation of the aerosol results in a therapeutic dose of insulin being administered to the deep lung, where it crosses into the bloodstream. It has been demonstrated that  efficient pulmonary delivery is more effective than  subcutaneous injection as a means of delivering insulin into the bloodstream. An additional advantage is the avoidance of first-pass hepatic metabolism,  thus ensuring a longer systemic half-life.
The extensive range of clinical needs that  may be met by inhalation technologies is exemplified in Nektar's wide-ranging product  pipeline (Figure 1). Nektar is partnering with Chiron (now merged  with Novartis) to develop tobramycin for lung infections in cystic fibrosis patients;  this therapy is currently in Phase III clinical
trials. In preclinical development, ciprofloxacin is being co-developed with Bayer Healthcare for chronic lung infections by Pseudomonas aeruginosa in cystic fibrosis. In addition to these  antibacterial  therapeutics, dronabinol  is in Phase II clinical trials for multiple indications. Dronabinol is the active ingredient  in Marinol®, capsules that  are prescribed as an appetite stimulant  in HIV patients  and as an antiemetic  for chemotherapy-induced nausea  in cancer patients. This compound is being developed  with Solvay Pharmaceuticals.

Delivering Diabetes Treatment

Although Nektar Therapeutics and Pfizer were pioneers for inhaled insulin, 'fast followers' are looking to capture their market share. Aradigm (in collaboration  with Novo Nordisk) and Alkermes (in collaboration  with Eli Lilly) both have inhalable formulations  of insulin in clinical development; these  will be discussed in the following profiles.
Other products  in development include MannKind's Technosphere®  drug delivery technology.  In the US, in March 2006,  this product  entered Phase III development for both types of diabetes.  The company's proprietary Technosphere technology  consists of diketopiperazine derivatives of proteins that  self-assemble into an ordered lattice at a low pH. The insulin formulation  is pH sensitive, and turns to liquid on the lung surface, thus allowing for quicker absorption. This formulation  is delivered with Mannkind's  MedTone™  inhaler.
Kos Pharmaceuticals has an inhaled insulin formulation  in Phase II development for which it anticipates approval in 2010.  Kos' formulation  is excipient-free and is
a mixture of crystalline recombinant insulin containing  only water and a non-CFC propellant.  The clinical development of insulin has stagnated as Kos seeks a partner  with whom to commercialise this product.
In collaboration  with Quadrant  (which was acquired by, and merged  into, Innovata in August 2005), MicroDose Technologies is developing fast-acting  insulin for pulmonary delivery. This development benefited from a brief spell with Bristol Myers Squibb,  which licensed the compound for 2 years, driving forward development of the therapy into Phase I, before returning  the rights to the Innovata/MicroDose partnership in December 2005. Innovata/MicroDose are now completing  preparations for an IND submission. This collaboration  exploits Innovata's formulation  and particle-engineering expertise to produce  dry-powder  formulations.  These methodologies include micronisation,  blending,  spray drying and polyol stabilisation. Controlled and sustained  release can be achieved using either sugar derivatives or hyaluronic acid. The delivery device is MicroDose's electronic dry-powder inhaler that  uses piezo-electronics  to deliver a broad range of compounds efficiently and independently of patient inhalation flow rate.
Coremed  is a US-based, privately funded  biotech company founded in 1994.  It has developed  an inhalable form of insulin, Alveair™, now in Phase I development, which is based on a proprietary new platform for drug delivery. Coremed  cites Alveair's advantage over other inhaled formulations  of insulin in development as the high level of bioavailability (near 100%)  of the compound.
This is the result of the company's development of a novel polymer/bio-adhesive  drug delivery platform that  allows drug delivery without  modifications  to the three- dimensional structure  of molecules. Coremed's insulin formulation  is completely soluble in water,  vaporised before inhalation and delivered in a generic hand-held device. The company is partnering with two large Chinese companies
- Fosun Pharmaceutical and Wanbang Biochemistry
- in a tripartite agreement to develop Alveair.
The product  in the earliest stage  of development is BioSante's inhaled insulin; currently in the preclinical development. Using BioSante's proprietary calcium phosphate nanoparticulate (CAP) delivery system, BioAir™, a suspension  of CAP, polyethylene glycol (PEG) and insulin is generated for pulmonary delivery. It appears  that  this
therapy is not being actively developed  at the current time.

Profile: Aradigm

The competitiveness of the 'pulmonary delivery' interest area is emphasised when you compare  Nektar's pipeline (Figure 1), with Aradigm's pipeline (Figure 2), and view the overlap in compounds in clinical development. Aradigm's proprietary technology  to reformulate drugs for pulmonary delivery is AERx®. The AERx system is composed of a
Strip™  dosage  form and inhalation device. The Strip is the central element  of Aradigm's system and contains a disposable nozzle to ensure performance every time the patient  inhales medication.  The nozzle's patented design can be adjusted  for various formulation  characteristics  and treatment requirements so that  the particle size and thus the primary deposition  area of the therapy are regulated. The nozzle is used in conjunction  with Aradigm's second- generation of inhaler Essence™, which uses a piston mechanism  to expel formulation  from the Strip.
Likely to be launched  as the next diabetes  drug after Exubera is Aradigm's AERx insulin Diabetes Management System (iDMS), currently in Phase III clinical trials. Aradigm has partnered with Novo Nordisk to commercialise iDMS since 1998.  In contrast  to Pfizer's Exubera dry powder formulation,  Aradigm's formulation  is liquid. APT Pharmaceutical's formulation  of hydroxychloroquine  (HCQ) is being developed  for delivery in conjunction  with Aradigm using the AERx system, and entered into Phase II clinical trials in July 2005 for asthma and chronic obstructive pulmonary disease (COPD).
Also in Phase I development is an AERx formulation  of a compound for an undisclosed respiratory indication with an undisclosed partner.  In late 2005,  Aradigm signed
two preclinical alliances for the pulmonary delivery of drugs using AERx: with an undisclosed pharmaceutical company for the delivery of nicotine for the treatment of tobacco  dependency; and with United  Therapeutics for the delivery of trepostinil for treating  pulmonary arterial hypertension.
From Aradigm's internal development programme, an application has been made for Orphan Drug Status for a pulmonary-delivered liposomal ciprofloxacin formulation. The company is developing a liposomal-encapsulated formulation  of ciprofloxacin, utilising the AERx system, as a prophylactic for serious respiratory infections, such as those associated  with cystic fibrosis. Ciprofloxacin entered preclinical development in December 2004.

Profile: Alkermes

Alkermes' proprietary pulmonary delivery technology,  AIR®, was developed  by Advanced Inhalation Research (AIR),
a private company that  was acquired by Alkermes. AIR technology  is based on research showing that  relatively large, low-density drug particles can be inhaled into the lungs with high efficiency and can, therefore, be used for the systemic delivery of small molecules, peptides,  proteins and other macromolecules. The AIR delivery system is an inhaler that  can deliver a broad range of doses. The system can provide local or systemic sustained  release of drugs.
Looking at Alkermes' product  pipeline (Figure 3), the inhaled therapy that  is in furthest  stage  of development is an AIR formulation  of insulin. This product  is being co-developed  with Eli Lilly in an alliance that  started  in April 2001.  The AIR pulmonary drug delivery system is a breath- activated device that  will deliver a powdered formulation of insulin plus a lung surfactant - a natural phospholipid already present  in the lung. The inhaled formulation  is currently in extensive worldwide Phase III clinical trials. Altogether,  Lilly is partnering with Alkermes in four of the latter's AIR formulation  development programmes.
Lilly invested in Alkermes' large-scale commercial production facility for AIR-based inhaled pharmaceuticals in February 2002,  following the already successful insulin collaboration.  Targeting the US$17 B US market for osteoporosis, Lilly and Alkermes next signed a deal in January 2006 for an inhaled formulation  of parathyroid hormone (PTH) for the treatment of osteoporosis, to be based on Forteo®   (teriparatide), which is already launched as an injected formulation.  For the new inhaled formulation,  currently in preclinical development, Alkermes will receive research and development funding,  an upfront  fee and milestone payments.  Lilly will have the worldwide rights to the product  and will pay royalties based on product  sales. Much earlier, in February 2000, the companies  agreed  to develop an AIR formulation  of human  growth  hormone (somatotrophin); this is presently in Phase I development. Also in Phase I development, but unpartnered, is an inhaled formulation  of adrenaline  for treating  anaphylactic shock.
With the current investment  in pulmonary delivery, it seems likely that some of these inhaled therapies  will be set for success within the next decade. As pulmonary delivery has proven to be both efficacious and safe for systemic distribution,  it is interesting  to muse on whether injectables for chronic conditions may have had their day.