It has become increasingly clear over the last couple of years that winning approval for generic respiratory drugs represents a major challenge. News yesterday of Mylan's purchase of Pfizer’s generic Advair project shows that some are still having a go, but the likelihood of a directly substitutable product reaching the market any time soon, particularly in the US, remains low.
Coming at the problem from a different direction is Prosonix, a UK company that is applying a novel particle engineering technology employed successfully in the minerals industry to respiratory drugs. Having raised £11.4m ($18.2m) of venture capital in June, completed successful pilot tests with its version of GlaxoSmithKline’s fluticasone propionate and received encouraging feedback from European regulators, the company is on track to seek approval for what it believes could be the first directly substitutable version of the blockbuster asthma drug in 2013. With other monotherapy and combination products in early stage development, the company hopes to start the search for partners in the not too distant future.
Root of problem
Current respiratory products are made through a process called jet milling, whereby the large active pharmaceutical ingredient is essentially crushed to give a particle size suitable for inhalation. This creates unstable particles with variable and unpredictable performance and, according to Prosonix, is at the root of the failure of generic manufacturers so far to prove to regulators the bioequivalence of their own products.
Using a technology that can control the size, shape and form of the active pharmaceutical ingredients, the company believes it can more easily prove its version of these drugs act the same way and have the same effect as the original.
“We are engineering the particles up, rather than down,” says chief executive David Hipkiss. “That is why our technology is disruptive.”
Prosonix’s lead product is PSX1001, a generic version of fluticasone propionate. Glaxo’s inhaled formulation of the corticosteroid, sold to treat asthma, is still without a generic challenger despite losing patent protection in 2005. Sold as Flixotide the drug is expected to generate sales of $1.24bn for the pharma giant this year.
“It’s a challenging molecule, there are good chunky sales, and it’s a good opportunity to show the benefit of particle engineering in a regulatory environment for the first time,” Mr Hipkiss says.
In 2009 European regulators set out guidelines for the approval of generic inhaled products. The first and most challenging step is to prove similarity in a very sensitive in vitro assay. But if that is achieved, the product can be filed for approval without having to carry out pharmacokinetic and pharmacodynamic studies. In pilot tests PSX1001 passed the in vitro stage, and the company is now scaling up to carry out the official pivotal testing that will allow the drug to be filed, hopefully in 2013.
“Three weeks ago we met with the European regulatory agency and they approved our approach,” says Jim Philips, Prosonix’s chairman. “We got a clear green light to develop the product through this route, not having to do clinicals providing we meet the in vitro bioequivalence [in the pivotal tests].”
Prosonix’s second monotherapy project PSX1002 is a reformulation of glycopyrrolate, a long acting muscarinic antagonist that is also in late stage development by Novartis, under the code name NVA237. Licensed from Prosonix’s domestic rival Vectura, patents around the active ingredient have long expired although versions of the drug in inhaled form have yet to reach the market.
Prosonix has managed to formulate the active ingredient so it can be delivered via a simple metered dose inhaler, something no other company has achieved before, it claims. Among other benefits this makes the product more suitable for emerging markets, where the price of more complex and expensive dry powder inhaler devices are unlikely to gain much traction.
“Testing with glycopyrrolate has been very encouraging so far,” Mr Hipkiss says, adding that the company believes its version of the drug should overcome some of the issues of the Novartis formulation that have caused some to question whether NVA237 will make it to market as a once-a-day drug, particularly in the US.
Because glycopyrrolate is not yet on the market in the inhaled form, PSX1002 will require clinical studies; Prosonix plans to complete phase IIa trials by the end of next year. If all goes well, a partner will then be sought.
“For an ambitious generics company that’s moving into the branded area it's an ideal product – potentially second to market in its class with some IP protection around it from our technology,” Mr Phillips says.
Manufacturing generic versions of the mega-blockbuster combination therapies that dominate asthma and COPD, Advair and Symbicort, sold by Glaxo and AstraZeneca respectively, certainly represents the final frontier for this space.
Both Teva and Sandoz have backed away from their attempts to launch these products in the US, a very cautious regulatory environment caused by safety concerns around the long-acting beta 2 adrenoreceptor agonist (LABA) class is largely to blame for this.
Without the means to convince on direct substitutability in the lab, those pushing on in Europe have had to conduct large studies - Sandoz presented phase III data on its generic Advair at the European Respiratory Society conference a couple of months ago. A decision from European regulators on the product is awaited with interest.
Again, Prosonix believes its UMAX platform offers a solution to this, by creating multi-component particles that combine two or more drug molecules, in consistent and pre-determined ratio, in every particle of the formulation.
“We have categorically established that the particles are 100% co-associated, they have the right ratio of material in them, and the same ratio of the drug substance is delivered to each site of impact, which has never been done before,” Mr Hipkiss says. “That opens up a whole range of potential for dose sparing, better clinical efficacy, better compliance. And because it's a simple, low cost technology and we’ve demonstrated it in capsules or MDI (metered dose inhalers), the device question goes out of the window as well,” he says.
Dose sparing is certainly one aspect that will be music to regulators’ ears, particularly in the US. Novartis recently failed to win US approval for as high a dose as it wanted for its new LABA, indacaterol, and delays to filing NVA237 are also thought to be over the FDA's dose concerns, events that have created something of a cloud over the pharma giant's respiratory ambitions.
However, Prosonix is likely to have a long way to travel with its combination projects, although it should know in the next couple of years whether its attempts with a monotherapy will be successful.
The company will look for a partner for fluticasone when the drug is filed, for glycopyrrolate after phase IIa, and once proof of concept is in hand for its first combination project, the identity of which should emerge later next year.
However, the respiratory space is certainly not for the faint hearted, and with even the big players struggling to make progress, signing up partners will present a challenge in itself.