LONDON – Pluristem Therapeutics Inc.'s PLX placenta-based cell therapy has been selected for the EMA adaptive pathways pilot, a designation the company said will save a lot of money and cut three to four years from the development timeline.

There are further details to be decided, but Yaky Yanay, president and COO, said PLX cell therapy could now reach the market and be reimbursed on the basis of a 150-patient phase II trial in critical limb ischemia (CLI).

In addition to being smaller than the 700-patient trial that would usually be required to demonstrate efficacy, the phase II CLI trial will also be faster. Rather than the single endpoint of amputation-free survival, there will be a combined endpoint.

"We need further discussion with the EMA, but this will involve surrogate endpoints with shorter follow-up times," Yanay told BioWorld Today.

The adaptive pathways pilot project is responding to the clamour for access to new therapies by setting out to reformat clinical development pathways to allow for early marketing authorization and reimbursement.

While products will be allowed on the market with a limited data package, companies will be required to collect real-world evidence to demonstrate a therapy is effective and to pave the way for further indications to be added to the label.

"That is something beautiful," Yanay said. "Our application to the pilot included other indications in addition to CLI." Pluristem will face the expense of collecting the evidence, but Yanay said the additional requirements are "nothing major" compared to the usual postmarketing monitoring.

The PLX cell therapy has completed a phase I/II European trial in muscle injury and also is in phase II development in intermittent claudication, peripheral artery disease that can progress to CLI, with several of the trial sites in Europe.

The EMA launched the adaptive pathways pilot in March 2014, with the aim of transforming drug approval from a binary process where the winner takes all (or not) on the basis of positive phase III data, to a continuum where data about how a drug performs in a real world setting is gradually built up.

It is hoped that this will help to bridge the divide from demonstrating efficacy in phase III to showing a product is effective in use.

Having come through the stage I selection process, Pluristem now needs to agree the finer details of phase II development in consultation with the EMA adaptive pathways group, which includes representatives of health technology assessment bodies, payers, patients' groups and clinicians.

The company will then submit a formal application to carry out the trial. Yakay said it is hoped the CLI study will start later this year. The product could reach the market as soon as 2018.

Haifa, Israel-based Pluristem also is pursuing expedited approval for its PLX cells in Japan and has applied for the accelerated pathway for regenerative medicine designation, which came into effect in November 2014. This will allow therapies to receive conditional, time-limited approval for marketing and be eligible for reimbursement, upon proof of safety and initial proof of efficacy. Safety and effectiveness need to be confirmed within seven years of the conditional approval.

"This is very similar to the EMA's adaptive pathway, though a little more flexible in terms of surrogate markers," said Yakay.

Pluristem's expanded placental cells have a complex mechanism of action, acting in response to prompts generated by the specific disease pathology, to release cytokines, chemokines and growth factors. These reach the target tissues through the bloodstream following intramuscular injection. Injected cells do not migrate and remain in the muscle for only a few weeks.

In a hind limb mouse model of CLI, intramuscular administration of PLX cells results in a significant increase of blood flow in the affected limb, regardless of which limb is injected. Two phase I studies in CLI in the U.S. and Germany met all their primary endpoints.

In addition to angiogenesis, Pluristem is developing placental cells for treating hematological, immunological and neuronal disorders.

A total of 58 products were submitted to the EMA adaptive pathways pilot, of which 17 were selected for in-depth discussions with the company in a safe harbor setting that allowed all aspects to be considered without prejudice.

As of the end of March, 10 of these stage 1 discussions had taken place, with eight products chosen to go through to stage 2. However, it is down to the companies concerned to announce their selection and Pluristem is the only one so far to have opted to do so. "As of today, fewer than 10 companies have been approved. We are one of them and we're very proud of that," Yanay said.