Upcoming events: Rett data for Neuren while NPS awaits Natpara approval

Welcome to your weekly digest of approaching regulatory and clinical readouts. Phase II results are expected in the fourth quarter from Neuren’s Rett syndrome agent NNZ-2566. As an IGF-1 analogue its safety and tolerability is expected to be sufficient, but efficacy remains a hurdle.

Meanwhile NPS Pharmaceuticals is awaiting a decision on US approval for its hypoparathyroidism project Natpara by October 24, though a delay is likely after an advisory panel raised safety worries.

Neuren Pharmaceuticals: NNZ-2566

Rett syndrome is a neurological disorder that occurs in around 1 in every 10,000 live female births, with an average life expectancy of the mid-40s. It is caused by a mutation on the X chromosome in the MECP2 gene, which codes for a protein involved in the development of the central nervous system, especially synaptic and circuit maturation. 

Following apparently normal development for the first six months of life patients experience a decline in hand use and communication and many have recurrent seizures, as well as a variety of motor problems including increased muscle tone and abnormal movements.

A treatment to normalise the connection between nerve cells and alter synaptic function could potentially correct the biology of Rett and improve the symptoms of the disease, and this is something that Neuren hopes NNZ-2566 will achieve.

The project's phase II, double-blind, placebo-controlled trial tested oral NNZ-2566 in 60 female patients with Rett syndrome aged between 16 and 45. NNZ-2566 was tested at two different doses and given as a powder in flavoured solution, administered twice daily for 28 days; patients were followed for approximately two weeks.

NNZ-2566 has not previously been tested in Rett, so the primary endpoint of the phase II trial is safety and tolerability. Secondary endpoints include a number of physiological, behaviour and functional measures to determine the potential efficacy.

The agent is an analogue of glypromate, which is cleaved in the brain from naturally occurring insulin-like growth factor 1 (IGF-1). This is said to be neuroprotective, inhibiting inflammatory cytokines and restoring synaptic signalling. In animal models glypromate was effective at reducing symptoms of Rett syndrome, and in the same model NNZ-2566 showed a lengthening of neurons and an improvement in survival.

Analysts note that the phase II trial is likely to meet the safety endpoint. There have been no safety concerns to date, and NNZ-2566's development both as an oral and IV treatment in traumatic brain injury and autism have not identified any safety issues.

The Rett programme received US fast-track designation, with Neuren intending to seek orphan drug status after completing the current clinical trial. The project is also in trials for fragile X syndrome, where it has fast-track and orphan designations; results are expected in the second quarter of next year.

There are no consensus forecasts for NNZ-2566, the Australian company’s lead project. Bell Potter analysts give $557m in peak global sales, but with a 14.5% probability of success. With just A$22.5m ($20m) in cash the company needs the efficacy outcomes to deliver if it wants partners to take any notice.

NPS Pharmaceuticals: Natpara

In September the hypoparathyroidism project Natpara scraped through an advisory panel, which narrowly voted 8-5 in favour of approval. Alongside questions over clinical meaningfulness of the primary endpoint and suboptimal dosing there were concerns over hypo/hypercalcemia and osteosarcoma risk.

This raised the potential for labelling restriction on patients at elevated risk, or demands from the FDA for further studies and safety monitoring. Shares fell 16.5% on the news, but on release of briefing documents just a week earlier the stock was up 25.1%.

Natpara forecasts provided before the panel meeting give $552m by 2020, according to consensus from EvaluatePharma.

NPS’s lead product, the short bowel treatment Gattex, has suffered lacklustre sales, and 2020 forecasts have been slowly dropping. In April consensus was $724m, but now this stands at $636m, according to EvaluatePharma.

The company will be hoping that Natpara can make up the revenue shortfalls, but at the minimum a delay to approval appears to be on the cards.

Project Trial ID
NNZ-2566 NCT01703533

To contact the writer of this story email Joanne Fagg in London at [email protected] or follow @JoEPVantage on Twitter

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