Biocurious: ASX drug developers see silver lining in FDA’s interventionist approach

• The FDA has requested more data from a slew of ASX drug developers requesting marketing approval, or permission to undertake a trial
• Telix has received two FDA ‘complete response’ letters, but the company says investors should not be concerned
• Neurizon CEO Dr Michael Thurn stresses the importance of strong patient advocacy in the FDA review process

Australian drug developers have seen a flurry of US Food & Administration (FDA) knockbacks, with the powerful agency either disallowing – or delaying – clinical trials and therapy approvals.

The agency’s actions have resulted in sharp share selloffs, most recently last Thursday’s 17%, $1 billion rout of radiopharmaceuticals developer Telix’s shares.

But have investors got it right?

Companies lament that investors have perceived the FDA as ‘rejecting’ their drug, whereas the reality is far more nuanced.

They argue the agency’s guidance is perversely positive, as they now know the actions they must take in order to win approval.

Telix Pharmaceuticals (ASX:TLX) last week revealed the FDA had issued a ‘complete response letter’ (CRL), in relation to the company’s marketing application for its kidney cancer diagnostic, Zircaix.

The advanced programs of Neurizon Therapeutics (ASX:NUZ) and Argenica Therapeutics (ASX:AGN) have been placed on ‘clinical hold’.

These companies are developing novel therapies for motor neurone disease and strokes, respectively.

As with a CRL, a clinical hold means the regulator requires more information – clinical or otherwise – and generally related to safety.

Last month, Syntara (ASX:SNT) shares halved after the FDA advised the company to carry out an additional trial, rather than leapfrog to a phase III-style clinical study.

This intervention was by way of standard feedback, rather than a clinical hold.

While the jury’s out, in at least in some cases the delays are linked to the turmoil and resourcing problems afflicting the FDA.

“Dossier reconstruction exercise”, says Telix

Telix’s CRL follows similar correspondence in relation to its approval application for a glioma imaging agent, TLX-101 (Pixclara).

The CRLs surprised investors and management alike.

Telix CEO Chris Behrenbruch says the Pixclara and Zircaix processes should not be “conflated”.

Pixclara was more a case of “moving clinical goalposts”, while Zircaix related to manufacturing issues.

(The FDA wants to be assured about the compatibility between small-scale manufacturing for trial purposes and full-scale commercial manufacture).

Behrenbruch dubs the Zircaix process as “a dossier reconstruction or resubmission exercise, rather than a new data gathering exercise”.

He believes the company can assuage the regulator’s concerns.

“We have a bunch of data that wasn’t included in the original biologics licence application, so I don’t feel we have any significant time delays in collecting the data,” he says.

Behrenbruch says Zircaix is a “super novel” product (it’s the first radiopharmacy to use a monoclonal antibody coupled with a radio isotope).

“We are breaking new ground and speed bumps can – and do – occur”.

He adds the Zircaix has FDA fast-track status, which puts the onus on the agency to consider reviews submissions swiftly.

That said, the CRL has delayed approval – and thus the commercial rollout – of Zircaix.

Behrenbruch won’t be drawn on how long, but one analyst suggests a 12-month delay.

For Syntara, a quick phase III is not 2b  

Syntara is road testing its candidate amsulostat for the difficult blood cancer myelofibrosis.

The company has completed phase IIa successfully.

Management had hoped to morph from that trial to a registrational phase III effort, but the FDA wants an additional, phase IIb study.

“All that happened is we applied for one route and they have given us a slightly different one,” says Syntara CEO Gary Phillips.

“We haven’t had a clinical trial failure; the FDA is not flagging a concern over product development.

“It’s actually a positive: they have clarified our program is worthwhile and this is the best way to get to an approval.”

As with Telix, Syntara’s timelines are affected.

Phillips argues the program has become de-risked, because the phase III endpoints can be set after the phase IIb stage, rather than phase II.

This increases the prospect of setting the right goals. The phase III trial is also likely to be smaller and cheaper.

Phillips describes the process as “iterative” – not a case of the FDA handing down the tablets, Moses-like, from the Mount.

“We don’t have to agree with everything they have given us; we can make a scientific argument as to why we should pursue [a particular direction],” he says.

“It’s not a rejection. It’s guidance on what we should do next, which we have to listen to carefully.”

The FDA asked, Neurizon delivered

Last December, Neurizon filed an Investigational New Drug Application (IND) – permission to start a US based clinical trial – for its motor neurone disease candidate NUZ-100.

A repurposed animal drug, NUZ-100 targets amyotrophic lateral sclerosis, ALS, the most common form of the debilitating disease.

The FDA put a clinical hold on the program in January, having identified safety issues.

The envisaged phase II/III study is to be done via a platform called Healey, which tests a number of ALS candidates at the one time.

“When the FDA came back to us in February, they only had one issue,” CEO Dr Michael Thurn says.

“It was a straightforward, succinct paragraph”.

The FDA’s concerns related to Neurizon’s earlier animal data (from rat and dog studies).

The agency opined the data didn’t provide enough ‘exposure margin’ – the difference between a deemed safe dose for humans opposed to animals.

The FDA wants a safety margin of ten times for humanoids.

Thurn admits he is frustrated because the company subsequently carried out a phase I human study, dubbed Mend.

This trial showed “excellent long-term tolerability and promising efficacy”.

Monepantel also has a long safety history across veterinary and human uses.

The drug’s maker, Elanco, has substantial historic data in its vaults.

“We could have gone back to the FDA and argued the point [about the human safety data],” Thurn says.

“But we generated [animal] data they thought was missing, with two pharmacokinetic bridging studies”.

FDA resourcing issues frustrate timelines

Neurizon submitted its response to the FDA in July. The agency set an August 23 timeline for a decision, which it pushed out to October 3.

The company says this did not reflect the quality of Neurizon’s application.

Rather, it resulted from the “broader strain in the FDA’s capacity caused by agency-wide restructuring and staffing reductions under recent administrative reforms”.

This has “impacted the FDA’s ability to maintain timely review cycles”.

Thurn says the company has patients ready to be dosed.

Argenica gets ahead of the game

In June the FDA imposed a clinical hold on Argenica’s proposed phase III trial of its proposed stroke drug ARG-007.

Argenica CEO Dr Liz Dallimore says the company can’t mount the trial immediately anyway, until it completes its 92-patient phase II study across eight Australian hospitals.

“We didn’t expect to go into the US until mid-next year anyway, so filed our IND really well in advance,” she says.

“We were pretty confident we had a good IND package, but we also knew there were some issues with the FDA in terms of timeframes and responses.”

In mid-August the company said the agency had requested three additional cell culture studies.

“These are small studies that can be completed quickly and build on existing data we have generated.”

The company also has another weapon: the top-line results of its phase II study. Argenica shares yesterday entered a trading halt, with the results due out as early as today.

Argenica intends to use these results as part of its FDA response.

The company is developing ARG-007 to reduce brain tissue injury after ischemic strokes caused by blood clots.

What doesn’t kill you makes you stronger

Companies at the receiving end of the FDA’s unwanted attention reckon their drug programs will emerge stronger as a result.

In effect, it’s a case of ‘what kills you makes you stronger’.

Telix’s Behrenbruch labels the CRLs as an “interesting and frankly educational experience”.

“I’m trying to be philosophical about the situation,” he says.

“While I would prefer not to learn at shareholders’ expense, we are definitely doing a new class of product that will [involve] a learning curve from a regulatory perspective.

“We are not seeing that just with the FDA, but all drug regulators globally.”

Syntara’s Phillips rues that had he communicated differently to investors; their reaction could have been very different.

“In hindsight, if I told the market we were applying to the FDA for guidance on the next steps forward – and not told them what we thought they were going to be – we would have seen an increase in the stock price.”

In other words, the company created investor expectations of a faster route to a clinical trial, which ultimately it could not fulfil.

Patients are your friend

Neurizon’s Thurn says a key learning from the FDA process was the importance of patience advocacy in shaping the agency’s views.

Last week, the FDA approved an IND from a fellow ALS drug developer, the Nasdaq-listed Coya Therapeutics.

The agency was to have adjudicated by July 30, with stretched resources also blamed for the delay.

Thurn says the  ALS Association has used Neurizon and Coya to highlight the importance of enabling access to potentially better therapies.

“There aren’t may drugs in clinical development and patients have to pay an arm and a leg to get access to drugs that only provide them with minimal life extension.”

The company has also been in contact with the Washington-based Rare Diseases Coalition, which has direct links with the FDA.

“A major learning is how important patient advocacy can be used in the process,” he says.

He encourages  companies not to wait until they in their final stretch of regulatory engagement, but to engage early with these patient groups.

“Hopefully that puts us in a good position to put pressure on the FDA and facilitate an early review.”

At Stockhead, we tell it as it is. While Neurizon and Argenica are Stockhead advertisers, they did not sponsor this article.