SAN FRANCISCO – Anyone expecting to hear breaking news from PTC Therapeutics Inc. during its presentation at the J.P. Morgan Healthcare Conference (JPM) came away disappointed. The low-key presentation by CEO Stuart Peltz recounted the ex-U.S. commercial trajectory for Translarna (ataluren) in Duchenne muscular dystrophy (DMD) across the first full year, restated the company's plans for additional regulatory filings and repeated the company's mantra about the potential of Translarna to treat patients across multiple rare disease indications.

Peltz devoted only four slides to the company's spinal muscular atrophy (SMA) program with Roche AG, of Basel, Switzerland, and the SMA Foundation, which includes the phase II asset RG-7800 – on clinical hold due to an undisclosed "eye finding" in a preclinical animal study that did not occur in humans – and a second compound, RG-7916, that recently moved into phase I. In mouse models of SMA, compounds from the program, which alter the splicing of the protein SMN2, suggested the ability to alter the course of the disease. (See BioWorld Today, Aug. 8, 2014.)

The business-as-usual approach by Peltz, never given to great drama, may be just what the doctor ordered as two other companies in the DMD space – Biomarin Pharmaceutical Inc., which presented at JPM earlier in the week, and Sarepta Therapeutics Inc., conspicuously absent from the meeting this year – await the fate of their drugs, Kyndrisa (drisapersen) and eteplirsen, respectively. (See BioWorld Today, Jan. 12, 2016.)

No matter what the FDA's decisions, PTC can only benefit from watching the process, Peltz said.

In fact, the South Plainfield, N.J.-based company already has gained valuable insights. Responding to the first question during the JPM breakout session, Peltz said PTC learned three important points from Biomarin's advisory committee meeting, which was a baffling mix of questions about the design of the Kyndrisa studies and concerns about using production of dystrophin as a biomarker. (See BioWorld Today, Nov. 25, 2015.)

One takeaway from the panel was a focus on what Peltz called "the weakness of the clinical data in terms of expression," adding that his company "will put a little bit more time into that" before its expected adcom.

In terms of efficacy, Biomarin's FDA adcom panelists made clear that they wanted to see consistency in the data across the primary and secondary endpoints, which, Peltz said, Translarna already demonstrated. Data from the phase III ACT DMD trial, which enrolled a broad cross-section of ambulatory DMD patients, suggested treatment with Translarna can alter the course of DMD disease progression, despite the fact that patients in the intent-to-treat population showed a 15-meter benefit (p = 0.213), missing statistical significance. (See BioWorld Today, Oct. 16, 2015.)

Patients in the pre-specified population with a baseline measurement of 300 to 400 meters on the 6MWT, however, achieved a highly significant benefit of 47 meters (p = 0.007), similar to findings from the company's phase IIb trial. Moreover, no patients in the pre-specified group who were treated with Translarna lost ambulation (0/47) compared to four patients in the placebo group (4/52) who did.

In terms of a sensitivity analysis the FDA conducted for Kyndrisa, "we thought what the FDA did was interesting so we did that ourselves," Peltz said, maintaining that the company is prepared to show that Translarna produced "clinically meaningful and statistically significant differences" no matter how the data were sliced.

PTC also has collected "incredibly strong" safety data on Translarna, dating back to 2005. "When you put that together, we think it's a very strong package," Peltz said.

Similarly, PTC is waiting to see how the FDA handles the safety and efficacy dataset for Sarepta's eteplirsen, scheduled for an advisory committee review on Jan. 22. The drug has a Feb. 26 PDUFA date.

"It's always nice to see opportunities to prepare for whatever analyses they do, be ready for that and put that into our adcom book," Peltz said. "We're so different than the exon-skippers, but we're going to learn a bit."

Translarna is the only drug in development for DMD patients with the nonsense mutation in the dystrophin gene, borne by 10 percent to 15 percent of DMD patients, which causes the cells to stop synthesizing the protein before the process is done. The therapy interacts with the ribosome, enabling the ribosome to read through premature nonsense stop signals on messenger RNA and allow the cell to produce a full-length, functional protein.

'YOU WANT TO FIND AS MANY WINNERS AS YOU CAN'

In the meantime, the commercial launch of Translarna in Europe has ramped up to 206 patients, despite the need to progress country-by-country. The oral, small-molecule drug first gained conditional approval in the EU in 2014 to treat nonsense mutation DMD in ambulatory patients 5 years and older. (See BioWorld Today, May 27, 2014.)

"The team has been very aggressive," Peltz said. "Through a combination of expanded access and commercialization, to get to 206 patients in a year is an impressive effort."

PTC submitted the ACT DMD results to the EMA to fulfill the principal condition of full approval in the EU, with a decision also expected midyear.

All told, Translarna is available commercially in 18 countries and targeting 35 countries – including the U.S., where pre-commercialization activities are under way – by year-end. PTC completed its rolling new drug application submission for Translarna to the FDA last year and expects a decision mid-year.

Despite its commercial footprint, PTC is seeking to collect two full years of data on patients enrolled in trials before converting them to commercial use, Peltz said. The company has a registry in Europe where it is accruing data on long-term "real-life experience" by patients, in addition to extension studies.

"The thing to recognize is that we are the first company to launch a drug in Duchenne muscular dystrophy," said Mark Rothera, PTC's chief commercial officer. "Think about cystic fibrosis 20 years ago. Any company launching today launches into a market that's already quite well established. One of the areas of focus that we have brought to this is the necessity to genotype effectively, making sure the right patients are getting Translarna. There's a lot of focus and attention on that."

He cited the example of a saliva-based genotyping kit the company deployed in Brazil, where 1,000 patients were genotyped over a nine-month period who would not have been identified otherwise.

PTC already has a fully enrolled phase III trial of Translarna under way in nonsense mutation cystic fibrosis (CF) – the only product in development targeting that CF variation. Another major goal for the company this year is to expand Translarna's development in other indications caused by a nonsense mutation, potentially including metabolic, muscle, eye, skin, neurological and pulmonary disorders.

For the road forward, it's a balancing act between choosing targets with no existing treatments and those with less effective drugs. Although it might be easier to blaze a path through a space with no existing therapies, pioneering companies often face challenges establishing biomarkers and outcome measures, Peltz pointed out.

Once a drug's value is proven, "you want to find as many winners as you can," he said. "That's how I think about how to expand."

On Wednesday, which saw another broad sell-off in the markets, the company's shares (NASDAQ:PTCT) closed at $22.66 for a loss of $1.21.