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GSK give-back puts pressure on Ionis in TTR race

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By Jennifer Boggs
Managing Editor

With would-be competitor Alnylam Pharmaceuticals Inc. hot on its heels, Ionis Pharmaceuticals Inc. has little time to spare if it wants to maintain potential first-mover advantage after partner Glaxosmithkline plc bailed on transthyretin (TTR) antisense inhibitor inotersen, only a few months after the drug yielded positive phase III data.

The announcement was not wholly unexpected, given that the London-based pharma firm indicated its imminent exit from rare diseases when it disclosed a pipeline reprioritization late last month. But the timing did surprise Jefferies analyst Eun K. Yang, who wrote that she had not anticipated a decision until after Alnylam disclosed data from its TTR drug, patisiran, especially since positive data for patisiran could mean a negative impact for inotersen. Patisiran data are expected in September. (See BioWorld, July 27, 2017.)

Despite solid efficacy, investors latched onto the safety signals that cropped up during Ionis' phase III trial, the NEURO-TTR study, testing inotersen (formerly IONIS-TTRRx) in polyneuropathy caused by TTR amyloidosis, namely reports of thrombocytopenia and renal dysfunction. GSK's decision "may increase investor scrutiny on TTRRx's safety profile" in data presentations later this year, wrote Leerink analyst Paul Matteis in a research note.

And now, the exit of its big pharma muscle "may also put [Ionis] behind the curve with respect to launch preparedness," he added.

For their part, Ionis executives appeared to have already been contemplating such a scenario, aiming to reassure investors during a Friday morning conference call. The company is "well-prepared and on track to file for marketing approval for inotersen in the U.S. and EU this year," said Chairman and CEO Stan Crooke.

Sarah Boyce, chief business officer, elaborated further, pointing to Ionis' efforts since the two firms entered the early stage deal back in 2010. "We have been responsible for the entire development program," including managing regulatory interactions. GSK helped prepare for commercialization and the pharma is "working very closely with us to make sure work they performed is transferred to us in a timely fashion."

While it conducted the NEURO-TTR study, Ionis also "gained a thorough understanding of the disease and patient journey through our efforts," Boyce added, building relationships with the medical community and patient advocacy groups.

Going forward, the firm is considering forming a commercial subsidiary to commercialize or co-commercialize inotersen in North America and looking for a new global partner, a process Ionis has already started.

"We recognize that we have a lot of work to do to be sure that we're ready to market and that we have a partner," Crooke said.

Inotersen targets TTR amyloidosis and is designed to inhibit production of all forms of the TTR protein – that includes the hereditary forms such as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), also known as FAP, as well as wild-type forms. Patients with hATTR-PN experience TTR buildup in major organs, resulting in widespread nerve damage and progressive loss of motor function, eventually leading to death.

In the NEURO-TTR trial in FAP, inotersen met both primary endpoints, achieving over the 15-month period a statistically significant benefit compared to placebo in the modified Neuropathy Impairment Score +7 (mNIS+7) as well as the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (p<0.0001 and p=0.0006, respectively). (See BioWorld Today, May 16, 2017.)

"The p values are amazing," Crooke said, noting that the FDA "strongly preferred" the quality-of-life endpoint as a co-primary, "and we think that's a grand slam for this drug."

The safety issues, he added, require "straightforward" monitoring and management plans that will be included as part of the regulatory submissions.

"As we interrogated the data with GSK over the last month, we continue to gain insight into the performance of the drug, and the performance of the drug looks better and better," Crooke said.

Ionis also has pointed to rival patisiran's less convenient intravenous administration, though Alnylam's TTR-targeting siRNA candidate is dosed less frequently than inotersen – every three weeks vs. once weekly.

Both drugs have orphan designation in the U.S. and Europe and fast track status in the U.S.

Long-term strategy

Ionis execs declined to speculate on the timing for a new partnership, though analysts expect a deal to be signed well ahead of commercialization, but probably not until after Alnylam's phase III study of patisiran, dubbed APOLLO, reads out.

In terms of the scope of interest, Crooke described hearing from existing partners as well as "from other companies that we've dealt with on a large number of occasions that have been interested in other assets that we've had [and] interest from other companies we haven't had any interactions with. So a broad mix."

He added that the ideal partner would be ready to hit the ground running, with an aggressive launch strategy and field reps in place, while Ionis optimizes "our commercial participation in the context of our long-term strategy." That includes making sure "we participate as much as possible in the profitability we think this drug will bring."

Ionis also expects a deal to include "substantially greater" terms than were offered in the GSK deal.

The option deal came with $35 million up front and up to $155 million in pre-licensing milestones for the five programs included in the collaboration. But a lot has changed in the past seven years. (See BioWorld Today, April 1, 2010.)

"The partnership with GSK was a research partnership, and GSK has paid for all discovery, all development, all of the activities to date with this drug," Crooke said. "It's rather remarkable to get an incredible asset like inotersen back after all that investment, but it happens. Strategies change.

"So the terms of the GSK transaction were excellent terms for a research-stage transaction. Today, we have a registration-ready drug with an extremely positive phase III data and a well-defined and large market opportunity." He added, "This is an extraordinary opportunity for us."

Ionis also has plans to accelerate work on its TTR program for patients with cardiomyopathy due to TTR amyloidosis. The company noted that roughly 50 percent of patients in the NEURO-TTR study had some type of cardiac involvement.

Work will also advance on a TTR-targeting drug from its LICA, or Ligand-Conjugated Antisense, technology, designed to be more potent than inotersen and with more convenient dosing.

In addition to inotersen, GSK also is declining an option on IONIS-FB-LRx, a LICA compound in development for complement-mediated diseases. Ionis plans to start a phase II trial later this year in patients with dry age-related macular degeneration and move into additional indications in 2018.

Since infectious diseases remains one of its focus areas, GSK will continue advancing IONIS-HBVRx and IONIS-HBV-LRx, both of which are in phase II testing in hepatitis B virus.

Ionis, which reported its earnings earlier in the week, posted second-quarter revenue of $104.2 million, with much of that linked to spinal muscular atrophy drug Spinraza (nusinersen), including $27.6 million in royalties from partner Biogen Inc. – Biogen reported net sales totaling $203 million for the quarter – and a $50 million milestone payment on EU approval.

Net loss totaled $11.2 million, or 9 cents per share. As of June 30, the company had cash, equivalents and short-term investments of $855.7 million.

Shares of Ionis (NASDAQ:IONS) closed Friday at $46.76, up $1.20.