Timing of the launch, how to identify new patients and the retry for approval in Europe along with, of course, price became topics of talk in the aftermath of Kynamro's approval Tuesday by the FDA for homozygous familial hypercholesterolemia (HoFH).
The injected apolipoprotein B synthesis inhibitor developed by Isis Pharmaceuticals Inc., of Carlsbad, Calif., and partnered with Genzyme, a unit of Paris-based Sanofi SA, a systemic antisense drug, and it squares off against oral Juxtapid (lomitapide), the microsomal triglyceride transfer protein inhibitor from Aegerion Pharmaceuticals Inc., approved in December.
Kynamro is the first systemic antisense drug to win FDA approval and, by extension, the first RNA therapeutic, "and that's hugely important for the field," said Kleanthis Xanthopoulos, CEO of Regulus Therapeutics Inc., who called the news "transformative."
He added that he was "always bullish" on the compound, which squeaked past an FDA advisory panel in October and was spurned by authorities overseas. Whether Kynamro's once-per-week shot can beat the daily Kynamro pill is "an excellent question, and I think there are some very good answers. In a year, we'll know" for sure, Xanthopoulos said. (See BioWorld Today, Oct. 19, 2012.)
Meanwhile, he pointed to drawbacks with Juxtapid: Patients must remember to take their meds, which are dose-adjusted by a doctor's supervision, and about half of those on the drug end up with gastrointestinal complaints, mainly diarrhea, so they must change their diets.
"I'm not sure it's a slam-dunk for Aegerion, as some investors assume," Xanthopoulos said, citing drug-drug interactions as another potential problem for some patients.
The main disadvantage to Kynamro, he said which will be priced at a significant discount to Juxtapid is the injection-site reaction, most likely specific to the drug, "which is using chemistry that is 10 or 12 years old." Others working in the field, such as Alnylam Pharmaceuticals Inc. and Santarus Inc., have encountered few such problems, he said.
Fatty liver, which concerned the FDA panel, is common to both drugs and is likely target-related. Neoplasms found in mice and humans did not trouble Xanthopoulos, either. "It's very interesting that they only showed up in the middle dose, not in the higher or lower dose" in mice, he said, and the neoplasms in humans were "random." More than 500 had been exposed to Kynamro vs. around 50 for Juxtapid, and "it's a numbers game, before you see something like that," he said.
"I was surprised by some of the neoplasms like a lot of people, but if you look carefully, I think you can dissect and get comfortable," Xanthopoulos said. "I don't believe that this is an issue, but I'm glad there are post-approval monitoring studies. We'll figure that out. I won't say it's a trivial point, but it's not a point of concern, any way you look at this." Nor, to him, were the (non-neutralizing) antibodies that some Kynamro patients developed, though they do represent a mystery worth investigating.
He told BioWorld Today he was surprised that analysts, busy weighing the two drugs' chances against each other, overlooked another possibility. HoFH patients show "an incredible amount of [low-density lipoprotein] circulating in their blood, and these are two distinctly different mechanisms," Xanthopoulos noted. "I'm sure there are going to be doctors that say, 'For this extremely high risk population, [let's use] both of them.' There's no reason not to combine them."
'Optimistic' About European Approval
Paula Soteropoulos, vice president and general manager in charge of cardiovascular research and development for Genzyme, told investors during a conference call that the launch of Kynamro "could be four weeks [away], six weeks, but it could be less," she said, depending on managed-care plans and how fast reimbursement can happen.
"We won't be providing the level of detail [that Aegerion has], in terms of targets," she added, though Genzyme has been working to find more patients. Stanley Crooke, chairman and CEO of Isis, said he was "very impressed with the groundwork Genzyme's been doing in the last couple of years" in that regard.
Asked if he had ideas regarding why Europe's gatekeepers turned Kynamro away, Crooke replied, "We do, but we're not going to discuss that today," adding that a renewed attempt to win approval in Europe is under way and he was "very optimistic that will be successful."
Soteropoulos declined to provide the price of Kynamro, but said it is "consistent with currently available therapies, such as apheresis. We'll be talking about that fairly soon as we launch the product." Apheresis costs about $100,000 per year.
Juxtapid costs about $295,000 per year. But, in life-threatening orphan indications such as HoFH, price is less of a factor than in others, wrote Deutsche Bank analyst Robyn Karnauskas in a research bulletin. Karnauskas found the injection-site reactions with Kynamro a significant matter. "Our doc checks suggest that patients on Kynamro had severe injection-site reactions (welts)," Karnauskas wrote. In trials, 23 percent of patients dropped out after a year of treatment because of adverse events. The same percentage of those remaining discontinued in the following 12 to 24 months.
Juxtapid also looked better in terms of liver-fat elevation at 52 weeks in their respective trials, in numbers cited by Karnauskas. Median hepatic fat change for Kynamro was 5 percent and 13 percent at weeks 26 and 52, respectively. Juxtapid's change was 5.7 percent and 4.4 percent for the same periods.
Piper Jaffray analyst Edward Tenthoff predicted Genzyme's U.S. sales of Kynamro will add up to about $15 million this year, $42 million next year and $52 million in 2015, reaching as high as $101 million in 2020. Of this, he wrote in a research report, Isis will get about $4.6 million this year, $12.5 million next year and $16.8 million in 2015, growing to $34 million by 2020.
Isis' stock (NASDAQ:ISIS) closed Wednesday at $14.69, up $1.31. Shares of Aegerion (NASDAQ:AEGR) ended the day at $27.85, down 67 cents.