Novartis is conducting additional trials to determine whether the antipsychotic iloperidone has a dose-dependant QTc prolongation side effect before it files an NDA for the agent.

The trials will look at 20 mg and 24 mg daily doses of iloperidone because results from an earlier trial (Study 3005) "gave a hint that there might be a slight, dose-dependent QTc prolongation, but still not clinically significant," Pharmaceuticals Chemical R&D Head James Shannon told an investor teleconference Oct. 11.

"It is fair for us to go and really examine this. In fact, FDA will want us to do that before filing to clearly demonstrate if there is a dose-dependency with QTc," Shannon said. "We need to define what level or how high we can go right now in a safety-conscious FDA environment."

"All antipsychotics, if you dose them high enough, will have side effects, including QTc prolongation," he maintained. "The question is at what level do you get efficacy and maintain a reasonable tolerability and side effect profile. At the doses we have studied, we have not seen any problems with any of the major side effects including [extra-pyramidal symptoms], weight gain, etc."

"It is likely as we put the drug onto the market that the dose that will be used by most patients will not even be as high as 20-24 [mg], but rather will be in the 12, 16, 20 [mg] range," he noted.

Novartis and its iloperidone partner Titan announced in July that the NDA filing would be delayed in order to allow additional studies. The companies also said that the proposed tradename, Zomaril, is likely to be changed (¹ Also see "Another Novartis product delay" - Pink Sheet, 30 July, 2001.).

Pfizer's entry in the antipsychotic market, Geodon (ziprasidone), was delayed by two years after FDA deemed the agent "not approvable" pending further data on QTc prolongation. Geodon was approved by FDA in February (² Also see "Pfizer Ziprasidone Labeling Stops Short Of Second-Line Use; QT Effect Noted" - Pink Sheet, 12 February, 2001.).

Novartis expects to file the new iloperidone data 12 to 15 months from the time the trials commence, which is expected to be before the end of the year.

While the drug's efficacy is not "really superior to the other new neuroleptics," iloperidone's side effect and tolerability profile "really looks better than what is available," making it a potential "product of first choice" among the elderly, Shannon declared.

Regarding the ongoing Zelnorm appeal, Novartis still expects it will be "weeks or months until we can tell you really something substantial," CEO Daniel Vasella said. Zelnorm (tegaserod) was issued a "not approvable" letter in June, which Novartis is appealing (³ [A#00630260003]).

As part of the appeal process, Novartis submitted to FDA a white paper produced by "22 independent gastroenterologists" about Zelnorm's efficacy and side effects.

The paper's "absolutely clear conclusion is that there is in all probability no relationship between drug treatment and abdominal surgery. There is no rationale for this connection," he said. "They don't believe there is a signal for an increased risk due to drug treatment."

Novartis also plans to present FDA in the "next few weeks" with a strategy to address issues from FDA's July 5 "complete response" letter for the anti-asthma/allergy antibody Xolair (omalizumab).

"Until we have that meeting with FDA and reach an agreement with them on how much additional data we need to supply, it's too early yet to give an exact timing for submission," Shannon said. Novartis will seek a narrower Xolair label, initially concentrating on adult allergic asthma (⁴ Also see "Genentech/Novartis Xolair Indication Narrowed To Adult Allergic Asthma" - Pink Sheet, 16 July, 2001.).

The European Agency for the Evaluation of Medicinal Products' Committee for Proprietary Medicinal Products asked Novartis to "outline a patient population which would have the most benefit from Xolair," Shannon said.

In the most severe patients, "we saw a greater than 50% reduction in exacerbations," which "directly relate to the death rate of this population," he said. Novartis has refilled the analysis and is awaiting a hearing with CPMP.

Novartis will decide whether to move forward with the cholesterol-reducing drug pitavastatin in time for the company's Oct. 30 R&D day, Vasella said.

Vasella said he was "pretty confident" that Novartis would complete the analysis of Phase II data and be able to address two questions upon which pitavastatin's future hinges: the competitive profile versus marketed statins (namely Pfizer's Lipitor) and pitavastatin's appropriate dosing levels.

In assessing pitavastatin's prospects, Vasella said: "one needs to look at the patent life, at existing franchises, at profitability and take a net present value approach...if you would have equivalence to Lipitor. Then we will make the decision."

"Certainly the answer that I can give you is that if it is weaker [than Lipitor], then it's a no-go," he added.

Following Bayer's Baycol withdrawal, Novartis is on "high alert for the potential for side effects" of rhabdomyolysis with pitavastatin, Vasella said.

The withdrawal could potentially complicate a pitavastatin launch, as the drug would compete against the safety profiles of existing products.

Novartis licensed pitavastatin in Europe from Sankyo and Nissan Chemicals and is negotiating for U.S. rights (⁵ Also see "Novartis Bids On "Superstatin": Seeking U.S. Rights To Pitavastatin" - Pink Sheet, 11 June, 2001.). Sankyo has exclusive U.S. development and marketing rights, and shares rights with Nissan and Kowa in Japan.

Regarding pitavastatin's appropriate dosing levels, Vasella said: "What we need to find out is, [at] what dose do we get what kind of efficacy without having a significant increase in patients with elevated creatinine....We don't know where the cut-off is." Pitavastatin was dosed up to 32 mg in Phase II trials.

Novartis' marketed cholesterol drug Lescol (fluvastatin) "was obviously profiting to some degree from the Baycol event" during the quarter "and we have taken over some market share," Vasella said. (⁶ Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 August, 2001.). Lescol U.S. sales were up 9% to $165 mil. through nine months.

The oncologic agent Gleevec (imatinib) is already moving beyond its labeling indication of chronic myeloid leukemia, Oncology President David Epstein reported. Off-label use represented 10%-15% of the drug's total sales for the third quarter.

"About half" of the off-label use "is probably for GI stromal tumor," Epstein noted. Novartis expects to file for the indication in mid-October.

Gleevec achieved "quick initial penetration" following its May launch in the U.S., the exec said, predicting "much more growth ahead." Imatinib generated sales of $86 mil. in the third quarter; Novartis reported $32 mil. in sales at the end of June.

Epstein acknowledged that Gleevec's prescription trend, as tracked by IMS Health, has been "flattening" in recent months.

Novartis must "continue to educate physicians that cytogenetic response is the only real marker of success with the CML therapy and they need to begin to work to move their interferon-responding patients and their hydroxyurea patients over to Gleevec," he said.

The recent data also could reflect limitations of the IMS Health tracking system, Epstein maintained.

The IMS data "appears to underestimate the total sales, actually quite significantly....A large portion of the Gleevec business is actually in mail-order, and there is some sales that are actually dispensed directly to the hospital, so some of that is being lost."

Combined sales of the hypercalcemia agents Aredia (pamidronate) and Zometa (zolendronate) were up 25% in the first nine months; initial anecdotal switch reports from U.S. physicians are encouraging, Vasella said. Novartis is hoping to transfer as much of the Aredia market as possible to the newer agent (⁷ Also see "Novartis Zometa Acquisition Cost Of $713 Per Dose Is 2% Higher Than Aredia" - Pink Sheet, 27 August, 2001.).

Novartis expects to see Aredia generics soon. "It is unlikely that the U.S. market will go without a generic beyond the end of this year and frankly, a generic could launch as early as this month," Epstein said.

"It has now been 30 months since our initial litigation with [Boehringer Ingelheim's] Ben Venue, so it is possible that they could launch at any time," he said. B-I's Bedford Labs was approved for pamidronate injection April 30, but is not yet marketing the drug.

When asked whether Novartis would consider divesting its non-pharma businesses, Vasella said it would take a "really mind-boggling offer" to change the company's strategic course.

Novartis "has enough cash - and I'm not saying a cash pile - but [enough] cash to manage, and therefore, I don't think it would be appropriate to transform those businesses into cash," Vasella said. "We could make a swap," he added, "but that is theoretical and not really practical up to now."

Novartis Zomaril NDA Filing Awaits More Data On QTc Prolongation

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