Novartis is trying to convince FDA that its squalene vaccine adjuvant MF59 is a non-threatening vaccine component that does not deserve to get caught in a long regulatory review of new vaccine technologies.

The company is in ongoing discussions with FDA on the type of data necessary to bring the adjuvanted flu vaccine ( Fluad ) into the U.S. market. It has been marketed in Europe since 1997 with more than 30 million doses administered.

Novartis met with FDA as recently as June 2 to discuss the level of supporting data for a Fluad application.

During a June 5 vaccine day meeting with the financial community, Novartis Vaccines CEO Joerg Reinhardt said the company "is in an active dialogue" with the agency on MF59 and is discussing what previous clinical trial and experience data believed to be necessary for a product review.

"We are currently, at the request of FDA," Reinhardt reported, "compiling a comprehensive meta-analysis of all of our data that we have with MF59."

Because it is already marketed in Europe, Novartis has a lot of data on the product. In addition, by the first quarter of next year, the firm will have two-year surveillance safety data on 80,000 vaccinated individuals from Lombardia in Italy.

The size of the file that Novartis can provide to FDA on Fluad in advance of a BLA could cut both ways: the company hopes to avoid having to generate much new data, but FDA may face a big task just in terms of the amount of data to process.

"Even for the FDA, this is an enormous [amount] data that they will have to screen," Reinhardt commented.

After reading the meta-analysis, Novartis said, FDA will tell the company whether additional data are necessary. Reinhardt said the company has not received requests for a specific additional trial.

The BLA filing for Fluad is far off, into at least 2010, according to Novartis comments to the analysts. The company specifically cited a schedule to submit applications for the added use of Fluad in young infants in Europe by the end of next year. The FDA process was described simply as being in the discussion stage.

New Adjuvants Are A "Hot" Topic

Reinhardt acknowledged that the discussion of new adjuvants in the U.S. is a "hot" topic.

GlaxoSmithKline's Cervarix human papilloma virus vaccine is experiencing a long regulatory review from FDA, with most speculation on the delay centering on that product's novel AS04 adjuvant, a combination of the traditional vaccine adjuvant alum plus MPL, an agonist of the toll-like receptor 4. GSK announced in mid-December that FDA had declined to approve Cervarix on first review (¹ Also see "GSK Cervarix Setback: FDA Questions On HPV Vaccine Bode Well For Merck" - Pink Sheet, 7 January, 2008., p. 6).

The Novartis CEO acknowledged that this is a difficult time to try to bring a new concept like novel adjuvants through FDA and the regulatory process. "I believe it is obvious that the FDA at this moment is a little bit more concerned about safety in general than many other regulatory authorities across the world."

For an adjuvant to win FDA approval, Reinhardt said, "you will have to prove that there is a significant benefit that may potentially outweigh any kind of additional risk." Reinhardt suggested that FDA is looking closely at the potential for "specific autoimmune reactions" with new adjuvants.

Terming MF59 a non-threatening adjuvant, he went as far as to describe it as being a sort of adjuvant-lite.

Maintaining that the company has not seen autoimmune reactions from MF59, he characterized it as "an oil in water emulsion" that is "not a specifically highly active pharmacological agent."

Novartis does, however, attribute to MF59 the ability to increase the immune responses in two important categories of patients: young infants and the elderly. The product is currently used for patients over age 65 in Europe.

Novartis is collecting further data on Fluad in infants (age six to 36 months) to supplement a small trial reported in September 2007, which showed improved seroprotection for two strains of A virus and in influenza B virus compared to a marketed Sanofi product, Vaxigrip .

Ralf Clemens, head of global vaccines development, told the analysts that obtaining a flu vaccine for infants is an important target because "influenza is now seen as a disease of infancy" with babies infecting parents and grandparents. It would "be very important" if Fluad can be shown to be a vaccine that "works at the extreme ends" of the population - infants and the elderly. Clemens also said that protection against the B strain is crucial because "B strains are typically the ones that affect infants and young children."

The flu vaccine franchise is important to Novartis as the platform for its attempt to move into the top ranks of the vaccine business. Novartis bought into the flu business with the purchase of Chiron in 2006.

Meningitis Vaccines Seen As Blockbuster Franchise

The key to Novartis' future growth in the vaccine business is currently riding on successful completion of two development projects in meningitis vaccines: Menveo, a conjugated vaccine for protection against the ACWY strains and a meningococcus B vaccine that the company hopes will be the first to market for protection against the B strain.

Reinhardt and the Novartis vaccine team focused on the meningitis products during the June 4 meeting, saying that two products would create a "blockbuster" franchise for the Novartis vaccine effort, doubling sales and moving the company closer to the dominant market shares of Merck, GlaxoSmithKline, Sanofi-Aventis (each at about 25 percent of the market) and Wyeth (at about 15 percent).

Just over two years after the purchase, Novartis is still in an investment phase in the vaccine business. Sales from the vaccines/diagnostics business are growing at a good pace: up 25 percent in 2007 to $1.45 billion and up 21 percent in the first quarter of this year.

Operating margins are low, about 5 percent in 2007, but short-term margin improvement is not the major objective. "You cannot expect a significant margin improvement for this year," Reinhardt said. "If anything, we will stay at the level of last year."

The first filing for Menveo with FDA is targeted for the second half of this year, for use in the ages 11 to 55 population. The commercially important application for use in infants down to two months of age will not occur until 2009. Novartis will take on Sanofi-Aventis and Menactra in the meningitis ACWY market.

As part of the ongoing investments, Novartis has been upgrading production facilities and adding new plants with a projected cost of $1 billion for the five-year period after the Chiron purchase.

The company has also been retooling its management team. It is significant that the first executive personnel change highlighted by the company June 4 was Matt Stober, recruited from GlaxoSmithKline to head technical operations.

It is unusual for a biopharma company to give such prominence to a production exec when meeting with the financial community, but Novartis continues to try to convince the analysts that it has put the Chiron flu production problems from 2004 behind it. In addition to featuring Stober's recruitment, Reinhardt noted that "we also changed all of our management in the different production sites."

But analysts remain skeptical. Two of the first three questions pressed the company for assurance on its ability to meet production needs.

Reinhardt said that the Rosia plant in Italy which will make Menveo has just passed an FDA pre-approval inspection for a different product.

There will not be a problem with the sourcing for approved products being different from the product used in clinical trials, Reinhardt also said. Most of the Menveo Phase III program was supplied from the Rosia plant. The only issues regarding the number of products, he said confidently, will be the number of shifts and how fast the product grows in the marketplace. Reinhardt dismissed manufacturing skill developed by Sanofi-Aventis during over two years of Menactra commercial production as not "really a significant advantage."

The history of early introductions of conjugates, however, has been that a shortage develops as the difficult production process cannot keep up with demand. With an established competitor already supplying the market, Novartis may benefit in a perverse way by being shielded from the intense visibility about shortages.

On flu vaccine production, Novartis is again predicting that it will be able to deliver 40 million doses to the US market. Reinhardt said that creating the 2008-2009 season vaccine has been less difficult than was anticipated based on having to use three new strains instead of the typical one or two new strains. "Actually, so far, the production capacity is absolutely at the level that we would have hoped for," he said.

- Cole Werble (c.werble@elsevier.com)

Novartis Hopes To Avoid Long FDA Delay For MF59 Adjuvant in Flu Vaccine

More from Archive

More from Pink Sheet