FDA Approvals: Naglazyme, Trizivir, Levaquin

Yael Waknine

August 11, 2005

Aug. 11, 2005 — The U.S. Food and Drug Administration (FDA) has approved galsulfase 1-mg/mL injection to improve endurance in patients with mucopolysaccharidosis VI; combination abacavir sulfate, lamivudine, and zidovudine 300-mg/150-mg/300-mg tablets for use alone or in combination with other antiretroviral agents in the treatment of HIV-1 infection; and a 750-mg per day, five-day levofloxacin dosing regimen for the treatment of acute bacterial sinusitis.

Galsulfase (Naglazyme) Improves Endurance in Patients With Mucopolysaccharidosis VI

On May 31, the FDA approved galsulfase 1-mg/mL injection (Naglazyme, made by Biomarin Pharmaceutical, Inc.) to improve walking and stair-climbing capacity in patients with mucopolysaccharidosis VI.

The approval was based in part on data from a 24-week, double-blind, phase 2 clinical trial in 39 patients, demonstrating that galsulfase therapy significantly improved endurance relative to placebo, as evaluated via increases from baseline in 12-minute walk test (12-MWT) distance and rate of three-minute stair climb (109 ± 154 vs 26 ± 122 m; P = .025; 7.4 ± 9.9 vs 2.7 ± 6.9 stairs/minute; P = .053).

Although normal ranges were not achieved in the active treatment group, galsulfase bioactivitiy was confirmed by decreased levels of urinary glycosaminoglycans that were maintained for up to 144 weeks in two long-term extension trials involving 17 patients.

An open-label, 24-week extension trial in 38 patients from the original 24-week study demonstrated that continued treatment with galsulfase led to further improvements in 12-MWT distance and rate of stair climbing (36 ± 97 m; 3 ± 7 stairs/minute). Among patients originally randomized to placebo, corresponding improvements during this period were 66 ± 133 m and 6 ± 8 stairs per minute, respectively.

The most commonly reported galsulfase-related adverse events included headache, fever, arthralgia, vomiting, upper respiratory tract infections, abdominal pain, ear pain, cough, and otitis media. Infusion-related reactions commonly included fever, chills/rigor, headache, rash, and mild to moderate urticaria.

The FDA notes that evaluation of airway patency should be considered prior to initiation of galsulfase therapy, and treatment delay should be considered in patients presenting with acute febrile or respiratory illness.

Conditions of the approval include evaluation of galsulfase therapy on skeletal dysplasia in patients younger than one year, and a surveillance program to monitor postmarketing use of the product. No phase 3 extension studies were required.

Abacavir Sulfate/Lamivudine/Zidovudine Tablets (Trizivir) for HIV-1 Infection

On May 13, the FDA granted accelerated approval for combination abacavir sulfate, lamivudine, and zidovudine 300-mg/150-mg/300-mg tablets (Trizivir, made by GlaxoSmithKline), allowing their use alone or in combination with other antiretroviral agents for the treatment of HIV-1.

The approval was based on an analysis of 24-week data from a multicenter, double-blind study in which 562 therapy-naive adults were randomized to receive either abacavir sulfate or indinavir sulfate in addition to lamivudine and zidovudine.

Results showed that treatment response was similar between the abacavir and indinavir treatment groups for patients with baseline HIV-1 RNA plasma levels ranging from 10,000 to 100,000 copies per mL as well as those greater than 100,000 copies per mL (50% vs 48%; 48% vs 52%).

In subjects with baseline viral load greater than 100,000 copies per mL, 31% of patients receiving abacavir achieved HIV-1 RNA levels of 50 copies per mL or less, compared with 45% of those receiving indinavir. The FDA considers these data to be limited because of small sample size (n = 196).

Additional 48-week results showed an overall mean increase in CD4+ cell counts of about 150 cells per mm3 in both treatment groups. Clinical disease progression was observed in nine abacavir-treated patients (3.4%) and three indinavir-treated patients (1.5%).

A review of medical history is recommended prior to initiation of therapy with the combination tablet to avoid reintroduction of abacavir in patients with hypersensitivity to the agent that can result in a multiorgan clinical syndrome.

Levofloxacin (Levaquin) Short Course for Acute Bacterial Sinusitis

On Aug. 4, the FDA approved a new indication for a 750-mg per day, five-day levofloxacin dosing regimen (Levaquin tablets, injection, and oral solution, made by Ortho-McNeil Pharmaceutical, Inc.), allowing its use for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in adults.

The approval was based on results of a multicenter, randomized, double-blind study in 780 patients, showing that the regimen was similarly efficacious to a 500-mg per 10-day course of levofloxacin in achieving complete or partial resolution of ABS symptoms to the degree that no further antibiotic therapy was necessary (91.4% vs 88.6%).

In the trial, the in vitro susceptibilities of S. pneumoniae and H. influenzae to levofloxacin were both 100%. These results are consistent with existing in vitro data gathered for the last nine years via the Tracking Resistance in the United States Today study that has demonstrated the sustained susceptibility of S. pneumoniae (99%), H. influenzae (99.7%), and M. catarrhalis (100%) isolates to levofloxacin.

The short-course fluoroquinolone therapy is available in Leva-pak format and was previously approved for the treatment of community acquired pneumonia due to penicillin-susceptible S. pneumoniae (excluding multidrug-resistant strains), H. influenzae, Haemophilus parainfluenzae, or Mycoplasma pneumoniae.

Levofloxacin is a fluoroquinolone antibiotic indicated for the treatment of infections caused by susceptible strains of Gram-positive and Gram-negative microorganisms and to prevent the development of inhalational anthrax following exposure to Bacillus anthracis.

Reviewed by Gary D. Vogin, MD