Day of the Orals

September 30, 2009: The Day of the Orals

Oral disease modifying agents for MS took a further leap today.

1. Merck KGaA (MKGA.Y; MRK) announced that the have filed an NDA with the FDA.

2. The preliminary results from Novartis' (NVS) FREEDOMS trial were released.

FREEDOMS:

This is a phase III, 2-year ex-U.S. randomized, double-blind, placebo-controlled comparing two doses of oral fingolimod (FTY720) and placebo. The primary endpoint was reduction in annualized relapse rate.

- The placebo annualized relapse rate was 0.40 (number of subjects=418);

- Lower dose fingolimod (0.5 mg) was 0.18, representing a 54% reduction (n = 425); and

- Higher dose fingolimod (1.25 mg) was 0.16, representing a 60% reduction (n= 429).

Earlier, the TRANSFORMS study -- a phase III, 1-year, global, randomized, double-blind, double-dummy, avonex (interferon bet-1a intramuscular) - controlled study -- demonstrated a reduction in the annualized relapse rate as well:

- The avonex annualized relapse rate was 0.33 (number of subjects=431);

- Lower dose fingolimod (0.5 mg) was 0.16, representing a 52% reduction (n = 429); and

- Higher dose fingolimod (1.25 mg) was 0.20, representing a 38% reduction (n= 420).

This seems consistent with FREEDOMS and makes sense -- the placebo arm in FREEDOMS had a higher relapse rate than the avonex arm in TRANSFORMS (0.40 vs 0.33) and the fingolimod arms all had an annualized relapse rate of 0.16 - 0.20.

So, how does this compare to cladribine and tysabri (natalizumab)?

CLARITY, a phase III, 2-year, global, randomized, placebo-controlled trial of oral cladribine in two doses vs. placebo revealed:

- The placebo annualized relapse rate was 0.33 (number of subjects=435);

- Lower dose cladribine (3.5 mg/kg) was 0.14, representing a 57.6% reduction (n = 430); and

- Higher dose cladribine (5.25 mg/kg) was 0.15, representing a 54.5% reduction (n= 454).

So, most important the placebo in CLARITY had the same annualized relapse rate as the avonex arm in TRANSFORMS.

AFFIRM was a phase III, global, randomized, double-blind placebo-controlled tria comparing IV (intravenous) tysabri to placebo:

- The placebo annualized relapse rate was 0.74 (number of subjects=315);

- Tysabri (300 mg) was 0.25, representing a 66% reduction (n = 627).

So, what this highlights is the difference in the patient population in different studies (the placebos are different -- annualized relapse rate:

- AFFIRM - 0.74;

- CLARITY - 0.33;

- FREEDOMS - 0.40

and in TRANSFORMS, the comparator was avonex and the annualized relapse rate was 0.33; compare this to REGARD - rebif 0.30 and copaxone - 0.29 and BEYOND - betaseron regular dose - 0.35, betaseron double-dose 0.34 and copaxone - 0.34.

While we are always cautioned not to compare between (or among) trials (how much is this fueled by the pharmaceutical industry?), the comparator in TRANSFORMS (avonex) is in-line with modern clinical trials of the other FDA approved injectable disease modifying agents.

SENTINEL, CLARITY and FREEDOMS do, however, have varied placebo (and supposedly treatment arm if well randomized) characteristics. In the absence of comparative trials (not likely unless government mandated -- and funded?), treatment decisions will need to be made based on potential side effects (and risk taking/aversion behavior by both the neurologist and the patient) and other endpoints (such as disability).

An important preliminary result of FREEDOMS is the fact that the cancer risk may have been overblown in TRANSFORMS, but keep in mind that this is only preliminary and FREEDOMS is ex-U.S., as opposed to TRANSFORMS (being global) and FREEDOMS-II, which is a U.S. study (with a lot more monitoring, as mandated by the FDA).

With the FREEDOMS results, will Novartis be ready to file with the FDA?

Well, Novartis will almost certainly file with the Europeans (European Medicines Agency -- EMEA), but will the FDA accept an ex-U.S. 2 year placebo-controlled trial and a one year active comparator trial, when it clearly wanted more safety data, as required in FREEDOMS II?

I guess we will have to wait and see.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org