How Effective Is Cladribine for Multiple Sclerosis?

Cladribine is a medicine, and US sales will reach $ 150 million in 2016.

Cladribine

Right!

Cladribine is a medicine, and US sales will reach $ 150 million in 2016.

Chinese name

Cladribine

Developer

Merck Serono

Indication

Multiple sclerosis

Sales expectations

Global sales will reach $ 350 million

A two-year crossover study of 24 patients with chronic multiple sclerosis showed that the neurological function of patients using the drug was significantly restored.

In 2016, US sales will reach $ 150 million.

76%. Cladribine for injection was approved for the treatment of tumors a few years ago, and Cladribine, which is administered orally, will become a "star of hope" for multiple sclerosis. Doctors and patients are very excited about this drug, because in addition to being oral, it also has the potential to replace the interferon injections and keparsonone (Gratisere acetate, Copaxone) that were previously used for multiple sclerosis treatments. But most experts believe that it will take a long time for cladribine and other oral drugs to become first-line treatments for multiple sclerosis. It is expected to be approved in June 2010. lead

How the doctors and patients treat the drug will be very interesting. In terms of medication decisions, neuroscientists will be very conservative, and they believe that the risk of oral cladribine is higher. We are very eager to see the attitude of patients with multiple sclerosis, because they are very experienced in drug selection and are willing to take risks.

In other respects, the safety characteristics of all three drugs are similar. FDA clinical review expert Lourdes Villalba said that controlled trials showed that 8.5% of patients in the fingolimod 0.5 mg dose group had SAE, and 8.5% and 10.6% of the 5 mg and 1.25 mg dose groups, respectively. SAE. Similarly, the incidence of SAE was 3.5% in the cladribine dose group and 9% in the 5.25 mg dose group, while the incidence of SAE was slightly lower in the laquinimod 0.3 mg and 0.6 mg dose groups, respectively, at 5.1%. And 2.8%.

Since all three drugs work on the immune system, infection problems such as herpes have appeared in all trials. In patients taking fingolimod and laquinimod, liver enzyme abnormalities were present, and a few cancer cases were considered by researchers to be unrelated to the test drug, but the FDA may take fingolimod and carat seriously These problems occurred in the Dr. Bin test.

All three drugs have sufficient evidence to prove their efficacy, and the FDA says Novartis' key trial on fingolimod "provides strong evidence that fingolimod can reduce the incidence of clinical exacerbations of relapsing-remitting MS" frequency".

The article on the CLARITY trial stated that in patients taking either dose of cladribine, "the relapse rate was significantly lower than in the placebo group." The article also added that patients who took cladribine had a higher relapse-free rate, a lower risk of continued disability progression within 3 months, and a significant reduction in the number of intracranial lesions detected by magnetic resonance imaging (MRI).

For laquinimod, the 0.3 mg dose was not effective, but the 0.6 mg dose reduced the average cumulative number of radon-enhancing lesions found in the last four baseline-corrected MRI scans by 40.4%.

Piper Jaffray said that for Serono produced by Merck, there is still some uncertainty about Cladribine's patent issue, and this patent will expire in 2013 before the new intellectual property is approved for release. On the bright side, the European Medicines Agency has accepted Serono's marketing authorization application. If it is approved, it may be granted a 10-year exclusive period, and it may be approved as soon as the third quarter of 2010. In the United States, if the drug is approved this year, it will become a generic drug by 2015.

Reducing the relapse rate of relapsing-remitting multiple sclerosis (RRMS) is an important part of treating RRMS, which will greatly reduce the mortality and disability caused by repeated attacks. Disease-Modifying Drugs such as -interferon, Grammer, mitoxantrone hydrochloride, natalizumab, etc. are currently proven effective and have been used in clinical drugs, but these drugs are mostly given by long-term parenteral Drug models often increase the burden on patients and reduce compliance with drug application. With the recent FDA certification process for Fingolimod and cladribine, two oral drugs for multiple sclerosis, we look forward to the application of these drugs in clinical treatment of relapsing-remitting multiple sclerosis. The drug mode is that the annualized relapse rate (ARR) is significantly reduced.

In fact, the results of the multicenter randomized controlled double-blind trials of Fingolimod and Cladribine (FREEDOMS, TRANSFORMS, CLAIRITY) were published earlier this year in the New England Journal of Medicine. These studies compared the effects of Fingolimod and placebo, Fingolimod and intramuscular -interferon 1a, and oral cladribine tablets and placebo on relapsing-remitting multiple sclerosis.

Fingolimod works by reducing the number of self-invasive lymphocytes that enter the central nervous system. Fingolimod (FTY720) is a sphingosine 1-phosphate receptor modulator that prevents lymph nodes from releasing lymphocytes. Fingolimod is phosphorylated to become an antagonist of the sphingosine 1-phosphate type 1 receptor, causing the receptor molecule to invade. Fingolimod is a lipophilic drug that stably penetrates the blood-brain barrier and phosphorylates in the central nervous system. By interacting with sphingosine 1-phosphate receptors on nerve cells, Fingolimod may also have neuroprotective and neural regeneration functions.

Cladribine has an immunomodulatory effect due to its selective action on lymphocyte subtypes. Cladribine's active metabolite, 2-chlorodeoxyadenosine phosphate, accumulates in cells, leading to the destruction of cell metabolism (inhibition of DNA synthesis and repair) and cell apoptosis. Cladribine mainly acts on lymphocytes, because lymphocytes have a relatively large number of deoxycytidine kinases on the 5-terminal nucleotide enzyme, and lymphocytes rely on adenosine deaminase activity to maintain intracellular nucleotide triphosphate concentration Of stability. Aggregation of cladribine nucleotides results in rapid and long-lasting reductions in CD4 + and CD8 + cells. At the same time, cladribine can also reduce the levels of inflammatory cytokines, reduce the expression of adhesion molecules and reduce the migration of monocytes.

The three published studies all used the annual recurrence rate as the main endpoint. The results showed that cladribine has better efficacy than placebo and Fingolimod than placebo and interferon in relapsing-remitting multiple sclerosis. The two drugs also performed better than the control group on secondary endpoints. These secondary endpoints included: active or new lesions on MRI, time to progression to stable disability, proportion of patients without relapse, and distance from first relapse. Time, etc.

At the same time, the convenience of short-term administration (8-20 days / year) of cladribine in the study also makes it quite attractive in the treatment of relapsing-remitting multiple sclerosis.

Studies have shown the side effects of cladribine and Fingolimod. Among them, the common side effects of cladribine include: 1. Lymphopenia 2. Infection (common with shingles infection), mostly herpes infection with localized skin. Correlation studies have shown that in the cladribine-treated group, the lowest absolute value of lymphocytes was negatively correlated with the incidence of infection. 3. Tumors, such as benign uterine fibroids, melanoma, pancreatic cancer, ovarian cancer, etc. However, studies have shown that the relationship between tumorigenesis and taking cladribine is unclear.

Common side effects of Fingolimod include herpes virus infection, slowed heart rate, atrioventricular block, mildly increased blood pressure, macular edema, skin cancer, and elevated liver enzymes. Slow heart rate and atrioventricular block appear mostly after taking Fingolimod for the first time, most of them are asymptomatic, and only a small number of patients feel dizzy, chest discomfort, palpitations, and continued taking Fingolimod did not show heart rate reduction and atrioventricular block Lagging performance.

Fingolimod and cladribine represent a major change in the current treatment of multiple sclerosis. These studies provide new hope and more options for the treatment of multiple sclerosis. Of course, long-term follow-up to further evaluate the risks of these new treatments needs to be carried out. in.

Results of phase III clinical trials of three other oral multiple sclerosis treatment drugs (teriflunomide, Laquinimod, and BG00012) are expected to be published in 2011-2012.