Merck KGaA has submitted a European filing for cladribine
Report from May:
New oral multiple sclerosis drugs edge closer to market
Published:07-May-2009
By Datamonitor staff writer
With little market-shifting information announced across most neurological conditions at this year's AAN conference, it was left to the multiple sclerosis field to take center stage. Notably, Merck KGaA and Novartis presented positive Phase III data for their front running pipeline agents oral cladribine and FTY720 respectively. However, safety issues remain a concern for both products.
For the second year running, developments in the multiple sclerosis (MS) field have dominated the annual American Academy of Neurology (AAN) conference. Of the five late-stage oral pipeline developments, the two most clinically advanced, Merck KGaA's oral cladribine and Novartis's FTY720, are reaching crunch time. With US and EU regulatory filings planned for later this year, both companies used the meeting to announce previously unpublished positive Phase III data. Although notable safety issues have arisen with both products, raising questions about which line of therapy they would best serve, Datamonitor believes that the drugs represent considerable therapeutic advancements and should successfully gain marketing approval in the next couple of years.
Additionally, with Tysabri safety concerns highly prominent in healthcare news over the past couple of years, it was no surprise to see Biogen Idec using this year's conference as a platform to establish a more positive perception for the drug among the medical community.
Mid-2009 US/EU filing planned for oral cladribine
Merck KGaA reported full two-year data from the completed CLARITY study showing that compared to placebo, its oral cladribine tablets significantly cut the rate of clinical relapses, disability progression and brain lesions in patients suffering from relapsing-remitting MS (RRMS), echoing preliminary data reported in January this year. Over two years, 80% of the patients receiving low-dose oral cladribine and 79% of those in the high-dose group experienced no clinical relapse, compared to 61% of those on placebo. Cladribine treatment was also shown to cut the risk of disability progression by more than 30%.
As with Novartis's FTY720, concerns have arisen with cladribine's safety profile. Lymphopenia, an event related to the drug's mechanism of action, was unsurprisingly reported to be more frequent among cladribine-treated patients. Of greater significance was Merck's announcement that four patients in the cladribine group had developed cancer during the study period, with a further case emerging six months after the study ended. While one patient died as a result, there were no occurrences of cancer in the placebo arm. With the cancers all in different organ systems (cervical, melanoma, ovarian and pancreatic cancer) a causal effect would be difficult to establish. However, it remains too early to dismiss a potential relationship between cladribine and the occurrence of malignancies and as such this may influence future uptake.
Merck plans to use the data from this 1,326 patient Phase III study to form the basis of an EU and US regulatory filing in mid-2009. Granted FDA Fast Track status in September 2006, Datamonitor believes cladribine could be made available to MS patients by mid-2010 with the FDA likely to request to see data from the ongoing ONWARD study prior to approval. And, as with Tysabri, an extensive patient monitoring program is likely to be required.
Datamonitor forecasts oral cladribine to achieve peak seven major market sales of approximately $235m by 2018, based on a comparatively low price-point in the assumption that it will be positioned as an add-on therapy for the majority of patients.
FTY720 shows impressive efficacy data mixed with ongoing safety concerns
Data presented from the one-year Phase III TRANSFORMS study showed that 80-83% of patients taking Novartis's oral FTY720 were relapse-free compared with 69% of patients on Biogen Idec's market-leading therapy, Avonex (interferon beta-1a). These data reinforce results announced in December 2008 showing that the annual relapse rate was 52% lower compared to Avonex.
Although Novartis stated that 87% of patients on FTY720 had completed one-year on study, the announcement of a patient death six months after therapy discontinuation due to aspiration pneumonia adds to the product's long-term safety concerns. Concerns first emerged during Phase II studies and resulted in the FDA requesting the monitoring of certain safety issues (ophthalmic screening, pulmonary function and heart rate) in Phase III testing. Of particular concern in the TRANSFORMS study were the seven cases of localized skin cancer that were diagnosed in FTY720-treated patients (four basal cell carcinoma and three melanoma) compared to one case of non-skin squamous cell carcinoma in the Avonex group. Although all of these localized skin lesions were successfully removed, it represents an important additional patient-monitoring burden that could hamper the drug post approval.
With data from the two-year FREEDOMS study expected later in 2009, Novartis remains on track for both US and EU regulatory filings for end of the year. With the safety-efficacy ratio still remaining in the drug's favor, Datamonitor believes FTY720 will successfully make it to the market and forecasts it to achieve seven major markets sales of just under $1.1 billion by 2018.
Promising Tysabri usage and safety stats
Biogen Idec presented encouraging utilization and safety results for Tysabri (natalizumab) including details from the TOUCH and TYGRIS prescribing programs. With 52,000 Tysabri-treated patients as of March 2009, it remains highly unlikely that Biogen will achieve its previous guidance of 100,000 by the end of 2010. However, while previous announcements of newly confirmed cases of progressive multifocal leukoencephalopathy (PML) have dampened the patient add-rate, the post-marketing incidence of PML is currently 1.2 per 10,000 patients, and so remains considerably lower than the 1-in-1,000 risk rate that is on the drug's label and that seen in pre-approval clinical trials.
Additionally, of the six confirmed cases of PML, five remain alive today. So not only does the outcome of patients with PML appear better than observed in clinical trials, it also shows the success of the two prescribing programs and Biogen Idec's continued efforts to identify methods to minimize the risk of and treat newly identified PML cases - such as plasma exchange investigated in the PLEX study. Although Datamonitor continues to remain confident of Tysabri, long-term growth firmly hinges on the incidence and management of new PML cases.
Of the 31 individual poster presentations regarding Tysabri, one demonstrated that the drug promoted regeneration and stabilization of damage to the myelin sheath, as measured by advanced MRI technology. What these MRI data suggest is that Tysabri may not only be able to stop some of the signs of disease progression, but that it may also have the capacity to repair and possibly restore some of the damaged myelin sheath that protects nerve fibers. With all current therapies essentially indicated to slow the rate of disease progression, this would be a first for any approved MS therapy and, if it were supported by additional clinical evidence, would see Tysabri further establish its position as the most efficacious approved disease-modifying MS therapy available.
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