The American Academy of Neurology (AAN) meeting will be held during the last week of April. Several pills are in later stages of development for the treatment of multiple sclerosis (MS) and good efficacy data has led to anticipation of FDA approval of one or more of these agents over the next few years. This report will detail findings on cladribine and FTY-720, the two oral drugs that are furthest along in development and analyze their strengths and weaknesses in an increasingly more crowded arena. The larger report here adds further details about 3 more oral drugs in development.
Cladribine is a purine analog that inhibits adenosine deaminase, an enzyme essential for DNA repair. IV Cladribine is FDA approved to treat Hairy Cell Leukemia (HCL), a rare disorder. Studies of IV cladribine in MS showed excellent efficacy regarding relapse rate and Gadolinium enhancing T1-weighted lesions with less definite effects on disability. Merck KGaA (OTCPK:MKGAY) is developing the drug for multiple sclerosis. Because cladribine is already FDA approved for HCL, only one pivotal study for the treatment of MS will be necessary for FDA submission. Additionally, because of the large pool of data from IV and SC dosing studies, Oral Cladribine (Mylinax) went straight to Phase III testing after initial Phase I studies. The Pivotal Phase III study, CLARITY, comparing two dosing regimens of cladribine to placebo is complete. An additional Phase III study, ORACLE, will look at the same 2 doses against placebo in clinically isolated syndrome (early or pre-MS) and a Phase I study, ONWARD, will add cladribine or placebo to Rebif.
Topline data from the Phase III CLARITY study was released 1/23/09. The study enrolled 1326 patients to high dose cladribine (5 days in a row, every 12 weeks first year and then every 24 weeks), low dose cladribine (5 days in a row every 24 weeks) or placebo in a 96 week long study. Released data showed a relapse rate (RR) of 0.33 in the placebo, and 0.14 in the low dose and 0.15 in the high dose or a reduction in relapse rate of 58% for the LD and 55% for the HD. MRI data was not released but was reported to have endpoint goals. Tolerability was reported to be good with laboratory data showing some lymphopenia, as expected, based on prior study experience. Of note, 4 cases of cancer were noted in the cladribine treated patients, but not in the placebo group.
Analysis of Efficacy
Efficacy, as measured by reductions in relapse rate, was excellent, better than pivotal studies of the interferons or Copaxone, though still below those of Tysabri. As had been seen in other studies over the past decade, placebo groups continue to perform better in this decade than they did in the 1990’s. The extreme low activity of the placebo group (only 0.33 relapses/year) means less than ½ of the untreated patients experienced an exacerbation. MRI data is less likely to lose significance between treated and untreated because it is more sensitive than RR. However, disability data is generally less sensitive than RR reduction and a less significant reduction in disability accumulation is a possible finding, given the low level of aggressiveness in this cohort. Interferons were approved without disability data. The bar has been raised with efficacy for MS disability progression shown for other drugs and if reduction of disability data is not shown, it is uncertain whether the FDA will approve on a single pivotal study if the disability data does not back up the RR and MRI data. Delay, while waiting for further studies to report will cause Cladribine to lose its one year lead over FTY-720 to be the first oral drug on the market..
Analysis of Tolerability
Minor to moderate adverse effects affect the tolerability of a drug. Despite excellent safety data, many patients stop taking Avonex (Biogen - BIIB; Elan - ELN), Betaseron (Bayer - OTCPK:BAYRY) or Rebif (EMD Serono - OTCPK:MKGAY) due to systemic side effects of flu-like symptoms. Other patients report headaches or other mild, but troublesome symptoms. Furthermore, the subcutaneous interferons and Copaxone (Teva - TEVA) can all lead to skin. Cladribine appears to be well tolerated. Lymphopenia was expected to occur, though the incidence, and clinical significance, of this laboratory abnormality is uncertain. The tolerability of cladribine seems reasonable and will likely be better or similar to the tolerability of the interferons.
Analysis of Safety
The safety of a medication is related to the more severe adverse effects that may occur. Often, these severe adverse effects are very rare and some may be related to duration of treatment. Thus, some drugs may enter widespread use without a significant safety concern being noted during the studies.
A good example is the appearance of 2 cases of PML with Tysabri (Biogen) in 2005. Four cases of malignancy were reported among the approximately 900 patients who received cladribine compared to no cases in the smaller number on placebo. This finding is especially important as patients treated with cladribine for HCL have an increase rate of secondary malignancies. Additionally, many patients have a lymphopenia lasting 4 or more years. As a purine analog, cladribine is an inhibitor of both DNA synthesis and repair. Whether more cases of malignancy will develop in the MS patients treated with cladribine is unknown as cladribine’s effects on the immune system may last years after treatment is stopped.
Thus, because of this possible long term effect, switching from cladribine to another agent may add to the risk of the more recent agent. There were no severe infectious disease adverse effects reported.
However, due to the mechanism and long term effect on the immune system, this likely remains a risk. Cladribine is category D. This designation will require effective birth control. The duration of this requirement is unclear but will need to be clarified to gain the comfort of prescribing neurologists.
Merck Serono will present more details from CLARITY on Wednesday 4/29/09. ONWARD is fully enrolled and data could be reported by 1Q2010. ORACLE is still enrolling.
Cladribine has proven efficacy and requires only one pivotal study for submission to the FDA. Therefore, they will be the first oral medication approved if the FDA does not require prolonged safety data. If prolonged safety is required, an additional year may suffice. I believe submission will be allowed as other studies are ongoing and will allow further safety data to be collected. A RiskMAP may be needed because of prolonged lymphopenia and occurrence of secondary malignancies in HCL patients. The 2 cycles/year dosing will be well received by both doctor and patient. As DNA repair and not just DNA synthesis is affected, I will need to see further animal studies and further data (if available) from oncology use showing no delayed teratogenicity before I could prescribe to a woman who may desire children in the future. Even with these studies, this unknown factor will slow the switch from current medications to cladribine in younger females with potential for future pregnancy.
FTY-720 (Fingolimod) is a sphingosine 1-phosphate receptor agonist that has been shown to reversibly sequester circulating lymphocytes into the lymph nodes, reducing their ability to enter the CNS. Additionally, it may have additional effects on S1P receptors on astrocytes and oligodendrocytes. A cell culture study has shown FTY720 may increase survival of premature and mature oligodendrocytes that form the myelin sheath of axons. Whether the CNS or peripheral immune mechanism plays a more important role is unknown. It is being developed by Novartis (NVS) for the treatment of multiple sclerosis.
A six month Phase II study of 281 patients comparing 1.25 mg FTY-720, 5 mg FTY-720 and placebo was performed and showed a 53% and 55% reduction in relapses, compared to placebo, in the 5 mg and 1.25 mg treated groups, respectively. An extension study showed that a low relapse rate continued up to 24 months. In December, 2008, Top-line data from the TRANSFORMS Phase III study comparing two doses of FTY-720 to Interferon beta-1a (Avonex) was released. Annualized relapse rates for Avonex, 1.25 mg FTY-720 and 0.5 mg FTY-720 were 0.33, 0.20 and 0.16, respectively. Thus, the lower dose showed a 52% RR reduction compared to Avonex and the higher dose showed a 38% reduction in RR. The medicine was fairly well tolerated with a few more upper respiratory infections than the Avonex treated group but much less flu-like symptoms than the interferon.
However, there were two deaths in the 1.25 mg arm, one with herpes encephalitis and one with disseminated varicella. Additionally, 4 basal cell carcinomas and 3 melanomas occurred in the FTY-720 treated cases compared to one case of skin cancer in the Avonex treated group.
Analysis of Efficacy
Efficacy of FTY-720 studies against an active comparator was excellent with 52% further reduction in RR compared to Avonex. MRI and disability data will be reported later. The FREEDOMS I and II studies comparing these same two doses of FTY-720 against placebo are currently in progress and highly significant improvement in RR would be expected. Importantly, the design of TRANSFORMS will allow FTY-720 to claim clinical superiority to Avonex if marketed.
Analysis of Tolerability
Though complete data has yet to be reported, the two studies doses of FTY-720 appeared to be well tolerated with nasophayngitis and fatigue being the only frequent side effect noted more with FTY-720 than with Avonex. In the phase II, there were also complaints of shortness of breath, early on in the FTY treatment. Although these side effects were higher in FTY-720, flu like symptoms were seen with 37% of the Avonex patients, but only 4% of the FTY-720 subjects. Dropout rates in the Avonex, 1.25 mg FTY-720 and 0.5 mg FTY-720 groups were similar at 12%, 15% and 10%. Some transient bradycardia was observed with FTY-720 and there were several cases of macular edema, though the severity of this particular side effect is unclear.
Analysis of Safety
In this study, there were two deaths, both due to herpes type viruses and seven cases of skin cancer, including 3 melanoma, that were successfully excised. Melanoma is not a common skin cancer, and the occurrence of 3 cases is troubling. Melanoma may be kept in check by immune surveillance, and the 3 cases may not be random. Interestingly, FTY-720 inhibits tumor vascularization in a murine model of metastatic melanoma. When Freedoms I and II are reported, a more accurate picture of the safety of FTY-720 may emerge. Herpes encephalitis and disseminated varicella are potentially treatable with anti-viral medication though mortality can occur in up to half of the cases. If skin cancers or other malignancies continue to be reported with FTY-720 in further studies, approval of the medication could mandate a Risk-MAP that may affect potential uptake of the drug.
More data from TRANSFORMS will be presented on 4/29/09 and an in vitro study investigating fingolimod’s impact on myelin production and on oligodendrocytes and precursors will be presented 4/30/09. FREEDOMS is fully enrolled and the study should end this year.
FTY-720 has proven efficacy but still needs the results of one more Phase III for submission. This data will be available by 4Q2009, allowing submission by mid 2010. I am concerned about the high rate of melanoma with this drug. Though the occurrence may not be high enough to prevent approval, a RiskMAP may be necessary and uptake may be slowed by this concern. Acceptance by patients and enthusiasm by neurologists will be slowed if safety issues continue.
With top-line data from only two Phase III studies reported to date, handicapping the FDA approval process and deciding how these medicines will best fit into the MS armamentarium remains to be determined. Even with studies ongoing, cladribine and FTY-720 appear to have sufficient efficacy and tolerability to justify submission to the FDA.
The main issue with both will be safety, specifically, will there be too many infections and malignancies in the extension studies and further Phase III studies to prevent approval. Though both may ultimately be approved, the path forward will not be as easy as first thought. Cladribine may need to wait for data from a second Phase III to submit to the FDA. Further fatalities and serious adverse effects may doom FTY-720’s chance for approval. If approved, an expensive Risk MAP, similar to TOUCH for Tysabri and close follow-up of a subset of patients, as with TYGRIS for Tysabri, may be necessary to ensure that the cancer and infectious disease risks do not increase sufficiently in the post marketing setting.
What Do Neurologists Think?
Starting a new medication or switching from an existing one is a mutual decision between the doctor and patient after discussion of risk and benefit. We generally are most concerned about efficacy and safety but know that tolerability is important for good compliance. Most neurologists I know are glad to see more alternatives around the corner but will be reluctant to switch, without pause, a patient who is clinically stable and tolerating a current medication. However, as we are all curious, most of the people who see a lot of MS will want to quickly gain some experience with a new drug. Initially, I would anticipate that patients who are failing current therapy may be switched to cladribine or FTY-720 if approved. If a patient who is stable requests a change, some neurologists will agree and switch and others will be more likely to recommend that stable patients remain on current therapy.
What Do Patients Think?
Many MS patients are very well informed, though more do not keep up with all the twists and turns of MS research. Patients want a pill and are more excited about the new medications than the neurologists. As I see my MS patients, we will often have conversations about drugs in development. Patients fall into several categories. Some patients clearly want a pill for convenience, regardless about how well they are doing and may or may not want to follow my advice if I recommend otherwise. Other patients who are stable will think about the pills but ultimately decide to stay on therapy that is working. The largest group will generally follow their doctor’s advice.
Novartis is a large pharmaceutical companies with a market cap over 80 billion. Merck Serono has a market cap around 14 billion. Therefore, success or failure at the FDA has most potential to affect the price of Merck Serono. Peak sales of the oral medications will likely surpass, but not dominate, the injectible medications by 2014 or 2015 as many existing patients gradually switch over a several year period and new patients opt for simpler therapy. This will also have ramifications in the decision to go forward with large Phase III studies in agents currently in Phase II, if significant results are not stellar.
Disclosure: Author holds a long position in Elan. He has served on advisory or speakers' boards for Biogen and Merck Serono.