Will the new oral MS therapies be a hard pill to swallow?

Will the new MS therapies be a hard pill to swallow?

At least once a day I hear “Have they come out with the pills yet” from a Multiple Sclerosis patient. Inherent in this question is the desire to find an effective treatment that will be less painful, better tolerated and less intrusive than current therapy options. MS patients are unique individuals and do not all put efficacy, comfort, tolerability and safety in the same order. This is not only because of differences in severity and aggressiveness of each person’s disease course, but also because of personality traits and individual benefit to risk calculations. Not surprisingly, neurologists and patients do not always see eye to eye on these issues.

The American Academy of Neurology (AAN) meeting will be held during the last week of April. Traditionally, many studies and updates will be presented during the science part of the meeting, from Tuesday 4/28/09 to Thursday 4/30/09. Several pills are in later stages of development for the treatment of multiple sclerosis 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 recent findings for the 5 oral drugs that are furthest along in development and analyze their strengths and weaknesses in an increasingly more crowded arena. The most data is available to analyze for Cladribine and FTY-720.

CLADRIBINE
Overview
Cladribine is a purine analog that inhibits adenosine deaminase, an enzyme essential for DNA repair. Some cellular specificity is obtained because lymphocytes and monocytes are most sensitive to this agent as other cells more effectively destroy cladribine before enzyme inhibition occurs. Cladribine, in IV form, is FDA approved to treat Hairy Cell Leukemia (HCL), a rare disorder, and is also used at times in the treatment of other hematological disorders. Studies of IV and subcutaneous cladribine for the treatment of MS showed excellent efficacy regarding relapse rate and Gadolinium enhancing T1-weighted lesions with less definite effects on disability. This led Ivax to license cladribine from Ortho to develop an oral form of the drug. Serono partnered with Ivax and later bought out that company and then merged into Merck KGA in 2006. 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. Prior studies supported the use of intermittent dosing. Three studies were designed. The Pivotal Phase III study, CLARITY, comparing two dosing regimens of cladribine to placebo is complete with initial date released 1/23/09. 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.

Study results
Topline data from the Phase III CLARITY study was released 1/23/09. The study enrolled 1326 patients in a 1:1:1 proportion to high dose cladribine (5 days in a row, every 12 weeks first year and then every 24 weeks), low dose cladribine (4 to 5 days in a row every 24 weeks) or placebo in a 96 week long study. For each cycle, the dose was 0.875 mg/kg. Patients who progress clinically may switch to Rebif. 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 (Teva), though still below those of Tysabri (Biogen and Elan). 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 even one 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. However, 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. However, if significance in disability progression reduction is obtained, cladribine will have ample proof of efficacy.

Analysis of Tolerability and Ease of Use
Minor to moderate adverse effects affect the tolerability of a drug. Despite excellent safety data, many patients stop taking one or another of the interferons (Avonex-Biogen;Betaseron-Bayer and Rebif-Merck Serono) 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 can all lead to skin reaction that can range from mild (erythema, itching) to moderate (lipoatrophy) to severe (skin necrosis). Cladribine appears to be well tolerated, though we must wait for more detailed clarification after all data is reported. Lymphopenia was expected to occur, though the incidence, and clinical significance, of this laboratory abnormality is uncertain. Thrombocytopenia and anemia may also occur, based on IV data. All in all, the tolerability of cladribine seems reasonable and will likely be better or similar, on average, to the tolerability of the interferons.

In the studies, cladribine was ingested for 4 to 5 days in a row either 2 or 4 times a year, making compliance very easy for MS patients. This is an advantage over daily medicines where compliance may drop off over time. Because of its mechanism of action, cladribine would be expected to be teratogenic and female patients will need to be on contraceptives if of childbearing age.

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 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 Hairy Cell Leukemia have an increase rate of secondary malignancies over time. 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. Surprisingly, despite being a known teratogen, IV cladribine is category D. Since about half the MS patients are women of child-bearing age, 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.

Calendar
Merck Serono will present more details from the CLARITY study at the late-breaking session Wednesday 4/29/09 starting at 5:15 pm. ONWARD is fully enrolled and data could be reported by 1Q2010. ORACLE is still enrolling.

Cladribine Summary
Cladribine (Merck Serono) 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. As 1/3 of patients are male, and more than half of current female patients have completed their family, this concern will only affect about 25-33 percent of patients.

FTY-720
Overview
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, this highly lipophilic compound readily crosses the blood brain barrier 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. It missed a study endpoint of non-inferiority to mycophenolate mofetil (Cellcept) in organ rejection.

Clinical Studies
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, 0.5 mg FTY-720, 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. This is better than the smaller and shorter Phase II study where the 53-55% reduction in RR was compared to placebo. 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 and Ease of Use
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. As a once a day medication, FTY-720 should be easy for MS patients to take.

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. Confounding factors in the two deaths were reported in the press release, but details have not been presented. A case of focal hemorrhagic encephalitis has also been reported. 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. Teratogenic studies have not been reported. Due to its effect on cellular migration and angiogenesis, FTY-720 will likely be contraindicated in pregnancy with a category D pregnancy rating likely.

Calendar
More data from the TRANSFORMS study will be presented at a Scientific Session during the early afternoon 4/29/09 and an in vitro study investigating fingolimod’s impact on myelin production and on oligodendrocytes and precursors will be presented the next afternoon. FREEDOMS is fully enrolled and the study should end this year. NDA submission will likely be in early 2010.

FTY-720 Summary
FTY-720 (Novartis) 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.

Teriflunomide
Overview
Teriflunomide is a de novo inhibitor of pyrimidine synthesis through dihydro-orotate inhibition that inhibits proliferation of activated lymphocytes leading to a down-regulated immune response. It is being developed by Sanofi-Aventis. It is chemically and functionally related to Leflunomide, a drug FDA approved for rheumatoid and psoriatic arthritis with known myelosuppressive and liver toxicity side effects. Teriflunomide is an active metabolite of leflunomide that is better tolerated than the parent compound. It is also believed to work through the transcription factor, Nf-kB, which has been found to be up-regulated in some autoimmune disorders.  It is being developed by Sanofi-Aventis.

Clinical Studies
A Phase II study of 179 with MS (92% RRMS, 8% SPMS) was performed comparing placebo to 7 mg/day and 14 mg/day teriflunomide for 36 weeks. The annualized relapse rate was 0.81, 0.58 and 0.55 for placebo, 7 mg teriflunomide and 14 mg teriflunomide, respectively. This represented a non-significant 28% and 32% reduction in RR for the two doses in this small study. MRI data was significant with a reduction in the median number of combined unique activity per scan from 0.5 to 0.2 and 0.3 in the 7 mg and 14 mg doses. Significantly fewer patients on the higher dose showed disability increase. The number of adverse effects was similar between placebo and active treatment with a mild increase in nasophayngitis and nausea being noted. TEMSO and TOWER are ongoing Phase III studies comparing 7 mg and 14 mg of teriflunomide to placebo. The TOPICS study is looking at teriflunomide in clinically isolated syndrome. Two smaller studies are comparing teriflunomide to Copaxone and Interferon.

Analysis of Efficacy
The Phase II data suggested that teriflunomide will have some efficacy for the treatment of MS. However, there was not significance in RR reduction. Larger Phase III studies will likely show a significant difference between placebo and one or both of the doses. This difference is more likely to be modest, in the 30% neighborhood of current interferon of Copaxone therapy. If efficacy is not better than existing therapy, then tolerability will become very important.

Analysis of Tolerability and ease of Use
The Phase II study showed a very favorable tolerability profile, much better than the chemically related leflunomide had shown in rheumatoid arthritis studies and post-marketing experience. This will need to be replicated in the larger Phase III studies. As a once a day pill, teriflunomide should have good compliance.

Analysis of Safety
There were no safety concerns in the small Phase II study. Teriflunomide appears to have much less liver toxicity than leflunomide. Of concern, leflunomide has shown myelosuppression with increased infection and a possible link to lymphoma. Furthermore, there has been a case of PML reported with leflunomide. However, despite these concerns, in the Phase II study there were no safety issues raised. I believe more will occur in the larger and longer Phase III studies, though a low incidence might be acceptable. Leflunomide is pregnancy risk category X. Therefore, teriflunomide will likely be a category X (contraindicated) during pregnancy.

Calendar
TEMSO is set to announce Topline data. Recruitment was complete 2Q2008 and top line data should be available by the end of 2010. No major presentations are expected at AAN.

Laquinimod
Overview
Laquinimod is an immunomodulator, related to linomide, developed by Active Biotech (ACTI) and being developed with Teva as a treatment for Relapsing Remitting MS. Linomide was previously studied for MS but a Phase III trial needed to be shut down shortly after full enrollment was reached due to unacceptably high serious cardiopulmonary events including myocardial infarction, pericarditis, pleural infusion and deaths. Analysis of data collected at study closure showed a modest benefit on MRI parameters but the study was too short to obtain useful clinical data. Laquinimod is a related compound that appears to be better tolerated. Laquinimod is a neuromodulator that has several proposed mechanisms of actions. It causes a TH1 to Th2 shift with an anti-inflammatory profile and also down regulates MHC class II necessary for antigen presentation to T cells. Data to be presented at AAN later this month also implies a modulatory role in cellular adhesion and that it may alter the dendritic cell compartment.

Clinical Studies
In a 306 patient 24 week long RRMS Phase II study of placebo, 0.3 mg Laquinimod and 0.6 mg laquinimod, the higher dose led to a 51% reduction in Gadolinium positive lesions on MRI and a 33% decrease in annualized relapse rate. The MRI data reached significance, while the relapse data did not, likely due to the small sample size. The drug was well tolerated at both doses and there was a single serious adverse effect of portal vein thrombosis (Budd-Chiari syndrome). Laquinimod is now involved in two Phase III studies for RRMS, ALLEGRO comparing 0.6 mg laquinimod to placebo and BRAVO comparing 0.6 mg laquinimod to standard dose Avonex. .

Analysis of Efficacy
The Phase II study was fairly short and not powered for efficacy measures. The MRI improvements are more modest than many of the other agents in development. Given the non-significant improvement in annualized relapse rate, the 0.6 mg may not be the most optimal dose. Clearly 0.6 mg was more effective than 0.3 mg, which in turn was more effective than 0.1 in the first phase II study. If the effects on relapse rate are modest in the larger phase III study, then significance may not be reached. Additionally, in BRAVO, the drug may not prove equal to or superior to Avonex.

Analysis of Tolerability and Ease of Use
From the two Phase II studies, laquinimod appears to be very well tolerated, possibly better than some of the other oral agents under development. Laquinimod will be convenient as a once a day treatment. Further tolerability data will be forthcoming from the two larger and longer duration Phase III studies.

Analysis of Safety
Studies with the related compound, linomide, were stopped due to severe cardiac and pulmonary toxicity in some patients. So far, laquinimod seems to be a much safer medicine and there was only one serious AE, related to hypercoagulability with confounding factors that were not specified. If this safety holds up, then a more modest efficacy may be balanced out by good safety and tolerance. Teratogenic studies have not been presented. As linomide has been shown to be teratogenic in rats, a category D or X is expected.

Calendar
Enrollment for ALLEGRO was reported to be complete in November, 2008, suggesting that top-line data will likely be available in 1Q2011

BG12
Overview
BG12, or dimethyl fumarate is a small molecule currently approved for use in plaque psoriasis in Germany that is undergoing studies for use in relapsing remitting MS. Biogen-Idec (BIIB) initially licensed the worldwide rights for BG-12 (ex Germany) from Fumapharm and then purchased Fumapharm in 2006. Fumaderm was approved for use in moderate to severe psoriasis in Germany in 1994 and became the leading oral agent for that indication in Germany. BG-12 is an enteric coated medication that was derived from Fumaderm (mixed fumarate acid esters) and is felt to have better gastrointestinal side effect profile. BG-12 has two putative mechanisms of action that can lead to downregulation of inflammation and possibly neuroprotection. It has been shown to inhibit Nf-kB activation that plays an important role in the upregulation of the immune response. Additionally, it activates the Nrf1 transcription pathway that has been shown to defend against oxidative stress induced neuronal death. Data to be presented at he AAN implies a suppressive action on macrophage function.

Clinical Studies
Results from a Phase II study for 24 weeks that was extended to 48 weeks were reported in October, 2008. 247 patients were randomized to receive 120 mg BG-12 daily, 120 mg three times daily or 240 mg 3 times daily and compared to a placebo group. At 24 weeks, placebo patients were placed on 240 mg three times a day. Primary endpoints were MRI based on new lesions on MRI at weeks 12, 16, 20 and 24. Annualized relapses were calculated from 24 and 48 week data. The higher dose reduced Gadolinium enhanced lesions by 69% between weeks 12 and 24, compared to placebo and performed well on other MRI criteria. Further study showed a possible neuroprotective effect with fewer gadolinium positive lesions evolving into new T1 hypointense lesions. The annualized relapse rate was reduced 32% during the first 24 weeks and reportedly decreased further during the second 24 weeks (not placebo controlled). Side effects included abdominal pain, flushing and hot flash sensation. There were no serious adverse effects. Two large Phase III studies are underway. DEFINE will compare 240 mg BG-12 twice a day or three times a day to placebo with the primary endpoint being proportion of patients relapsing over two years. CONFIRM will compare these two doses of BG-12 to Copaxone with the primary endpoint being annualized relapse rate at two years.

Analysis of Efficacy
BG-12 met its primary MRI endpoints and showed a 32% reduction in relapse rate in a study with 4 cohorts not powered to prove clinically efficacy. Though numbers were not presented, further reduction in relapse rate was noted between weeks 24 and 48, implying a possible lag in efficacy. Efficacy is likely similar to the interferons, though unlikely to be as strong as cladribine or FTY-720. Compared to Laquinimod, the relapse rate reduction was similar and the MRI data was mildly more robust. Only the higher dose significant MRI efficacy, while lower doses of BG-12 were less effective. As with Laquinimod, it is uncertain whether there could be higher efficacy on higher doses. The finding that relapse rate reduction improved further during the second 24 week period predicts that the Phase III studies might show an even more robust clinical response. The Phase I study was not powered or long enough for disability measures to be measured. These will be determined in the Phase III studies.

Analysis of Tolerability and Ease of Use
Enteric coated BG-12 appears to be better tolerated than its precursor, Fumaderm, but continues to have some GI side effects that apparently improve over time. If confirmed in the Phase III studies, the drug should be fairly well tolerated by most patients. Compared to the other oral drugs, BG-12 has a disadvantage in requiring three times a day dosing. This might decrease compliance in some patients compared to those who would be on once a day medication.

Analysis of Safety
The Phase II study showed no serious adverse effects during the 48 weeks. One aspect of safety that separates BG-12 from the other oral compounds is that the related Fumaderm has been marketed for 14 to 15 years with an excellent safety record. Therefore, opportunistic infections and malignancies would not be expected to rise above background levels. Though not being tested as an add-on medication, the probable good safety profile may leave open the possibility of combining interferon with BG-12. Fumaric acids have not been found to be teratogenic and BG12 is likely to be a pregnancy risk category C.

Calendar
The DEFINE study of BG-12 and placebo became fully enrolled 1Q2009 and the CONFIRM study of BG-12 and Copaxone will be enrolled by 2H2009. Thus, phase III data should be available in 2Q2011

Conclusions

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 cladribine and FTY-720 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 study 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. The other three drugs, Teriflunomide, Laquinimod and BG12 still need to definitely prove efficacy and it is probable one or more of these drugs will fail to meet the primary endpoints. Additionally, especially in the case of laquinimod and teriflunomide, where related compounds have proved to have more safety concerns, longer term safety data from the Phase III studies will be essential. BG12 has less safety concerns as it has been used for plaque psoriasis for many years without severe safety concerns. As MS studies seem to be enrolling a healthier and less aggressive population, proving reductions in disability progression will be especially difficult.