Cladribine Update

Further details of the CLARITY study comparing cladribine to placebo and further safety from the extension data was presented yesterday at AAN.   This adds to the review of the topline data contained  in the 4/19/09 “Will the new oral MS therapies be a hard pill to swallow” post.    This study of 1326 patients over two year had 3 groups:  placebo (PBO), low dose 3.5 mg/kg (LD) and high dose 5.25 mg/kg (HD).  The primary endpoint was annualized relapse rate (ARR) reduction.  The placebo arm had an ARR of 0.33 compared to 0.14 and 0.15 in the LD and HD groups, respectively, representing a 55-58% reduction.  Relapse free proportion of patients were 61%, 80% and 79% in the PBO, LD and HD groups, respectively.  New data relewased at AAN includes a 33% and 31% reduction in disability progression, compared to placebo, in the LD and HD groups, respectively.  MRI T1 Gadolinium positive lesions were reduced 86-88% in the treated groups compared to the placebo group.

The drug was generally tolerated well.  However,  lymphopenia and leukopenia were seen about 10 times as commonly in the two treatment groups (2% placebo and 21% LD and 31% HD, compared to controls.  Additionally, there were cases of zoster in the 2 treated groups (2% of each group) and none in placebo.  There were 6 deaths during the study, 2 in each groups.  One placebo group death was due to hemorrhage and one to suicide.  One LD cladribine group death was due to myocardial infarction and one to pancreatic cancer.  One HD cladribine group death was due to cardiac arrest but also to pancytopenia and tuberculosis, while the other death was due to drowning.  There were 4 malignancies in the cladribine groups during the study and none in the placebo group.  These cancers were cervical, ovarian, malignant melanoma and pancreatic death (this one leading to death).  In the extension study a case of choriocarcinoma occurred and was treated.

Analysis of the new data:  The excellent ARR efficacy data was confirmed with further significant differences in reducing disability progression and reducing MRI lesions.   Efficacy is at least as potent as the interferons, and probably a little better.  Tolerability is good.  The verdict is still out on safety with 5 malignancies being reported.  They are all in different organ systems so no clear trend has arisen.   But, the lack of an ‘organ at risk’ will make cancer screening difficult.  Lymphopenia/leukopenia was very common but may be a manageable event.  It is possible that dosing intervals may be extended in patients with low counts.  Thus, the drug could be taken at 6 month intervals when blood counts have returned to normal and held for several months longer, until counts improve, for other patients.   This could impact revenue models, assuming the drug is approved and adjusting for lymphopenia or leukopenia is suggested.  Given that the HD was no more effective than LD and the HD had more lymphopenia, I would expect the lower dose to be the recommended dose for FDA review.   The bottom line is that efficacy and convenience will need to be balanced with possible increased risk of cancer and infection (zoster) and possible risk of prolonged lymphopenia.   The new data has not changed my opionions from 4/19/09