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Sunday, 08/17/2008 3:58:46 AM

Sunday, August 17, 2008 3:58:46 AM

Nature biotechnology volume 26 number 8, Aug 2008 by Ken Garber Ann Arbor, Michigan

Infections cast cloud over Novartis’ MS therapy

Novartis’ small molecule FTY720 (fingolimod), now in phase 3, is a potential threat to Biogen Idec’s lucrative multiple sclerosis (MS) franchise. But in June Novartis reported that two phase 3 patients had suffered devastating viral infections, one fatal. Nevertheless, as one of several compounds aiming to become the first orally available drug for MS, FTY720 may still be on track to gain a major slice of the ~$6 billion worldwide market for this disease.

FTY720’s phase 2 extension data released in April were impressive: more than two- thirds of MS patients remained relapse-free after three years—the same efficacy range as Tysabri (natalizumab), marketed by Cambridge, Massachusetts–based Biogen Idec and Dublin-based Elan. But this news has been tempered by phase 3 data showing that one patient on FTY720 died from varicella zoster (chicken pox) and the other fell into a coma due to herpes encephalitis. Shreeram Aradhye, Novartis’ global medical director for the FTY720 program, says the dead patient was also on high-dose steroids for an MS attack (potentially contributing to the outcome); indeed, the data safety monitoring board unanimously recommended that the trials continue with increased vigilance for infections.

But the announcement has cast a pall on FTY720. “Any time a patient dies on a drug, one has to question mechanism,” says Brett Kaplan, an analyst at SG Cowen in Boston. “The more we see [of FTY720], the more safety becomes a concern.”

The future of FTY720, which Yoshitomi Pharmaceutical Industries of Saitama, Japan out-licensed to Novartis in September 1997, now hinges on the remaining patients in the three phase 3 trials avoiding serious infections. “There have been two very serious outcomes at this point,” says Daniel Mikol, a neurologist at the University of Michigan in Ann Arbor who is participating in one of the trials. “If there were any other cases like this, it might make it harder to even continue the trial.”

Others outside the MS community are also watching FTY720’s fate closely. The drug is a first-in-class immunosuppressant that binds to sphingosine-1 phosphate (S1P) receptors, which have become popular targets in biotech and big pharma. The FTY720 molecule itself pointed the way to these targets and helped open the field. In 1992 scientists in Japan synthesized the drug by structurally modifying myriocin, a fungal metabolite isolated from a vegetative wasp. The compound was later found to sequester naive and central memory T cells in the lymph nodes and thymus, whereas effector memory T cells continued to circulate, maintaining some cellular immunity. S1P receptors—expressed on immune cells, including T cells, B cells, dendritic cells, natural killer cells and monocytes— are important for directed cell movement, though exactly how they control lymphocyte trafficking has yet to be fully elucidated.

As FTY720 sequesters T cells in lymph nodes—as opposed to wiping them out—it is thought to preserve the host’s ability to respond to infectious agents. “Unlike many of the immunosuppressants, it really doesn’t destroy lymphocytes, it doesn’t seem to have major effects on their ability to be activated, to proliferate,” says Novartis’ Aradhye. “Humoral responses seem relatively intact.”

Five pharmaceutical and two biotech companies are pursuing candidates that either neutralize the sphingolipid S1P or block its receptors. At least one of these compounds is indicated not for MS, but for cancer. For example, Lpath in San Diego is currently testing Asonep (sonepcizumab/LT1009), a humanized monoclonal antibody (mAb) targeting the S1P lipid, in phase 1 trials in patients with solid tumors. Asonep’s antibody acts mainly through an antiangiogenic effect, and may also promote apoptosis. Swiss companies Actelion of Allschwill and Roche of Basel are also developing an oral S1P1 receptor agonist—R-3477—currently in phase 1 trials for undisclosed autoimmune disorders. Novartis has another oral S1P receptor modulator BAF-312, which recently completed phase 1 trials.

FTY720 has impressively opened the S1P field but is clearly no miracle drug. The drug’s kidney transplantation anti-rejection trials were discontinued in 2004, partly due to unexpected side effects. FTY720 “is relatively nonselective, ”notes Jonathan Bromberg, a transplantation researcher at the Mount Sinai Medical Center in New York. “It binds to and interacts with four of the five S1P receptors. And that’s probably one of the reasons why it failed in clinical trials in transplantation.”

Until the June infections, FTY720’s MS prospects were almost uniformly positive, but there were some hints of potential problems. Cases of skin cancer were seen in phase 2, although it’s not clear whether FTY720 was the cause. In the phase 3 trial, the patient with herpes encephalitis was taking FTY720 mono- therapy, whereas the two Tysabri patients who died several years ago from progressive multifocal leukoencephalopathy (PML) were on combination therapy. If FTY720 alone leads to infections, that would be a serious setback. “I wouldn’t be surprised if fingolimod is going to be associated with PML,” says Bibiana Bielekova, an MS researcher at the National Institutes of Health. Novartis plans to file for US Food and Drug Administration registration in late 2009, although Kaplan thinks that date may be pushed back about six months, due to the new safety concerns. Timing might be crucial, because three other oral agents for MS are in phase 3 (Table 1).

Even if most or all of these drugs win regulatory approval, that won’t render obsolete current injectable treatments, such as Biogen Idec’s Tysabri and Avonex (interferon (IFN)beta), Darmstadt, Germany–based Merck Serono’s Rebif (IFN-beta) or Jerusalem-based Teva Pharmaceutical’s Copaxone (glatiramer acetate). “If you’re on an injection therapy, doing well and tolerating it fairly well, you have to ask yourself whether you want to make a switch to a drug where…the long- term safety isn’t known,” says Mikol. But oral delivery is where the MS field is going. “People hate interferons,”says Bielekova. “A really large proportion of patients get tired and achy, and they hate giving themselves a shot. So there is absolutely a huge demand for oral therapies.”

Several injectable immunomodulating mAbs are also in advanced development for MS (Table 1). But by far the best-performing antibody for MS is Campath IH (alemtuzumab) from Genzyme in Cambridge, Massachusetts. Campath, already approved for treating B-cell chronic lymphocytic leukemia, binds the glycoprotein CD52, which is expressed on the surface of T and B cells, and indirectly kills them. Phase 2 results in MS were dramatic: patients taking Campath had a 73% reduction in the risk of relapse compared to IFN treatment. “That’s something that could potentially impact the [MS] landscape,” says Aaron Reames, an analyst at Wachovia Capital Markets in Boston. Unfortunately, Campath can cause immune thrombocytopenia purpura, a condition that results in abnormal bleeding from low platelet counts. Campath “is by far the most effective drug for MS,” says Caroline Stewart, an analyst at Piper Jaffray in New York. “It’s also the most dangerous.”

In the end, market dominance will come down to safety, for FTY720 and for its competitors. But none of them is the final answer for MS. “The biggest question is [whether MS is] only immune system driven or is the immune system responding to something that is happening in the brain?” says Bielekova. “If we can completely tackle the immune system part, can we cure the disease? And I think we don’t know that.”

Table 1 Selected MS therapies in advanced development