Acorda Therapeutics (www.acorda.com) recently completed enrollment of its Phase III trial of Fampridine-SR in multiple sclerosis (MS). The study, which is based on a Special Protocol Assessment issued by the FDA, is evaluating the safety and efficacy of Fampridine-SR in improving walking ability in people with MS.
Secondary outcomes include measurements of leg strength and muscle spasticity. Data from this trial are expected in the third quarter of 2006.
According to a report produced by the AEI-Brookings Institute, MS patients collaborate closely with their physicians about their therapeutic choices, preferring the freedom to risk severe side effects in return for finding a drug to prevent their inexorably progressive disabilities.
Tysabri marketer Biogen Idec (www.biogen.com) supported the collection of the data described in the report, which was presented at a March meeting of the FDA’s Peripheral and Central Nervous System Drug Advisory Committee. The Committee voted in February to return Tysabri to the market for patients with relapsing MS with the caveat that patients and their physicians must enroll in a mandatory registration program. The FDA is expected to make a final decision regarding the drug’s return to market this month.
Tysabri, an anti-integrin monoclonal antibody, was voluntarily removed from the market in February 2005 by its manufacturers following two fatal cases of progressive multifocal leukoencephalopathy (PML) in three MS patients receiving the drug (two of whom had also received Interferon beta 1-a). PML, an inflammatory infectious brain disease, is caused by a virus normally kept in check by the immune system. These occurrences led to the drug’s withdrawal from the market after only four months.
The FDA’s willingness to allow its return to the market speaks to several issues: the lack of therapeutic alternatives for MS patients, Tysabri’s clinical benefits, and the determination of articulate and well-informed MS patients to find effective drug options.
While the risk of developing PML for MS patients receiving Tysabri over a two-year period is 1 in 1,000, clinical study results established a significant improvement in efficacy compared to current-generation treatments: the antibody given in combination with Interferon beta-1a reduced the annualized rate of clinical relapse by 68% (0.75 to 0.24) and the number of new or enlarging brain lesions by 83%, according to Biogen Idec.
Tysabri’s risks and benefits, as well as the lack of efficacy of currently available drugs, have challenged drug developers to come up with immunomodulatory MS therapies that are more disease-specific and less likely to compromise normal immunity against pathogens. Like Tysabri, most marketed MS therapies act nonspecifically to modulate immune system function.
Tysabri works by preventing lymphocytes from crossing into the brain, thereby reducing numbers of activated disease-causing myelin-reactive T cells in the central nervous system and preventing the cascade of immune reactions that result in myelin destruction. Other current therapies include powerful immunomodulatory cytokines like interferons that can reduce disease exacerbations but cause debilitating side effects.
The six FDA-approved currently marketed drugs used to treat MS include recombinant human Interferon beta 1-a produced in mammalian cells (Avonex, Biogen-Idec); recombinant human Interferon beta produced in bacterial cells, (Betaseron, Berlex); modified human Interferon beta 1-a produced in mammalian cells (Rebif, Serono); glitaramer acetate (Copaxone, Teva); Mitoxantrone, an immunosuppressive anticancer drug (Novantrone, Immunex) that acts as a nonspecific inhibitor of cell proliferation; and natalizumab (Tysabri, Biogen-Idec and Elan).
Of these, Copaxone may come closest to MS specificity. This drug may induce myelin peptide-specific suppressor T cells in the peripheral blood circulation that moderates destructive antimyelin immune responses.
Ideally, MS therapies would selectively modify only MS-specific immune system activity. Several biotech companies have focused on molecularly specific therapies, aiming to control the destructive activity initiated by the autoimmune antimyelin T cells characteristic of MS patients.
The T-Cell Attack on Myelin
The attack against MS patients’ myelin by their own immune system occurs through the activation of myelin-specific T cells (MRTCs) specifically directed against myelin protein components. The current understanding of MS pathogenesis involves T-cell-mediated inflammatory activity followed by selective demyelination (erosion of the myelin coating of the nerve fibers), then neurodegeneration. While both healthy individuals and MS patients have autoreactive T cells that recognize a variety of self-antigens [e.g., myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG)], these cells form part of the normal T-cell repertoire and do not cause autoimmune disease.
Individuals, however, with predisposing genetic backgrounds have increased susceptibility to activation and clonal expansion of myelin-autoreactive T cells. In MS patients these usually dormant cells become activated outside the CNS, possibly by recognizing epitopes that are common to autoantigens and foreign antigens, such as bacterial proteins, at the same time.
Once activated, the cells may cross the blood-brain barrier and infiltrate the healthy tissue of the brain and spinal cord. The ensuing cascade of pathogenic events eventually destroys the myelin sheath and prevents normal nerve impulse conduction.
Activated MRTCs in MS patients initiate destructive responses when a receptor on their surfaces binds to myelin components, causing Type 1 helper T cells (Th1 cells) to produce pro-inflammatory cytokines such as Interferon gamma and lymphotoxin; Th-1 type reactions are generally associated not only with inflammatory immune responses but also delayed hypersentitivity reactions.
While MRTCs from normal individuals induce Type 2 helper cells associated with antinflammatory effects, the myelin-reactive T cells from MS patients provoke pro-inflammatory Th-1-mediated responses.
The biofirms discussed below are developing therapeutics aimed at controlling MS-specific aspects of immune activation and responses. These include, for example, blocking the interaction between T cells and myelin antigens necessary for triggering Th-1 type responses and inducing immune responses against myelin-reactive T cells to reduce their numbers. In theory, these approaches would avoid compromising the immune system and allow normal immune surveillance mechanisms to operate.
PharmaFrontiers’ (www.pharmafrontierscorp.com) Tovaxin consists of MRTCs removed from an individual MS patient’s blood, expanded in cell culture in the presence of three myelin-derived peptides (MBP, PLP, and MOG) recognized by myelin auto-reactive T cells, then irradiated, rendering the cells nonreplicative but viable. When these attenuated MRTCs are injected subcutaneously into the MS patient, the body recognizes them as foreign and mounts an immune response against them, destroying not only the injected cells, but also the circulating, myelin autoreactive T cells carrying the peptide-specific T-cell receptor molecules.
The myelin-reactive T cells comprising Tovaxin, once returned to the patient via subcutaneous injection, stimulate anti-idiotypic and anti-ergotypic [a response that recognizes the state of activation of T cells irrespective of their TCR specificity] responses, differentiating this therapy from other products, explains Jim C. Williams, Ph.D., PharmaFrontier’s COO.
The key to the technology, continues Dr. Williams, is that Tovaxin can dampen or eliminate Th-1 type responses and increase Th-2 responses, and induce cytotoxic lymphocytes to destroy MS-specific pathogenic cells.
Two years ago, according to Dr. Williams, the reaction to autologous therapy was very cool in the investment community. Since then, we have amassed a lot of clinical data suggesting this approach may have significant promise in the treatment of MS, he says.
PharmaFrontiers has also developed a monitoring procedure that, points out Dr. Williams, will help us determine whether, pre-therapy, patients have the cells we use to make the vaccine. We also plan to use the assay to determine how long, post-vaccination, MRTC cells remain depleted.
The company is focusing on developing a vaccination schedule that maintains anti-myelin T-cell depletion for a year.
In PharmaFrontiers’ Phase I/II studies, Tovaxin (administered to MS patients in four injections over 3 months annually) reduced relapses more than 90% with virtually no side effects, according to the company. Additionally, approximately 40% of the MS patients treated with Tovaxin experienced a reversal of disability, while the remainder of patients (except for one relapse) experienced no progression of disease.
Based on the results of the Phase I/II studies, the company will begin a Phase IIb clinical trial to study Tovaxin therapy in 2006. The trial will enroll 150 patients (100 treated, 50 placebo) with early-stage disease, where the company expects that Tovaxin therapy will be most likely to have its greatest impact. The primary endpoint will be lesion evaluation (the total number of gadolinium-enhancing lesions) using MRI with a secondary endpoint being annual Artielle ImmunoTherapeutics (www.artielle.com) is developing autoimmune therapeutics based on Recombinant T-cell Receptor Ligands (RTLs). Artielle licensed RTL technology from the Oregon Health & Science University (OHSU), and says that the ligands, recombinantly produced proteins that comprise part of the MHC class II receptor molecule of antigen-presenting cells, can be tailored to treat a range of autoimmune diseases.
Their potential versatility and specificity lies in Artielle’s ability to produce RTLs with the desired antigen fragments covalently tethered in the appropriate molecular configuration. In the case of MS, by presenting MS patient myelin-reactive T cells with myelin antigen in a truncated, MHC class II molecular context, MS therapeutic candidate RTL1000 partially inhibits their activation.
Furthermore, the company says, T cells produce anti-inflammatory cytokines, such as IL-10, which generate auto-antigen specific bystander T-cell suppression useful for treatment of complex auto-immune diseases. Artielle’s approach to creating its MS therapeutic combines the molecular context in which antigen-presenting cells (APCs), like macrophages, present antigens to immune effector cells with the antigens themselves (in this case, peptides that mimic myelin components attacked by activated T cells).
APCs present antigens to T cells using protein complexes on their surfacesMHC moleculesthat physically bind the antigens. Artielle’s RTL1000 is a recombinant protein produced in E. coli that is made up of two of the four domains that form a complete MHC Class II DR molecule, plus an MS-related peptide. The two MHC protein domains, alpha-1 and beta-1, form a groove that holds the peptide; the entire genetically engineered protein spontaneously self-assembles once purified from E. coli.
According to Artielle’s vp of product development, Andrew Goldstein, This molecule promotes inhibition of myelin reactive T cells rather than the activation that causes them to attack myelin by initiating Th-1 proinflammatory responses.
The specificity of the approach lies in the myelin peptide, since only myelin reactive T cells would be expected to recognize and react to RTL1000.
In animal models of MS (mice injected with myelin peptides that produce an autoimmune encephalomyelitis with symptoms similar to multiple sclerosis), The drug has been quite effective in rescuing the animals from the severe autoimmune responses created by injecting them with myelin peptides, notes Goldstein. Also, we have not seen any severe side effects of the drug, even at very high doses.
The company is optimistic that we will be entering Phase I clinical trials during 2006, continues Goldstein, saying we believe this approach to be safe and effective in the animal model but it’s still a long way from efficacy in animals to efficacy in humans.
Relapsing MS Therapeutic Vaccine
MS and other autoimmune disorders may result, in part, from a failure of normal regulatory (tolerance) mechanisms that limit the numbers of disease-causing autoreactive T cells. Scientists at Immune Response(www.imnr.com) were among the first to show that MS patients have lower than normal levels of a type of regulatory T cell that in healthy individuals helps control the activity of myelin-reactive T cells. These regulatory T cells can be detected by their content of a specific gene marker called FOXP3.
The company announced in April that NeuroVax, its candidate MS vaccine now in Phase II clinical trials, continues to stimulate MS-specific cell-mediated immune responses in all patients treated thus far. The firm presented the results of a one-year, open-label trial that enrolled 25 patients who received monthly NeuroVax injections.
At 52 weeks following the first injection, 14 of 17 patients tested for FOXP3 cells showed increases in FOXP3 mRNA and protein expression, compared to their diminished baseline levels, some of whom had higher post-treatment levels than those seen in healthy controls.
NeuroVax consists of a mixture of three T cell Receptor (TCR) peptides that represent specific amino acid fingerprint sequences for three over-expressed TCR families in MS patients combined with Freund’s Incomplete Adjuvant.
Our data have shown that 90% of MS patients over-express one or more of three subfamilies of T-cell receptors, explains Richard M. Bartholomew, Ph.D., executive director of research operations. Our vaccine candidate is composed of three short peptide sequences that mimic the fingerprint on these 3 TCR sub families.
Pointing out that in MS, T cells are both the culprits (pathogenic T cell) and the solutions (regulatory T cells), Dr. Bartholomew said that in addition to stimulating and replenishing the FOXP3 regulatory cells, other key immune cells may also be induced by NeuroVax, including Killer T cells (CD8+ cytotoxic T cells, or CTLs), T cells and/or B cells that secrete inhibitory cytokines, such as IL10, and natural killer cells (NK cells), all immune events more characteristic of Th-2 type responses.
If FOXP3 cells turn out to be as important a part of this regulatory system as we think they are, we will like the fact that our product does not block but instead reestablishes a healthy system. This makes our product candidate unique in its mechanism of action, explains Dr. Bartholomew.
Based on these promising results and earlier indications of potential clinical benefits, the company will initiate a 200-patient, Phase II blinded, controlled clinical endpoint study in Eastern Europe and the U.S. in the second half of this year using MRI measurement of the number of CNS lesions as the objective indicator of clinical effect.
Bayhill Therapeutics(www.bayhilltherapeutics.com) is developing its therapeutic technology platform, BHT-DNA, for a number of autoimmune diseases, including MS. The technology was discovered at Stanford University by neurology professor Lawrence Steinman, M.D., and Hideki Garren, M.D., Ph.D., of Bayhill. BHT-DNA consists of plasmid DNA-expressing autoimmune-disease associated antigens. The company’s BHT-3009 for MS treatment expresses full-length MBP. Results from the company’s 30-patient Phase I/II clinical trial indicated trends toward improvement in active brain lesions as detected with MRI. The company has initiated a Phase IIb trial, and intends to enroll 252 patients with reduction in MRI-detectable active lesion formation as a primary endpoint.
Bayhill’s CEO, Mark Schwartz, Ph.D., explains that activation of myelin-destructive T cells associated with MS require two activation signals, one of which is antigen presentation. Our drug, Dr. Schwartz says, is a plasmid encoding the MS autoantigen, MBP. When BHT-3009 is injected intramuscularly, we believe that antigen-presenting cells pick up the DNA, express MBP intracellularly, and process it, then present the antigen to T cells. In the absence of other co-stimulatory factors, tolerance to the MBP antigen rather than T-cell activation occurs.
Dr. Schwartz said that in Bayhill’s Phase I/II trial, four of six patients with active MBP T cells treated with BHT-3009 showed a marked decrease in anti-MBP T cells as measured in T-cell proliferation assays. Patients’ T cells were assayed in vitro for their response to MBP and tetanus antigens. (Most adults have been vaccinated against tetanus and would be expected to have tetanus-antigen reactive T cells.) In plasmid-treated MS patients, marked decrease in proliferation of the MBP T cells occurred, whereas the normal, expected proliferation in response to tetanus antigen was unchanged, indicating that the plasmid had specifically reduced myelin reactive T-cell levels without affecting the immune response to non-MS antigens.
All of these approaches aim toward treating MS in an antigen-specific manner, effectively treating patients and stopping disease progression without compromising normal immune function.