At Barts-MS we have been pushing the B-cell hypothesis based on circumstantial evidence when a lot of genomic, and other data, make it clear that T-cells are also involved in the pathogenesis of MS. Now that the first non-depleting BTKi (Bruton Tyrosine Kinase Inhibitor) is effective in MS does this change our central hypothesis?
Yes, I am eating my hat. I predicted that unless a BTKi was depleting it would not work in MS. Why?
I am convinced that EBV causes MS and that the only way to control MS was to deplete the peripheral blood and lymph nodes of B cells, in particular, memory B cells, to reduce the EBV viral load. EBV lives in memory B cells and provides these cells with a survival advantage by stimulating a signaling or messaging pathway, which is independent of antigen stimulation. The B cell needs this EBV-induced signal stay alive and proliferate.
Another pathway to keep B cells alive is via antigen stimulation. For the antigen stimulation to work, the B cell needs Bruton tyrosine kinase (BTK) activation, which plays a crucial role in B cell maturation. Mutations in the BTK gene cause a rare primary immunodeficiency syndrome that is X-linked (the gene is on the X-chromosome) called agammaglobulinemia or Bruton's agammaglobulinemia. Patients with this type of agammaglobulinemia have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. Based on this genetic disorder many Pharma companies have been targeting BTK as a treatment for lymphoma and autoimmune disease.
There is a licensed BTKi called Ibrutinib that is licensed for B cell lymphomas. About 2-years ago the Mouse Doctor and I had quite detailed conversations with Abbvie about doing an investigator-led, proof of concept study, to test Ibrutinib in MS. Abbvie were very supportive of this, but Janssen who co-developed Ibrutinib had cold feet, so our proposal never got off the ground. I made the argument that Ibrutinib, a depleting BTKi, would be superior to the non-depleting BTKi in development.
Therefore, I was somewhat surprised to see the press release from Merck last week confirming that the evobrutinib phase 2b study was positive in MS. This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards. This puts T-cells back on the agenda, possibly downstream of B cells. I personally can't wait to see how effective evobrutinib is at suppressing MS disease activity. It will need to be as good as anti-CD20 therapy to have a chance in the marketplace. Let's hope we get to hear the results of the trial at ECTRIMS. I am also aware of at least two other Pharma companies with their own BTKi about to go into clinical trials in MS. It is quite amazing how Pharma seems to get things much quicker than the wider MS community in terms of therapeutic targets; c'est la vie!
Now will Merck develop evobrutinib as a monotherapy or will they leverage the mode of action of oral cladribine (Mavenclad)? Cladribine is currently being used as a SIRT (selective immune reconstitution therapy). However, most pwMS will relapse or have a recrudescence of disease activity at sometime after receiving cladribine. Could cladribine be turned into a true induction treatment followed by evobrutinib as a maintenance therapy? We have shown that cladribine has a profound effect on B cells, in particular, memory B cells. Could evobrutinib post-cladribine maintain the remission very, very long term? This is how I would develop at least one of the trials in the phase 3 programme.
What about evobrutinib post-alemtuzumab? With alemtuzumab, I would use a BTKi in parallel. A BTKi may not only be effective in preventing recrudescence of MS disease activity it could possibly prevent the secondary autoimmunity post-alemtuzumab. Maybe this is the logic behind Genzyme's recent licensing agreement with Principia Biopharma to develop PRN2246 a BTKi in MS.
Biogen also has a BTKi (BIIB068) that is currently being tested in lupus. Will they let Merck and Genzyme steal a march on them? As the dominant pharma company in MS, I suspect they won't.
Evobrutinib appears to have triggered a BTKi Lemming Syndrome (a psychological quasi-condition in which the afflicted person/pharma-company becomes subject to the whims of a portion of popular culture, and bends his/her entire persona/company to conform to the norms dictated by the media-moguls/other pharma companies in charge of a said trend ;-).
Who said it wasn't an interesting time to be in MS? We clearly in a new era where we are unpacking the pathogenesis of MS and autoimmunity, in general, using new biological targets. Roll on ECTRIMS the evobrutinib results are going to be one of the highlights, if not the highlight of this year's meeting. MERCK KGaA DARMSTADT, Germany, March 7, 2018 /PRNewswire/ -- Primary endpoint met for evobrutinib (Bruton's Tyrosine Kinase Inhibitor - BTK) in relapsing multiple sclerosis (MS) First proof of concept for BTK inhibitor in MS.
Merck KGaA, Darmstadt, Germany, a leading science and technology company, today announced positive results from its Phase IIb study of evobrutinib (Bruton's Tyrosine Kinase Inhibitor - BTK) in relapsing multiple sclerosis (MS). The study has met its primary endpoint, demonstrating that evobrutinib resulted in a clinically meaningful reduction of gadolinium enhancing T1 lesions measured at weeks 12, 16, 20 and 24 in comparison to patients receiving placebo.
"We are encouraged by these early positive results of evobrutinib in relapsing MS," said Luciano Rossetti, Head of Global Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "The trial will continue so as to further inform our clinical development strategy for evobrutinib in MS."
Evobrutinib, discovered by Merck KGaA, Darmstadt, Germany, is also in Phase IIb studies in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).
Evobrutinib (M2951) is in clinical development to investigate its potential as a treatment for multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is an oral, highly selective inhibitor of Bruton's Tyrosine Kinase (BTK) which is important in the development and functioning of various immune cells including B lymphocytes and macrophages. Evobrutinib is designed to inhibit primary B cell responses such as proliferation and antibody and cytokine release, without directly affecting T cells. BTK inhibition is thought to suppress autoantibody-producing cells, which preclinical research suggests may be therapeutically useful in certain autoimmune diseases. Evobrutinib is currently under clinical investigation and not approved for any use anywhere in the world. SANOFI-GENZYME
• Clinical-stage oral drug candidate (PRN2246) with the potential to treat multiple sclerosis • Principia to receive $40 million upfront payment, future milestone payments could total $765 million
Thursday, November 9, 2017 7:48 am EST, Paris, France and South San Francisco, Calif
Sanofi will develop Principia Biopharma Inc.’s experimental oral treatment that shows promise in multiple sclerosis (MS) and, potentially, other central nervous system (CNS) diseases.
Under the license agreement signed this week, Sanofi will develop Principia’s Bruton's tyrosine kinase (BTK) inhibitor (PRN2246), which was designed to access the brain and spinal cord by crossing the blood-brain barrier and impact immune cell and brain cell signalling. This may help treat MS and other CNS diseases. PRN2246 is currently in clinical development.
“Our agreement with Principia is an example of Sanofi’s strategic commitment to build our drug discovery and development pipeline in MS and neurological diseases,” says Rita Balice-Gordon, PhD, Global Head of MS/Neuroscience Therapeutic Research Area at Sanofi. “Complementing our own internal R&D expertise, external relationships like this may accelerate delivery of new treatments to patients living with these serious diseases.”
“Sanofi is an ideal partner for PRN2246. The agreement allows Principia to maximize the BTK opportunity in neurology with a strong partner for PRN2246 while focusing internal resources on our lead BTK inhibitor in another therapeutic area.” said Martin Babler, Chief Executive Officer of Principia Biopharma. “PRN2246 is a blood brain barrier crossing, highly potent BTK inhibitor, that we believe is especially well suited for the treatment of MS and other neurological disorders.”
...... Analysts at Jefferies have found that Biogen ($BIIB) has quietly sneaked a lupus candidate into the lab for initial testing, coming as it does after the Big Biotech has in recent months cut its lupus research programs.
...... But in a note to clients posted today, Jefferies said that the company has now put forward a Bruton’s tyrosine kinase (Btk) inhibitor, known as BIIB068, into the clinic.
...... According to clinicaltrials.gov, the experimental candidate is targeting systemic lupus erythematosus (SLE) in a Phase I trial of 52 patients, which is expected to enroll by December.
...... Jefferies noted that while lupus “remains a challenging condition,” some Btk inhibitors have shown “signals of promise” in early trials.........