Acceleron "Luspatercept" drug increases RBC count blocking a type of protein

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Acceleron Pharma's most advanced drug in development may be aiming at the same disease as its Cambridge neighbor, bluebird bio, but CEO John Knopf says there's room in the market for the two very different approaches to the same rare disease.
In today's Boston Business Journal, I wrote a profile of Knopf where I focused on how he came to head the Central Square biotech that went public last year. The next few weeks will be important for Knopf and Acceleron (Nasdaq: XLRN) as both it and bluebird (Nasdaq: BLUE) present head-to-head data at the American Society of Hematology conference Dec. 6-9 in San Francisco. Both companies are targeting beta-thalassemia, an inherited blood disorder in which patients don't have enough red blood cells, albeit their treatments are very different.
Bluebird has been focusing on a gene therapy treatment, which involves transplanting red blood cells with new DNA. Acceleron's approach is a biologic agent called luspatercept, which increases red blood cell count by blocking a type of protein. There are no treatments for the disease, which is present in "thousands" of infants born every year around the world, according to the National Institutes of Health. Knopf said that while some patients may not respond to luspatercept, others will not be eligible for blood transfusions, meaning there's room for both Acceleron and bluebird to succeed.
In Acceleron's case, the data to be given next month will be initial results from a midstage trial of up to 50 patients being conducted in partnership with Celgene. The reason it's important is this drug will begin a Phase 3 trial next year in patients with the same disease — the first late-stage trial for the 10-year-old company, and one which will form the basis of an application for approval.
Luspatercept is also being tested in patients with myelodysplastic syndromes, a bone-marrow disorder. Acceleron has three other drugs in midstage trials aimed at a variety of diseases, including cancer, which are based on the same approach. That approach is based on drugs that block proteins in a group known as transforming growth factor beta protein superfamily. That's the initial focus Knopf had when he began the company in 2004, a few years after after the biotech bubble had risen and waned and a time when he said biotech firms had to be "a little more rigorous" with their science.
Acceleron was very much a company which first came up with a drug, and only later found a disease which it could be used against, said Knopf.
"It was really emerging around that time that there was this family of proteins emerging that had these pretty remarkable activities," he said in a recent interview.
Animal tests confirmed that another of Acceleron's early drugs, sotatercept, increased red blood cell count. Then the company found two kinds of anemia which correspond to the way that drug makes cells. Since Celgene (Nasdaq: CELG) was already a leader in developing drugs for MDS, the New Jersey company ended up being an ideal partner for both sotatercept and luspatercept. Of the two, luspatercept is the only one which the company has slated for a Phase 3 trial.
"It turned out by doing the science ... we appreciated that that was a disease ideally suited for our particular product," Knopf said.

Link: http://www.bizjournals.com/boston/blog/bioflash/2014/11/acceleron-drug-for-rare-blood-disorder-slated-for.html?page=all

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Offline Sharmin

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Thank you for sharing catchR - this is all very exciting and positive. 

Andy, I am assuming this drug is likely most helpful to thal intermedias who have some ability to form blood - as opposed to beta zeros?

What are your thoughts?

Sharmin
Sharmin

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Offline Bostonian_04

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andy, what are your thoughts on this? Will it help thal majors?
Quis custodiet ipsos custodes ? - Plato

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Offline Andy Battaglia

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Sharmin,

Trials will eventually include both non-transfusing and transfusing patients. If I understand this correctly, this is completely different from attempts to raise the HbF level. To put it simply, red blood cells are destroyed in the bone marrow before they can become mature, useful RBC's. The object of this drug is to allow the RBC's to reach full maturity. I cannot predict how much the Hb can rise from this, but their short term goals seem to be based on the belief that a significant rise in Hb will occur within the first two months of treatment.

The study is currently recruiting participants. http://www.clinicaltrials.gov/ct2/show/NCT02268409?term=Luspatercept&rank=2
Andy

All we are saying is give thals a chance.

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Offline Sharmin

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Thank you Andy,

It is so great to see various avenues being pursued.  Patients have different outcomes with different treatments so the more options the better. 

I wonder if gene therapy were to increase hemoglobin to some extent - if the effects can be supplemented with this drug?

Sharmin
Sharmin

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Offline Andy Battaglia

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There are so many different approaches to treating thalassemia that are under investigation and most show promise, and it is likely that various treatments could be used together to free patients from transfusion.

But there is constantly one thing working against them and that is lack of funding. Most major drug companies do little to no research of their own on orphan diseases like thalassemia, so that source of funding is usually absent. Typically, it is small time researchers with little funding pursuing these ventures, many falling by the wayside from lack of funding and not because there is a lack of science. If somehow they can get enough funding to develop a drug and run trials that show positive results, then some Big Pharma giant will buy the drug with the hopes of making huge profits, as we have seen in the past year with Novartis paying $30 million for a new chelator. Eventually, they stand to make billions if the drug is a success. Something is wrong with this system. I've talked to researchers with fantastic ideas who have trouble raising $30,000 to continue their research. The pharmaceutical business is the most profitable industry, yet the money does not necessarily flow into research. More money is actually spent on advertising. As long as we have a pharmaceutical industry, and much of the medical industry with profit as its only true motive, progress will not be at the pace we would like to see.
Andy

All we are saying is give thals a chance.

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Offline CrazyPharm

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The research on this drug is quite promising and exciting. More information regarding phase 2 trial results in Thalassemia patients was released and was quite promising. Keep on the lookout for this drug in the future :D


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Offline Parin

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Thank you for sharing the updats..keep us updating.


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Offline sofear

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Fresh update on Luspatercept:
http://www.bizjournals.com/boston/blog/bioflash/2015/05/acceleron-gains-and-bluebird-falls-in-blood.html


More on latest study from Acceleron - Luspatervept: http://investor.acceleronpharma.com/releasedetail.cfm?ReleaseID=910306

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In the higher dose groups (0.75 to 1.75 mg/kg administered subcutaneously every three weeks):
  • 54% achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy.
  • 36% of patients who received red blood cell transfusions during the 8 weeks prior to treatment in the study achieved transfusion independence for at least 8 weeks during the study.

Ring sideroblasts (RS) are a type of abnormal red blood cell (RBC) precursor cell in the bone marrow. These ring sideroblasts are associated with ineffective erythropoiesis and anemia. When at least 15% of the cells in an MDS patient's bone marrow are ring sideroblasts, this patient is considered RS positive. At least 30% of all MDS patients are RS positive, and the proportion is likely even greater within the lower risk segment of all MDS patients.

In the RS positive patients in the higher dose groups treated with luspatercept,
  • 63% achieved IWG HI-E
  • 39% achieved transfusion independence

Just in case someone wants to know what exactly that means. I had to search for it, too:


Source: http://www.bloodjournal.org/content/bloodjournal/108/2/419.full.pdf

I'm currently a bit confused what the difference between Sotatercept and Luspatercept is. I haven't been following the studies in detail. The website of Acceleron states:

Quote
Sotatercept and luspatercept are biochemically distinct molecules and may have unique pharmacological attributes that enable their preferential use in particular anemia indications.  Notably, unlike sotatercept, luspatercept does not bind with high affinity to activin A.  In preclinical studies, luspatercept promoted red blood cell (RBC) formation in the absence of erythropoietin (EPO) signaling, had distinct effects from EPO on RBC differentiation, and acted on a different population of progenitor blood cells than EPO during RBC development.  In these studies, luspatercept did not promote significant increases in bone mass.
Source: http://www.acceleronpharma.com/products/luspatercept/

I found a topic on the forums with that exact question, but it has not been answered, yet: Luspatercept vs. Sotatercept

I found some old data on Sotatercept in a presentation. It's interesting how dosage and change in Hemoglobin correlate with each other:


Full presentation: http://www.cooleysanemia.org/PowerPoint/A536-04.pptx

The presentation also mentions the following:

Quote
Further dose escalation is ongoing; longer-term extension studies are planned

The Luspatercerpt doses seem to be in the same area as the the Sotatercept ones, but the recent results seem to include 'higher dose' groups, which receive 0.75 to 1.75 mg/kg every three weeks, while the Sotatercept presentation only mentions maximum doses of 0.8 mg/kg.

I found another study where Sotatercept doses of up to 1.5 mg/kg are mentioned: Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia
« Last Edit: May 20, 2015, 06:05:31 PM by sofear »

 

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