Topic: Narsoplimab & TA-TMA

I figured it is time to start this thread in prep for tracking revenue from HSCT patients.

Here is the due diligence on Addressable Market, done by a member of the email group I belong to.

Once we know average amount used to treat and the cost of narso, we'll be able to estimate revenue.
I'm sure we are all familiar with the company's slide summarizing severe TMA occurences.

25,000-30,000 allogeneic transplants
40% TMA incidence
Up to 80% severe

Doing math, that's 8,000-9,600 annual severe TMA incidents. Or to be more accurate, "up to" 8,000-9,600. Studies I've seen indicate 1/3 US and 2/3 EU. I find it interesting that there are none in other geographies.

I saw a link on ST (https://www.onclive.com/view/narsoplima … k-hsct-tma)
to a presentation in which TMA incidence was identified as 12%-39%. A wide range.

The 39% figure appears to come from Jodele (2014), which was 39/100 patients.

That pioneering study, noted for its identification of criteria for diagnosis, also referenced other studies, including Laskin (2011), which had TMA incidence at 20%-30% (unclear to me if allogeneic or total).

Jodele had 90 allogeneic and 10 autologous procedures. All TMA cases were in allogeneic transplants. So while many cite the Jodele 39%, the more appropriate math is 39/90=43% (allogeneic). Also, not surprisingly, it has been confirmed in other studies that TMA incidence in autologous procedures is very low. Jodele appears to be a study of patients ages 2-15 years, average age 7 (per its Table 1), in 2010-2011, at a center in Cincinnati.

Shimoni (2004) found TMA incidence estimated at 20-28% in allogeneic procedures.

Willems (2010) found TMA allogeneic incidence of 14%.

Nakamae (2006) found 18%.

The Jodele authors believed that their study had a higher incidence of TMA than others because they included all TMA cases, not just severe cases. Also, prior to Jodele there really weren't agreed-to criteria for diagnosis of TMA and severe TMA.

Autologous is where the stem cells come from the patient, whereas allogeneic are where they come from a donor.

Allogeneic has also been broken down into transplants coming from a related or unrelated donor, by the CIBMTR, which has been tasked by DHHS with keeping these data for the US.
https://www.cibmtr.org/ReferenceCenter/ … ex.aspx#cw

Here is their database link.
https://bloodstemcell.hrsa.gov/data/don … statistics

The WHO study I cite above says there are "more than 50,000" total transplants each year allogeneic and autologous).

The HRSA/CIBMTR study (link above) says there were 22,863 total transplants in the US in 2017. Of these, 4,972 were from unrelated donors.

Here is a very helpful summary of US procedures, though the data appear to be kept on procedures outside the US as well (slide 2).
https://www.cibmtr.org/ReferenceCenter/ … sting.pptx

As you can see in that deck (slide 3), the number of allogeneic procedures in the US has steadily risen, to about 8,600/year (2019), though there are more autologous (14,000 in 2019) than allogeneic procedures. The ages have also shifted to older recipients, over time (slide 15).

Recall that OMER has said 25,000-30,000 allogeneic procedures globally/year. The US data are clear, at 8,600 in 2019, but growing.

For EU the data show 42,000 procedures in 2016, 20,000 of which were allogeneic, growing consistently over time.
https://ashpublications.org/blood/artic … -Stem-Cell

So EU and US are in the 25,000-30,000 range cited by OMER. As of today 30,000 is the better estimate, and the number was growing through 2019. Not sure about COVID effect for 2020.

As regards "severe" TMA incidence (company says "up to 80%"), Jodele found 18 of 39 (46%) were severe.

As referenced above, what constitutes severe TMA is not clear, and especially pre-Jodele.

Sample calcs:
8,600 US allogeneic procedures
30% incidence of TMA
46% severe
That's about 1,200 cases/year
Or 1,550 at 40% TMA/46% severe
Or 2,750 at 40% TMA/80% severe

EU is 20k in place of 8,600, so 2.3x the US. And that is based on a 2016 EU number vs 2019 US, so EU is really more like 2.4 or 2.5 x US.

Call it US 1,500 cases. At $200k/patient that's $300 million/year. Apply 7x multiple that's $2.1 billion in value.

EU at 2.5x that's $750 million/year. At 7x that's $5.3 billion in value.

Also, again, the market is growing. And that excludes Asia and anywhere other than US and EU.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

And assuming $200K, which would be a nice discount to Solaris


Re: Narsoplimab & TA-TMA

I'd prefer to assume nothing.
CV19 is a wild card.
If CV19 income is so great, even  at a low price, but made it cheaper to treat other things, I'll be quite happy.

The CHEAPER Naso is for HSCT, the less severely ill patients can be given it earlier and avoid the TMAs.

I'd rather treat all 8000 at $100,000 than 4000 at $200,000.

Plus, IMO $200,000 makes no sense.

Narso will be sold by the ML.
aHUS patients need treatment every couple of weeks then, say, once or twice a month for the rest of their lives.

Soliris/Ultomiris cost about $10,000/week

HSCT-TMA patients may need treatment for a month or two. At $10k/week that is less than $100,000.

But, you might say, it now costs them $1 million or more and then they die. Yeah, you can charge $20k/week until you get another indication, like aHUS. You charge that much for aHUS you will sell NADA.

Even for IgAN, which may require 2 to 6 times the length of treatment as TA-TMA.

Then complicate it with selling for Covid.

Say 4 weekly treatments.
If it is $10k per week how many patients will you treat per year compared to if it was $5000/wk?

Will you treat so many EIS patients at $5000/week that you can afford to charge the same to people in all the other indications?

Omeros has to figure this out (and I am sure they have a number of scenarios). I presume these treatment prices affects what specific CV19 indications  they want, or what money up front they want, or what kind of supply deal they would settle for.

We do not know and there are so many alternatives, probably some completely unknown to us, that IMO we should not make a judgment or presume we know.

I don't really care to brag, like ALXN, about OMER's expensive treatment.

I want to brag that Omeros is saving more lives, has a $100B market cap and its longterm investors make a bundle of money.

There is a price where more lives will be saved and more money will be made. The "sweet spot".

Before CV19, it depending on the price of treating aHUS, IMO. Now it depends on the price treating Covid.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

I posted this elsewhere but it is more useful here for treatment of Transplant-caused TMA.
TMA, a Rare Complication of Stem Cell Transplants
The title of this post is somewhat misleading in that the word ‘complication’ may conjure up a host of reasons why not to consider stem cell transplants (SCT). To the contrary. This post actually will turn out to be GOOD news.

First, what is TMA? TMA is shorthand for thrombotic microangiopathy (more in a bit). In specific, this post is about stem cell transplant related TMA (HSCT-TMA). The treatment regimens that we are familiar with (conditioning regimen prior to transplant, toxicities associated with immune-suppressive drugs as well as infections that may occur during our treatment), may cause injury to endothelial cells. Graft-versus-Host-Disease (GvHD) in allo stem cell transplants is also a leading cause for TMA. The endothelium is a single, fragile, layer of cells that line all the blood and lymph fluid carrying vessels in the body, including the chambers of the heart as well as the ‘filters’ in your kidneys. You may not know that it exists,  but it plays a vital role in keeping you alive. An average person has about 1 kg (2.2 lbs.) of endothelium and its total surface inside the body is estimated to be between 4,000 to  7,000 square meters (or 40,000 to 70,000 square feet – approximately  1 to 1.5 acres).

And what does the endothelium do?

Monitors and controls the release of water and electrolytes in the blood
Controls blood pressure by relaxing and contracting blood vessels, in response to hormonal or other signals
Prevents blood from clotting inside the blood vessels by releasing anti-clotting factors when needed
It keeps things OUT of blood vessels that shouldn’t be there and keeps things INSIDE blood vessels that shouldn’t be elsewhere
Grows and repairs blood vessels
It does not take much imagination to start thinking of a number of health problems that may result from injury to the endothelium or to endothelial cells from our treatment for cancer. Transplant associated TMA is increasingly identified as a complication seen in both auto and allo stem cell transplants. If not promptly diagnosed and treated, it can lead to significant long-term organ damage. Thrombotic microangiopathy means that tiny blood clots have formed inside the smaller/smallest blood vessels and often manifests itself as kidney damage and kidney failure. There has been no approved treatment, to date, for the treatment of HSCT-TMA.

The good news for today, though, is that the US Food and Drug Administration has accepted the regulatory submission for the compound narsoplimab a few days ago. The Agency had labeled this drug with its rare ‘Breakthrough Therapy Designation’ and has granted its developer (Omeros Corporation) Priority Review. For all practical purposes, this means that we may say this drug come to market and into clinical practice as early as July 2021. Patients that have been treated with this drug, in accordance with the study protocol, during its clinical investigation showed a 65 % complete response rate.

This medical milestone is summarized in the Company’s press release:

‘Endothelial damage, which activates the lectin pathway of complement, plays a central role in the development of HSCT-TMA. The condition occurs in both autologous and allogeneic transplants but is more common in the allogeneic population. In the United States and Europe, approximately 25,000 to 30,000 allogeneic transplants are performed annually. Recent reports in both adult and pediatric allogeneic stem cell transplant populations have found an approximately 40-percent incidence of HSCT-TMA, and high-risk features may be present in up to 80 percent of these patients. In severe cases of HSCT-TMA, mortality can exceed 90 percent and, even in those who survive, long-term renal sequalae (e.g., dialysis) are common.’

This news may not be of value to all of us, myeloma patients, but is certainly a welcome development for those of us who will be walking the road of allo stem cell transplants.

Find more myeloma news and information on www.myelomacrowd.org

Paul Kleutghen
Paul Kleutghen - I am a patient diagnosed in 2014 with primary plasma cell leukemia (pPCL), a rare and aggressive variant of multiple myeloma and have been very fortunate to find treatment at the division of Cellular Therapy at the Duke University Cancer Institute. My wife, Vicki, and I have two adult children and a grandson who is the ‘light of my life’. Successful treatment has allowed Vicki and I to do what we love best : traveling the world, albeit it with some extra precautions to keep infections away. My career in the pharmaceutical industry has given me insights that I am currently putting to use as an advocate to lower drug pricing, especially prices for anti-cancer drugs and, very specifically, CAR-T therapies, with recent contributions posted by Health affairs, the Institute for Clinical and Economic Review and the Centers for Medicare and Medicaid Services.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Alan, if Omeros had a market cap of $100 billion, what stock price (approximately) does that translate to at reasonable valuation?


Re: Narsoplimab & TA-TMA

With most Notes converted into shares, more options incentive awards and all employee options converted in a couple/few  years, approximately: $100B/85M :

Only $1176/share

I suggest you don't spend it quite yet.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

So is it fair to say that this conversion of market cap to share price is a fair way to gauge whether OMER is at fair value or not?  IOW, at $100B market cap, the stock is worth $1,176/share, therefore at $50B market cap the stock is worth $550/share, and so on?


Re: Narsoplimab & TA-TMA

That calculates the share price for Market Cap (MC), not enterprice value (EV).


MC= #shares fully diluted X share price

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Right, duh.  MC and share price are two sides of the same coin, so to speak, given some fixed number of shares.  Thanks.


Re: Narsoplimab & TA-TMA

I just estimated future "fully diluted" (all options and convertibles changed into stocks).

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

The wild card here is now many notes get converted into shares.  Greg is surely trying to minimize this.

12 (edited by Alan Robert Ross 2021-02-10 11:13:54)

Re: Narsoplimab & TA-TMA

I hope he doesn't blindly follow through with the initial plan (surely presented by the Underwriters as a bright idea).

At whatever time the Capped Call is cashable, there is no reason to blindly call the Note. To call ALL the Notes you still need $19 to $21/share IN ADDITION to the capped call proceeds to pay for the Notes and cancel the underlying shares.

So there is two questions:
1. When will the company have $200 million extra cash to do that?
2. Wouldn't the money be handy to accelerate bring new narso indications and/or pipeline (like cancer) drugs to FDA approval?

I think Greg is not just going to blindly waste a cash hoard that gives him choices UNLESS the company is swimming in money because of revenues and deals.

Maybe he'll like the idea of the SA author who wrote today's whacko article suggesting Omeros partner for only CV19.

I should add what I've said before: that IMO the convertible notes have been a stupid idea for Omeros and benefitted underwriters and note buyers while only causing trouble for OMER (including making the chronic short interest look larger) and the raising of 100s of $millions to gamble on Capped Calls.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Coming Attractions


original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

These docs get a lot of consulting fees.  This one mentions some heavy hitters


Re: Narsoplimab & TA-TMA

Yes, the KOLs make up their lost income from academic/scientific work with income from sponsors and companies who pay for their expertise and prestige/credibility.

Some say that Greg could have been making more money as a surgeon than he has been making from his >$1M salary at Omeros.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

http://www.trustintelligence.com/viewto … 5624#p5624

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

The following mumbo jumbo is describing the monetary part of Omeros's presentation to CMS, seeking a code for narso payment in 2022.


The whole document is here:
https://www.federalregister.gov/documen … ls-and-the

And you will find Naso start on page 25,282. It is easiest to open a search box and type in "narsoplimab" and your browser will take you to the page.

The exact method and definitions used by CMS are not known to me but it appears that Omeros is asking for $272,861 as the average cost.

See what you think.

If you read the rest of the OMER section, you will see that the CMS reviewers commented a lot about the Omeros-provided information being less than adequate for them. Presumably Omeros has experts who prepared their submission and may have submitted supplementary info, which CMS repeatedly asked for in the text.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

To be delivered at the European Hematology Association meeting.
https://library.ehaweb.org/eha/2021/eha … arsoplimab

Author(s): Miguel-Angel Perales, Mitchell Cairo, Rafael Duarte, Sergio Giralt, Vincent Ho, Jeffrey Laurence, Nelson Leung, Olaf Penack, Alessandro Rambaldi, Michael Scordo, Narinder Nangia, Steve WhitakerEHA Library. Perales M. 06/09/21; 324649; S241
Miguel-Angel Perales

Miguel-Angel Perales
All contributions
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Abstract Discussion Forum  (0) Rate & Comment (0)
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S241

Type: Oral Presentation

Session title: Stem cell transplantation - Clinical

Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation that is associated with significant mortality and morbidity and for which there is currently no approved therapy. TA-TMA results from endothelial injury caused by conditioning regimens, immunosuppressants, infection, and GVHD, which in turn activates the lectin pathway of complement.

Narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway and an activator of the coagulation cascade, was studied for treatment of TA-TMA.

This was a single-arm open-label pivotal trial in adult TA-TMA patients (NCT02222545). All patients provided informed consent. Protocol-specified treatment consisted of IV narsoplimab 4 mg/kg or 370 mg once weekly for 4 or 8 weeks with a 6-week follow-up period. The FDA-agreed primary endpoint required clinical improvements in each of 2 categories: 1) laboratory markers of TMA (platelet count and LDH) and 2) organ function (kidney, pulmonary, gastrointestinal, or neurological) or freedom from transfusion (platelets and/or red blood cells). Secondary endpoints included change from baseline in platelet count, LDH, hemoglobin, and haptoglobin. Patients receiving at least 1 dose of narsoplimab (full analysis set [FAS]; N=28) and patients receiving the protocol-specified narsoplimab treatment of at least 4 once-weekly doses (per-protocol [PP]; N=23) were analyzed.

Patients were at high risk for poor outcomes and had multiple comorbidities: kidney and neurological dysfunction were present in 75% (21/28) and 57% (16/28) of patients, respectively, at baseline. Patients received a range of 2–8 scheduled doses of narsoplimab (mean 6.3 doses) and median duration of treatment was 8 weeks. Narsoplimab treatment resulted in clinical response (achievement of the primary endpoint) in 61% (17/28) of the FAS and in 74% (17/23) of the PP population, based on improvements in both laboratory TMA markers and clinical status (organ function and transfusion burden). The time to hematological response (defined as time from first narsoplimab dose to time of achieving both platelet count and LDH primary endpoint criteria) was as early as 7 days (median 36 days) after start of treatment. There was a sustained improvement in platelet count and LDH change from baseline (Figure 1). Five patients never achieved platelet engraftment following transplant and were not included in the platelet count analysis. Improvements in kidney function, neurological function, or gastrointestinal function were observed in 67% (18/27), 50% (3/6), and 100% (1/1), respectively, in the FAS and 68% (15/22), 50% (3/6), and 100% (1/1), respectively, in the PP. No patients were evaluable for improvement in pulmonary function. Of patients who received transfusions at baseline, 48% (12/25) in the FAS and 55% (11/20) in the PP achieved freedom from platelet and red blood cell transfusion. Six patients died during the core study period: 1 of septic shock, 2 of progressive AML, 2 of neutropenic sepsis, and 1 of GVHD and TMA. These deaths occurred 3–42 days following the last narsoplimab dose.


In this high-risk patient population with TA-TMA, there were no safety concerns observed with narsoplimab, and treatment resulted in clinically meaningful improvements in laboratory markers of TMA and in organ function or freedom from transfusion.

Keyword(s): Complement, Stem cell transplant, Thrombotic microangiopathy, Treatment

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

MAXIM put out the post-Q1 report and kept price target at $25.
The analyst postponed TA-TMA revenue in the EU until 2023.

Q3'21 $9,301
Q4'21 $21,703
2021 $31,004
2022 $105,939
2023 $162,898

IMO, if this is all Narso sells, for HSCT-TMA, the Market will be quite disappointed.

If you want a copy, I can send one. Email me at agrossfarm@gmail.com

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Did he assume a low selling price?


Re: Narsoplimab & TA-TMA

I don't think he says the selling price but I have not read carefully, yet.
Busy selling stocks!

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

People are talking more about the new cse study published, from late yesterday.
SEATTLE--(BUSINESS WIRE)--May 13, 2021-- Omeros Corporation (Nasdaq: OMER) today announced that data on organ function improvement from Omeros’ pivotal trial of narsoplimab for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) will be shared as an oral presentation at the 2021 European Hematology Association (EHA) Virtual Congress. The presentation, entitled Narsoplimab (OMS721) Treatment Contributes to Improvements in Organ Function in Adult Patients with High-Risk Transplant-Associated Thrombotic Microangiopathy, will be delivered by Miguel-Angel Perales, M.D., Chief of Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center.

Dr. Perales’ oral presentation will be available on demand through the EHA Virtual Congress platform to registered meeting attendees beginning Friday, June 11, 2021 at 9:00 am CEST / 3:00 am EDT. The presentation abstract (S241) can be accessed on EHA’s website.

About Hematopoietic Stem Cell Transplant-associated Thrombotic Microangiopathy

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a significant and often lethal complication of stem cell transplantation. This condition is a systemic, multifactorial disorder caused by endothelial cell damage induced by conditioning regimens, immunosuppressant therapies, infection, graft-versus-host disease, and other factors associated with stem cell transplantation. Endothelial damage, which activates the lectin pathway of complement, plays a central role in the development of HSCT-TMA. The condition occurs in both autologous and allogeneic transplants but is more common in the allogeneic population. In the United States and Europe, approximately 25,000 to 30,000 allogeneic transplants are performed annually. Recent reports in both adult and pediatric allogeneic stem cell transplant populations have found an approximately 40-percent incidence of HSCT-TMA, and high-risk features may be present in up to 80 percent of these patients. In severe cases of HSCT-TMA, mortality can exceed 90 percent and, even in those who survive, long-term renal sequalae (e.g., dialysis) are common. There is no approved therapy or standard of care for HSCT-TMA.

About Narsoplimab

Narsoplimab, also known as “OMS721,” is an investigational human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a novel pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Omeros controls the worldwide rights to MASP-2 and all therapeutics targeting MASP-2.

A biologics license application (BLA) is under priority review by the U.S. FDA for use of narsoplimab in the treatment of HSCT-TMA, and the drug is in Phase 3 clinical programs for immunoglobulin A (IgA) nephropathy and atypical hemolytic uremic syndrome (aHUS). Narsoplimab is also being evaluated for the treatment of COVID-19 as a part of the I-SPY-COVID-19 platform trial sponsored by Quantum Leap Healthcare Collaborative. The FDA has granted narsoplimab breakthrough therapy designations for HSCT-TMA and for IgA nephropathy; orphan drug status for the prevention (inhibition) of complement-mediated thrombotic microangiopathies, for the treatment of HSCT-TMA and for the treatment of IgA nephropathy; and fast track designation for the treatment of patients with aHUS. The European Medicines Agency has granted orphan drug designation to narsoplimab for treatment in HSCT and for treatment of primary IgA nephropathy.

About Omeros Corporation

Omeros is a commercial-stage biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market and orphan indications targeting inflammation, immunologic diseases (e.g., complement-mediated diseases and cancers) and central nervous system disorders. Its commercial product OMIDRIA® (phenylephrine and ketorolac intraocular solution) 1%/0.3% continues to gain market share in cataract surgery. Omeros’ lead MASP-2 inhibitor narsoplimab targets the lectin pathway of complement and is the subject of a biologics license application under priority review by FDA for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy. Narsoplimab is also in multiple late-stage clinical development programs focused on other complement-mediated disorders, including IgA nephropathy, atypical hemolytic uremic syndrome and COVID-19. OMS906, Omeros’ inhibitor of MASP-3, the key activator of the alternative pathway of complement, is in a Phase 1 clinical trial, and the company’s PDE7 inhibitor program OMS527, targeting addiction and movement disorders, has successfully completed a Phase 1 trial. Omeros’ pipeline holds a diverse group of preclinical programs including a proprietary-asset-enabled antibody-generating technology and a proprietary GPCR platform through which it controls 54 GPCR drug targets and their corresponding compounds. One of these novel targets, GPR174, modulates a new cancer immunity axis recently discovered by Omeros, and the company is advancing GPR174-targeting antibodies and small-molecule inhibitors. For more information about Omeros and its programs, visit www.omeros.com.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

article about the Phase 2 trial.
OMER is retelling this every chance it gets to educate MDs in order to increase the adoption rate once narso is approved. Below is part of the article. For the rest of the short article, use this link:
https://www.targetedonc.com/view/narsop … ma-subtype

Narsoplimab Exceeds Expectations Across High-Risk HSCT-TMA Subtype
May 14, 2021
Jessica Hergert
Targeted Therapies in Oncology, May 2021, Volume 10, Issue 7 Page: 76

Administered narsoplimab in patients with high-risk hematopoietic stem cell transplant– associated thrombotic microangiopathy resulted in a response rate of 61% among all patients treated with the monoclonal antibody

figure image
Alessandro Rambaldi, MD

Administered narsoplimab (OMS721) in patients with high-risk hematopoietic stem cell transplant– associated thrombotic microangiopathy (HSCT-TMA) resulted in a response rate of 61% among all patients treated with the monoclonal antibody (n=28; 95% CI, 40.6%-78.5%; P<.0001), according to results from a phase 2 trial (NCT02222545). In patients treated per protocol with at least 4 doses of narsoplimab (n=23), the response rate was 74% (n=17; 95% CI, 51.6%-89.8%; P<.0001).

The MASP-2 inhibitor demonstrated high response rates and a significant improvement in laboratory markers and organ function irrespective of subgroup in adult patients, according to findings presented during the 47th Annual Meeting of The European Society for Blood and Marrow Transplantation, which was held virtually in March.1

“Based on external advisory feedback, the estimated response rate for this patient population was 15%, and this was indeed the FDA-agreed efficacy threshold for the primary end point in this clinical trial,” said lead study author Alessandro Rambaldi, MD, a professor in the Department of Oncology and Hematology-Oncology at the University of Milan and head of the hematology and bone marrow transplant unit at ASST Papa Giovanni XXIII in Bergamo, Italy, during his presentation of the data.

Moreover, responses were observed with narsoplimab in the overall population irrespective of subgroup, including age (<65, 58%; ≥65, 75%), sex (male, 65%; female, 50%), acute graft-versus-host disease (GVHD, 63%; no GVHD, 56%), significant infection (yes, 63%; no, 50%), multiple organ TMA involvement (yes, 64%; no, 57%), mismatched donor (yes, 60%; no, 61%), and transfusion within 2 weeks prior to first narsoplimab dose (yes, 56%, no, 100%) (FIGURE 11).

Additionally, patients responded regardless of baseline platelet count (≤20 × 109 /L, 60%;>20 × 109 /L, 61%), kidney dysfunction (yes, 57%; no, 71%), pulmonary dysfunction (yes, 40%; no, 65%), neurological dysfunction (yes, 63%; no, 58%), or gastrointestinal dysfunction (yes, 100%; no, 59%).

Endothelial injury syndromes such as HSCT-TMA, GVHD, veno-occlusive disease/sinusoidal obstruction syndrome, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage are common pathways for many early transplant complications caused by conditioning regimens, immunosuppressive agents, infections, and alloreactivity.

“TMA is a serious and life-threatening syndrome that is underrecognized and can occur in up to 40% of patients undergoing stem cell transplantation. TMA may coexist with other endothelial injury syndromes, such as GVHD, thus leading to an increase in morbidity and mortality after transplantation,” Rambaldi said.

Narsoplimab is an investigational, fully human immunoglobulin (Ig) G4 monoclonal antibody that inhibits MASP-2, an effector enzyme of the lectin pathway of complement. In HSCT-TMA, narsoplimab blocks the lectin pathway activation that results from endothelial injury. The agent also blocks MASP-2– mediated coagulation and activation of kallikrein. In turn, narsoplimab leaves the effector function of the adaptative immune response intact to fight infection.


original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Here is another article out recently: https://www.clinicaltrialsarena.com/com … l-utility/

Omeros’ narsoplimab to replace Alexion’s Soliris as go-to stem cell-associated TMA therapy, with broad clinical utility to lead to strong market traction, say experts
By Sean Rai-Roche
29 Apr 2021 (Last Updated April 29th, 2021 09:44)
Omeros’ (NASDAQ:OMER) narsoplimab in hematopoietic stem cell transplant-associated thrombotic microangiopathies (HSCT-TMA) will easily replace Alexion Pharmaceuticals’ (NASDAQ:ALXN) Soliris (eculizumab) as the current off-label standard of care (SOC) when approved, experts said.

Omeros’ narsoplimab to replace Alexion’s Soliris as go-to stem cell-associated TMA therapy, with broad clinical utility to lead to strong market traction, say experts
Narsoplimab will replace Soliris as a treatment for HSCT-TMA as it has a superior response rate in patients. Credits: ustas7777777/Shutterstock.com.
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High mortality and poor existing options result in widespread uptake
Soliris price point and some payer pushback make replacement ideal
Experts confident in approval given rare indication and Phase II results
Omeros’ (NASDAQ:OMER) narsoplimab in hematopoietic stem cell transplant-associated thrombotic microangiopathies (HSCT-TMA) will easily replace Alexion Pharmaceuticals’ (NASDAQ:ALXN) Soliris (eculizumab) as the current off-label standard of care (SOC) when approved, experts said.

Soliris has a response rate of 50% or less in patients and can cause infection, making narsoplimab a much more attractive option, experts said. Soliris has only been examined in retrospective studies so far, while narsoplimab posted strong registrational Phase II (NCT02222545) efficacy and safety results, they noted. Soliris’ costliness also had some physicians noting they are keen for a replacement.

Market uptake will be widespread because HSCT-TMA is associated with a high mortality and there are already poor clinical outcomes for patients with current forms of care, including Soliris, said experts. Narsoplimab can be administered to patients regardless of the reason for initial transplant. Patient co-morbidities linked to HSCT-TMA will also not negatively influence uptake, they said.

Besides the positive efficacy and safety results, the study’s composite primary endpoint is well-chosen and clinically relevant. In turn, FDA approval is likely, experts said. Narsoplimab has a 17 July PDUFA date.

GlobalData forecasts narsoplimab sales to reach $575m globally in HCST-TMA by 2027. The Phase II trial also tests the drug in atypical haemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenia (TTP). It is also being assessed in a Phase III (NCT03608033) trial for immunoglobulin A nephropathy and is being evaluated in COVID-19 as part of the I-SPY platform study (NCT04488081).

Omeros, which has a market cap of $1.12bn, did not respond to a request for comment.

Comfortably displaces incumbent with strong safety profile
Narsoplimab will replace Soliris as a treatment for HSCT-TMA as it has a superior response rate in patients, experts agreed. Phase II data showed narsoplimab produced a 61% objective response rate (ORR) in the full analysis set of 28 patients (P<0.001) and a 74% ORR in the per-protocol group (n=23). Per-protocol patients underwent at least four weeks of treatment, with the trial designed to administer over eight weeks of treatment, and the full analysis set included patients who stopped treatment early.

While Soliris elicits a response in almost all aHUS patients, its activity in HSCT-TMA was lower than 50% in the 50 patients he has treated, said Dr Gianluigi Ardissino, paediatrician, Centre for aHUS Control, Prevention and Management, Milan, Italy. He would treat all new patients with narsoplimab over Soliris because of the higher response rate from the Phase II data, but would be reluctant to switch treatments for a patient on Soliris until any switching data was available. In the trial, patients who had used Soliris in the past three months were excluded. Soliris is approved for paroxysmal nocturnal haemoglobinuria (PNH) and aHUS, according to the FDA label.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

I found this on an IV board. It goes through narsoplimab revenue potential for HCT-TMA I hope it will format correctly (but that is unlikely). I can put it on a share-able spread sheet if I can't get it to be readable. The author presumes $300k per patient. I think that is a high assumption on the price because of of the eventual need to price other indications. It could be correct and then, potentially, the drug price would be revised downward when other indications are approved.
Of course, the market, used to $300k/pt for TA-TMA will freak out if it is reduced to $250k or $200k.
Note that the author presume the US and Europe will pay the same amount for treatment. That is quite unlikely, too.
Here is my spreadsheet on possible narso sales in tma. I assume $300,000 per patient, could be higher or lower. Only 83 centers perform 85% of the transplants in the US, so uptake should be fairly rapid. You can pick your number from the table.

Performed Transplant    20000    40000    60000
Alogenic transplants    12000    20000    32000
Tma Incidence       40,00%    40,00%    40,00%
Patients with TMA       4800    8000    12800
High Risk Tma Incidence    80,00%    80,00%    80,00%
High Risk Tma Patients      3840     6400    10240
( Mortality without Narso 90%)

Treatment revenues per patient
(100 days mortality rate down 5 fold)    $300 000    $300 000    $300 000
Potential Revenues per year
100% Penetration in high risk Htma.    $1 152 000 000    $1 920 000 000    $3 072 000 000
Potential Revenues per year
100% Penetration 100% Tma    $1 440 000 000    $2 400 000 000    $3 840 000 000

At 50 percent penetration of high risk    $576 000 000    $960 000 000    $1 536 000 000
At 50% of alogenic (Prevention)      $1 800 000 000    $3 000 000 000    $4 800 000 000

80% high risk plus 20% non high risk...........3264.............5440...............8704
                                                       $979 200 000    $1 632 000 000    $2 611 200 000

From Study 2010  US    Centers    Alogenic Transplants    Average
Low volume centers           42                     1900    45
High Volume centers            41                     9637    235
total                                 83                  11537    139

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

"Moreover, the risk of progressing to mechanical ventilation or death was 26% for those getting the drugs and corticosteroids, compared with 33% in those getting standard care."

July 6, 2021
1:03 PM -05
Last Updated 3 hours ago
Healthcare & Pharmaceuticals
WHO recommends Roche, Sanofi drugs for COVID-19 to cut death risk
John Miller

3 minute read
The logo of Sanofi is seen at the company's headquarters in Paris, France, April 24, 2020.  REUTERS/Charles Platiau
The logo of Sanofi is seen at the company's headquarters in Paris, France, April 24, 2020. REUTERS/Charles Platiau

ZURICH, July 6 (Reuters) - The World Health Organization on Tuesday recommended using arthritis drugs Actemra from Roche (ROG.S) and Kevzara from Sanofi (SASY.PA)with corticosteroids for COVID-19 patients after data from some 11,000 patients showed they cut the risk of death.

A WHO group evaluating therapies concluded treating severe and critical COVID patients with these so-called interleukin-6 antagonists that block inflammation "reduces the risk of death and the need for mechanical ventilation".

According to the WHO analysis, the risk of dying within 28 days for patients getting one of the arthritis drugs with corticosteroids such as dexamethasone is 21%, compared with an assumed 25% risk among those who got standard care. For every 100 such patients, four more will survive, the WHO said.

Moreover, the risk of progressing to mechanical ventilation or death was 26% for those getting the drugs and corticosteroids, compared with 33% in those getting standard care. The WHO said that meant for every 100 such patients, seven more will survive without mechanical ventilation.

"We have updated our clinical care treatment guidance to reflect this latest development," WHO Health Emergencies official Janet Diaz said.

The analysis covered 10,930 patients, of whom 6,449 got one of the drugs and 4,481 got standard care or a placebo. It was done with King’s College London, University of Bristol, University College London and Guy’s and St Thomas’ NHS Foundation Trust and published on Tuesday in the Journal of the American Medical Association.

The U.S. Food and Drug Administration last week issued emergency use approval for Actemra for COVID-19. That's after its off-label use in the pandemic drove up sales by around a third to some $3 billion in 2020. read more

Kevzara sales rose 30% last year, Sanofi reported.

Still, testing Actemra and Kevzara for COVID-19 patients involved trial and error, as several failures emerged as the companies tried out the medicines on different patient groups. read more

The WHO also called for more to be done to boost access to such medicines in the lowest-income countries now facing surging COVID-19 cases and virus variants, coupled with inadequate vaccine supplies. read more

"Those are the people these drugs need to reach," Diaz said.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

The material below is Continuing Medical Education sponsored in part by Omeros. Both presenters are consultants for OMER and others, like ALXN, but Laurence is more for OMER. I am going to copy the whole thing for those of you who want to see what they are telling MDs who deal with transplant patients who may exhibit TMA, and what they are telling them about it, and its treatment.

Dr. Laurence, near the beginning, tells the MDs enrolled in this course that about 20% of HSCT patients have this problem. Omeros on the other had, in their presentation slides, estimates it to be 40%.

Omeros admits that there is a problem with defining the disorder because there was never any real approved treatment... yet if you read the course material below, they discuss the treatment of this poorly defined problem... and you can see there are already a number of treatment options (or they'd have nothing to discuss).

Once narso is approved it will be the only approved treatment. But if the addressable market is half the size, so will be the revenue. Perhaps when narso is successful, it will help define the problem better and the addressable market will increase to Omeros' estimate of 40% of allogeneic transplant patients. This is an unknown.

What is not an unknown is that if people treating these patients think there are only half the cases, fewer cases will be treated than we'd estimate going by Omeros's figures (which may be an estimate of AM after it has been better defined). If you are a futurist who doesn't care about the time value of money, the Addressable Market in 2025 or 2030 may be of interest, but it is not to me, because present value declines very substantially over time... and I am interested in what happens soon. This year and next year.

When I try to get an idea of 2021 revenue and 2022 revenue, I care about the current real market size and how much narso will sell.

Will the doctors treating HSCT-TMA give up the non-narso drugs they  currently use to adopt narso, right away?

IMO very few will do it right away. They will wait to hear the experience of their colleagues who are brave enough to try something new.

I am concerned whether there is actually 100 eligible patients a week or 200. IOW is it 20% of patients or 40%?

The first earnings report, showing narso revenue is much more likely to be a disappointment and cause massive dumping of shares if there are minimal revenues. The same will happen when Q1'22 revenues are reported, is Omeros estimates are too high and their own consultants are contradicting them (Jeffrey Laurence in this case...Jodele is still not really on the Omeros team).

If you read, or at least skim the educational materials below, you will see that, even though HSCT-TMA has no approved treatment, narsoplimab has and will have competitors they must displace. It will not be as easy as saying "narso is safer and more effective". As we know, for superior market performance, you need to do better than expectations, especially when you are from the wrong side of the tracks, as OMER has been market-love-wise.
Updates in HSCT-TMA: New Therapies and What They May Mean for Patient Care. Authors: Jeffrey Laurence, MD; Sonata Jodele, MD

Activity Transcript
Jeffrey Laurence, MD: Hello, I'm Jeffrey Laurence, professor of medicine at Weill Cornell Medical College in New York. I want to welcome you to this program titled, "Updates in HSCT-TMAs: New Therapies and What They May Mean for Patient Care." And joining me today is Dr Sonata Jodele. She's a research professor of pediatrics in the Division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children's Hospital Medical Center. Welcome.

First, I want to provide an overview of HSCT-TMA. As in all thrombotic microangiopathies, they're characterized by recognition of a microangiopathic hemolytic anemia, thrombocytopenia, and at least 1 damage to an organ. These occur in about 20% of allogeneic stem cell transplants in adults. Dr Jodele is going to talk to you about her experience in children, including autologous stem cell transplants.

Traditionally, we've said that about half of these TMAs may resolve following withdrawal of a calcineurin or mTOR inhibitor. Recently, that has become controversial, and some people believe that you do not need to stop the mTOR or the calcineurin inhibitor, and that there is much less of a chance you're going to get resolution of those TMAs by doing such as a simple maneuver. The most important thing to remember is that outcomes are quite poor when these TMAs persist.

Now, there are multiple risk factors for TMAs occurring in the stem cell transplants: infections, and the big 3 are Aspergillus, cytomegalovirus, and adenovirus, but any infection may trigger one of these TMAs; a high-grade (> grade 2) of graft versus host disease; the use of preconditioning radiation; the use of calcineurin and mTOR inhibitors, as I mentioned before; as well as advanced age, female sex, and the extent of the HLA mismatch. And the most important thing, in terms of recognizing these TMAs and the fact that there is a wide disparity in terms of incidence among different groups reported for these TMAs, is how you define them.

There are several working groups that have listed a variety of criteria. All of these working groups require evidence of hemolytic anemia that's microangiopathic, so recognition of schistocytes is very important on peripheral blood. The teaching point here is just look at the peripheral blood every day when you suspect a TMA. Schistocytes may not appear until many days after an inciting event. Platelet counts should be decreased. Different groups have different criteria about exactly how much a platelet count should be decreased, but most of them say at least about 25% to 50% of the baseline for the patient. LDH should definitely be increased, as evidence of any hemolytic anemia. Haptoglobin, we ordinarily think of as being decreased in a hemolytic anemia. The teaching point here is that haptoglobin is also an acute-phase reactant, so that a haptoglobin of 150 mg/dL, which we may consider within your normal range, could be low for patients whose haptoglobin really ought to be 1000 mg/dL.

There could be an increasing transfusion required, both the red blood cells and platelets, and different groups specify effects on organ function differently. So, some working groups have said that you're required to have an increase in serum creatinine, while other people recognize that might happen a little bit too late in the course of the disease. You should check for proteinuria, microscopic hemoglobinuria, and hypertension -- new hypertension -- as evidence of an incipient TMA. Direct Coombs test, if specified, should be negative, the caveat here being, if you have a multiply transfused patient, the direct Coombs may be positive in the absence of a hemolytic anemia.

Coagulation studies should be normal, and we're not talking about DIC, another type of thrombotic microangiopathy. We're talking about a stem cell transplant-associated TMA. And then, finally, if you measure the ADAMTS13 activity, they should be within the normal range. And virtually all TMAs associated with stem cell transplantation are not of the TTP variety. They're more of a complement-mediated disorder that is much more like an atypical HUS. Therefore, your ADAMTS13 should not be < 5% to 10% of normal. Given that introduction, Sonata, perhaps you can continue. What are some of the unique aspects of stem cell-associated transplantation in your pediatric population?

Sonata Jodele, MD: Thank you, Jeffrey. It's definitely important to discuss the unique aspects of pediatrics vs adults since we're collaborating very nicely on TMA projects at this time. In children, we've been running several prospective studies, and we have some better understanding of the presentation, risk factors, and diagnostic features. As you were mentioning, the diagnostic criteria are slightly updated in the pediatric population. So, in our prospective studies, we noticed that some features like LDH, proteinuria, and hypertension present very early in children with TMA and could give a hint that this problem is evolving. Also, we noted that proteinuria and complement activation serve as the high-risk features in pediatric TMA that currently we use for diagnostics, disease activity assessment, and therapeutics.

It's very important to understand the differences from adults, so we can work together. And in children, we know that disease-specific risk factors exist. Some children's immune deficiencies are at much higher risk of developing TMA, which with adults, technically, transplant occurs in more patients with malignancies. That would be very interesting to assess in the adult population. We also noted clearly that Black race is associated with high risk for TMA. We assume that should be across ages, but we still need to study this. So, I think it's very important for us to work together and to try to replicate some of the information we obtain in pediatrics in the adult population.

Dr Laurence: Thank you. Now, I've mentioned before that the TMAs in the stem cell transplant setting are not of the TTP variety. They're more complement mediated, and we'll delve a little bit more into the complement pathway later, but Sonata, could you provide an overview of the currently available, although they're off-label, approaches for the treatment of stem cell-associated transplant TMAs?

Dr Jodele: Currently, the best we know of the therapies are from complement inhibition. As we showed in our prior work, that complement system is very important in the pathogenesis of TMA. We know that it's not the only pathway that's active in TMA, but it's the pathway that we can intervene. And I will summarize just a couple of sentences. As we know that injury occurs in TMA from many factors in transplantation -- it could be from infections, as you mentioned, from chemotherapies. And when we injure the endothelium, the endothelium tends to activate the complement system, and the terminal complement activation, again, is destructive to the endothelium. So, this is 1 of the systems that we know is involved in pathogenesis. And we now know that all 3 complement pathways -- lectin, classical, and alternative -- are also involved in the pathogenesis of TMA, which is kind of different from other thrombotic microangiopathies.

We have some targets we can use there for our treatment of TMA. The best we know so far is about terminal complement blockade, and mainly in pediatrics, our most experience is in using eculizumab, which is a C5 blocker. So, this eculizumab, at least in our institution, we treated 64 pediatric patients, and I want to note we only offered this therapy to patients with very high-risk TMA, those who met the high-risk features -- this proteinuria and complement activation.

Those patients, untreated, as based on our prospective studies, had very poor survival. Their 1-year survival was 16.7%, and overall survival was < 10%. So, these patients required some attention, and by using eculizumab in a PK/PD-guided dosing strategy, we were able to improve those survivals up to 66%, which it's a good effort compared with their poor survival, but it's still not ideal because we would like to get better. Again, those were very, very high-risk patients, so not across-the-board all TMAs that were just diagnosed. As you see by the percentage, there was a lack of response in some patients. Definitely, we need to understand better how to use complement blocking agents in our population, and maybe we have to also understand other pathways so that we can do combination therapies, and those studies are currently ongoing.

Dr Laurence: Thank you, Sonata. I want to emphasize 2 important points that you made. The first is that, in the pathophysiology of these disorders, the inciting event appears to be in the fetal cell damage. In fact, if you look at most of the risk factors for these stem cell TMAs, things like the calcineurin and the mTOR inhibitors, things like accompanying radiation, things like graft versus host disease and certain infections, damage to the endothelium is often an inciting event.

The second thing is that you spoke about is that there are 3 parts to the complement pathway: the lectin pathway, the alternative pathway, and the classic pathway. At the moment, most physicians, as you said, have been treating with eculizumab as a C5 inhibitor, blocking the alternate pathway of complement. I'm going to talk now about the lectin pathway of complement because the lectin pathway of complement is activated whenever there's tissue damage, endothelial cell injury. You expose certain molecules, known as DAMPs, which serve as binding sites for proteins called MBL, which binds to an enzyme known as MASP-2, and MASP-2 is a protease, which activates the lectin pathway, which amplifies the alternative pathway of complement.

And so, it not only sets up a proendothelial cell injury milieu, but it also sets up a proinflammatory milieu. And then, finally, MASP-2 is also involved in the activation of prothrombin to thrombin. So not only are you damaging endothelial cells in the process of forming a TMA in the transplant setting, but you're setting off the coagulation pathway, and you're activating a complement component that perpetuates the activation of the clotting system. So, you get this positive feedback loop between endothelial cell injury, complement activation, particularly at the lectin pathway, and activation of blood clotting. And if you can't shut that off, you eventually may develop the disorder that we call a TMA. And that's one of the rationales for looking at specific inhibition of MASP-2 and the lectin pathway of complement in these disorders.

And one of the first studies to look at this was the use of narsoplimab, which is a monoclonal antibody that specifically targets MASP-2 and prevents its activity. And it's already been evaluated in a single-arm, open-label trial. It's given intravenously as a single infusion once a week, and it was either given for a total of 4 weeks or a total of 8 weeks in the setting of a documented stem cell-associated transplant TMA. And these were in adults, with 28 patients so treated. Their mean age was 48, and 71% of these individuals were male.

And the findings from this study, presented earlier this year, was there was a 61% complete response rate in the set that was fully analyzed and a 74% complete response in those patients that stayed and completed the protocol. And for the purposes of this study, a complete response was defined as clinical improvements in laboratory markers, such as platelet count and LDH, and either improvement in an organ function, such as the kidneys or the brain, or freedom from blood and platelet transfusions.

The 100-day survival postdevelopment of a TMA was 68% in all patients in this trial, but 94% among those who completely responded to narsoplimab infusions. The median survival in the full set was about 270 days, and the median survival actually has not yet been reached in those who completely responded to narsoplimab. All of this occurred in the setting of no major adverse events, and there's going to be a follow-up of this at the European Hematology Association meeting this summer in 2021. It also documented the marked increase in platelet counts and the marked decrease in LDH in patients with stem cell-associated TMAs treated with narsoplimab. So, we know that the lectin pathway of complement is an active player in the stem cell-associated TMAs, and that an inhibition of this pathway, an inhibition of MASP-2, appears to be a good thing to do in terms of clinical response and laboratory markers, but there are other potential targets in these TMAs that may also be of interest. And, Sonata, could you summarize for us some of these?

Dr Jodele: Yes, several drugs are now in the pipeline, so it's still coming back to complement inhibition. I wanted to mention that there's a phase 3 trial on ravulizumab in pediatric and adult patients, which is a long-acting eculizumab. There's also another terminal complement blocker called nomacopan or Coversin, which is a bifunctional inhibitor of C5 and also leukotriene B4, that also blocks terminal complement activity. There are very few cases of TMA in transplant patients treated with those drugs, so, for both, we should definitely study the pharmacokinetics of these drugs in the bone marrow transplant population, including children and adults, since these medications were not really studied yet in our population, and as we know, our patients usually process and use the drugs in a different way.

I also wanted to mention that there've been some anecdotal data in defibrotide maybe working for TMA. We know it's a good drug for VOD, which is another endothelial injury syndrome. I think we need to understand how to use this drug since patients with TMA have a high risk of bleeding, and one of the side effects of defibrotide is bleeding, but probably if it is used early enough, it could be a drug to study.

Definitely, you would want to mention plasma exchange, a procedure that has been used in the past with some success. I think the main point in our experience with plasma exchange is that, if you use it early, it could be helpful if you use it in certain situations when patients have pretty high cytokine storms. One thing to remember is that plasma exchange removes certain medications, so you cannot combine all therapies with it. You need to be thoughtful about it.

Also, we are now studying and looking to other agents from other pathways since we know, in TMA, the interferon pathways are involved, and also neutrophil extracellular traps are gaining attention to be evaluated as an inciting factor for complement activation in TMA. Hopefully, those studies will be coming in the future, but none of these pathway drugs are yet in the TMA world in the bone marrow transplant population.

Dr Laurence: Thank you, Sonata. Those are very important points. I actually want to add a caveat to the use of plasma exchange in this setting, at least in adults, in that 3 large studies, 3 large international studies that looked at the efficacy of plasma exchange in adults with established TMAs found an excellent response rate in terms of increases in platelet counts, in terms of decreases in LDH, in terms of increases in haptoglobin. The issue was that there was absolutely no difference in survival whether you use plasma exchange or you didn't. So, in the vast majority of these patients, at least the adult patients in these studies, plasma exchange made the numbers look good. The patients died, but they died with normal numbers. And it's an important thing to consider, not only in the transplant-associated TMAs, but also in atypical HUS in general, where the use of plasma exchange has a remarkable ability to change a lot of the hematologic parameters but may not ultimately make an impact on survival.

I think the novel therapies you mentioned are quite important, and they're going to be investigated. People have also looked at the possibility of combinations of therapies, maybe using something affecting the complement pathway in combination with something that may affect platelets, such as defibrotide, which could be of use, but all of this is experimental.

In terms of talking about side effects for some of these interventions in these stem cell-associated TMAs, it's important to recognize that there are certain clear differences. For example, eculizumab requires the use of prophylactic antibiotics to prevent development of certain infections. In adults, these are usually limited to Neisseria meningitidis and N gonorrhoeae, but in the pediatric population, there are also other encapsulated organisms that you may need to prophylax for, and certainly immunize against, both in the adult and pediatric population.

Narsoplimab is a little bit different. Narsoplimab does not require the use of prophylactic antibiotics or vaccinations against these organisms. And, as Sonata had mentioned, defibrotide may be associated with some bleeding risks, so it's something to watch out for. Also, in terms of differentiating the pediatric and the adult populations when it comes to making a diagnosis and potentially predicting outcomes, children are different than adults. And Sonata, could you address that in terms of the stem cell-associated TMAs?

Dr Jodele: Yes. I wanted to mention about our experiences with predisposing genetics, especially at complement genes. In pediatrics, we performed a prospective study looking at complement genetics and fingerprints in predisposing patients to TMA. We noted that quite a few patients, about 65% of those who developed TMA, had at least 1 variant in the complement gene panel, and we specifically structured the gene panel for 17 genes from what we usually test in HUS and other diseases. An interesting observation was that it was not 1 particular gene that predisposes patients to TMA, but a clustering of those variants. So, it's important to note that probably this variance, in regular life when you're not undergoing such a procedure as a transplant, would be irrelevant to life or cause any illness, but under such acute stress like a transplantation procedure, those variants increase susceptibility to TMA. And patients, especially of Black race, there's multiple complement variants, and they have very severe TMA, and they usually succumb to this disease.

So, clustering of the variants, and the more variants you have, the more susceptible you are to this complication. In adult teams, very nice work from Dr Gavriilaki in Greece has shown that in the adult population, there are similarities. There are also complement variants and ADAMTS13 gene variants in the adult population. Interestingly, both studies showed that the recipient DNA, and not the donor DNA, is what matters. So, I think this is important to remember since when we transplant our patients, then later when they engraft the donor cells, the blood is already from the donor. So, the 1 obstacle and 1 challenge, looking at genetics, is that you need the recipient's DNA, and that DNA either must be obtained prior to transplant like when we do an HLA typing or a buccal swab, but it still could be contaminated with donor cells.

But, interestingly, adult and pediatric studies showed kind of similar findings that complement genetics predispose those patients to TMA. In patients with multiple variants in the complement or in ADAMTS13 genes, there is increased risk for toxicity from TMA and transplant. So, this is something to keep in mind, but I think we are striving to find some functional studies that would be reflecting genetics that could be done quickly and at any time after the transplant, so we don't have to go back to genetics, which is a much more cumbersome test to do. So, we're striving to identify such a test.

Dr Laurence: Thank you. I think the last point that you mentioned is especially important because in our own study here at Cornell of adults who develop persistent TMAs after allogeneic transplants, we found no reported published mutations in complement or complement regulatory genes, but we found multiple unpublished polymorphisms in both ADAMTS13 and in the complement-related genes. It's just, in the absence of functional studies, we don't really know what their meaning is. And 1 more thing, the only time where you may also need to do not just the recipient genetics pre-transplant, but the donor genetics, is in the face of a complement regulatory protein that is on cell membranes -- that is perhaps a donor who had an MCP mutation where you transplant that kidney, and that potentially, I guess, could be at risk.

Dr Jodele: Interestingly, you mentioned about the published vs not published variants. And when we did the in silico modeling and when we looked at our patients, some of these variants were very functionally active in our RNA-seq studies, even though, in the databases, they're listed as nonpathogenic. So, I think we still need to learn what's important in our patient population. And, again, it's a stress vs susceptibility balance. In HUS, for example, you have a high genetic predisposition, and you don't need much stress to present with disease. Well, probably in the transplant setting, you have an underlying predisposition, and this very severe transplantation stressor provokes it much better than regular life events. So, I think it's still to be confirmed, and even though we don't do genetic testing as of yet as a standard procedure, or we might not do it in the future, I think it just teaches us a lot about functionality and what to expect in certain populations.

Dr Laurence: Very important points. Thanks.

At the moment, I would say that our key takeaway is that 1 of the most important things you can do in terms of exposure to a transplant-associated TMA is to make that diagnosis early. Recognition of this disease will permit earlier intervention. As you mentioned, perhaps using the plasma exchange early on will do something when later studies have not found benefit. So, recognizing the signs and the symptoms of a stem cell-associated TMA and how they may be different in adults and pediatric cases, as you've pointed out, Sonata, is very critical.

The second thing is, because these are so unusual -- and even many transplant surgeons that I talk to who have referred patients to our unit are not familiar with these TMAs -- seek expert opinion. If you have a difficult case, talk to all of us, people who have had more experience maybe than you do in your particular center in terms of the recognition and treatment of these disorders. And, again, additional trials with agents that block various parts of the complement pathway and continuing trials with narsoplimab are very important to the ultimate cure of this disease.

Sonata, thank you for this great discussion, and thanks to the audience. Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.

28 (edited by dorcse 2021-07-15 09:54:57)

Re: Narsoplimab & TA-TMA

Let's say the incidence is more like 20% rather than 40%.  Does that not support ultra "ultra" orphan pricing for Narso?  ALXN has had little trouble making a ton of money with a high priced drug and relatively few patients.  And Omeros has a better drug with opportunity for many more indications that are not orphan anything, no?  Obviously yes.

I do agree if that 40% number Greg keeps referring to is half that, it will be more ammo for the naysayers.  Sure hope Omeros' efforts to help docs recognize TMA and early TMA is successful.

29 (edited by Alan Robert Ross 2021-07-15 12:00:28)

Re: Narsoplimab & TA-TMA

Temporarily it is possible but even that is ONLY if there NO approval for Covid...or UNTIL there's an approval for Covid.

IMO the obsession with high pricing is wrong on many levels.
It is morally wrong because it is a life-saving drug.
It is foolish business-wise if the high price reduces usage too much so that 80% of the addressable market cannot afford.

Narso for CV and Long CV and other similar disorder, just in developed markets must be somewhere between 100 and 1000 times the market for HSCT-TMA.

OMER data says 25k to 30k allogenaic transplants and 40% have TMA, so that is 10,000 to 12,000 in US+Europe per year, with HALF that number being 5,000 to 6,000 and more in Europe, which is 20+% larger so let's say US between 2000 and 3000 patients per year.

Europe will NOT pay for it if the price is too high.
NOW we reduce the number because OMER says only 80% have at least 1 High Risk symptom.
Will the doctors use narso if there is only ONE? Or will they require 2 or 3?
If we assume ALL 80% that is 1600 to 2400 patients per year and between 400 and 600 per Q in the USA.
That is 123 to 185 patients per week.

see page 9 of this presentation to see my the OMER position on this
https://investor.omeros.com/static-file … 366365c37f

Treatment of TMA and Covid seems to be the same 2 infusions per week with a maximum of 4.
How many people per week can you treat with Covid, if the price is right?

The USA had a bit more than 4700 severe cases, yesterday. This group has new entrants daily and some are discharged, downgraded or die, daily, so let's assume 3 week turnover, so a rounded off 1600 people per week.

So if narso would treat 10 times the people with severe covid than with severe TMA if there was 100% market penetration in the USA.

If narso is priced for CV, it will also treat the US HSCT-TMA patients AND it will be more close to economic for Europe to use it for Covid, but almost definitely accept the price for HSCT in Europe.

And if it is cheap enough for Europe it will be cheap enough for use in much of the rest of the world.

Before I totally demolish the idea of super high prices, let us look at some examples.

- TA-TMA with a cost of $240,000/ person is $30,000 per infusion. $480,000 cost per person is $60k/infusion
- Treatment for CV19 is the same number of infusions, although on average is was 7 in the CUP.
- In the USA the Govt. is unlikely to pay $240k for each person. IMO, it is not going to pay $120k per person. Maybe it would pay....$24,000/person?
- Can we estimate that 1 treatment costs Omeros $1000? 

OK...If that is not a strong enough argument, I bring in the closer.
THE CLOSER IS the IGAN Phase 3 trial treatment regimen. 

To treat IgAN it take more than 4 weeks of 2 treatments per week. It is more likely that treatment could last for 6 months and then be restarted. Here is a quote from the Phase 3 IgAN protocol:

The study consists of five periods: Screening, Run-In, Initial Treatment (Weeks 1-12), Response Evaluation (Weeks 13-36), and Follow-Up (Weeks 37-144). Patients are assessed for re-treatment based on their response to 24-hour UPE. Additional treatment may be given to patients whose 24-hour UPE is > 1 g/day following the Initial Treatment Period and who relapse during the Response Evaluation and Follow-Up periods. Patients may be qualified for Open-Label Treatment with OMS721 after Week 72.

So, CV & TA-TMA 8 treatments and IgAN (let's guess twice a week for 15 weeks=30).

At those prices you will only treat people who they are sure will die.
And that discounts all the repeat treatments and the initial Run In preloading.

If you say that you can get payment if it is $450,000 to treat severe IgAN then that means you have to only charge $120,000 to treat TA-TMA

If you want to have an addressable market of people with >1g proteinuria, instead of >2, to increase your AM by 100,000 to 150,000 people in the US alone, you may be able to only charge $250k for the narso, which brings TA-TMA down to $60,000 cost.

And if you want to treat some large number of the 300 MILLION people with IgAN in China what price can you charge?

For that matter, how much can you charge the millions of Americans and Europeans with Long Covid?
There are constants in using narso. You have to give enough of it to stop 80% or more of the Masp2 to shut down the LP and you must retreat again before the effect wears off.

I do not know what Omeros is going to do with pricing.
My guess is that they will start with a high price for TA-TMA and then lower the price substantially if/when they get another approval that makes it PAY to lower it.

A 99.9% Gross margin is very nice and approximately the margin on Omidria, which does not sell enough.
If you can sell another million doses a year, the business is likely quite viable with even a 50% gross margin.

Someone with accurate numbers on cost and addressable markets, knowing the rollout plan and timing is presumably working on this, or already decided on a strategy.

I can guess it would be Market suicide for OMER to get TA-TMA approval and announce a $60,000 price or even a $160,000 price. Whiners will be out at $200k or even $250k.

Almost surely, there will be no EUA for CV19 prior to TA-TMA approval... so OMER can try to get a large Govt. order for CV19 and then maintain the price for TA-TMA, at least until they have to price IgAN (or until a smart analyst brings up the price for IgAN in the future).
Note that the exact numbers are not what I am predicting.
I am only illustrating how narso must be priced for all indications, consistently, EVENTUALLY and this tends to have the most narso-intensive indication set the maximum price for everything else.
Undercutting the price for a special indication, like CV19, undermines pricing for everything else unless supply can be effectively controlled (to not have CV19 narso used for IgAN, for example).

I also add the ULTRAorphan pricing will effectively reduce OFF-LABEL use, probably significantly and possibly  much more in $ terms than the extra money from charging $500k/TA-TMA patient (or more?).

Plus the trend, especially with the current US Govt. is to REDUCE prices.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

All excellent points Alan and thank you.  Pricing is a tricky proposition and I'm sure this has consumed a lot of time at the Seattle office.  Will Omeros get it right?  And even if they do, will the market recognize it?  It's not like Omeros gets the benefit of the doubt.. like ever. 

Anyway, thanks again for the thorough and thoughtful breakdown.  For what it's worth, I agree with you a more manageable price for Narso is the better play here.  I'll be eagerly awaiting word on pricing post approval.


Re: Narsoplimab & TA-TMA

The problem is that everyone will be waiting for the pricing.
IMO Omeros will not say the price is temporary even if that is the intention.
In the last presentation, Greg gave an indication in answer to a question, if I recall correctly, that narso would be price in a way that is appropriate for the orphan indication.

So I am expecting at least $200k for the average patient.

Then if/when narso is approved for a non-orphan, like CV19, the price will be reduced, possibly only for that new indication.

It may look better to the market that they keep the price high for TA-TMA even though they charge as low as $10k for CV19 "emergency" treatment.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Great article about pricing.  I think the whole Covid 19 thing has thrown off Greg's plans because of a small use drug priced high they can be more of a broad based drug with a much lower price.

I think a wider market at lower price deleverages the risk and act as a bit of a barrier against competitors that work almost as good for say 10% of the cost.


Re: Narsoplimab & TA-TMA

And it is great public relations and a way to get to be known by MDs.

But this was ALWAYS going to be an issue because the amount of narso  was always the most per person in aHUS, moderate in IgAN and smallest in TA-TMA...just the reverse order of approval.

This suggested that pricing aHUS at $500,000 to compete with ALXN limited IgAN to half of that approximately and TA-TMA to 1/4 of it (roughly) once all 3 indications were approved.

CV19 treatment may be identical or maybe half the amount of narso for TMA, but there will be a tradeoff between AM size and price. Higher the price the lower the addressable market.

Remember that ORPHAN has up to 200,000 people per year. And IgAN is close to that, but severe IgAN is much less... maybe 20,000 in USA. At a cheaper price, to keep people OFF dialysis (cots $100k/yr) maybe insurers will allow treatment of 80,000 moderate to high IgAN.

IMO being famous for high price treatment makes you a target for politicians.
NOT good in this day and age.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Alan Robert Ross wrote:

And it is great public relations and a way to get to be known by MDs.

IMO being famous for high price treatment makes you a target for politicians.
NOT good in this day and age.

You are welcome and that is very true about not wanting to be famous for sky high prices.  How about being famous for being able to effectively treat bad cases of covid 19.


Re: Narsoplimab & TA-TMA

"...being famous for being able to effectively treat bad cases of covid 19."

We hope.
Better late than never, although now many of those to be saved, and paid for by the Govt., presumably, have purposely left themselves vulnerable and risked the health of others, without giving a Sh*t.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Another company with delayed PDUFA just got an approval after 45 days of a 3 month extension.
Even a similar disease in HSCT.

See the PRs here"
http://www.trustintelligence.com/viewto … 8076#p8076

This would lead to an approval in the first week of September, if there was a similar event for narsoplimab.

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

I suppose I should not that July 17th was the original Narso PDUFA date.

PDUFA is not Oct. 17th.

Based on the case I reported yesterday we can hope that the approval is made public sooner than scheduled.

How could the FDA fail to approve narso for HSCT-TMA when it saves 85% of the patients, almost all of whom would otherwise die?

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.


Re: Narsoplimab & TA-TMA

Transplant-Associated Thrombotic Microangiopathy: New Insights, Emerging Treatments
July 22, 2021
Christina T. Loguidice
OncologyLive, Vol. 22/No. 14, Volume 22, Issue 14

An expert of panelists provide an overview of TA-TMA, including findings that raise suspicion of this complication, strategies they use for making the diagnosis, and how they intervene given limited treatment options.

figure image
Samer Khaled, MD

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication of stem cell transplants that can occur with peripherally mobilized stem cells or bone marrow-derived stem cells. “TA-TMA remains a difficult complication to address, with a high mortality rate and a lack of standard diagnostic criteria and limited therapeutic options,” Samer Khaled, MD, said during a recent OncLive Peer Exchange®.

Khaled was joined by a panel of adult and pediatric hematology-oncology experts who provided an overview of TA-TMA, including findings that raise suspicion of this complication, strategies they use for making the diagnosis, and how they intervene given limited treatment options. They also discussed some off-label treatments and the emerging treatment narsoplimab (OMS721), a human monoclonal antibody that is under review by the FDA.

Overview of TA-TMA
TA-TMA is triggered by injury to endothelial cells, such as from radiation, use of calcineurin or mTOR inhibitors, infections, or chemotherapy. However, this first hit to the endothelial cells is not considered sufficient to cause TMA. A second hit is needed, which the panelists explained is activation of the complement system, a part of the immune system made up of many distinct plasma proteins that react with one another in a cascade to destroy pathogens and fight infection. The same factors that damage endothelial cells also activate the complement system, the panelists noted.

“Injured endothelium exposes certain molecules, known as DAMPs [damage-associated molecular patterns], which bind a molecule known as MBL, mannan-binding lectin. MBL then activates MASP-2 [mannan-binding lectin-associated serine protease-2], which is an important enzyme in the cascade of a part of a complement system known as the lectin pathway. When activated, the lectin pathway itself can also then turn on the alternative path-way of complement. It is always on at very low levels waiting for a foreign invader or endothelial cell injury. Now you have marked activation of the lectin pathway and the complement pathway and the alternative pathway of complement in this system. If you can’t shut it off and it’s progressive, that can lead to 1 of these TA-TMAs,” Jeffrey Conrad Laurence, MD, explained.

figure image
Jeffrey Conrad Laurence, MD

The panelists said that there are some key differences with TA-TMA in pediatric vs adult patients. One distinction is that they are seen almost exclusively with allogeneic transplants in adults, whereas they occur with both autologous and allogeneic transplants in children. Only Khaled reported seeing a few cases in adults undergoing autologous transplants. “At City of Hope we had a protocol for an autologous transplant for scleroderma, and I saw a couple of cases on that protocol,” he said, noting that he has also seen 1 or 2 cases over the last 12 years in patients who received autologous transplants for myeloma.

Another key distinction is that TA-TMA in pediatric patients appears to have a genetic component, whereas in adults no gene polymorphisms appear to contribute to the condition. “[In a study by Jodele et al1], upward of 30% to 40% of her pediatric patients who developed TMA had some recognized mutation in a complement coagulation or complement-regulatory factor gene. Whereas in our studies at Weill Cornell Medicine, we never found that. In many other series in adults, it’s incredibly rare to find those kinds of genetic mutations. There may be something special about that [pediatric] population with higher underlying inability to control complement that makes the incidence much greater,” Laurence said.

Determining the incidence of TA-TMAs is challenging because diagnostic criteria did not exist until relatively recently and those now available also vary somewhat. “In fact, it depends on whether you really want injury to happen and then make a diagnosis, or do you want early diagnosis. The more stringent the criteria you apply, the less the incidence will seem,” Parameswaran Hari, MD, MRCP, said. Nevertheless, based on his experience, he suspects the incidence in adult patients to be in the 10% range for TA-TMAs that are of clinical consequence following a first allogeneic transplant. He noted that the incidence increases with a second transplant, reaching 15% to 20%.

figure image
Parameswaran Hari, MD, MRCP

In pediatric patients, the panelists noted the incidence is higher than in adults, ranging between 20% and 30%. “When I think about the difference between the adult and pediatric populations and the incidence, one of the questions that comes to mind is: Is it a difference in the patients, is it a difference in the treatment, or is it a difference in the providers?” Christine N. Duncan, MD, said. She explained it’s probably a combination of these factors, but that one of the main contributors is likely the screening criteria that were developed for children, which have helped raise awareness of the disease in the pediatric setting.

figure image
Christine N. Duncan, MD

Diagnostic Criteria for TA-TMA
A variety of diagnostic criteria for TA-TMA now exist, including those by the LeukemiaNet International Working Group, Blood and Marrow Transplant Clinical Trials Network, and the Jodele criteria, among others.2-4 In pediatric patients, Duncan said “there is relatively uniform acceptance of the Jodele criteria” (Table4). “We’re looking if you can meet 4 of the 7 criteria...but we don’t necessarily always say you have to meet all those points. If we have someone who has hypertension and proteinuria, we’re not going to wait and check everything else off to make sure they absolutely fulfill the criteria,” Duncan said.

Table. Laboratory and Clinical Markers Indicating TMA per Jodele Criteria4

figure image
The other available diagnostic criteria look at many of the same measures, with some also examining additional markers, such as the direct Coombs test, which should be negative in the setting of TA-TMA; coagulation studies, which should be normal; haptoglobin levels, which may be decreased; and creatinine levels, which may point to TA-TMA when elevated to twice the baseline level.2,3 The panelists proceeded to discuss the clinical and laboratory markers that they pay particular attention to. Hari said lactate dehydrogenase (LDH) level is a big marker at his institution, which implemented a policy to check patients’ LDH levels twice weekly while they are in the hospital following transplantation. He said this measure has helped them identify more TA-TMA cases. On the pediatric side, Duncan said they also test LDH levels in all patients once or twice weekly. “You don’t even have to think about it much if that is part of your routine on an inpatient, and if you see that with your lab values, that helps to trigger [a diagnosis],” she said. Duncan said another red flag in the pediatric setting is hypertension since this population rarely has it as a preexisting condition, though some degree of blood pressure elevation is expected from use of calcineurin inhibitors, steroids, and other agents.

Although ADAMTS13 activity is not part of any diagnostic criteria for TA-TMA, Laurence and Hari said they perform this test on all their transplant patients to help rule out thrombotic thrombocytopenic purpura (TTP). Making the distinction is important because patients with TTP can benefit from plasma exchange, whereas those with TA-TMA do not. “I noticed that in 3 large transplant studies5 the aggregate hematologic response to plasma exchange in a TA-TMA was 55%; that included a decrease or normalization of the LDH, increase in haptoglobin, and increase in platelet count. That 55% response rate to plasma exchange had no impact on mortality...the patients died with normal numbers,” Laurence said. He added that he no longer performs therapeutic plasma exchange for his TA-TMA patients.

Treatment Approaches for TA-TMA
One of the key treatment strategies for TA-TMA is to stop any offending agents, including any calcineurin or mTOR inhibitors. “We recommend substituting higher doses of steroids and CellCept [mycophenolate mofetil],” Laurence said. He explained another important measure is to look for and treat any underlying or coexisting conditions, such as infections, graft-vs-host disease (GVHD), or hypertension. The literature suggests these measures may be sufficient to resolve 50% to 60% of TA-TMA cases.6 The remainder require consideration of a variety of off-label or experimental agents, Laurence said, particularly agents that target the complement system, such as eculizumab (Soliris), defibrotide (Defitelio), or narsoplimab, since there are currently no approved treatments for TA-TMA and resolution of TA-TMA is imperative for improving overall survival (OS).


Eculizumab is a monoclonal antibody that inhibits complement protein C5.7 It is approved by the FDA for the treatment of atypical hemolytic uremic syndrome (aHUS), another complement-mediated disease. “[In TA-TMA,] it’s probably more used in pediatric population than in the adult population,” Khaled said.

Thus far, eculizumab has been studied in a small clinical trial of 64 pediatric patients with high-risk TA-TMA and multiorgan injury.8 One year after hematopoietic stem cell transplantation (HSCT), the survival was 66% in the eculizumab-treated group. This was a significant improvement from the 16.7% survival rate observed in a previously reported untreated cohort that had the same high-risk TMA features. Patients with a higher sC5b-9 level at the start of eculizumab therapy were found to be less likely to respond to treatment and to require more drug doses.8

“We use [eculizumab] quite frequently. If [a patient has received a diagnosis] of TA-TMA and has any degree of significance or injury to them, there’s always a conversation,” Duncan said. She noted that there are several key challenges with the use of eculizumab, including a lack of consensus on how long patients need to be treated, uncertainly regarding optimal dosing (eg, when to go up, how to space), and challenges receiving authorization for this drug in the outpatient setting. Additionally, its use requires prophylactic immunization and antibiotics against a variety of infectious organisms, including Neisseria meningitidis and N gonorrhea in adults, as well as a variety of encapsulated organisms in pediatric patients.7


Defibrotide was approved by the FDA for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD) with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation in 2016,9 but Hari said this drug has been used for decades in Europe. While its precise mechanism of action remains unknown, he said “it’s an anti-inflammatory agent [that] can be thought of as an endothelial stabilizing agent.”

Defibrotide has shown some promise in treating TA-TMA. “There is definitely a subgroup of people who respond to it—not as promising as a dedicated mannose-binding lectin pathway inhibitor, perhaps, but I think that 1 hit of the endothelium might be able to be helped by this agent,” Hari said. However, a challenge is its bleeding risk, which is especially problematic in a patient population that is already at high risk of hemorrhage. Cost is another issue. “We don’t use too much of [it], unless we have some evidence of liver damage, because of the payment issues, at least in this country,” Hari said.


Narsoplimab is an inhibitor of MASP-2, which is the effector enzyme of the lectin pathway of the complement system.10 The FDA has granted this agent breakthrough therapy designation for high-risk HSCT-TMA and orphan drug designation for the prevention of complement-mediated TMAs and for the treatment of HSCT-TMA.10 The drug’s manufacturer, Omeros Corporation, has submitted a biologics license application to the FDA for narsoplimab as a treatment of HSCT-TMA, and the FDA has extended its review period, setting a new action date of October 17, 2021.11

Narsoplimab has shown benefit in a small, single-arm, open-label pivotal trial that included 28 adult patients (median age, 48 years) with HSCT-TMA and high comorbidity burden.12,13 Protocol-specified treatment was IV narsoplimab 4 mg/kg or 370 mg once weekly for 4 or 8 weeks, with a 6-week follow-up period. The primary end point was complete response (CR) rate, which required improvement in 2 categories: laboratory markers of TMA (ie, LDH, platelet count) and organ function (ie, kidney, pulmonary, gastrointestinal [GI], neurological).

“The complete response rate was actually very appealing: It was 61% of all treated patients and 74% for the per-protocol set....Those are the patients who received 4 weeks or more on protocols,” Khaled said. Among both cohorts, 72% of patients showed substantial improvement in organ function, with greater than 65% showing improvements in kidney function, 50% showing improvements in neurological function, and 100% showing improvement in GI function.13

When looking at the median OS, it was 274 days for all treated patients and 361 days for the per-protocol patients, with the median OS not reached in patients who had a CR.12 “This is really compelling data for this molecule, Khaled said. The other panelists agreed. “I think the availability of a pathophysiologically targeted agent addresses what really is at the bottom of the problem,” Hari said.

What makes the data even more compelling is that narsoplimab appears to have a highly favorable safety profile. Unlike eculizumab, it does not require the use of prophylactic immunization or antibiotics and it was found to be well-tolerated, even in a population with a high comorbidity burden. The most common adverse effects (AEs) included pyrexia, diarrhea, vomiting, nausea, neutropenia, fatigue, and hypokalemia, all of which are common in the setting of HSCT.12 In total, 6 patients died during the core study period, with the causes of death being common in HSCT (eg, septic shock, GVHD, TMA).

Looking Ahead
In addition to narsoplimab, several other agents are in late-stage development, including ravulizumab, a long-acting C5 inhibitor engineered from eculizumab. It is currently being studied in 2 phase 3 trials, including 1 in pediatric patients (NCT04557735) and 1 in adolescent (≥ 12 years) and adult patients (NCT04543591).14,15 Another promising agent is nomacopan (Coversin), a bifunctional inhibitor of C5 and leukotriene B4 that is being studied in a phase 3 trial in pediatric patients aged 6 months to 18 years who develop TMA within 100 days of HSCT, which is the period when most TMAs requiring intervention occur.16

In his concluding remarks, Laurence encouraged health care providers to think about the pathophysiology of TA-TMA when caring for their HSCT patients. “Don’t just tread water doing things like plasma exchange or Rituxan [rituximab] unless there’s a specific indication for an autoantibody present. Think about trials of these newer experimental agents, which look very promising,” he said.

Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016;127(8):989-996. doi:10.1182/ blood-2015-08-663435
Ruutu T, Barosi G, Benjamin RJ, et al; European Group for Blood and Marrow Transplantation; European LeukemiaNet. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007;92(1):95-100. doi:10.3324/haematol.10699
Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(8):571-575. doi:10.1016/j. bbmt.2005.06.001
Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191-204. doi:10.1016/j. blre.2014.11.001
Khosla J, Yeh AC, Spitzer TR, Dey BR. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies. Bone Marrow Transplant. 2018;53(2):129-137. doi:10.1038/bmt.2017.207
Chapin J, Shore T, Forsberg P, et al. Hematopoietic transplant-associated thrombotic microangiopathy: case report and review of diagnosis and treatments. Clin Adv Hematol Oncol. 2014;12(9):565-573
Soliris. Prescribing information. Alexion Pharmaceuticals; 2020. Accessed June 29, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/125166s434lbl.pdf
Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. doi:10.1182/blood.2019004218
Defitelio. Prescribing information. Jazz Pharmaceuticals Inc; 2016. Accessed June 29, 2021. https://www.accessdata.fda.gov/drugsatf … 000Lbl.pdf
Narsoplimab. Omeros. Accessed June 24, 2021. https:// www.omeros.com/narsoplimab/
Omeros announces extension of FDA review period for narsoplimab in HSCT-TMA. News release. Omeros Corporation. May 20, 2021. Accessed June 24, 2021. https:// bwnews.pr/3xNvfCI
Khaled SK, Cairo MS, Duarte RF, et al. Narsoplimab (OMS721), a MASP-2 inhibitor, for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). Trans Cell Ther. 2021;27(suppl 3):S24-S26. doi:10.1016/S26666367(21)00052-X
Perales MA, Cairo M, Duarte R, et al. Narsoplimab (OMS721) treatment contributes to improvements in organ function in adult patients with high-risk transplant-associated thrombotic microangiopathy. Presented at: 2021 European Hematology Association Virtual Congress; June 9-17, 2021. Abstract S241. Accessed June 29, 2021. https://library.ehaweb.org/eha/2021/eha … ss/324649/
Ravulizumab in thrombotic microangiopathy after hematopoietic stem cell transplant. ClinicalTrials.gov. Updated April 27, 2021. Accessed June 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04543591
Study of ravulizumab in pediatric participants with HSCTTMA. ClinicalTrials.gov. Updated April 27, 2021. Accessed June 15, 2021. https://clinicaltrials.gov/ct2/show/ NCT04557735
Nomacopan (rVA576) in transplant associated thrombotic microangiopathy. ClinicalTrials.gov. Updated March 5, 2021. Accessed June 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04784455

original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.