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Omeros Corporation: The Subcutaneous Question

|About: Omeros Corporation (OMER), Includes: ACHN, AKTX, ALNY, ALXN, CCXI, RARX

Summary

Omeros' lead antibody has great potential in many complement driven disorders, including aHUS, IgAN, LN, and HSCT-TMA

However, some have questioned the competitiveness of the antibody's delivery and dosing schedule

I show that not only can Omeros deliver OMS721 subcutaneously, but that only they have the capability of developing once monthly subcutaneous dosing.

For those unfamiliar with Omeros Corporation (OMER), I suggest starting with a comprehensive review written here on Seeking Alpha. The purpose of this article is to discuss some of the critical PharmacoKinetic (PK) properties of Omeros’ lead antibody, OMS721, targeting mannose-binding protein-associated serine protease 2 (MASP-2) for complement inhibition. These PK properties have important implications for the competitiveness of OMS721 as a complement inhibitor in several high value rare disease markets, one of which, Atypical hemolytic uremic syndrome (aHUS), is the domain of Alexion Pharmaceuticals’ (ALXN) blockbuster antibody Soliris. Finally, a discussion of how OMS721’s PK properties compare with Soliris and other several complement inhibitors in development will be presented.

Omeros’ ability to produce a subcutaneous (SC) version OMS721 with a convenient dosing schedule has been the subject of much speculation since late June of this year, particularly in light of Alexion’s development of a longer acting C5 inhibitor with the potential for once weekly SC dosing. Regardless of its delivery or dosing schedule, OMS721 is unlikely to face near term competition in their most valuable potential indications, IgA Nephropathy (IgAN), Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), or Lupus Nephritis (LN). However, the potential of OMS721 in aHUS makes this discussion worth having. Although Omeros’ has affirmed its ability deliver OMS721 subcutaneously, the company’s reluctance to release PK data has raised questions. Alexion has shown a graph of PK data from a SC dose of ALXN1210 in healthy adults, and plans to begin a phase 3 trial of SC ALXN1210 in 2018, so these questions might concern investors. However, one should note that the y-axis of the graph was logarithmic, and no scale was provided. Thus, a factor of ten difference in concentration would be difficult to distinguish without knowing the scale which makes underlying data unknown. So Alexion never actually revealed their PK data, which, as noted by Omeros, for competitive reasons is an unwise thing to do. So while Omeros is justified in not releasing this data, resolving these questions would do much to ease investors concerns. While the PK data Omeros has collected in humans remains hidden, enough data exists in the literature to answer these key questions. Surprisingly, after four months of speculation, no one has done so. Thus, the motivation for this article. Some general facts use wikipedia or online medical information sites for references, but most references are academic papers. I’ve used open access papers where possible, but one will likely need access to a university library to read many of these references. I recommend reading an overview of the Complement here. Wikipedia is also not a bad place to start for those unfamiliar.

To begin, it helps to understand the reasons why no SC versions of Soliris exist, and why the development of a SC version of ALXN1210 is challenging.  

  • C5 is one of the most abundant components of human blood. The typical person has between 0.09 and 0.172 grams per liter (g/L) of C5 in their blood, which is a little less than one tenth of the amount of hemoglobin in your blood.

  • There are four C5 convertases and no single antibody or small molecule can inhibit them all, thus C5 inhibitors must bind directly to C5 - if they are to prevent its cleavage, and thereby block (terminal) complement activation.  

  • Blocking C5 doesn’t prevent the complement cascade from depositing C3b, and producing more active C5 convertases.  This means an effective C5 inhibitor must bind to nearly every C5 molecule in circulation.

  • The concentration of the C5 inhibitor must be maintained at a high enough level to bind to almost all of the C5 produced between treatments.  

  • Whilst a 20-minute IV every two weeks may be able to accomplish these requirements, SC injections are limited to 1-2ml of volume.  

Thus, no SC version of Soliris, and why the development of a SC version of ALXN1210 is a challenging task. Let’s compare this to OMS721’s target, MASP-2:

  • It is present in blood at about 0.3mg/L.

  • By looking up the molecular weights of C5 and MASP-2, and doing a few basic calculations you’ll find that MASP-2 exists in concentrations roughly 200 times smaller than that of C5.

  • How much OMS721 does one need to inhibit the lectin pathway? Not a lot. The binding affinity of OMS721 is pretty high, the concentration required to inhibit 50% of MASP-2 activity (IC50) is on the order of one nanomole per liter (1nM).

  • Based off this information, we can crudely estimate the amount of OMS721 that is typically included in its IV dose (no company discloses the dose) to be on the order of a 100 micrograms per kilogram (ug/kg).

Let’s back these points up with some research.  

The university of Leicester jointly hold some of the intellectual property for OMS721.  They published this thesis in 2013.  (In the thesis OMS721 is referenced interchangeably with an antibody called ‘OMS646-016’.) It is common for the names of antibodies and drugs to be changed during the development process, which occurred while during the long process of this thesis being written. The paper itself states a particularly relevant bit of information - that OMS721 doesn’t bind to mouse MASP-2 as well as it does human MASP-2.

OMS646 has a patent, which along with the binding affinities (used in the bullet points above), states:

“These results demonstrate that OMS646 provides potent, effective blockade of lectin pathway activation under physiological conditions, thereby providing support for the use of low therapeutic doses of OMS646.  Based on these data, it is expected that OMS646 will block >90% of the lectin pathway in the circulation of a patient at a plasma concentration of 20 nM (3 μg/mL) or less.  Based on a plasma volume of a typical human of approximately 3 L, and the knowledge that the bulk of antibody material administered is retained in plasma (Lin Y. S. et al., JPET 288:371 (1999)), it is expected that a dose of OMS646 as low as 10 mg administered intravenously will be effective at blocking the lectin pathway during an acute time period (i.e., a transient time period, such as from 1 to 3 days).  In the context of a chronic illness, it may be advantageous to block the lectin pathway for an extended period of time to achieve maximal treatment benefit.  Thus, for such chronic conditions, an OMS646 dose of 100 mg may be preferred, which is expected to be effective at blocking the lectin pathway in an adult human subject for at least one week or longer.  Given the slow clearance and long half-life that is commonly observed for antibodies in humans, it is possible that a 100 mg dose of OMS646 may be effective for longer than one week, such as for 2 weeks, or even 4 weeks.  It is expected that a higher dose of antibody (i.e., greater than 100 mg, such as 200 mg, 500 mg or greater, such as 700 mg or 1000 mg), with have a longer duration of action (e.g., greater than 2 weeks).”

Of course, a claim that one can provide effective complement cascade blockage for four weeks sounds great, but let’s see if we can verify that statement in a bit more detail.  In this patent, you’ll find a comparison of mice dosed SC with OMS721, and mice given an Intraperitoneal injection.  This shows that OMS721 effectively blocked C4 deposition for over six days after SC administration.

If you look at Figure 21 closely along with Figure 54 the patent, you’ll see why a loading doses are included in the aHUS clinical trial protocol. So everything is consistent with the company’s statements. Shocking, isn’t it. In Figure 55B you’ll see a SC dose of OMS721 effectively blocking the complement deposition for at least 300 hours, and over 90% inhibition up to 600 hours. That’s well over 16 days of complement inhibition, in mice, with a single SC dose of OMS721.



Now at this point you might be wonder how well all this mice PK data translates into humans. Fortunately, because the translation of animal PK data into humans is very important to drug development, there’s been a good deal of research done into the topic.  In general, the half-life of antibodies is much longer in humans than in mice as antibody clearance rates scale inversely with body mass. For the therapeutic antibodies tested in this paper, the half-lives scale from mice to humans as a linear function with a slope of about three. Thus, 16 days of complement inhibition in mice would likely translate to 48 days in humans. And then let’s remember the earlier finding - that OMS721 binds far better to human MASP-2, than it does to mice MASP-2.  

Add it all up, and you can see how it might be possible for OMS721 to be administered as a once a month SC dose. At this point you might wondering why Omeros is using once daily SC injections in their aHUS trial if they can deliver once monthly SC dosing? We can only speculate to the reasons, but the answer is likely that the company is playing it safe until the antibody gets approved. Their goal, as stated by the CEO on the first quarter 2017 earnings call, is to get OMS721 on the market, for any indication, as quickly as possible. While there have been no safety concerns to date, and one expects safety concerns to be minimal because most MASP-2 deficient individuals are asymptomatic, the company likely doesn’t want to risk uncovering unexpected safety concerns by delivering higher doses of OMS721 until after it reaches the market. So it is very likely the company will test higher SC doses after approval to support the development of more convenient dosing schedules, which may well exceed once per month. Add the potential that Omeros might offer OMS721 at a price point lower than Soliris, and it is difficult to see how OMS721 might not be competitive for aHUS.

So we know Omeros will start OMS721 as a once weekly IV or daily SC injection upon approval. They will then likely enroll a new trial, probably in IgAN, because of the larger patient population, for longer dosing schedules. Meanwhile Alexion will begin a phase 3 trial of once weekly SC ALXN1210. Let’s now turn our attention to some of the other competitors in the complement space. This article here on Seeking Alpha did a great job of summarizing Alexion’s, and Omeros’  by extension, most advanced competition. So we’ll follow his list, focusing on the discussion of dosing.

  • Achillion (ACHN) has an oral small molecule (ACH-4471) inhibitor of Factor D, a target of interest in one of Soliris’ indications, paroxysmal nocturnal hemoglobinuria (PNH). This is not an indication that OMS721 will compete in, but Achillion may pursue indications relevant to OMS721 in the future, and PNH will likely be the first indication pursued by Omeros’ second complement inhibiting antibody, OMS906. Oral dosing spares the use of needles, but ACH-4471 requires three times daily dosing. This is known to cause compliance issues which will render the treatment less effective. I have other reasons for believing that Factor D is not a good target, but will leave that discussion for my next article on IgAN.

  • Two companies, Apellis and Amyndas are developing C3 Inhibitors. C3 is present in the blood at concentrations of 0.75-1.65g/L with similar molecular weight to C5, thus is roughly ten times more abundant than C5. So this represents an even more difficult target for the development of convenient SC dosing. Further, these inhibitors are peptides which carry short half-lives on the order of a day or less. The prospect of convenient dosing in the face of such challenges is dim.  

  • Ra Pharma (RARX) has a peptide C5 inhibitor, ra101495, under development, which combines the disadvantages of C5 inhibitors and peptide drugs. The drug won’t have much use besides beyond patients with a select C5 polymorphism which prevents Soliris binding. Of course, inhibiting MASP-2 makes getting around this polymorphism unnecessary.  

  • Alnylam’s (ALNY) RNA interference therapy, Cemdisiran, for the knockdown of C5 expression is an interesting approach, and would offer convenient dosing once every four weeks, but this approach is not meant to be a stand alone therapy. Targeting MASP-2 would make such an approach unnecessary, so this adjudicative therapy is of little relevance to Omeros’ OMS721.   

  • Akari Therapeutics’ (AKTX) Coversin is yet another C5 inhibitor which will offer daily SC dosing, which faces similar challenges in extending the dosing schedule. They working on a modified antibody which promises to extend dosing to once per week.

  • ChemoCentryx (CCXI) Avacopan is an small molecule inhibitor of the C5a receptor. This drug won’t prevent terminal complement activation, but will reduce the inflammatory responses invoked by C5a. It does offer twice daily oral dosing, but without inhibition of the terminal complement cascade, it is difficult to see this drug as an effective stand-alone therapy for aHUS. Development is still in early stages for aHUS, so there is no immediate threat of competition for OMS721, but one should keep an eye out for additional data in case Avacopan proves to be more efficacious than expected.

Based on the above list, and the preceding paragraphs, I believe Omeros to be the only company capable of delivering once monthly subcutaneous dosing for the complete inhibition of the complement cascade in aHUS. Therefore, so long as no issues arise from increasing the dose, OMS721 will will likely achieve a greater penetration in the aHUS than analysts currently believe. Half of the the nearly two billion dollar aHUS market at 50% discount to Soliris pricing easily nets 500M in annual sales.

Disclosure: I am/we are long OMER.