The Atypical HUS Foundation

LONDON Mtg. NEWS - 4 Complement Inhibitors Possible in the aHUS Pipeline (Aug: updated to 5!)

  

     

Atypical HUS Drug Pipeline – 2017 Update from the aHUS Alliance

Click above to view updated information regarding Therapeutics now in development

Original Article Below:

Dr. Wynne Weston-Davies of Volution Immuno Pharmaceuticals presented information on potential new aHUS therapeutics at the June 28th meeting of the aHUS Alliance convened in London.  Volution is a privately held, Swiss-based firm whose focus is development of anti-complement and anti-inflammatory molecules that may be utilized for the treatment of a wide range of rare diseases. Dr. Weston-Davies has a been involved with biopharmaceutical development for more than 25 years, and formerly was the EU medical director of Bristol Myers Squibb before joining the team at Volution in the area of Medical and Drug Development. 

      Dr. Wynne Weston-Davies provided an overview of 4 new complement inhibitors in clinical development for potential use to treat aHUS patients, to include the Volution Immuno Pharmaceuticals’ product , Conversin® .   Since all present were familiar Soliris® (trademark proprietary to Alexion Pharmaceuticals) as the only FDA-approved drug for treating atypical HUS, Dr. Weston-Davies also provided a comparison between Conversin® and Soliris®.  From the Volution website, “VIP’s lead molecule, Coversin, is a second generation complement inhibitor which acts on complement C5 preventing release of C5a and formation of C5b – 9, the membrane attack complex (MAC). Complement C5 inhibition is growing in importance in a wide range of autoimmune diseases including paroxysmal nocturnal haemoglobinuria (PNH), myasthenia gravis, Guillain Barré syndrome and in conditions such as antibody mediated transplant rejection.” 

     The following information was presented to the twelve nations aHUS patient organizations of the aHUS Alliance by Dr. Weston-Davies in London on June 28th 2015, with this following summary of his presentation provided Linda Burke, as the representative of The Atypical HUS Foundation.  Details provided are courtesy of Dr. Wynne Weston-Davies, with links provided by Linda Burke as a convenience to our readership.

Important NOTES Descriptions below are provided by Dr. Weston-Davies with regard as to how Conversin®, a complement inhibitor under investigation by Volution Immuno Pharmaceuticals may be viewed in comparison to other potential advancements for the treatment of aHUS patients.  The Atypical HUS Foundation does not endorse any treatments, drugs, or therapies nor does it offer medical advice.  Individuals should contact their own medical team for information or regarding questions related to patient treatment options.

 

Potential New Compliment Inhibitors Under Investigation

COMPANY                MOLECULE            MECHANISM                       INDICATIONS               STAGE*

ALNYLAM                 ALN-CC5              C5 gene knockdown               PNH                                 PI/II

APELLIS        Compstatin®/APL-2        C3 inhibitor                             PNH                                 PI/II

OMEROS        OMS721®/MASP-2         Lectin pathway inhibitor     TMAs including aHUS           PII  ^

VOLUTION            Coversin®                C5 inhibitor     PNH, aHUS, Guillain Barre syndrome      PI/II

Note:  New Information* as of Aug. 2015 from RA Pharmaceuticals, not included at Dr. Weston-Davies July 2015 presentation

Ra Pharma           RA101495                 C5 inhibitor                             PNH, initially                      PI

      *Stage of Development, Definitions                         ^ OMS721 is currently in Clinical Trial, details HERE

 

 

ALN-CC5®  (Trademark of ALNYLAM)   Note:  As described by Dr. Weston-Davies during his June 28th 2015 presentation to the aHUS Alliance gathering of nations convened in London. 

  • Gene silencing therapy (siRNA) targeting liver produced C5
  • Delivered by subcutaneous injection

–      Interval and dose not yet determined

–      Possibly twice a week to once every two weeks

  • Currently in trials for PNH
  • Takes several days/weeks to have maximum effect

–      Not suitable for emergency use

  • Other possible drawbacks are incomplete C5 inhibition, off-target side effects and tolerance

Click this link for more info about ALN-CC5®

 

 

Compstatin®/APL-2  (Trademark of APELLIS)     Note:  As described by Dr. Weston-Davies during his June 28th 2015 presentation to the aHUS Alliance gathering of nations convened in London. 

  • Small synthetic peptide molecule

–      Relatively easy to produce

–      May have cost benefits

  • Targets C3 so likely to be effective in many diseases including aHUS
  • Can be delivered by subcutaneous injection (maybe even by mouth?)
  • Targets an earlier stage in the complement cascade so disadvantages may include greater risk of infection than C5 inhibitors

Click this link for more info about  Compstatin®/APL-2

 

 

OMS721®/MASP-2  (Trademark of OMEROS)     Note:  As described by Dr. Weston-Davies during his June 28th 2015 presentation to the aHUS Alliance gathering of nations convened in London. 

  • Monoclonal antibody which can apparently be delivered by subcutaneous or intravenous injection at monthly intervals
  • Targets MASP-2, an early component of the lectin pathway
  • Possible advantages claimed by Omeros include sparing of the classical pathway and therefore a lower risk of infection than C3 or C5 inhibitors
  • Not affected by C5 mutations
  • As yet it is unproven that lectin pathway inhibition can fully control diseases such as aHUS and PNH

Click this link for more info about OMS721®/MASP-2

 

Coversin® (Trademark of VOLUTION )     Note:  As described by Dr. Weston-Davies during his June 28th 2015 presentation to the aHUS Alliance gathering of nations convened in London.  Disclaimer:  Dr. Weston-Davies is part of the Volution Immuno Pharmaceutical team.  Soliris® is the registered trademark of Alexion Pharmaceuticals.)

 

  • Small protein C5 inhibitor with identical mechanism of action to Soliris®
  • Delivered by daily subcutaneous injection

–      Small volume, fixed dose

–      Should be possible for patients to self administer

  •  Not affected by the ‘Japanese’ C5 mutation
  • Should be as effective as Soliris in aHUS and PNH
  • Possible disadvantage would be immunogenicity

–      Development of neutralising antibodies over time which would make it less effective

–      No evidence of neutralising antibodies in animal studies

Click this link for more info about Coversin®

Click this link for more info about Soliris® 

Click this link for more info about the ‘Japanese’ C5 mutation.

 

 

 

Coversin® (Trademark of VOLUTION ) as compared to Soliris® (Trademark of ALEXION PHARMACEUTICALS)         Note:  As described by Dr. Weston-Davies during his June 28th 2015 presentation to the aHUS Alliance gathering of nations convened in London.  Disclaimer:  Dr. Weston-Davies is part of the Volution Immuno Pharmaceutical team.  Soliris® is the registered trademark of Alexion Pharmaceuticals.)

  • Coversin® is a small compact protein –  Soliris®is a monoclonal antibody
  • Coversin®’s small size means that it is quickly excreted via the kidney so it needs to be given more frequently than Soliris®
  • Coversin® and Soliris® bind to slightly different regions of the C5α domain of C5
  • Coversin® avoids the site of the ‘Japanese’ mutation and therefore appears to be effective in Soliris® resistant patients

Click this link for more info about Coversin®

Click this link for more info about Soliris® 

Click this link for more info about the ‘Japanese’ C5 mutation.

 

ADDITION:  New Information*

A Post-Blog Update - MORE News in the Biotech and Orphan Drug Arena

 

Ra Pharmaceutical’s C5 Complement Inhibitor: RA101495

 

     Based in Cambridge Massachusetts, Ra Pharmaceuticals, notes complement inhibitors and other immune targets among their Current Programs.  It appears that PNH (Paroxysmal nocturnal hemoglobinuria) patients are Ra’s immediate targeted patient population, with RA101495 apparently to enter into human studies in late 2015.

     From their Current Programs tab on Ra Pharmaceutical’s corporate site:

“RA101495 is a peptide inhibitor of complement C5. It binds to the C5 protein with extremely high affinity, inhibiting both the C5 convertase-mediated cleavage to C5a and C5b and the subsequent assembly of the C5b-9 MAC complex. As assessed by in vitro assays of complement activation, RA101495 is a potent inhibitor of complement-induced red blood cell lysis-- a key indicator supporting its use in diseases such as nocturnal paroxysmal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS); see “Complement & PNH”.

RA101495 is being developed as an alternative to eculizumab therapy, initially for patients with PNH. With a convenient self-administered subcutaneous administration, more rapid clearance from the circulation, and a simpler and more cost-effective manufacturing process (chemical synthesis vs. biological production process), RA101495 provides multiple benefits over eculizumab therapy. In addition to eliminating the potential for complications and the life-style burden associated with bi-weekly IV infusions, a more convenient product is suitable for addressing a wider range of diseases than possible with a monoclonal antibody.”

CLICK HERE TO READ our full blog about Ra Pharmaceuticals and RA101495

 

 

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Comment by Grace on July 13, 2015 at 10:17pm

Thank you, Linda, for sharing this valuable information. I look forward to viewing the videos whenever they may be available.

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Did you know...

CFH (Serum Complement Factor H) is a regulatory protein. The secreted protein product of CFH consists of 20 repetitive units named "short consensus repeats" or SCRs (each approximately 60 amino acids). In patients with aHUS the last 5 "pearls" in the twenty pearl strand protein, SCR16 - SCR20, should bind to protect cells but do not- they are defective in one or more of the last 5 SCR locations. If they cannot bind or stick to the kidney to protect that tissue, the platelets clump into clots that affect the glomeruli of the kidney -potentially causing acute renal failure.
  
• • • • • • • • • • • •
  
It is estimated that there are about 2 cases of aHUS in the U.S. per 1,000,000 of population, and about 60% of aHUS patients are diagnosed as children. The condition is potentially life threatening, and either can be chronic or can recur at intervals.
  
more factoids...

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