Pipeline

Expanding the pipeline beyond Ruconest®

With validation secured from the approval of the first product from our transgenic platform, we will now seek to initiate new projects on this platform.

Our transgenic platform remains the only technology that to date can deliver recombinant versions of certain complex human proteins in an economically viable way: this is a result of the low cost of capital investment required to start up a suitable founder herd, the fact that the herd is easily scalable and the high yield of product obtained.

Our goal is to focus on indications that have a high unmet medical need using biologics to help patients that otherwise have limited choice in treatment.

Expanding Beyond The Pipeline

rhC1INH (Ruconest)

Recombinant human C1 inhibitor (rhC1INH) is a recombinant human C1 inhibitor protein. Natural C1 inhibitor DNA from a human source is used in Pharming’s protein production technology to ensure expression of the C1 inhibitor protein. Human C1 inhibitor is a human plasma protein involved in the regulation of the complement and contact parts of the immune system. It is a controlling protein in early stages of these cascades and in that way a regulating factor of the immune system.
By inhibiting these systems, the abnormal inflammation can be controlled. This is also the mechanism by which an HAE attack can be treated with C1 inhibitor.

rhFVIII (Factor VIII)

Recombinant human Factor VIII is a natural human blood clotting factor and is in early-stage development for treatment of Haemophilia A. Haemophilia A is a hereditary disorder caused by defects in the Factor VIII gene. Lack of functional Factor VIII diminishes the body’s clotting ability, which in turn can lead to damaging- or fatal bleeding episodes. On this project, Pharming has a service agreement with Renova Life to provide Pharming with founder rabbits.

Haemophilia A is an X chromosome linked hereditary disorder caused by defects in the Factor VIII (FVIII) gene that lead to lower levels of the functional FVIII protein. Lack of functional FVIII diminishes the body’s clotting ability, which in turn can lead to damaging or fatal bleeding episodes.

rhC1INH (Ruconest)

Potential additional indications for Ruconest (rhC1INH) in development stage

Recombinant human C1 inhibitor (rhC1INH) is a recombinant human C1 inhibitor protein. Natural C1 inhibitor DNA from a human source is used in Pharming’s protein production technology to ensure expression of the C1 inhibitor protein. Human C1 inhibitor is a human plasma protein involved in the regulation of the complement and contact parts of the immune system. It is a controlling protein in early stages of these cascades and in that way a regulating factor of the immune system. By inhibiting these systems, the abnormal inflammation can be controlled. This is also the mechanism by which an HAE attack can be treated with C1 inhibitor.

Acute pancreatitis

Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas for which there are currently no approved medical therapies.  With approximately 300,000 hospitalizations per year (an increase of more than 2-fold since 1988), AP represents the single most frequent gastrointestinal cause of hospital admissions in the US.

Based on the broad anti-inflammatory properties of C1INH, pdC1INH and rhC1INH have been studied in a variety of clinical conditions and animal models of numerous conditions involving contact and complement system activation with a vascular/capillary leak component.  These studies have included models of pancreatitis, sepsis, thermal injury, xenotransplantation, and ischemia-reperfusion injury (e.g., myocardial infarction, stroke, delayed graft function in transplantation).  Together, this experience suggests that rhC1INH may be able to interrupt the pro-inflammatory processes in patients with AP, and thereby resolve the ongoing SIRS to ultimately prevent organ failure.

rhFVIII (Factor VIII)

Factor VIII (rhFVIII)

Haemophilia A is an X chromosome linked hereditary disorder caused by defects in the Factor VIII (FVIII) gene that lead to lower levels of the functional FVIII protein. Lack of functional FVIII diminishes the body’s clotting ability, which in turn can lead to damaging or fatal bleeding episodes.

Recombinant human Factor VIII is a natural human blood clotting factor and is in early-stage development for treatment of Haemophilia A. Haemophilia A is a hereditary disorder caused by defects in the Factor VIII gene. Lack of functional Factor VIII diminishes the body’s clotting ability, which in turn can lead to damaging- or fatal bleeding episodes.

As the first step in the assessment of develop-ability, Pharming signed a service agreement with Renova Life (RLI). The agreement covers the development and supply of founder transgenic rabbits from RLI to Pharming. The founder rabbits will enable Pharming to start the commercial production breeding process.

Collaborative Product development: Strategic Collaborations with SIPI

In addition recently we have entered a strategic collaboration for the development, manufacture and commercialisation of new products based on the Pharming technology platform with The Shanghai Institute of Pharmaceutical Industry (SIPI), a Sinopharm Company based in China.

sipi logo

Under the terms of the agreement, Pharming will transfer the Pharming technology platform and manufacturing know- how to SIPI, such that joint global development for new products will take place at SIPI’s facilities in Shanghai and benefit from both the cost advantages of the Pharming platform and the competitive development and manufacturing costs structures at SIPI.

The first projects to be jointly developed and manufactured at SIPI will be  recombinant C1-inhibitor (conestat alfa) and Factor VIII.

Products

Ruconest       EU_Flag

Ruconest (conestat alfa) is a recombinant human C1 esterase inhibitor approved for the treatment of angioedema attacks in patients with HAE in the USA, Israel, all 28 EU countries plus Norway, Iceland and Liechtenstein.

Ruconest is distributed in the EU by Swedish Orphan Biovitrum. Ruconest is partnered with Salix Pharmaceuticals Inc. in North America.

Medical need

C1 esterase inhibitor (C1INH) is a protein that naturally occurs in the human body. It belongs to the class of serine-protease inhibitors or serpins. It regulates several inflammatory pathways in the body by inhibiting certain proteins (proteases) that are part of the human immune system. Deficiency of functional C1 inhibitor leads to excessive activation of the complement system and other immunological and haemostatic pathways, giving cause to angioedema attacks. These attacks are characterized by acute and painful swellings of soft tissues. Administration of C1 inhibitor protein can normalize the low C1 INH levels and stop the angioedema attacks.

Pharming’s therapy

Patients who suffer from hereditary angioedema (HAE) have a deficiency of functional C1INH resulting from a mutation in the C1 inhibitor gene. For them, Pharming’s Ruconest provides a causal treatment with an excellent efficacy and safety profile. The GMP conform proprietary production and purification technology allows for the commercial manufacturing of large quantities of high-grade product of outstanding quality. Ruconest does not carry the risk of transmission of plasma related human infectious agents, as it is not isolated from human blood sources.

Additional Information:       EU_Flag

1. What Ruconest is and what it is used for 
Ruconest contains conestat alfa as the active substance. Conestat alfa is a recombinant form of human C1 inhibitor (rhC1INH) and is produced using recombinant DNA technology from the milk of rabbits.
Ruconest is to be used by adults and adolescence with a rare inherited blood disorder, called Hereditary Angioedema (HAE).
These patients have a shortage of the C1 inhibitor protein in their blood. This can lead to repeated attacks of swelling, pain in the abdomen, difficulty breathing and other symptoms.

The administration of conestat alfa (Ruconest) is to resolve the shortage of C1 inhibitor and will lead to reduction of symptoms of an acute attack of HAE.

2. What you need to know before you use Ruconest

Do not use Ruconest:

If you are or think you are allergic to rabbits
If you are allergic to conestat alfa or any of the other ingredients of this medicine.

Warnings and precautions
Talk to your doctor before using Ruconest.

If you experience allergic reactions e.g. hives, rash, itching, dizziness, wheezing, difficulty breathing or your tongue swells up following the administration of Ruconest, you should seek emergency medical assistance so that symptoms of your allergic reaction can be treated urgently.

Children and adolescents
Do not give this medicine to children and adolescents under 12 years old.

Other medicines and Ruconest
Tell your doctor if you are taking, have recently taken or might take any other medicines.
If you are receiving acute treatment for blood clots, you should not be treated with Ruconest at the same time.

Pregnancy and breast-feeding
It is not recommended to use Ruconest during pregnancy or breast-feeding.
If you plan becoming pregnant, discuss with your doctor before starting to use Ruconest.

Driving and using machines
Do not drive or use machinery if you feel dizzy or suffer from headache after using Ruconest.

3. How to use Ruconest
Ruconest will be given to you directly into a vein over a period of approximately 5 minutes by your doctor or by a nurse. Your dose will be worked out based on your weight.
Most of the time a single dose is sufficient, but a second dose may be needed. No more than 2 doses should be given within 24 hours.
The instructions for use are clearly described in the doctor’s information leaflet and are attached.
If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If your symptoms get worse and/or you develop a rash, tingling, difficulty breathing or your face or tongue swells up, get medical attention immediately.
This may indicate that you have developed an allergy to Ruconest.

Some side effects may occur during treatment with Ruconest:
Common (affect 1 to 10 users in 100): headache
Uncommon (affect 1 to 10 users in 1,000):  sensation of tingling, prickling or numbness in the skin or limb (paraesthesia), dizziness, throat irritation,  abdominal pain, diarrhoea, nausea, hives and swelling of the skin.
If you get any side effects, talk to your doctor.

This includes any possible side effects not listed in the leaflet.

5. How to store Ruconest
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date, which is stated on the carton and on the label of the vial after EXP.

The expiry date refers to the last day of that month. Do not store above 25°C.
Store in the original package in order to protect from light.
Before Ruconest can be administered, it needs to be dissolved in water for injections, by a healthcare professional.
Once reconstituted, the product should be used immediately.
Do not use this medicine if you notice particles in the solution or if the solution is discolored

Please see accompanying Summary of Product Characteristics     EU_Flag

Research & Development

Pharming develops and produces recombinant human proteins using its transgenic technology platform.

The development of a therapeutic drug up to marketing approval by the competent authority is a lengthy process and starts by the generation and selection of a transgenic animal line. During this time a research project must proceed through the early stages of genetic characterization of the transgenic animal line as well as the recombinant protein produced in milk.

In this section of the website you can find information on Pharming’s technology and intellectual property.

For more information please contact: Bruno M. Giannetti via b.giannetti@pharming.com

Transgenic Production Technology Platform (TPTP)

After the discovery of DNA and recombinant DNA techniques in the past decades it became possible to transfer genes between different organisms, such as plants and bacteria. Scientists discovered how to transfer mammalian genes into the genetic material of other animals, and breed transgenic animals with specific (mixed) characteristics. This new scientific approach of recombining genetic material from different biological sources became known as recombinant DNA technology and the animals generated with such technology as transgenic animals.

Therapeutic proteins from milk

Pharming’s predecessor company GenPharm was founded to commercialize this innovative technology. The Pharming scientists were able to breed animals that could produce human-like proteins in their milk. The company further improved this technology and made it fully compliant with regulatory guidelines that apply in the United States and Europe.

Large-scale manufacturing

For commercial purposes, Pharming also developed large scale purification methods for separating the human proteins from the other natural components in milk. The purification process for our lead product Ruconest was successfully up-scaled and transferred to the current manufacturing partner Sanofi Chimie. All production facilities and processes comply with regulatory GMP-guidelines and are suitable for large-scale production of the highest quality pharmaceutical products.

High quality in sufficient quantity

Pharming can produce complex therapeutic proteins in the mammary glands of rabbits or cattle and purify the protein from milk for its therapeutic application. This production method has the advantage of delivering high quality human proteins in sufficient quantities and consistently high quality. Pharming is the first company in the world to obtain regulatory approval for a recombinant protein pharmaceutical produced in milk of transgenic rabbits. The technology platform has been developed such that consistency of the product attributes is easily maintained through scaling up of the production process. Furthermore the transgenic rabbit platform has been optimized by Pharming to produce large quantities of recombinant proteins in a controlled, easily transferrable and scalable fashion.

High potential

There is a need in the industry for new means to produce over 900 protein therapeutics that are currently in development. Pharming believes that its production technology offers significant competitive advantages and will enable the development of better, safer and more cost-effective therapeutic products.

As of July 2013, Pharming has partnered the technology platform with The Shanghai Institute of Pharmaceutical Industry (SIPI); a Sinopharm Company.
This strategic collaboration for the development, manufacture and commercialization of new products based on Pharming’s technology platform, allows SIPI access to Pharming’s technology and know-how such that a joint global development of new products can benefit both parties.

Intellectual Property (IP)

The company owns and has in-licensed a significant number of patents and patent applications worldwide, broadly covering the technology for the production of recombinant proteins in the milk of transgenic animals, as well as the specific products under development. Protection for recombinant proteins currently produced in milk as well as methods of generating transgenic animals will last beyond 2020.

Typically, various aspects of manufacturing and use of Pharming’s products are covered by separate patents, trade secrets and know- how, thus creating several independent layers of protection around each product. For instance, Pharming’s IP position in the production and use of Ruconest not only covers the therapeutic compound itself, but also methods of production and purification, improved versions of Ruconest, and therapeutic use in a large number of medical indications, including (but not limited to) HAE and other diseases linked to C1 inhibitor deficiency.

In the field of transgenic technology, Pharming’s portfolio includes the following IP:

  • Generation and use of transgenic cattle
  • Milk specific expression in transgenic animals
  • Animals carrying large transgenes (> 50kb)
  • Purification of biopharmaceuticals from milk
  • Structure and design of transgenes for high level production
  • Fusion proteins for high level expression
  • Generation of animals using nuclear transfer technology
  • Oocyte activation for nuclear transfer
  • Transgenic antibody production
  • Sperm mediated gene transfer

For applications outside of Pharming’s core activities, this IP is available for licensing.

Research Collaboration

University of Poitiers

Clinical indication: kidney transplantation

Publications:

THE WORLD TRANSPLANT CONGRESS 2014 ABSTRACT SUPPLEMENT American Journal of Transplantation. Supplement: 2014 World Transplant Congress Abstracts June 2014; 14(S3): A.

University of Wisconsin

Clinical indication: kidney transplantationPublications:

COMPLEMENT BLOCKADE PREVENTS DELAYED GRAFT FUNCTION IN A NON-HUMAN PRIMATE MODEL OF KIDNEY ALLO-TRANSPLANTATION. J. Danobeitia, L. Zitur, E. Van Amersfoort, A. D’Alessandro, B. Oortwijn, X. Ma, S. Capuano, K. Brunner, J. Torrealba, L. Fernandez. American Transplant Congress 2013.

University of Bari

Clinical indication: kidney transplantationPublications:

COMPLEMENT-DEPENDENT NADPH OXIDASE ENZYME ACTIVATION IN RENAL ISCHEMIA/REPERFUSION INJURY. Simone S, Rascio F, Castellano G, Divella C, Chieti A, Ditonno P, Battaglia M, Crovace A, Staffieri F, Oortwijn B, Stallone G, Gesualdo L, Pertosa G, Grandaliano G. Free Radic Biol Med. 2014; 74: 263-73

ENDOTHELIAL-TO-MESENCHYMAL TRANSITION AND RENAL FIBROSIS IN ISCHAEMIA/REPERFUSION INJURY ARE MEDIATED BY COMPLEMENT ANAPHYLATOXINS AND AKT PATHWAY. Curci C, Castellano G, Stasi A, Divella C, Loverre A, Gigante M, Simone S, Cariello M, Montinaro V, Lucarelli G, Ditonno P, Battaglia M, Crovace A, Staffieri F, Oortwijn B, van Amersfoort E, Gesualdo L, Grandaliano G. Nephrol Dial Transplant 2014; 29: 799-808.

THERAPEUTIC TARGETING OF CLASSICAL AND LECTIN PATHWAYS OF COMPLEMENT PROTECTS FROM ISCHEMIA-REPERFUSION-INDUCED RENAL DAMAGE. Castellano G, Melchiorre R, Loverre A, Ditonno P, Montinaro V, Rossini M, Divella C, Battaglia M, Lucarelli G, Annunziata G, Palazzo S, Selvaggi FP, Staffieri F, Crovace A, Daha MR, Mannesse M, van Wetering S, Paolo Schena F, Grandaliano G. Am J Pathol. 2010; 176: 1648-59.

US Army Institute of Surgical Research

Clinical indication: severe blood loss due to battlefield injuriesPublications:

INFLAMMATORY RESPONSES IN BRAIN FROM SWINE SUBJECTED TO TRAUMATIC HEMORRHAGE AND TREATED WITH A C1 INHIBITOR. MA Dubick, Y Li, DL Grubbs, JL Barr, JJ Dalle Lucca. Shock 2014; 41: 65.

INDICES OF INFLAMMATION IN SWINE SUBJECTED TO TRAUMA/HEMORRHAGE AND TREATED WITH A C1 INHIBITOR. M Dubick, Y Li, D Grubbs, M Simovic, J Barr, J Dalle Lucca. Critical Care Medicine 2013; 41, A53.

EFFECTS OF C1 INHIBITOR ON TISSUE DAMAGE IN A PORCINE MODEL OF CONTROLLED HEMORRHAGE. Dalle Lucca JJ, Li Y, Simovic M, Pusateri AE, Falabella M, Dubick MA, Tsokos GC. Shock 2012; 38: 82-91.