Pipeline

(accurate November 2018)

Expanding the pipeline beyond Ruconest®: New forms of Ruconest® administration and additional products

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 strategy:

  • New forms of administration for RUCONEST® for HAE
  • Expansion of rhC1INH clinical development in pre-eclampsia, contrast induced nephropathy and other potential large indications
  • Clinical development of protein replacement products in Pompe and Fabry diseases

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.

New formulation development of RUCONEST®

  • The “RUCONEST® liquid” formulation (from 14ml to 3ml) can be used as starting material for the generation of subcutaneous, intra-muscular & intradermal application systems
  • New proprietary ‘painless’ intradermal delivery applications are being developed. A dissolving point device and a reservoir device. 
  • These painless versions should differentiate RUCONEST® from competitors, all of whom have painful injections

New activities with rhC1INH (RUCONEST®)

Initial Therapeutic Indications selected:

  • New Potential Indications using existing formulation
    • Organ damage after contrast media application: Contrast-induced Nephropathy (CIN) recent positive results investigator-sponsored study
    • Tissue Damage after Toxic Event: Pre-Eclampsia; study to start Q4 2018
    • Tissue Damage after Hypoxic Event: Delayed Graft Function (new Investigator initiated study)
    • Shock response after trauma: Hypovolemic Shock – ongoing preclinical research projects with the US Army and US Air Force
  • Brand New IP:
    • New Pharming patents filed in 2018 covering the new indications
    • Patents cover all forms of rhC1INH

Positive Phase II results in Contrast-induced Nephropathy (CIN)

Positive results from a Phase II investigator-initiated study of RUCONEST®

In a DBPC study with 75 patients, RUCONEST® showed a statistically significant effect (p=0.038) in reducing Neutrophil Gelatinase-Associated Lipocalin (NGAL).

  • Clear results in sub-group of patients (n=30) undergoing PCI.
  • Median increase in peak urinary NGAL concentration within 48 hours of 1.8 ng/ml compared with an increase of 26.2 ng/ml in the placebo arm (p=0.04).
  • Median percentage change in the peak urinary NGAL level within 48 hours of 11.3% vs  205.2% in the placebo arm (p=0.001).
  • Overall patients undergoing invasive procedures requiring high volumes of contrast media experienced a stronger benefit from the RUCONEST® treatment.

Next steps:

  • Design of additional clinical development to establish efficacy and efficiency of RUCONEST® treatment in patient groups likely to experience the greatest benefit.

…read more in our press release here.

Market size estimation presented at Captial Markets Briefing 21st June 2018

 

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.

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 project to be jointly developed and manufactured at SIPI will be  recombinant C1-inhibitor (conestat alfa).

RUCONEST®

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.

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.