16 May 2013 1

Plasma proteins: drugs, orphan drugs or “ultra-orphan” drugs ?

Jan Over Sanquin Blood Supply, Plasma Products division

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 2

Outline

1) Orphan drug regulations ‘worldwide’

2) Numbers of orphan drugs

3) Plasma proteins as orphan drugs

4) “Ultra-orphan” plasma derivatives

5) Some thoughts / considerations

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 3

Rare diseases and orphan drugs

• Definition by WHO:

“Rare diseases are rare and often debilitating or even life-threatening diseases or conditions with a prevalence of 0.65 – 1 per 1,000.”

• Orphan drugs are medicinal products to diagnose, prevent or treat rare diseases

• About 5,000 – 7,000 rare diseases world-wide, with some 250 new ones identified annually

• Affecting > 55 million people in the US and EU; 10% of all people worldwide

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 4

Background of orphan drug regulations

Every patient has the right to have access to adequate diagnosis and medical care....

but – for purely economical reasons – (very) rare diseases are not attractive for industry

Orphan drug regulations aim to reduce this barrier, by providing (economical) incentives, like

• technical advice and protocol assistance by regulatory bodies • acceptance of clinical trials of limited size • tax exemptions, fee waivers • exclusivity period in the market

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 5

Orphan drug regulations, a global comparison

USA Singapore Japan Australia EU Taiwan South Korea

Year of legislation 1983 1991 1993 1998 1999 / 2000 2000 2003

Regulatory body FDA / OOPD HSA MHLW / OPSR TGA EMA / COMP DOH KFDA

Disease prevalence per 10,000 inhab.

7.5 (< 200,000 pats.)

50 (compass. use)

4 (< 50,000 pats.)

1.1 (< 2,000 pats.)

5 1 4 (< 20,000 pats.)

Marketing exclusivity (yrs)

7

None

10

5

10

10

6

Tax credits / fee reductions

Yes / yes

N.a.

Yes / yes

No / yes

Member state dependent

/yes

Unknown

No / yes

Research grants

Yes (NIH)

N.a.

Yes (government)

No

Yes (nationally)

Yes (government)

Yes

Technical advice, protocol assist.

Yes

N.a.

Yes

Yes

Yes

Yes

Yes

Fast track approval

Yes

(Yes)

Yes

Yes

Yes (centralized)

Yes

Yes

Reconsideration of OD status

No

(No)

Yes

Yes (every yr)

Yes (after 6 yrs)

Unknown

Unknown

Adapted from a.o.: P.Song et al., Intractable and Rare Disease Research 2012; 1(1), 3-9 DL Scott et al., Drug Information Journal 2001; 35, 1-16

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 6

Some aspects of orphan drug regulations

• A prerequisite: orphan drugs should be as safe and effective as normal drugs

• An orphan drug designation (ODD) and OD status hold for the combination of the drug and its clinical indication

• New OD status possible for the same combination of component and clinical indication if clinically superior

• ODD dependent on region E.g. thalassemia is highly prevalent in (sub)tropical countries, but not in the EU as a whole; Factor XI deficiency is more frequent in Israel than in most other countries

• Loss of market exclusivity when patient number exceeds prevalence criterion

• Loss of market exclusivity when manufacturer cannot meet clinical demand (EU)

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 7

Other factors of importance

• Status of diagnostic system: timely diagnosis, presence of specialized expertise and care centers; registries of rare disease patients

• Public awareness and the patient’s voice: - patient groups and organizations: NORD, GA (USA), EURORDIS (EU), IDIC (Japan), AGSA (Australia), KORD (South Korea), TFRD (Taiwan), Orphanet (France), … - the internet, social media, ….

• Patent protection • Price setting • Reimbursement policies: none in the US and some EU member states,

stringent in Japan • Health technology assessments

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 8

Orphan drug designations in US, EU and Japan

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 9

Orphan drug sales worldwide

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A few numbers (as of April 2013)

USA EU Australia Japan (June 2012)

Approved OD designations

2,799

930

250

277

Market authorizations

434

76

59

175

Plasma derivatives OD designations OD approvals ODs expired ODDs withdrawn

Rec. plasma proteins OD designations OD approvals ODs expired ODDs withdrawn

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 11

A few numbers (as of April 2013)

USA EU Australia Japan (June 2012)

Approved OD designations

2,799

930

250

277

Market authorizations

434

76

59

175

Plasma derivatives OD designations OD approvals ODs expired ODDs withdrawn

87 26 13 22

26 0 0 6

13 3 3 ?

? 5 2 ?

Rec. plasma proteins OD designations OD approvals ODs expired ODDs withdrawn

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 12

A few numbers (as of April 2013)

USA EU Australia Japan (June 2012)

Approved OD designations

2,799

930

250

277

Market authorizations

434

76

59

175

Plasma derivatives OD designations OD approvals ODs expired ODDs withdrawn

87 26 13 22

26 0 0 6

13 3 3 ?

? 5 2 ?

Rec. plasma proteins OD designations OD approvals ODs expired ODDs withdrawn

42 10 7 2

29 0 0 5

12 5 4 ?

? 1 ? ?

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 13

Registered plasma derivatives worldwide ODs in blue

- albumin - fibrinogen - immunoglobulin (G) - thrombin - IgM - fibrin sealant - factor VIII - prothrombin complex - factor IX - activated prothr. complex - factor VII - antithrombin - factor XI - alpha-1 antitrypsin - factor XIII - C1-inhibitor - protein C - haptoglobin - activated protein C - von Willebrand factor - plasma (pathogen inactivated)

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 14

New plasma derivatives in development (ODDs) • Plasmin Grifols • Plasminogen Kedrion, Prometic Biotherapeutics • Factor V Kedrion • Factor X BPL • Haptoglobin BPL • Apotransferrin Sanquin • TFPI Baxter • Butyrylcholinesterase Shire • Complement factor H Kedrion, Baxter, Octapharma • 123I-labeled serum amyloid protein LFB • Hyperimmune immunoglobulins

(Anthrax, HBV, CMV, RSV, Varicella Z., WNV, Staph. aureus, HCV, …) • (I.v.) immunoglobulin (new indications)

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 15

Recombinant plasma proteins (ODDs)

licensed in development transgenic • Factor VIIa (and long-acting versions) + + - • Factor VIII (and long-acting versions) + + - • Factor IX (and long-acting versions) + + - • Factor XIII - + - • Von Willebrand factor - + - • Fibrinogen - + + • Microplasmin - + - • Activated protein C withdrawn + + ? • Alpha-1-antitrypsin - + - • Antithrombin + + + • C1-inhibitor + + + • ADAMTS 13 - + - • Pentraxin-2 (serum amyloid P) - + -

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 16

Plasma products as orphan drugs - case 1

Factor IX in the USA Aim: treatment of hemophilia B

• ODD approved for Alphanine® in July 1990 market approval 31 Dec. 1990 market exclusivity until Jan. 1998

• ODD approved for Mononine® in June 1989 market approval Aug. 1992 exclusivity until Aug. 1999

• ODD approved for Benefix® in October 1994 market approval Feb. 1997 exclusivity until Feb. 2004

• ODD approved for FIX-Fc fusion protein (Biogen Idec) in Oct. 2008 ODD approved for FIX-albumin fusion protein (CSL Behring) in April 2012 ODD approved for PEGylated FIX (Novo Nordisk) in March 2013 ODD approved for FIX (Baxter) in Oct. 2012

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 17

Plasma products as orphan drugs - case 2

C1-inhibitor in the USA:

Aim: treatment of acute attacks and prophylactic use in hereditary angioedema

• Aug. 1990: ODD for Baxter’s C1-inhibitor VH® (now withdrawn) Oct. 1992: ODD for CSL Behring’s Berinert® Aug. 1996: ODD for Alpha Therapeutic Corp. July 2004: ODD for Viropharma’s Cinryze®

• Oct. 2008: market approval for Cinryze® for routine prevention Oct. 2009: market approval for Berinert® for acute attack treatment

• Feb. 1999: ODD for Pharming’s Rhucin® (transgenic) (market approval pending)

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 18

Poor economics of orphan drugs ? (1)

Some orphan drugs are quite successful: worldwide sales in 2012 *

- Rituxan (Roche) $ 7.2 billion - Gleevec (Novartis) $ 4.7 billion - Revlimid (Celgene) $ 3.8 billion - and 9 more….. $ 1 billion – 4 billion,

but some never make it to the market….. * source: EvaluatePharma, April 2013

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Poor economics of orphan drugs ? (2)

Plasma derivatives as orphan drugs:

- factor VIII - factor IX - antithrombin - (i.v. immunoglobulin)

Recombinant plasma proteins (sales in 2012):

- factor VIII: Kogenate $ 1.5 billion * Advate $ 2.2 billion * - factor VIIa: NovoSeven $ 1.5 billion * (OD will expire in Oct. 2013)

* source: EvaluatePharma, April 2013

| Sanquin Plasma Products Plasma Product Biotechnology Meeting, 13-16 May 2013 20

Sales price of ODs: is the sky the limit ?

• Orphan drugs serve only small patient groups; so, per orphan drug the impact on

the national health budget is very limited • But…. the number of orphan drugs is growing… • … and the economical crisis is ongoing • So, (in Europe) governments start to think about the cost effectiveness of orphan

drugs when sales prices are high: - Netherlands: Myozyme (alpha glucosidase; Genzyme/Sanofi) Fabrazyme (alpha galactosidase; Genzyme/Sanofi) - Belgium: Soliris (eculizumab; Alexion Pharm.) - Germany: Esbriet (pirfenidone; InterMune)

• Expectation: governments will want to have a say in the sales price

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“Ultra-orphan” drugs

• For very rare diseases: e.g. less than a few patients per 100,000

Unofficially: < 20,000 patients worldwide NICE: < 1 : 50,000

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“Ultra-orphan” drugs, EU example 1 Plasminogen

• sponsor: Kedrion, Barga, Italy

• clinical indication: ligneous conjunctivitis, a chronic inflammation of the eyes,

due to plasminogen deficiency, resulting in formation of pseudomembranes and possibly blindness; may be life-threatening due to associated lung disease

• current clinical treatment: plasma, in some cases (repeated) surgery

• number of patients: < 5,000 in EU (1.6 : 1,000,000 worldwide)

• OD designation granted: August 2007 (USA: June 2010)

• status: not recruiting yet (May 2012)

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“Ultra-orphan” drugs, EU example 2

Factor X

• sponsor: Bio Products Laboratory, Elstree, England

• clinical indication: congenital factor X deficiency

• current clinical treatment: plasma, prothrombin complex

• number of patients: < 1 : 1,000,000 (< 500 in the EU)

• OD designation granted: EU: September 2007 USA: November 2007

• status: patient recruitment for clinical trial ongoing; trial still active

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“Ultra-orphan” drugs, EU example 3

Apotransferrin

• sponsor: Sanquin, Amsterdam, The Netherlands

• clinical indication: congenital hypotransferrinemia

• current clinical treatment: plasma (and blood transfusions, iron chelation)

• number of patients: < 1 per million (6 patients known in EU, 17 worldwide)

• OD designation granted: July 2012 (EU)

• status: clinical trials ongoing (compassionate treatment) and recruiting patients

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An example from Japan

I.v. immunoglobulin

• sponsor: Benesis Corp. / JBPO, Osaka, Japan

• clinical indication: polymyositis/dermatomyositis, resistant to steroids

• current clinical treatment: methotrexate, azathioprine, cyclophosphamide

• number of patients: 10 per million annually, of which 20% steroid-resistant

6,257 in Japan (2003)

• OD designation granted: January 2000

• OD status granted: October 2011

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Some considerations (1)

• For some plasma proteins it may be questioned whether an orphan drug

designation/status is necessary, for others (“ultra orphans”) it deserves consideration whether incentives should be increased even further…

Extension of exclusivity period in case of poor product economics ? Allow a high sales price?

• What if a (plasma) product gets an OD status for a specific clinical indication, but can also be applied in other clinical conditions? E.g. IVIG, haptoglobin, butyrylcholinesterase, C1-inhibitor, ….

It will facilitate subsequent clinical developments, and/or it may lead to off-label use

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Some considerations (2)

• Which are the criteria by which a new (plasma) product for an orphan indication is judged to be superior to an existing orphan drug and will be granted market exclusivity?

USA: - the new product should be “clinically superior”, i.e. having greater effectiveness, or greater safety, or providing a major contribution to patient care - a head-to-head clinical trial may be required - a minor convenience over an existing product is not sufficient

EU: - there should be “significant clinical benefit” for the patient, “a clinically relevant change or a major contribution to patient care” - greater efficacy, greater safety, or (in exceptional cases) a major contribution to diagnosis or patient care

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Conclusions

• In the past plasma derivatives have been developed and marketed successfully without orphan drug regulations being in place: the low hanging fruit …. Nowadays, new plasma derivatives are much more difficult to bring to the market

• Patient groups and patient organizations play an important role in the orphan drug field

• OD legislation greatly facilitates the development and marketing of a variety of orphan drugs, including plasma proteins

• Convergence of OD legislation worldwide is taking place (Australia/USA, ICH), but should be stimulated further; the same holds for setting up an international classification (coding) system for rare diseases

• Future: more influence of (European) governments on sales price; USA will follow ?

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Acknowledgments

• Theo Evers, IPFA • Françoise Rossi, LFB • Tim Aldwinckle, BPL • Paul Strengers, Sanquin

• Dinesh Khokal, HSA, Singapore • Yasuhiro Kishioka, PMDA, Japan • Takehiko Iijima, Benesis Corp. / Japan Blood

Products Organization

• Scrip, “Ask the Analyst” Consultation