Somatropin Safety Review Highlights Lack of Alternatives

December 13, 2010 Somatropin safety review highlights lack of alternatives

A French study of 7,000 young adults once treated with somatropin has prompted the European Medicines Agency (EMA) to conduct a safety review, after flagging concerns that therapies containing the growth hormone increase the risk of death.

The EMA’s advisory committee is meeting over the next three days to discuss the review, and the FDA has yet to make any comment on the issue, so it remains unclear at this stage what sort of impact this might have on the somatropin market. A look at EvaluatePharma data shows this is a $3bn global market, dominated by Novo Nordisk and Pfizer, and set for steady growth over the next six years; limited alternatives are available (see tables below). Patient groups and the companies selling blockbuster somatropin products will be hoping that any restrictions will only apply to the highest doses of the hormone, which seemed to be most closely linked to an increased risk of death in the French study.

Extensively used

Somatropin is a synthetically-produced recombinant human growth hormone, derived from naturally-occurring somatotropin, extracted from the pituitary gland.

It has been used for extensive therapeutic purposes including promoting growth in children and addressing growth hormone deficiencies, increasing metabolism in metabolic disease patients, rebuilding muscle following disease-related wasting, short stature and Turner’s syndrome – a condition where a missing sex chromosome manifests itself in abnormal growth of body parts – as well being famously used by athletes as a performance- enhancing and muscle-building agent, and in cosmetics as an anti-aging serum.

The French medicines agency’s Santé Adulte GH Enfant (SAGhE) study sought to learn more about how childhood use of the growth hormone from the mid-1980s to the mid-1990s has affected individuals’ long-term health.

Higher than the recommended dose

This was an observational study, and a risk of death could not be absolutely attributed to the therapy without more in-depth analysis, the EMA said. The risk was also mainly associated with doses much higher than the normally recommended amount - in other words from off-label use of drugs.

Being a naturally-derived hormone, side effects from somatropin therapy are seldom seen within the recommended dose range and treatment timeline. Adverse effects such as hypoglycemia, acromegaly, carpal tunnel syndrome – a loss of hand function due to blocked nerves in the wrist – and temporary joint pain have been reported in the past, but are generally rare.

An unprecedented and serious safety scare would therefore be a shock, and could feasibly impact use of drugs that incorporate somatropin.

Growth of the market

The somatropin market is large and still growing, despite the presence of three biosimilars in the top ten (see table). In 2002 the market was worth $1.7bn, and is predicted to nearly double by 2012. Novo Nordisk’s Norditropin franchise, marketed for short stature, Turner’s syndrome, growth hormone deficiency and bone repair, is forecast to reach blockbuster status by that time. Somatropin market

Annual WW sales ($m)

Proprietary Rank Product Company Launch 2002 2006 2010 2012 2014 2016 Level

NDA + Norditropin Proprietary 31-May- 1 Novo Nordisk 262 557 864 1,004 1,099 1,167 SimpleXx Drug 99 Delivery

NDA 31-Dec- 2 Genotropin Pfizer (Patented 551 795 905 927 933 932 87 Compound)

NDA 08-Mar- 3 Humatrope Eli Lilly (Patented 329 416 430 416 405 362 87 Compound)

NDA 31-Dec- 4 Saizen Merck KGaA (Patented 124 209 280 304 312 318 89 Compound)

NDA 31-Jan- 5 Nutropin Roche (Patented 308 394 367 344 316 299 94 Compound)

NDA 23-Aug- 6 Serostim Merck KGaA (Patented 95.1 71.8 96 106 106 106 96 Compound)

NDA (ex. 31-Mar- 7 NutropinAq Ipsen - 19 64 83 91 95 USA Only) 03

Teva Tev- 11-Feb- 8 Pharmaceutical Biosimilar - 25 45 50 60 70 Tropin/Tjet 05 Industries

Biosimilar LG Life 31-Dec- 9 Eutropin (ex. USA - 37 31 32 31 31 Sciences 93 Only)

Biosimilar Dong-A 31-Dec- 10 Growtropin (ex. USA - 15 15 19 22 26 Pharmaceutical 99 Only)

Other products 65 41 13 0 0 0

Total 1,735 2,579 3,111 3,285 3,375 3,405

Aside from somatropin, also marketed for growth hormone deficiency are oxandrolone-based anabolic steroids, such as CSL’s Lonavar and Savient Pharmaceuticals’ Oxandrin. Oxandrolone is marketed as a weight-gain and muscle-building agent, especially for Aids patients experiencing muscle-wasting, known as cachexia.

The agent is most famous though for its popularity with bodybuilders – small doses can build lean muscle, while a short half-life means it can side-step drug tests. It has little effect on the body’s natural hormonal balance, and has supposedly few side effects. However users have reported adverse effects in the past, including development of masculine attributes in women. Oxandrolone is contraindicated in pregnant women as it can be severely toxic to the baby, and peliosis hepatitis – a potentially fatal condition where blood cysts appear in the liver and kidneys – has also been associated with its use.

Mecasermin, a synthetic version of IGF-1 (insulin-like growth factor-1), as used by Roche and Ipsen’s Increlex to treat short stature and growth hormone deficiency, and Astellas’ Somazon for pituitary dwarfism, stimulates the actions of somatotropin. Its safety profile however is not well-defined, and its use as a replacement for growth hormone therapy is not recommended.

Thin pipeline Ascendis Pharma’s ACP-001 entered phase II in mid-September, after demonstrating itself to be safe, well- tolerated, and a better IGF-1 generator, a biomarker of growth hormone activity, in phase I trials from a single injection, compared with seven daily growth hormone injections.

Alternatives in the pipeline include synthetic ghrelin mimetics; ghrelin stimulates natural production of growth hormone in the body. These include: tesmorelin (Egrifta), which was approved earlier this year to reduce abdominal fat in HIV-patients with lipodystrophy and is in phase II for growth disorders; Æterna Zentaris’ macimorelin (AEZS-130), which has shown promise in early stage cachexia trials, but is also in phase III as a diagnostic for growth hormone disorders; and pralmorelin, the active ingredient of Kaken Pharmaceutical’s GHRP Kaken 100 Injection, also a diagnostic of growth hormone secretion.

It is not yet clear how serious the mortality risk associated with somatropin-based therapies is, but what is clear is that there is little else to offer sufferers of growth disorders. This might be a worrying prospect for parents especially, as growth hormone disorders often manifest themselves at childhood and are treated while the body is still growing.

Should the European review confirm a long-term safety risk associated with somatropin use, the hope must be it is restricted to off-label high doses and that the risk is minimal at recommended doses. If broader restrictions are put in place the implications for patients and the market could be worrying indeed. Non-somatropin-based therapies for growth hormone disorders

Generic Pharmacological Product Company Indication Summary Name Class

Cachexia (wasting), AIDS related [Marketed]; Oxandrin Savient Malnutrition [Marketed]; Marketed / oxandrolone Pharmaceuticals / Steroid Growth hormone Lonavar Azanta / CSL disorders [Marketed]; Turner's syndrome [Marketed]

GHRP Kaken Kaken Growth hormone Growth hormone pralmorelin 100 Pharmaceutical secretagogue disorders [Marketed] Injection

Pituitary dwarfism Somazon mecasermin Astellas Pharma IGF-1 [Marketed]

Short stature in children Protropin somatrem Roche Growth hormone [Marketed]

Growth hormone Short stature in children Geref sermorelin Merck KGaA secretagogue [Marketed]

Short stature in children [Marketed]; Adult growth Increlex mecasermin Ipsen / Roche IGF-1 hormone deficiency [Phase I]

Growth hormone disorders [Phase III]; Lipodystrophy [Phase I]; AEZS- Growth hormone Cachexia (wasting), AIDS Phase III 130 (EP- macimorelin Æterna Zentaris secretagogue/Ghrelin related [Phase I]; 1572) receptor agonist Cachexia (wasting) [Phase I]; Renal insufficiency [Pre-clinical]

Adult growth hormone deficiency [Phase II]; Short stature in children hGH-CTP growth [Phase I]; Growth Phase II (MOD- hormone PROLOR Biotech Growth hormone hormone disorders [Phase 4023) (human) I]; Turner's syndrome [Phase I]; Cachexia (wasting), AIDS related [Phase I]

Growth hormone ACP-001 Ascendis Pharma Growth hormone disorders [Phase II]

Lipodystrophy [Approved]; Growth tesamorelin Growth hormone hormone disorders [Phase Egrifta Theratechnologies acetate secretagogue II]; Alzheimer's disease [Phase II]; Cystic fibrosis (CF) [Phase I]

KP- Kaken Growth hormone Short stature in children pralmorelin 102LN Pharmaceutical secretagogue [Phase II]

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