Sirtuins and ghrelins in the spotlight with Novartis-Elixir deal

Analysis

Novartis’ recent option deal with Elixir Pharmaceuticals to acquire the private US biotech or license Elixir’s oral ghrelin antagonist programme followed a decision by the Swiss pharma giant to drop its rights to another two of Elixir’s pre-clinical programs, sirtuins and ghrelin agonists (EP Vantage Interview - Elixir patiently waiting for Novartis takeout, June 8, 2009).

A review of pipeline data from EvaluatePharma for these novel classes of drug, that act on the sirtuin and ghrelin pathways with the potential to treat a wide range of disorders, not only provides an insight into why Novartis opted for the ghrelin antagonist. It also highlights some of the companies operating in this fledgling field that could be receiving renewed interest from other big pharma partners (see tables below).

Ghrelin agonists to the fore

The table below illustrates that the most advanced candidates which act on ghrelin, a naturally occurring hormone involved in stimulating appetite and food consumption, are all agonists designed to help treat wasting disorders like cachexia in patients suffering from cancer, COPD or AIDS.

Ghrelin pathway products: pipeline
Phase Pharma Class Product Company Originator Indication Summary
Phase II Ghrelin agonist Ipamorelin Helsinn Healthcare Novo Nordisk Post-operative ileus (POI) [Phase II]
Ghrelin agonist Anamorelin (RC-1291) Helsinn Healthcare Novo Nordisk Cachexia (wasting) [Phase II]
Ghrelin agonist SUN 11031 Daiichi Sankyo Asubio Pharma Cachexia (wasting) [Phase II]; Anorexia nervosa [Phase II]
Ghrelin agonist TZP-101 Tranzyme Pharma Tranzyme Pharma Post-operative ileus (POI) [Phase II]; Gastroparesis [Phase II]; Cachexia (wasting) [Pre-clinical]
Ghrelin agonist TZP-102 Tranzyme Pharma Tranzyme Pharma Gastroparesis [Phase II]; Gastro-oesophageal reflux disease (GORD/GERD) [Pre-clinical]
Ghrelin agonist GTP-300 Rose Pharma Rose Pharma Cachexia (wasting) [Phase II]
Ghrelin agonist GTP-200 Rose Pharma Rose Pharma Cachexia (wasting) [Phase II]; Other metabolic indications [Phase I]
Pre-clinical Ghrelin agonist BIM 28131 Ipsen Ipsen Cachexia (wasting) [Pre-clinical]
Ghrelin agonist EX-1314 Elixir Pharmaceuticals Bristol-Myers Squibb Cachexia (wasting) [Pre-clinical]; Gastroparesis [Pre-clinical]
Ghrelin agonist ST-1141 (RC-1141) Helsinn Healthcare Sapphire Therapeutics Constipation, opioid-induced [Pre-clinical]
Ghrelin agonist GTP3XX Rose Pharma Rose Pharma Other metabolic indications [Pre-clinical]
Ghrelin agonist AZP-01 Alizé Pharma Alizé Pharma Diabetes, type II (maturity onset) [Pre-clinical]
Ghrelin antagonist Ghrelin Antagonist Elixir Pharmaceuticals Elixir Pharmaceuticals Diabetes, type II (maturity onset) [Pre-clinical]; Obesity [Pre-clinical]
Ghrelin antagonist Ghrelin Antagonist Helsinn Healthcare Novo Nordisk Obesity [Pre-clinical]
Ghrelin antagonist Ghrelin Antagonists Æterna Zentaris Zentaris/University of Milan/University of Montpellier Obesity [Pre-clinical]
Anti-ghrelin aptamer NOX-B11 NOXXON Pharma NOXXON Pharma Obesity [Pre-clinical]
Anti-ghrelin vaccine CYT014-T2Qb Cytos Biotechnology Cytos Biotechnology Obesity [Pre-clinical]
Research project Ghrelin antagonist TZP-301 Tranzyme Pharma Tranzyme Pharma Obesity [Research project]

With seven agonist candidates in phase II, but only in the hands of five small to medium size companies, this suggests the field remains fairly narrow and has yet to attract the interest of big pharma.

Meanwhile the development of ghrelin antagonists, which have the potential to suppress appetite and increase insulin sensitivity, remains at a much earlier stage with just four candidates at the pre-clinical or research project phase.

Helsinn Healthcare’s recent acquisition of Sapphire Therapeutics, which held probably the most comprehensive portfolio of ghrelin agonists and antagonists, indicates that the ghrelin field is generating some interesting activity as companies jostle for position. The likes of Tranzyme Pharma and Rose Pharma, private US and Danish companies respectively, could therefore be receiving some new and renewed interest in their programmes since Novartis made its move on Elixir.

Glaxo ring-fenced sirtuins

The field of sirtuins received high profile exposure last year when GlaxoSmithKline paid $720m to acquire Sirtris Pharmaceuticals, one of the few companies developing a clinical stage pipeline of products which interact with these enzymes which regulate multiple metabolic pathways.

The table below reveals that Glaxo is now way ahead of the developmental competition for sirtuin-related products.

Aside from Glaxo and Elixir, only MethylGene and Santhera Pharmaceuticals have any research ongoing in this novel area, which has the potential to treat a wide range of disorders from diabetes to cancer to Huntington's disease.

Therefore, with Elixir’s sirtuin and ghrelin agonist pre-clinical programs some way behind the developmental competition, Novartis’ decision to go for Elixir’s ghrelin antagonist program instead looks like a wise one on the basis that this candidate represents the best chance of being first-in-class.

Sirtuin pathway products: pipeline
Phase Pharma Class Product Company Originator Indication Summary
Phase II Sirtuin (SIRT1) activator 184072 GlaxoSmithKline GlaxoSmithKline Diabetes, type II (maturity onset); Colorectal cancer; General blood malignancies
Phase I Sirtuin (SIRT1) activator 2245840 GlaxoSmithKline GlaxoSmithKline Diabetes, type II (maturity onset); COAD/COPD
Pre-clinical Sirtuin (SIRT1) modulator SIRT1 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals Diabetes, type II (maturity onset); General cancer indications; General inflammatory disorders
Sirtuin (SIRT1) inhibitor SIRT1 Inhibitor Elixir Pharmaceuticals University of California/Massachusetts Institute of Technology Huntington's disease; General cancer indications
Sirtuin (SIRT2) inhibitor SIRT2 Inhibitor Elixir Pharmaceuticals University of California/Massachusetts Institute of Technology Diabetes, type II (maturity onset); Obesity
Sirtuin (SIRT1) activator SIRT1 Activator Elixir Pharmaceuticals University of California/Massachusetts Institute of Technology Diabetes, type II (maturity onset); Obesity
Research project Sirtuin (SIRT2) modulator SIRT2 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals General cancer indications [Research project]; Other neurological indications [Research project]
Sirtuin (SIRT3) modulator SIRT3 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals Other metabolic indications [Research project]; General cardiovascular indications [Research project]
Sirtuin (SIRT4) modulator SIRT4 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals Other metabolic indications [Research project]; General cardiovascular indications [Research project]
Sirtuin (SIRT5) modulator SIRT5 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals Other metabolic indications [Research project]
Sirtuin (SIRT6) modulator SIRT6 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals General cancer indications [Research project]
Sirtuin (SIRT7) modulator SIRT7 Modulator Program GlaxoSmithKline Sirtris Pharmaceuticals Other metabolic indications [Research project]
Sirtuin inhibitor Sirtuin inhibitor program MethylGene MethylGene General cancer indications [Research project]
Sirtuin modulator SIRT deacetylase-modulators Santhera Pharmaceuticals Santhera Pharmaceuticals Other musculoskeletal disorders [Research project]

Related Topics

Share This Article