Therapeutic Focus – Growing interest in SGLTs as novel diabetic agents

Whilst the annual meeting of the American Diabetes Association (ADA) last week naturally focused on comparing and contrasting the merits of DPP-IVs and GLP1s as proven, but still relatively new anti-diabetic agents (ADA EventAnalyzer: 2009's winners and losers, June 10, 2009), a burgeoning class of novel diabetic drugs, sodium glucose co-transporter (SGLT) inhibitors, received renewed and growing interest.

The field’s most advanced candidate is Bristol-Myers Squibb’s dapagliflozin and having reported positive phase IIb data all eyes are now on phase III results due in the third quarter. A review of pipeline data from EvaluatePharma reveals 16 candidates in active development which target the SGLT metabolic pathway, mostly already in the hands of big pharma companies (see tables below). If the dapagliflozin data is positive the likes of Lexicon Pharmaceuticals with unpartnered early-stage SGLT assets could soon find a queue of hopeful partners outside their door.

Novel target

The bulk of pipeline candidates targeting the SGLT pathway specifically inhibit the sodium glucose co-transporter2 (SGLT2) protein. SGLT2 is largely responsible for the majority of glucose re-absorption and helps the body retain glucose, but for diabetic patients this can contribute to hyperglycaemia. Therefore, inhibiting SGLT2 stops glucose entering the bloodstream and instead more glucose is excreted in the urine.

The following table highlights the overall product portfolio of SGLT products in development, as well as the fact that four candidates have so far been abandoned having reached phase II. In addition, there are likely to be a number of research projects ongoing in this area but are not included in this analysis, as the companies have yet to reveal the specific target of their early-stage anti-diabetic candidates.

Count of product portfolio for SGLT inhibitors
Market Status Count
Phase III  2
Phase II  5
Phase I  7
Pre-clinical  2
Active projects 16
Abandoned - Phase II 4
Total 20

Japanese influence

The following table provides detail on the active pipeline candidates, the most advanced of which are all SGLT2 inhibitors. In total, 15 SGLT2s have been developed, including the four abandoned projects, and somewhat intriguingly 10 of these were originated by Japanese companies.

Alongside BMS who discovered dapagliflozin, the likes of Tanabe, Kissei Pharmaceutical and Taisho Pharmaceutical have all the led the way in research in this area.

 Pipeline for SGLT inhibitors WW annual sales ($m)
Phase Pharma Class Product Originator Company(s) Launch 2011 2012 2013 2014
Phase III   SGLT2 inhibitor Dapagliflozin Bristol-Myers Squibb Bristol-Myers Squibb + AstraZeneca  Dec - 2011  6  120  230  352
  SGLT2 inhibitor & biguanide Dapagliflozin & Metformin Bristol-Myers Squibb/Lipha Bristol-Myers Squibb + AstraZeneca  Dec - 2012  -  -  -  -
Phase II   SGLT2 inhibitor Remogliflozin (189075 / KGT-1681) Kissei Pharmaceutical GlaxoSmithKline + Kissei Pharmaceutical  Jun - 2012  -  17  40  80
Canagliflozin (TA-7284) Tanabe Seiyaku Mitsubishi Tanabe Pharma + Johnson & Johnson  Mar - 2016  - - - -
BI 44847 Ajinomoto Boehringer Ingelheim -  - - - -
BI 10773 Boehringer Ingelheim Boehringer Ingelheim -  - - - -
YM543 Kotobuki Astellas Pharma -  - - - -
Phase I   SGLT2 inhibitor LX4211 Lexicon Pharmaceuticals Lexicon Pharmaceuticals -  - - - -
CSG452 Chugai Chugai -  - - - -
R7201 Roche Roche -  - - - -
TS-033 (backup compound) Taisho Pharmaceutical Taisho Pharmaceutical -  - - - -
  SGLT1 inhibitor KGA-3235 / KGA-2727 Kissei Pharmaceutical GlaxoSmithKline + Kissei Pharmaceutical -  - - - -
  SGLT1/SGLT2 inhibitor SAR 7226 Sanofi-Aventis Sanofi-Aventis -  - - - -
  SGLT2 antisense ISIS-SGLT2Rx Isis Pharmaceuticals Isis Pharmaceuticals -  - - - -
Pre-Clinical   SGLT2 inhibitor LX4212 Lexicon Pharmaceuticals Lexicon Pharmaceuticals - - - - -
  SGLT2 antisense ISIS 388626 Isis Pharmaceuticals Isis Pharmaceuticals - - - - -

Hopes for SGLT2 inhibitors becoming a major new class of drug to help treat diabetes currently rest squarely on the shoulders of dapagliflozin. Phase IIb data presented so far have shown significant improvements across a number of glycaemic measures, as well as weight loss of up to 4-5kg. The fact the drug could become a once-daily oral tablet is also important.

BMS is developing the product with AstraZeneca, having formed part of a broader collaboration between the two companies in 2007 which also covered BMS’ DPP-IV inhibitor, Onglyza.

Assuming the phase III data is positive the product could reach the market in 2011 and analysts currently expect sales of $352m by 2014, with some predicting blockbuster potential.

After dapagliflozin, the most advanced phase II candidates are GlaxoSmithKline’s remoglifozin and Johnson & Johnson’s canagliflozin. In reference to the Japanese influence, remoglifozin was discovered by Kissei and canagliflozin by Tanabe.

The analysis also highlights that the bulk of the SGLT inhibitor pipeline is in the hands of either big pharma or major Japanese companies. As such, Lexicon’s SGLT2 inhibitor candidates, LX4211 and LX4212, in phase I and pre-clinical studies respectively, could be the subject of intense partnering discussions, especially if the dapagliflozin data is impressive.

Although the ADA meeting last week did not deliver much by way of pivotal clinical data for SGLT2s, it is clear that ADA 2010 should be more eventful and provide a more tangible insight into the potential of the class in general.

Minor setbacks so far

A review of the SGLT inhibitor products that have so far failed to make it past phase II trials reveals that they are all SGLT2 inhibitors, three of which were originated by Japanese companies.

Abandoned SGLT2 inhibitors - all at phase II
Product Originator Company(s) Termination date Comment
AVE-2268 Aventis Sanofi-Aventis Oct - 2008 Focus switched to SAR 7226
TS-033 Taisho Pharmaceutical Taisho Pharmaceutical Oct - 2008 Focus switched to backup compound of TS-033
Sergliflozin (869682 / KGT-1251) Kissei Pharmaceutical GlaxoSmithKline + Kissei Pharmaceutical Sep - 2007 Focus switched to remogliflozin
T-1095 Tanabe Seiyaku Mitsubishi Tanabe Pharma + Johnson & Johnson Nov - 2003 Focus switched to canagliflozin

Although these were setbacks that the companies would have preferred to avoid, it is a natural attrition rate for a novel pharma class of drugs. The fact that none of the abandonments were due to any serious safety signals is encouraging and in almost all instances the companies were able to revert to a follow-on compound.

Current safety concerns with SGLTs relate to the risk of developing hypoglycaemia, dangerously low blood glucose levels, and/or urinary tract infections. Following the FDA’s recently heightened safety guidelines for new diabetic agents the safety data for dapagliflozin will be almost as important as the efficacy results.

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