The decision by an FDA advisory committee to vote against approval of Bristol-Myers Squibb and AstraZeneca’s dapagliflozin due to concerns over breast and bladder cancer and potential liver damage is not only a blow to the two companies, but will undoubtedly cast a long shadow over the sodium glucose co-transporter (SGLT) inhibitor class as a whole.
Dapagliflozin was most certainly the poster boy for the field, making it to the regulator and showing some good data along the way, something that led many to believe a nod from the advisory committee was likely. But this has not been the only recent set back to the sector: Just two weeks ago Roche decided to hand back the rights to tofogliflozin, Chugai’s phase II product, and according to data from EvaluatePharma seven clinical stage products have been abandoned in the space in the last four years (see tables below).
The rest of the field
With the fate of dapagliflozin hanging in the balance (Dapa doubts validate Bristol-Myers decision to share the risk, July 20, 2011), attention will turn to the other ten SGLT inhibitors in development and in particular the four phase III compounds waiting in the wings. This list includes the second most advanced candidate, Astellas Pharma’s ipragliflozin, which is currently forecast to have sales of $160m by 2016, following a potential launch in Japan in 2012.
Astellas has run nine phase III trials with ipragliflozin, seven of which are listed as completed; all have taken place in Japan and the company does not appear to have released any of the data so far. Development in the US and Europe has only progressed to phase II.
|SGLT inhibitors in development||WW annual sales ($m)|
|Status||Product||Generic Name||Pharma Class||Company(s)||Originator||Launch||2012||2014||2016|
|Filed||Dapagliflozin||dapagliflozin||SGLT2 inhibitor||Bristol-Myers Squibb + AstraZeneca||Bristol-Myers Squibb||31-Mar-12||86||388||692|
|Phase III||ASP1941||ipragliflozin||SGLT2 inhibitor||Astellas Pharma||Kotobuki Pharmaceutical||31-Dec-12||7||63||160|
|Canagliflozin||canagliflozin||SGLT2 inhibitor||Mitsubishi Tanabe Pharma + Johnson & Johnson||Tanabe Seiyaku||31-Dec-13||-||21||46|
|BI10773||empagliflozin||SGLT2 inhibitor||Boehringer Ingelheim + Eli Lilly||Boehringer Ingelheim||30-Jun-14||-||4||35|
|Phase II||LX4211||-||SGLT1/2 inhibitor||Lexicon Pharmaceuticals||Lexicon Pharmaceuticals||31-Dec-16||-||-||200|
|TS-071||-||SGLT2 inhibitor||Taisho Pharmaceutical||Taisho Pharmaceutical||31-Dec-14||-||3||9|
|Phase I||DSP-3235||-||SGLT2 inhibitor||Dainippon Sumitomo Pharma||Kissei Pharmaceutical||31-Dec-16||-||-||-|
|GSK1614235/KGA-3235||-||SGLT1 inhibitor||Kissei Pharmaceutical + GlaxoSmithKline||Kissei Pharmaceutical||-||-||-||-|
|ISIS-SGLT2||-||SGLT2 antisense||Isis Pharmaceuticals||Isis Pharmaceuticals||-||-||-||-|
One drug that might see a change to its predicted sales and launch date is Johnson & Johnson and Mitsubishi Tanabe’s canagliflozin. Although the drug has yet to report any serious side effects, such as increased incidence of cancer, one of the side effects that worried the dapagliflozin advisory committee, an increase in urinary tract infections, has been reported in phase II studies of canagliflozin.
However, those wanting to see if this particular side effect intensifies, or new ones are thrown up as the drug moves through phase III trials involving over 12,000 patients will have to wait. The numerous pivotal studies the group is carrying out, including a vital long-term safety study, are not expected to complete until a period stretching from the first half of next year to the second half of 2013.
What the decision by the FDA advisory committee might do to Boehringer Ingelheim and Lilly’s empagliflozin is make the molecule a lot less valuable to Lilly. Earlier this year Lilly handed Boehringer $410m to secure empagliflozin and Tradjenta, a DPP-IV inhibitor, in order to create what it hoped would be a one stop shop across all the established and novel diabetes product classes (Lilly-Boehringer diabetes deal seeks safety in numbers, January 12, 2011).
If the problems with dapagliflozin do turn out to be a class effect then the deal could be a rather expensive one, as Lilly will be left with Tradjenta, a DDP-IV inhibitor in an increasingly crowded field.
Left on the shelf
For Chugai, which has been forced to carry on development of tofogliflozin on its own since Roche’s decision, the task of finding a new partner for territories outside of Japan will now be much harder. Chugai has, however, vowed to press on with filing for approval in 2013 in Japan.
The same difficulty in finding a partner might also apply to Lexicon’s phase II product, LX4211, which remains the only SGLT inhibitor not in the hands of a big pharma player.
What might make the fate of LX4211 less clear is that the drug is a dual inhibitor of SGLT1 and SGLT2. SGLT2 inhibitors work by stopping the uptake of glucose back into the body by the kidneys, while SGLT1 inhibitors stop the uptake of glucose back into the blood by the gut and to a lesser extent the kidneys.
While those without partners may well be worried now, what might concern the companies who already have deals is if they can now hang onto those partners.
The diabetes space has become a notoriously difficult one in which to get new drugs past the regulators and with everyone almost certainly waiting to see if upcoming phase III data points to a class effect on safety, what may happen is that development of drugs in phase II and I may be slowed.
If further safety signals emerge the seven products that have been abandoned in clinical trials in the space could be joined by more products.
|SGLT inhibitors abandoned in development|
|Status||Abandoned Date||Product||Generic Name||Pharma Class||Company(s)||Originator|
|Abandoned - Phase II||Jul-2011||CSG452 *||tofogliflozin||SGLT2 inhibitor||Roche (ex. Japan rights)||Chugai|
|Jul-2009||KGT-1681 (GSK189075)||remogliflozin||SGLT2 inhibitor||Kissei Pharmaceutical + GlaxoSmithKline||Kissei Pharmaceutical|
|Sep-2007||KGT-1251 (GW-869682)||sergliflozin||SGLT2 inhibitor||Kissei Pharmaceutical + GlaxoSmithKline||Kissei Pharmaceutical|
|Nov-2003||T-1095||-||SGLT2 inhibitor||Mitsubishi Tanabe Pharma + Johnson & Johnson||Tanabe Seiyaku|
|Jun-2010||BI 44847||-||SGLT2 inhibitor||Boehringer Ingelheim + Ajinomoto||Ajinomoto|
|Oct-2008||TS-033||-||SGLT2 inhibitor||Taisho Pharmaceutical||Taisho Pharmaceutical|
|Abandoned - Phase I||Dec-2008||SAR 7226||-||SGLT1/2 inhibitor||Sanofi||Sanofi|
|Abandoned - Pre-clinical||Dec-2008||LX4212||-||SGLT2 inhibitor||Lexicon Pharmaceuticals||Lexicon Pharmaceuticals|
|* Roche handed back WW ex. Japan rights; Chugai started phase III trials in Japan in November 2010 and still intends to file for approval in 2013.|