Partners sensing potential in Antisense


This year’s $1.9bn deal struck between Genzyme and Isis Pharmaceuticals shows that while antisense and RNAi technology has yet to produce a commercial success, hopes in the area remain high, and companies are willing to pay top dollar for access to promising looking candidates.

With all the phase III candidates partnered and a significant portion of the phase II candidates snapped up, 2008 might have already delivered the antisense “deal of the year”. But with research in the area gathering pace, and earlier stage projects building, the scene is unlikely to go quiet.

The table below, from EvaluatePharma, shows the spread of projects among the clinical stages.

Antisense therapies Product Count
      Filed 1
      Phase III 5
      Phase II 17
      Phase I 16
      Pre-clinical 56
      Research project 42
Total (Active) 137
      Withdrawn 2
      Suspended - Pre-clinical 2
      Abandoned - Phase III 3
      Abandoned - Phase II 17
      Abandoned - Phase I 6
      Abandoned - Pre-clinical 13
      Abandoned - Research project 14
      Disposed - Phase II 1
Total (Inactive) 58
Total (Antisense therapies) 195

Most advanced, although currently stalled, is a product from Genta, called genasense, which has been filed with the FDA in chronic lymphocytic leukaemia, and is being developed in other cancer types. The product received an FDA non-approvable letter in December 2006, and last month received another refusal, with the regulator citing insufficient “confirmatory evidence” of efficacy. Further trials are planned.

The failure of genasense, and the fact that none of the products under development have any sales forecasts from analysts (except a phase II Eli Lilly product, survivin ASO, with a significantly risk-adjusted $3m in 2012) illustrate how risky the area is still considered. Until one of the phase III candidates produces positive data, that situation is unlikely to change.

The product expected to generate results first is the Isis/Genzyme product Mipomersen (ISIS 301012), with an FDA filing anticipated next year. Mipomersen is in phase III trials for familial hypercholeseterolemia.

Market leader

Isis dominates the antisense space and has originated many of the candidates in late stage development. It developed the only antisense drug that has made it the market, Vitravene for cytomegaloviris retinitis in AIDS patients. The therapy was approved in 1998 but withdrawn a couple of years ago after demand plummeted as new anti-HIV drugs prolonged survival and improved the health of infected individuals.

The second phase III candidate, licensed to Atlantic Healthcare and Orphan Australia, is alicaforsen for ulcerative colitis and Crohn’s disease.

The other phase III candidate does not belong to Isis, but Opko Health with an RNAi candidate in phase III for macular degeneration. Results are expected in 2010.

In phase II development the name Isis once again dominates, with three in phase II, a multiple sclerosis candidate licensed to Teva and two oncology candidates licensed to OncoGenex Technologies and Eli Lilly. Unpartnered is ISIS 113715 for type II diabetes.

Merck also has a phase II project, for macular degeneration, which was originated by Sirna Therapeutics. Merck’s $1.1bn acquisition of the RNAi specialist in October 2006, paying a staggering 102% premium over the company’s share price to grab control, thrust the field firmly into the limelight.

That year marked a peak of the deals done in the field, the table below shows, with in-licensing activity particularly strong. With most clinically advanced projects now partnered, further big deals in the space are unlikely to occur for some while, and 2008 might not beat the peak of 2006.

Deal Date Antisense therapies: count of deals per year
2008 2
2007 12
2006 17
2005 14
2004 7
2003 8
2002 5
2001 8
2000 4
Total 77

Still, the terms of the deal Genzyme and Isis struck were much higher than expected, sending Isis shares soaring, so surprises could be in the wings. Of the top line value of $1.9bn, the antisense specialist banked $325m upfront, a significant amount of cash for a therapy area that has yet to make a splash in sales terms.

Antisense Therapies: In-depth tables

Technology - Antisense therapies (PII and above product portfolio)
Market Status (Current) Product Company Originator Therapeutic Subcategory 2012 WW sales (US$m)
Withdrawn (post-marketing) Vitravene Novartis Isis Pharmaceuticals Eye preparations -
  Vitravene Isis Pharmaceuticals Isis Pharmaceuticals Eye preparations -
Filed Genasense Genta Genta Other cytostatics -
Phase III Mipomersen (ISIS 301012) Genzyme Isis Pharmaceuticals Anti-hyperlipidaemics -
  Mipomersen (ISIS 301012) Isis Pharmaceuticals Isis Pharmaceuticals Anti-hyperlipidaemics -
  Alicaforsen (ISIS 2302/AP 1007) Isis Pharmaceuticals Isis Pharmaceuticals Gastro-intestinal anti-inflammatories -
  AP1007 Orphan Australia Isis Pharmaceuticals Gastro-intestinal anti-inflammatories -
  Bevasiranib Opko Health University of Pennsylvania Eye preparations -
Phase II Survivin ASO (LY2181308) Eli Lilly Isis Pharmaceuticals Other cytostatics  3
  Resten-MP AVI BioPharma AVI BioPharma Other cardiovasculars -
  Resten-NG AVI BioPharma AVI BioPharma Other cardiovasculars -
  ATL1102/ISIS 107248 Teva Pharmaceutical Industries Isis Pharmaceuticals MS Therapies -
  ATL1102/ISIS 107248 Isis Pharmaceuticals Isis Pharmaceuticals MS Therapies -
  EN101 Amarin Hebrew University of Jerusalem Other CNS drugs -
  ISIS 113715 Isis Pharmaceuticals Isis Pharmaceuticals Anti-diabetics -
  AEG35156 Idera Pharmaceuticals Idera Pharmaceuticals Other cytostatics -
  OGX-011/ISIS 112989 Isis Pharmaceuticals OncoGenex Technologies Other cytostatics -
  LY2181308 / ISIS 23722 Isis Pharmaceuticals Isis Pharmaceuticals Other cytostatics -



Antisense therapies: Company Acquisitions (2005-07)
Date of Acquisition Company Acquired Company Products transferred (active) Deal Value (US$m)
 05-Dec-07  Amarin  Ester Neurosciences  1  15
 27-Mar-07  Opko Health  Acuity Pharmaceuticals  5  -
 29-Dec-06  Merck & Co  Sirna Therapeutics  9  1100
 11-Jul-05  Silence Therapeutics  Atugen  8  10.8



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