Achieving an FDA breakthrough therapy designation is proving a hit-and-miss affair, with a success rate of about 50% so far for companies trying to demonstrate the ability of their candidates to transform how diseases are treated. It might therefore be useful for drugmakers to identify which therapy areas are likely to win this new super-fast-track status in order to assess whether it is worth trying.
Not surprisingly, cancer accounts for about half of the indications named so far, while areas with heavy research and development investment such as neurology have yet to make an appearance. US regulators have recently given the sector more clarity on what they are looking for from breakthrough candidates (FDA not such a soft touch on breakthrough therapies, June 26, 2013). The agency seems to be showing definite preferences.
The FDA says it has so far granted 21 requests for breakthrough status and rejected 21, while a further 22 are pending. The agency does not identify specific designations; none of the rejected requests have been disclosed, and so far only 16 of the granted ones have been revealed through company press releases or other public disclosures (see table).
|Disclosed breakthrough therapy designations|
|Date disclosed (all 2013)||Product||Indication||Phase||Company||2018 forecast($m)||NPV ($m)|
|January 6||Kalydeco||Cystic fibrosis*||Marketed||Vertex Pharmaceuticals||2,659||7,790|
|Kalydeco and VX-809||Cystic fibrosis*||Phase III||1,427||3,551|
|February 12||ibrutinib||Mantle cell lymphoma||Phase III||Pharmacyclics/Johnson & Johnson||1,401**||4,671|
|Waldenstrom's macroglobulinemia||Phase II|
|April 8||Chronic/small lymphocytic leukaemia||Phase III|
|March 15||LDK378||Non-small cell lung cancer (ALK-positive)||Phase III||Novartis||75||335|
|April 10||palbociclib||Breast cancer (ER-positive, HER2-negative)||Phase III||Pfizer/Onyx Pharmaceuticals||794||3,222|
|April 24||lambrolizumab||Melanoma||Phase II||Merck & Co||245||1,547|
|April 25||daclatasvir, asunaprevir and BMS-791325||Hepatitis C||Phase III||Bristol-Myers Squibb||520||1,659***|
|April 29||SD-101||Epidermolysis bullosa||Phase II||Scioderm||n/a||n/a****|
|May 1||daratumumab (HuMax-CD38)||Multiple myeloma||Phase II||Genmab/Johnson & Johnson||n/a||n/a|
|May 6||ABT-450, ABT-267 and ABT-333||Hepatitis C||Phase III||AbbVie||n/a||n/a|
|May 15||obinutuzumab (RG7159/ GA101)||Chronic lymphocytic leukaemia||Phase III||Roche/Biogen Idec||322||1,543|
|May 20||sebelipase alfa||Lysosomal acid lipase deficiency||Phase III||Synageva BioPharma||378||718|
|May 28||asfotase alfa (ENB-0040)||Perinatal, infantile and juvenile onset hypophosphatasia||Phase III||Alexion Pharmaceuticals||241||385|
|June 21||serelaxin (RLX030)||Acute heart failure||Phase III||Novartis||632||1,038|
|*Vertex has not disclosed the setting in which its two compounds have been granted breakthrough designation**Forecast for all indications***Combines forecasts and value from daclatasvir and asunaprevir****Private company|
What FDA officials have said they are looking for is treatments that are “transformative” to patients’ lives based on early clinical evidence, with the incentive of accelerated clinical programmes – and indeed, abbreviated ones, if the interim data are spectacular – for those companies willing to take a risk on truly novel approaches in difficult disease areas (Asco – FDA charms industry with talk of faster approvals, June 3, 2013).
In essence, regulators are saying to drug companies that it is fine to seek the designation for me-too drugs – those in established drug classes treating diseases with existing options – but in that case manufacturers can expect clinical and regulatory costs to be much higher. On the other hand, breakthrough therapies promise to be much more profitable, one of the driving forces behind the industry’s shift to orphan drugs in recent years (Orphan diseases’ appeal lies in return on investment, April 23, 2013).
Given that the FDA is offering to speed clinical development, is a bit surprising to see that so many of the breakthrough designations are in phase III, when filing already beckons. Cancer drugs are not alone in being measured for signs of efficacy in phase I, suggesting that developers could begin applying at that very early stage. Pharmacyclics’ ibrutinib impressed Johnson & Johnson enough that it signed the Bruton’s tyrosine kinase inhibitor after it had reported just phase Ib/II data, suggesting it could have won designation even then.
That cancer treatments have accounted for half the breakthrough designations should come as less of a surprise. After all, oncology accounts for over 30% of the more than 9,000 active R&D projects in the industry, according to EvaluatePharma data, and despite progress over recent decades many cancers remain terminal diseases once they become inoperable, making the unmet medical need clear.
Haematological cancers account for most of the cancer designations – again, a result that could be expected given that in diseases like multiple myeloma specialists and patients are hoping for effective treatments with fewer side effects in the elderly population it primarily strikes. Vaunted kinase inhibitor ibrutinib has three separate designations in the haematological cancers, along with two antibodies, the Genmab/J&J antibody daratumumab and obinutuzumab from Roche and Biogen Idec.
The two protein therapies sebelipase alfa and asfotase alfa also qualified; as replacements for vital metabolic modulators, neither one should come as too much of a surprise. The latter is being tested by Alexion Pharmaceuticals, which sells the ultra-orphan drug Soliris for a half-million dollars a year, making clear the attraction of these diseases; Sanofi and Shire have also found this a lucrative field in recent years.
But the chances of getting the designation does not seem at all attached to either small populations or immediacy of death. Two hepatitis C antiviral cocktails have made the list, and based on data Gilead Sciences’ sofosbuvir-lepidasvir combination should qualify easily if the California group is so inclined. Perhaps given the therapy’s late stage it does not see any benefit, but it would seem that attaining breakthrough status still could cut phase III costs.
The biggest surprise, given its mixed data, is Novartis’ serelaxin (RLX030) winning a designation. The need in acute heart failure is clear, but whether serelaxin is the answer is much less so, even with some positive survival findings; as EP Vantage has noted, the breakthrough status could also be a way for FDA to truncate a confirmatory phase III trial should interim data be compelling (Serelaxin continues charmed life with breakthrough designation, June 21, 2013).
The absence of CNS products and anti-infectives – other than the hep C products – is worthy of note. Both have been the target of heavy investment from pharma and worries from government and acadaemia because of a lack of new products. Non-addictive pain medications using a novel target or new broad-spectrum antibiotics would be obvious candidates for designation.
The regulatory landscape will evolve over coming months and years and the FDA has made it clear it will not be pulling punches on products that do not live up to breakthrough standards. Given the response just in the first year, there is no doubt that this new designation will be a strong incentive for companies to take bigger risks.