Monday, April 22, 2013

IDSA Update on Antibiotic Development - Hope or Stagnation?

In a recent publication in Clinical Infectious Diseases, the Infectious Diseases Society of America (IDSA) provides its view of the state of antibiotic development.  They report that there are seven new antibacterial agents that have reached phase II or later stages of development.  Of these, one is from Polymedix, which recently declared bankruptcy.  Their compound, brilacidin, had toxicity issues during clinical trials. So that takes us down to six.  Of these six, three are combinations of beta-lactams with a novel B-lactamase inhibitor, avibactam.  This compound was originally discovered in Roussel-Uclaf-Aventis then spun out with Novexel.  Novexel was purchased by Astra-Zeneca who has taken these combinations, with their partner Forest Laboratories, into phase II and III trials. Although this pipeline provides hope, the IDSA correctly notes that there are precious few compounds that provide coverage against highly resistant Acinetobacter and few deal with metallo-B-lactamases like NDM-1. 
Eravacycline, a new tetracycline, does provide improved activity against Acinetobacter compared to tigecycline, but whether this will translate in the clinic is as yet unclear.  A compound that has not yet reached late stage development and hence was not cited by the IDSA, aztreonam plus avibactam, should provide activity against metallo-B-lactamases assuming it can avoid toxicity during its ongoing (but currently on hold) phase I trials.

IDSA says that it was unable to identify phase II or III trials in community acquired pneumonia – but they must mean for drugs active against Gram negatives since Cempra’s solithromycin is currently being studied in phase III for this indication.

The IDSA states that much of antibiotic discovery and development is now centered in biotech.  This is clearly true. But, for the most part, they ignore the critical relationship between large pharma and academic researchers and biotech.  When I speak to investors (I do a great deal of this), they routinely tell me (confirmed at the last Brookings meeting) that the only exit they consider worthwhile is an acquisition.  So – the option of “going it alone” to the market and financing phase III by going to the public markets is not an option for investors at the beginning.  This becomes a poor second choice for them if they are unable to partner their company. When investors think of partners, they think of smaller companies like Cubist and Forest and the large pharma companies.  But even including these small companies, there are probably only six or so potential partners and this number remains unstable (just look at Astra-Zeneca).

Therefore, to keep investors interested in antibiotic start-ups, we need (desperately) deep-pocketed companies willing to invest.  I made this case at the last Brookings.  We MUST keep the current large pharma players in the game and we MUST attract new players if we are going to be successful. But we are not succeeding if the Astra-Zeneca situation is any sort of indicator. We also need a backup plan – in the likely case that we ultimately fail.

To keep the deep pockets in the game, push incentives and a clear pathway to an attractive (not just break even) economic return will be required. My own view of this is that tax credits are not nearly enough (except for small companies like Cubist or some publicly owned biotechs). But large R&D grants such as those provided by BARDA clearly work.  I remain a little skeptical about IMI – but if the EU taxpayers are willing to do this – who am I to argue?

In terms of the pull side, government market guarantees are also likely to be too risky a gamble for large pharma – just look at the mess our government is in to say nothing about a chronically dysfunctional Europe.  Value-based pricing seems like the way to go.  And even though payers seem willing to provide such prices, large companies like Astra-Zeneca simply don’t believe that this is true.  We must convince them.  It may be that no one will be convinced until it happens – I’m just not sure we will last that long. The first product to cross this finish line where a higher (but not the really high) price could be attained will, in fact, be Astra’s ceftazidime-avibactam.  They just need to persevere to get it across the finish line.

How about a backup plan?  We better figure out a way to train researchers in antibiotic research because this expertise is dwindling faster than a speeding bullet.  I believe that the best place to train new (or old) researchers is in industry – either large companies still active or in biotech who know what they are doing (there are only a few of those).  The NIH has said that they would help here (I have this on tape!).

Public-private partnerships have to be part of our back-up plan – but again, without adequately trained researchers we are going to waste a lot of money for a long time while these folks gear up.  I’m worried that investors will lose patience before we get where we need to be.

I applaud the IDSA’s efforts to keep us focused on this problem.  I would just ask that their own focus be a little more laser-like.

Monday, April 8, 2013

India, Novartis and Antibiotics

Disclaimer – I am certainly not a patent lawyer and can’t even play one on TV.  But this is an important story that we should all try and understand.

In a recent decision on Novartis’ patent for Gleevec, an anti-cancer drug, India’s Supreme Court ruled that its patent was invalid.  Gleevec, like some anti-viral drugs, is a miraculous controller of (but does not cure) chronic myelogenous leukemia, an otherwise fatal disease.  The drug must be taken chronically.  In the developed world, it sells for up to $70,000 per year while the generic version manufactured in India sells for $2500 per year according to the New York Times. The question is – is this ruling anomalous and specific for this particular situation or does it have serious repercussions for patients, physicians and the pharmaceutical industry beyond Gleevec itself?

The ruling is based on section 3 of India’s 1970 patent law, which states that a new form of a molecule that does not show increased efficacy cannot be patented. India passed a new patent law in 2005 to bring it more in line with those of World Trade Organization countries, but apparently limited this new law to drugs patented after 1995. Gleevec’s original patent was filed in 1993 (alpha crystal) followed by a separate patent for a different crystalline form (beta crystal) in 1998 in India (and elsewhere).  The beta form, it claimed, was superior for manufacture and made the alpha form obsolete. This argument is accepted for patentability by World Trade Organization member states. But since the new crystalline form apparently did not show or was not studied for increased efficacy compared to the original form, it was ruled that it was outside the 2005 and the 1970 patent laws in India and therefore not patentable.

The court in India was asked to provide a balance between India’s status as a trading partner in the world and its position as the pharmacy for the developing world. India is an important manufacturer of generic drugs for the developing world.  The New York Times noted that 80% of the active ingredients of all drugs are now manufactured in India and China.

At the same time, India, China and a number of emerging economies in Asia and elsewhere are rapidly growing markets for pharmaceuticals (at least until last year).  Bayer’s deal with Trius for sales of their antibiotic that just completed its phase III trials is an example of the industry recognition of this fact. This growth comes in large part from home-manufactured generics but also comes from multi-national branded products.  The reason for the latter is that there is a growing middle class population in these countries that can afford to pay for branded drugs and recognize that their home-grown generics are of variable quality.  An example of this is the fact that the FDA recently withdrew approval for 27 generic drugs in the US manufactured by Ranbaxy, an Indian generic manufacturer, for quality problems. Europe has done the same.

But for the industry to be able to have access to these growing markets, their patents will have to be recognized. If the markets of emerging economies are isolated from the rest of the world, they may have access to cheaper medicines, but those medicines may also be more dangerous and less well regulated than branded products. Lets also remember that generic companies do not develop new drugs.  Pharmaceutical companies that brand new products develop new drugs.  Without access to these emerging markets, the pharmaceutical industry will undergo even further consolidation and cost cutting.  This will of necessity lead to less research and fewer new drugs for all of us.  Is this the outcome that India wants?  Do any of us want this? 

We clearly need a pathway for those less fortunate in the world to have access to new medicines while at the same time preserving intellectual property.  The pharmaceutical industry has tried (perhaps not so successfully) to address with with various rebate and price reduction programs. They probably need to try harder. 

In the case of antibiotics per se – India is the epicenter of antibiotic resistance in the world.  NDM-1, one of the most resistant super-resistance elements around was born there and is endemic there.  It is spreading from India to the rest of the world. Does India want to risk being without needed new antibiotics to fight these infections?  Do any of us?

So lets hope that the Gleevec decision is an isolated one and that the industry will not see this as a retrenchment in India but rather as an anomaly.