Pharma’s Cutting Edge

I indicated in my year-end 2008 post that I was looking forward to a productive 2009 for the pharmaceutical/biopharmaceutical industry.  Indeed, there’s a good chance that the number of approved new molecular entities in 2009 in Europe and the US will be noticeably more than in the last several years.

I’ve selected some particularly interesting NMEs that have a reasonable chance of being approved and launched in either the US or EU some time during 2009 (my own estimatation).  The list below is not intended to be a complete list of all possible NME launches, nor does it include any non-NMEs that might launch in 2009 (e.g. reformulations, combinations, new indications, etc).  I focus on drugs, but I’m including some drug-like therapies here as well.   If you would like to add your own candidate to the list, just post a comment with your therapy candidate and your reason for including it. 

The list format is nonproprietary name (proposed brand name), sponsor(s), brief MOA, and probable lead indication, sorted alphabetically by nonproprietary name.

• Adult mesenchymal stem cells (Prochymal), Osiris, immunomodulator, steroid-resistant graft-versus-host disease (GvHD)
• Canakinumab, Novartis, IL1 beta-specific MAb, Cryopyrin-Associated Periodic Syndromes (CAPS)
• Denosumab, Amgen, human RANKL MAb, postmenopausal osteoporosis and osteoporosis in men
• Ecallantide, Dyax, plasma kallikrein inhibitor, acute attacks in herdeitary angioedema
• Iclaprim, Arpida, dihydrofalate reductase inhibitor, complicated skin and skin strcuture infections
• MalPEG-Hb in Lactated Ringer’s solution (Hemospan), Sangart, Cell-freecolloidal oxygen carrier and volume expander (pegylated hemoglobin), prevention/treatment of hemodynamic instability during orthopedic surgery
• Ofatumumab (Arzerra),  Genmab/GSK, human MAb against CD20, fludarabine-refractory Chronic Lymphocytic Leukaemia (CLL) and follicular NHL
• Oxidized glutathione aka disodium glutathione disulfide aka NOV-002, Novelos, glutathione mimetic chemoprotectant/immunomodulator, first-line therapy of non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel
• Prasugrel (Effient/Efient), Lilly/Daiichi-Sankyo, P2Y12 (ADP) receptor inhibitor, antiplatelet anticoagulant, adjuvant to percutaneous coronary interventions (PCI) in acute coronary syndromes (ACS)
• Retigabine, Valeant , potassium channel opener, refractory partial-onset seizures in adults
• Rivaroxaban (Xarelto), Bayer, Factor Xa inhibitor, VTE prevention, approved in Europe Q4 2008
• Rolofylline, Merck, A1 receptor antagonist, acute heart failure decompenasation with renal function protection
• Sipuleucel-T (Provenge), Dendreon, active immunotherapy targeting prostatic acid phosphatase, advanced androgen-independent prostate cancer (see also here and here)
• Sitimagene ceradenovec (Cerepro), Ark Therapeutics, AD5-mediated thymidine kinase gene therapy plus ganciclovir, surgical adjuvant for operable malignant glioma
• Telcagepant, Merck, Calcitonin-Gene Related Peptide antagonist, migraine
• Tocilizumab (Actemra), Roche/Chugai, IL-6 receptor MAb. Rheumatoid Arthritis
• Tolvaptan, Otsuka, V2 antagonist, hyopnatremia and autosomal-dominant polycystic kidney disease
• Ustekinumab (Stelara), J&J, human MAb for interleukin 12 (IL-12) and interleukin 23 (IL-23),  moderate to severe plaque psoriasis
• Vandetanib (Zactima), AstraZeneca, oral VEGF/EGF inhibitor for NSCLC

January 2nd, 2009 | Category: Technology | Leave a comment

In what has become an annual tradition, I give you my totally subjective choices for the top drug innovations of 2008.  In order to qualify the innovation must have been first available for salein the US or EU during 2008.  Sadly, it’s slim pickins again this year, with only seven finalists, but 2009 looks to be a better year.

1. (Tie) Romiplostim (Nplate, Amgen) and Eltromopag (Promacta, GSK). Both drugs are thrombopoeitin receptor agonists indicated for second-line treatment of refractory, chronic Idiopathic Thrombocytopenic Purpura.  The hackneyed phrase “paradigm-shift” has been applied to the TPO-agonist class, as it represents a potential major departure in the treatment of this uncommon, costly disease.  The closely spaced market appearance of the first two class members–essentially a tie to the US market–starkly illustrates the continued erosion of market exclusivity for therapeutic-class pioneers.  Further competition in the class is expected shortly.  If I had to give an innovation edge to one of these two pioneers, my vote would go to Promacta because it is orally available, while Nplate is administered subcutaneously.  A potential for marrow fibrosis with both drugs has led FDA to require fairly stringent REMS (risk evaluation and management strategies), probably slowing the adoption curve for the class.  On the other hand, I anticipate a fairly quick expansion to off-label use, as the drugs prove themselves safe and cost-effective.

3. Sapropterin (Kuvan, Biomarin).  The first drug approved in the US to treat Phenylketonuria, sapropterin is a synthetic tetrahydrobiopterin, a cofactor for the deficient/damaged enzyme phenylalanine hydroxylase (converts phenyalanine to tyrosine).  Kuvan isn’t a cure for PKU, it works in less than 50% of patients, and response to the drug can’t be predicted with currently available theranostics.  So why is it a top innovation?  Because, it’s the first non-dietary treatment for PKU that offers a chance for thousands of PKU patients to eat more normally without exceeding toxic phenylalanine levels, thereby making compliance with a low-phenylalanine diet more likely.  It’s a small step forward, but it’s a definite step.

4. Alvimopan (Entereg, Adolor). A periphery-restricted µ-opioid–receptor antagonist indicated for reducing GI recovery time following bowel resection with anastomosis (i.e. reduction of postoperative ileus).  Entereg was finally approved by the FDA after its third-cycle review; the initial NDA was submitted June 2004, and the drug was approved May 2008.  Cardiovascular safety concerns had precluded earlier approval.   Despite the delay, Entereg was the first peripherally acting µ-opioid–receptor antagonist to be approved in the US , and is the only one shown to improve GI recovery time following bowel surgery.  The other recently approved drug in this class, Relistor (below), appears not to work well in this condition.

5. Methylnaltrexone (Relistor, Progenics/Wyeth) periphery-restricted µ-opioid–receptor antagonist for opioid-induced constipation in advanced illness.  I separated these two drugs, because Entereg works to prevent post-operative ileus, whereas Relistor does not (at least based on a preliminary assessment). 

6. Etravirine (Intelence, Tibotec).  Intelence is nonspecific NNRTI that is indicated for use in combination with other agents for treatment-experienced adults with HIV-1 infection.  This NNRTI was discovered as part of a program aimed at targeting HIV strains with mutations that have rendered other NNRTIs impotent.  It is the first NNRTI to demonstrate activity in patients who have previously failed treatment with other NNRTIs. That said, the drug is susceptible to an accumulation of “nonclassical” HIV-1 mutations, which can render it ineffective with chronic use, particularly if given without other effective therapies  (see this review for details).

7. Lacosamide (Vimpat, Schwarz Biosciences). Rounding out this year’s list, Vimpat is a novel antiepileptic for adjunctive therapy of partial-onset seizures in adults. There is a clear need for treatments of drug-refractory seizures. Vimpat addresses this need to some extent, reducing the frequency of seizures when used as adjunctive therapy in drug-refractory partial-onset seizures. Unfortunately, however, only ~5% of patients remained seizure-free during a 12-week maintenance period (details here), highlighting a need for further innovations in this area.

December 16th, 2008 | Category: Technology | Comments (1)

According to the Pharma Marketing Blog, which gets its data from MEd Ad News and Nielsen, the industry spent over $5 billion USD globally in 2007 on DTC advertising (IMS Health pegs it at just under $5 Billlion).  The US is the major portion of this spend.  IMS Health puts the 2007 US DTC spend at $3.7 billion, representing 36% of total US promotion.  This level of spending implies a very attractive ROI from DTC; indeed, IMS estimated 2007 ROI from DTC at roughly 2x with a 1-year break-even. 

A 2x ROI with 1-year breakeven is quite acceptable for a riskless marketing investment.  But we know that DTC is not riskless, and for the last couple of years the risks of DTC have been discussed within the senior-most ranks of the industry, and not just behind closed doors.  The key risks are erosion of the learned-intermediary defense, which has offered some protection against failure-to-warn product liability risk, and brand “consumerization,” a catch-all for the potential trivilaization of disease and drug therapy, which can damage brand and industry credibility.

If the candor of the public discussion is a harbinger of where US DTC spend is heading, expect to see less of it, maybe much less.  This week, at a pharmaceutical conference sponsored by the Financial Times, William Burns, CEO of Roche Pharmaceuticals, called DTC “the single worst decision for the industry.”

On the other hand, other participants at the conference called for a relaxation of the ban against DTC in most of Europe, with Astra Zeneca CEO David Brennan saying DTC in Europe was “when, not if,” according to Jim Edwards of BNET Pharma.

December 5th, 2008 | Category: Advertising | Leave a comment

For the last few years, I have held an opinion contrary to most of my colleagues in the industry–that sponsors should be required to conduct large (simple) safety studies prior to marketing authorization for drugs intended to be used chronically in large, especially elderly, populations.  Such studies would have as their primary goal a safety evaluation including a systematic assessment (including independent adjudication) of fatal and serious, nonfatal adverse events.  See my prior posts, here and here for arguments I have proffered to support this judgment.

While I have seen limited softening of contrary opinion among my industry colleagues, there has been much more progress towards my viewpoint by regulators.  Consider an interview John Jenkins, FDA’s Office of New Drugs director, gave to Reuter’s Health the other day.  The piece focuses on heart safety, but the sentiments apply to chronic safety in general, with heart safety being the most urgent need.  Jenkins stated that FDA is ”changing how we look at how much data you need to get a drug approved” and that FDA “might look at more requirements for large studies after approval.”

It appears that drugs used to treat hyperglycemia in Type 2 diabetes will be the first to benefit (or suffer from, depending on your viewpoint) FDA’s revised view towards premarket risk evaluation.  Clearly, any new study requirements before launch will increase the cost and time to market for such drugs beyond historical norms.  No one likes to see longer more expensive drug programs, certainly not me.  But before condemning the coming changes for this reason, it is necessary to consider the positives to patients and to sponsors.

Liability risk
If drugs are properly vetted prior to marketing, sponsors’ commercial liability risk should be much lower and much easier to predict than today.  When I was last in Pharma in 2003, liability risk wasn’t even a consideration during portfolio planning.  These days, sponsors that don’t consider liability risk when determining the relative value of products in the pipeline are rightfully considered neglectful or naive.  Being able to better predict liability risk should improve portfolio prioritization, helping managers funnel investments to projects with the best risk-adjusted returns, for example. 

Consumer confidence and industry reputation
I don’t have objective evidence to support this assertion, but it seems to me that a negative surprise goes down a lot worse with consumers than a known issue, especially when the consumers are doctors.  I would bet that not only is a drug product at risk from post-launch surprises but also that the manufacturer’s brand value suffers as well.  Swift manufacturer response in the form of recalls, Dear Doctor letters, and the like can mitigate negative consumer reactions, but avoiding them in the first place should do wonders to improve the public’s confidence in our industry.

Therapeutic guidance for prescribers and unexpected benefits
Large studies mean many opportunities for individual case assessment.  Each case (i.e., systematically observed chronic drug use) is an opportunity to learn more about the full range of patient responses, both efficacy and safety, thereby providing sponsors with examples to use to guide clinicians in practice.

It’s been shown that clinicians rely more on their personal experiences with individual cases than aggregate study results to guide their future therapy choices; they tend to create an image of the ideal candidate for each therapy.  It might be the case that offering doctors detailed descriptions from a broad variety of cases, using examples from these large, diverse study populations, will enhance prescriber marketing.  This idea hasn’t been well-tested as far as I know, but it makes sense in theory.

The other side of the safety coin is benefit.  And so it is likely that as many new benefits of drugs will be observed as new risks during extended premarket evaluation.   From time to time, such benefits will equal or surpass the health value of the studied indication, leading to secondary indications or follow on products for different uses.  Such uses discovered during a sponsored trial are significantly more valuable to manufacturers than uses discovered outside of sponsored research.

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It can’t be determined at this time whether the financial benefits of prolonging the time to market for improved safety evaluation can counterbalance the costs, but for the reasons above, there is some reason to expect at least partial mitigation of the cost impact.  However, if I were a U.S. lobbyist working on behalf of PhRMA I would work diligently to convince legislators to revise the Hatch-Waxman patent restoration rules to accommodate regulatory demand for a longer clinical trial period.  Specifically, the current patent restoration maximum of five years should be increased to at least seven and preferably eight years total for chronic-use drugs to ensure that sponsors maintain an adequate time period for profit generation.

November 20th, 2008 | Category: Drug Safety, FDA, Public Perceptions, Sales and Marketing | Leave a comment