There is ongoing discussion as to how the cystic fibrosis mutation causes lung disease. The “low airway volume” is a widely accepted hypothesis. It proposes that depletion of “airway surface liquid” impairs ciliary beat and causes the retention of thickened mucus, which predisposes to lung infections. Thus there is considerable interest in developing therapeutic interventions that restore airway surface volume. That is what Inspire is trying to accomplish with denufosol, an agent that may restore airway hydration by activating an alternative ion channel (the P2Y2 receptor). The first denufosol phase III trial (TIGER-1) was technically positive, as it met the study’s primary endpoint. However, clinical results as a whole were not that impressive over 24 weeks, and pulmonary exacerbation results were of particular concern. Favorably, the trial’s open label extension suggests that denufosol may work slowly and steadily – but this observation needs confirmation in a controlled trial. This may be achieved with the second ongoing phase III trial (TIGER-2), which treats a larger number of patients for a longer period of time. Besides considerations of denufosol’s clinical worthiness, TIGER-2 needs to do better than TIGER-1 to avoid regulatory and commercial challenges from other approved and late-stage development airway hydrating agents as well as agents from other classes such as CFTR repair therapies (discussed in our Vertex report). The latter target the basic defect that causes CF, and could dramatically change the CF treatment paradigm in the medium future. Thus, a lot is at stake for TIGER-2. We refer you to our denufosol report for an in-depth discussion of clinical, regulatory and commercial challenges.

The legions of individuals who suffer from chronic idiopathic constipation or constipation-predominant irritable bowel syndrome (IBS-C) may soon have another therapy with which to address their discomfort. Ironwood Pharmaceuticals and its partners, Forest Laboratories and Almirall are developing linaclotide. It is an oral peptide that acts through GCC receptors in the intestinal tract — the same receptors activated by the bacterial toxins implicated in E coli diarrhea. Via this unique mechanism, linaclotide increases intestinal fluid secretion, thereby relieving constipation.

The companies have reported positive results for two phase III chronic constipation trials. The two pivotal phase III trials in IBS-C should complete soon and results should be released in Q4. The data so far are fairly encouraging, however there are some key questions. For example, are available results clinically relevant even if statistically significant? Does the program meet new standards for IBS therapies that FDA has just released? Will there be overhang from FDA’s experience with other IBS therapies withdrawn from the market due to postmarketing safety issues (think Zelnorm)? And most important, how will linaclotide fare in the marketplace against Amitiza? Check our latest report for an in-depth discussion of these questions.

Shingles (herpes zoster) is a viral infection caused by reactivation of dormant varicella zoster, the virus that causes chicken pox. Shingles affects roughly 1 million patients in the US alone each year. And although the associated rash usually resolves in two to four weeks, patients can suffer from chronic neuropathic pain for months or years afterward. The current standard of care for herpes zoster is a 7-day course of antiviral medication, of which three are currently approved in the US (acyclovir, valacyclovir and famvir). Inhibitex hopes its drug, FV-100 will be the fourth. FV-100 was specifically designed to target varicella zoster, and it possesses robust activity against the virus in vitro. Its pharmacokinetic profile makes it suitable for once-daily dosing (while current alternatives must be administered 3 to 5 times per day). FV-100 has a lot going for itself and it entered phase II just last year, with the first direct evidence of clinical activity in patients expected in Q4 2010. Phase II was designed to show superiority to an active comparator, valacyclovir, which would be an impressive result. Even a finding of non-inferiority may be sufficient for market approval, if the results are confirmed in phase III. However, Inhibitex plans to seek a development partner for FV-100 in the near term, and thus cannot wait for phase III results. Thus, the future success of FV-100 (not to mention Inhibitex itself) hinges on a successful outcome in phase II. In our latest report, we discuss the rationale for FV-100, factors that could influence the drug’s chance for success in phase II, market considerations that will weigh on Inhibitex and its potential collaborators alike. Finally, current treatment options for shingles are clearly suboptimal – thus there is a need for a better drug. Can FV-100 be it?

β-2 agonists, both short and long-acting (SABAs and LABAs) have been a mainstay of therapy for asthma and chronic obstructive bronchitis (COPD) since the introduction of albuterol many years ago. For almost as long, they have been surrounded by controversy, especially when used to treat asthma. Growing evidence suggests that, along with their many benefits, they also increase the risk of sudden, worsening bronchospasm that can lead to hospitalization, intubation, and even death. As that realization has grown, FDA has called numerous advisory panels to discuss the risk and the best way to minimize it. Most recently, the agency issued a statement outlining even more restrictive labeling language and its plans to mandate conduct of large safety trials. It then called yet another Advisory Panel meeting to discuss the optimal design for such a trial.

Into this context, Novartis developed an ultra-long-acting (once- instead of twice-daily) agent –  indacaterol – and filed an NDA seeking approval for use in the treatment of COPD. This decision to limit the initial application to COPD was most likely motivated by FDA’s assertion that the safety concerns do not apply to use in COPD – only to the asthma setting. In spite of those FDA statements and indacaterol’s approval in Europe, FDA issued a Complete Response Letter last October. In a recently issued report, we attempt to ‘read between the lines’ of Novartis’s limited disclosures relative to the content of that letter in an effort to determine the nature of FDA’s concerns, the path forward, the probability of eventual approval, and ultimately of market success.

Neurocrine Biosciences has just completed phase II trials of elagolix (an oral GnRH antagonist) for endometriosis. It also recently announced a partnership with Abbott. The path through phase II was difficult, as Neurocrine struggled to find the appropriate endpoints with which to measure the effect of treatment on disease-associated pain. The drug is clearly active: it suppresses estradiol and interrupts the menstrual cycle — the intended pharmacological effects suggested by its mechanism of action. However, the goal of showing that therapy consistently relieves pain was more elusive and early trials showed mixed results. Encouragingly, the last trial in the series, Daisy PETAL, demonstrated robustly positive efficacy. But the pending question is whether Neurocrine has finally identified a winning set of parameters for designing phase III trials, or whether the difficulties seen throughout the earlier trials will continue to haunt further studies. If it succeeds in pivotal trials, elagolix will enter a competitive market with various agents used on and off label for endometriosis. But Neurocrine and Abbott are betting that elagolix’s differentiated safety profile will provide the market edge it needs to capture greater market share. We refer you to LifeTech’s report for our take on elagolix and its prospects.

On June 23rd, Pfizer announced that FDA put its Tanezumab osteoarthritis phase III program on hold, following reports of worsening disease among patients receiving the antibody, which targets NGF (nerve growth factor). This came as no surprise to us. As we wrote back in November, “Tanezumab has titanic potential, but there are looming safety icebergs”.

NGF is involved in many vital physiological pathways, not just in the nervous system but also in the immune and neuroendocrine systems. Thus it is likely that other toxicities should emerge once the molecule’s action is blocked. As we discuss in our report, based on NGF’s role, possible consequences of its inhibition include peripheral neuropathy, dementia or other central nervous system dysfunction, increased rate of infection, slow wound healing or metabolic dysfunction. In fact, some evidence of these adverse effects has already been observed in phase II. In addition, it is certainly disturbing that there is sufficient rationale to test recombinant NGF itself (ie, the opposite pharmacologic effect of Tanezumab) as a treatment for Alzheimer’s disease – and such trials are underway by other companies. If that strategy is effective, doesn’t it suggest that anti-NGF therapies such as Tanezumab may accelerate or predispose patients to Alzheimer’s disease?

Our report provides an in-depth discussion of the observed and theoretical safety concerns of Tanezumab based on the known role of NGF. The chronic pain market potential is enormous. Pfizer is pursuing seven clinical indications, with a combined market potential of up to $6BN in the US alone. Osteoarthritis, the most advanced clinical indication, represents about a third of that opportunity. Even if osteoarthritis is out of the picture, the opportunity for Tanezumab is still huge – should it safety profile permit…

We just published a report on sodium oxybate – better known as GHB, a powerful nervous system depressant that gained notoriety in the 1990s as a  “date rape” drug. Despite its reputation and schedule I restriction, FDA approved a branded GHB formulation, Xyrem, for treating narcolepsy. In 2009, Xyrem sales accounted for about $97 million in revenue for Jazz Pharmaceuticals, which is now seeking to expand the market opportunity for Xyrem into fibromyalgia, a much more prevalent condition.

Jazz reported positive phase III studies last year and submitted its marketing application to FDA, putting it on track for a regulatory decision in mid-October. An approval would be a boon to Jazz. But will FDA view significant efficacy as sufficient to justify approval in a much broader population with a non-life-threatening condition, given the complex history and track record of GHB in other settings? In this report we weigh these and other issues as we attempt to gauge the likelihood of regulatory success for Xyrem this Fall in fibromyalgia

Since 2003, LifeTech has conducted in-depth analyses of hundreds of biotech & pharma products, devices and diagnostics. It is an amazing knowledge base that we are now opening to the outside world. We dig deep and provide opinions that are actionable and solid. We are doctors and scientists with unique experiences and perspectives. We know FDA well, we know many people who used to work there, and we collaborate with them on our projects. We ask critical questions around the design of clinical trials and interrogate the validity of study results. We know how clinicians make decisions to adopt new technologies. We understand reimbursement policy decisions that drive purchasing decisions, and we have a vision for the changing face of healthcare. Our reports are for those truly interested in an expert, independent opinion regarding a product’s chances for success measured on many fronts: clinical trial outcomes;  FDA approval and success in the marketplace. Interested to see the quality of our work? We welcome you to explore. Alternatively, please email us. We look forward to sharing our approach with you!

 We just published our report on Vertex’s experimental drugs for CF:  VX-770 is generating a lot of buzz among experts and patients. We examined what this excitement is all about and what it could mean for patients and – of course – for Vertex. In a nutshell, VX-770 is a CFTR modulator, a new treatment approach that attempts to fix the genetic defect that causes cystic fibrosis. If successful, it could theoretically alter the natural history of the disease. This would be huge for patients. The current phase III trial is focusing on patients with the G551D mutation, which is not very common. The million (or billion) dollar question for Vertex is not so much related to VX-770’s effects in the G551D mutation, but rather whether it might work on the ubiquitous F508del mutation. This mutation affects up to 90% of the patients. Our report details the history of VX-770 and its prospects for success in phase III and beyond … a fascinating story worth following closely.