Ista Pharmaceuticals’ REMURA – Will it bring tears to dry eyes?

Posted by lifetech on July 5th, 2011

Many patients seek to find relief, not from their tears, but rather from their dry eyes. But the answer to their problem is as complex as the tears they lack.

Several structures within the eye are involved in the production of the tear film, which is actually comprised of three layers. These are a basal mucous layer that aids the distribution of tears across the surface of the eye, a middle aqueous layer, and an outer oily layer that slows evaporation of the middle layer. Lacrimal glands, meibomian glands, tear ducts, and eye lids all play a role in the production and elimination of tears. Disease in any of those structures can affect the quality and quantity of tears which ultimately serve to protect the surface of the eye. Patients afflicted with dry eye suffer from an ongoing sense of ‘grittiness’ and eye irritation. In severe cases, the cornea becomes damaged, predisposing to ulceration, infection, and loss of vision.

ISTA seeks to fill the unmet need in dry-eye syndrome with REMURA, a new proprietary formulation of bromfenac. Bromfenac is a non-steroidal anti-inflammatory agent that ISTA has marketed in an earlier 0.09% form for use in the setting of cataract surgery – first branded as Xibrom for twice-daily use and now as Bromday for once-daily use. The new REMURA formulation uses a lower concentration of bromfenac and may have sustained release properties. It is currently under study in two phase III dry-eye trials.

The rationale for use of an anti-inflammatory agent such as an NSAID in dry eye seems strong, as evidence suggests that inflammation plays a central role in dry-eye syndrome, whether as the initiating cause or in response to irritation and damage caused by a reduction in the volume and/or quality of tears. However, a strong mechanistic rationale does not always guarantee program success. And the history of dry eye therapies is littered with failures. Explore the reasons for these failures and their relevance (or lack of thereof) to the REMUARA program through our latest report.

Cytokinetics’ CK-2017357 – Expanding the muscle contractility pipeline to skeletal muscle disorders

Posted by lifetech on May 4th, 2011

Cytokinetics’ CK-2017357 is a small molecule that improves skeletal muscle contraction. CK-2017357 is now in phase II testing for two orphan neuromuscular diseases: amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG), as well as a third indication, peripheral vascular disease (PAD) with claudication. Phase IIa trial results reported last December showed evidence of clinical activity after a single dose on a range of exploratory clinical endpoints in ALS patients. The drug was safe and well tolerated, though milder adverse events were very common. The first clinical data in MG and PAD are expected by the end of the year, and additional ALS studies are already planned for the second half of 2011.

CK-2017357 is still early in development, but the data generated over the next 12 months will provide critical evidence as to the long-term prospects of the drug. Will activity observed in ALS translate into clinical benefit in larger long term studies? Will CK-2017357 find broad applicability across neuromuscular diseases? Can CK-2017357 improve claudication, a condition caused by ischemia rather than a motor neuron signaling deficiency? How significant are mild but common neurologic adverse events for tolerability and safety? How will Cytokinetics balance the market opportunity of a prevalent but non-fatal condition like PAD with rare but severe orphan diseases like ALS? We explore these and other issues in our most recent report on this young but promising drug.

YM Biosciences’s JAK-2 Inhibitor for Myelofibrosis – Could this be the best in class?

Posted by lifetech on April 20th, 2011

The discovery of a JAK2 mutation in 2005 led many to believe that the future of myelofibrosis (MF), a chronic blood malignancy, was about to change, and several companies started to develop JAK2 inhibitors. Such hope was based on the successful Gleevec precedent which dramatically altered the outlook for chronic myeloid leukemia patients who carried the BCR-ABL genetic aberration. Yet, such hope was unfounded and expectations have appropriately toned down: JAK2 inhibitors seem less likely to change the natural history of MF. But interest remains high given that the class of agents is very active in MF;  JAK2 inhibition confers significant improvement in morbidity and quality of life primarily by shrinking the enlarged MF spleen and controlling constitutional symptoms. Incyte‘s and Novartis’ ruxolitinib is likely to be the first JAK2 inhibitor to reach the market, probably by year-end. But there is room for improvement as not all patients respond to tolerated doses and ruxolitinib does not correct anemia – an important predictor of survival. For this reason, YM Biosciences‘ intriguing early data for its compound CYT387 has generated a great buzz on the street. It seems to be associated with a highly impressive anemia response, which clearly differentiates it from the JAK2 inhibitor pack. If CYT387’s anemia effect is confirmed, it would represent a major marketing advantage. But is the effect real and why so many doubts? In our latest report, we dissect the CYT387 data trying to separate what is solid from what is problematic as a means to gauge whether this could be the true market leader.

Rigel’s and AstraZeneca’s R788 (fostamatinib) – an oral Syk inhibitor for rheumatoid arthritis

Posted by lifetech on March 30th, 2011

Rigel’s and AstraZeneca’s R788 is an oral, small molecule therapy in phase III rheumatoid arthritis (RA) trials. It modulates inflammation via inhibition of splenic tyrosine kinase (Syk). If successful, R788 will compete in a market currently dominated by biologics that inhibit TNF-α — all agents that are administered by injection or intravenous infusion. While a ‘pill’ would seem far preferable to a ‘poke’, particularly for a chronic disease, phase III trials still must show robust efficacy and an appropriate safety profile. The companies have reported data from all three phase II TASKi trials and have begun their phase III OSKIRA trial program. Of special interest, the TASKi3 trial results differed from those of the TASKi 1 and 2 trials. Our latest report explores the possible reasons for TASKi3’s failure and what that means for the ongoing phase III trials. The report also explores FDA guidance on RA drug development and the degree to which the ongoing phase III program meets those standards. Finally, phase II trials have identified some emerging safety signals which need further characterization. Thus, the question remains as to how much risk regulators, patients and the marketplace will accept in exchange for the convenience of an oral treatment for this debilitating disease.

BioMarin’s GALNS – enzyme replacement therapy for Morquio Syndrome A

Posted by lifetech on March 15th, 2011

BioMarin has built a portfolio of products for rare orphan conditions, which have proven to be valuable commercial opportunities despite targeting diseases with low prevalence. BioMarin’s latest product, GALNS, is an enzyme replacement therapy (ERT) currently in phase III testing for MPS IVA, a rare genetic disease also called Morquio syndrome A. MPS IVA causes severe disability and early mortality, and current treatment options are of limited benefit. However, similar diseases have been successfully treated with ERT, including two products developed by BioMarin itself: Aldurazyme for MPS I and Naglazyme for MPS VI. Thus, there is good rationale for developing ERT in MPS IVA.

In a pilot phase I/II study, GALNS showed evidence of clinical activity, as measured by biomarkers, respiratory function and physical endurance. But the trial was small and uncontrolled, so these early results must be confirmed in the ongoing placebo-controlled phase III trial. If phase III proceeds as planned, we anticipate top-line results in the third quarter of 2012. GALNS would make a fine addition to BioMarin’s ERT portfolio. Of course, regulatory success hinges on phase III outcomes, and the potential for commercial success will also depend heavily on GALNS’ clinical performance in a controlled trial. In our recent report, we explore these issues in greater depth.

Amarin’s AMR101, a prescription omega-3 fatty acid – is it worth the extra cost?

Posted by lifetech on February 24th, 2011

If approved, Amarin Pharmaceuticals’ AMR101, a synthetic omega-3 fatty acid, will enter a market filled with over-the-counter (OTC) fish oil supplements and Lovaza, a product that will be its only prescription competitor. Thus, Amarin must show that AMR101 not only warrants FDA approval as an effective therapy for elevated triglycerides, but that it also deserves the premium pricing associated with prescription products. Further, data must show competitive advantage vs Lovaza.

AMR101 contains only one omega-3 fatty acid – EPA. This contrasts with Lovaza which contains both DHA and EPA, the two omega-3s typically found in dietary sources of omega-3s (ie, fish), but in a more purified form than the OTC products, which are often simply fish oil extracts. Thus, part of the challenge entails showing that EPA alone is advantageous vs the established profile of available products.

Results from an initial trial (MARINE) that evaluated use of AMR101 in those with very high triglyceride levels (>500 mg/dL) seem favorable. That said, there are several broader issues that may impact FDA’s decision and market acceptance. Among them:

  1. Will results differ for ANCHOR, the second trial designed to support a broader indication in a population with less severe triglyceride increases?
  2. What are the differences in effect between EPA and DHA and will the fact that AMR101 only contains EPA impact its efficacy?
  3. Will AMR101 have the same adverse impact on LDL as Lovaza and thus similarly narrow AMR101’s approved uses? And what about the effects on HDL?
  4. What role do triglycerides play in cardiovascular risk?
  5. What is the evidence that fish oils have a beneficial effect on cardiovascular risk and will AMR101’s distinct profile affect that benefit?
  6. What is driving FDA’s request for initiation of a cardiovascular outcomes trial as a condition of broader approval?
  7. An ultimately – the big question – why a prescription product when an OTC product ‘just might do’?

 We hope that we have interested you enough to read our full report, available at

United Therapeutics’ Oral Treprostinil (UT-15C SR) – can it expand the treprostinil franchise to patients with milder disease?

Posted by lifetech on December 10th, 2010

Pulmonary arterial hypertension (PAH) is a rare disease, but it has nevertheless drawn significant interest from the biotech industry. Since 2001, FDA has approved six new agents from three different drug classes to treat PAH, dramatically improving patient outcomes for this serious and progressive disease. The next frontier consists of bringing the best treatment options to patients with less severe disease. Unfortunately, prostacyclins (the class considered to be the most efficacious) only exist in parenteral infusions or inhalable forms which deter their adoption among patients with milder disease – who obviously prefer the convenience of oral treatments.

United Therapeutics is working diligently towards developing an oral version of its successful prostacyclin analog – treprostinil – already available in IV, SC and inhalable versions. Oral treprostinil could significantly expand the market opportunity for the franchise. But the process of reaching adequate blood levels with oral delivery has posed some challenges. Aggressive dose titration led to the failure of UT-15C SR’s first phase III trial: many patients dropped out and few were able to escalate dose to therapeutic levels. The company has since developed lower strength tablets and two new studies are underway evaluating the “lower start /slow increase” approach. Favorably, the company states that drop-out rates in the ongoing trials are considerably lower. We can interpret this in two ways: first, it could be a sign that the gradual approach has indeed improved UT-15C SR’s tolerability and that patients can escalate to the therapeutic dose levels. But second, it could also mean that patients are using much lower doses; in which case the gain in tolerability may come at the expense of efficacy. Only the former interpretation bodes well for the outcome of ongoing trials. But meeting the primary endpoint in phase III may not be enough to ensure commercial success, given the competing treatment options already available. In our UT-15C SR report, we review the evidence to handicap the likelihood that ongoing trials will succeed, and discuss the commercial implications and market opportunity for UT-15C SR.

GSK’s and Theravance’s Relovair – Will it be a breath of fresh air or are there regulatory hurdles ahead?

Posted by lifetech on November 22nd, 2010

A few months ago, we reviewed indacaterol, a long-acting beta agonist (LABA) under development as monotherapy for chronic obstructive pulmonary disease (COPD). We revisit the LABA and respiratory spaces with a review of GlaxoSmithKline’s (GSK’s) and Theravance’s entrant – Relovair. In contrast to indacaterol, Relovair is a combination product. It combines vilanterol, a LABA, with fluticasone furoate, an inhaled corticosteroid (ICS). Respectively, both are analogs of salmeterol and fluticasone propionate, the components of Advair. In contrast to Advair, Relovair kinetics support once-daily administration, giving hope that it can effectively cannibalize the Advair market in advance of generic competition.

As with indacaterol, the effects of Relovair and its components seem consistent with their respective classes. However, a number of differences between the programs add layers of nuance to the regulatory prospects for Relovair, which we explore in depth in our report. Relovair is a combination LABA + ICS product and the sponsors are pursuing indications in both asthma and COPD (although with somewhat different regulatory strategies). Further, the programs differ enough that the ‘regulatory bumps in the road’ may not be the same for the two programs. Finally, FDA’s thinking around the complex issues related to LABA safety continues to evolve, sending mixed signals. Thus, Relovair provides a new reason and opportunity to look closely at this space again.

Nabi’s NicVAX – a vaccine to help smokers quit

Posted by lifetech on November 3rd, 2010

Smoking is the leading cause of preventable death in the world today, responsible for an estimated 5 million deaths each year from cancer, heart disease and respiratory disease. In the US alone, an estimated 47 million adults smoke. The majority of US smokers report that they would like to quit, and each year about 20 million make the attempt. However, real world success rates are very low, about 10% on average after one year, owing to the addictive nature of nicotine. Smokers trying to quit have several options to assist them, including nicotine replacement products as well as the prescription drugs Zyban and Chantix. However, the latter prescription drugs are associated with psychological side effects including depression and suicidality, and even in ideal clinical settings only one-third of smokers who use these drugs remain abstinent after 6 months.

Nicotine vaccination is a novel strategy to aid in smoking cessation. A nicotine vaccine contains a synthetic antigen that triggers production of anti-nicotine antibodies. When a vaccinated smoker smokes, nicotine enters the bloodstream as usual but it is bound by these antibodies and is unable to cross into the brain. In this way, the nicotine vaccine breaks the link between smoking and its instant gratification, which underlies the addiction. Three nicotine vaccines have completed phase II testing in the US – Nabi’s NicVAX, Cytos and Novartis’ NIC002, and Celtic Pharma’s TA-NIC. Of these, only NicVAX has entered phase III.

Despite the strong rationale behind nicotine vaccination, quitting rates have been modest in clinical testing to date, which may explain the delay in development of NIC002 and TA-NIC. Meanwhile, Nabi used the information gained in phase II to significantly modify its NicVAX phase III protocols, which the company hopes will enhance efficacy. The market opportunity is fairly large, and NicVAX could be the sole product on the market for a while, if it performs well in phase III. Still, much uncertainty remains about these programs. For our thoughts on NicVAX’s prospects and the nicotine vaccine market, please check the report in our online store.

Clinical Data’s vilazodone – is this novel antipressant any better than alternatives?

Posted by lifetech on September 16th, 2010

The US antidepressant market is estimated at $12 billion per year, and includes some of the best selling drugs on the market today – the serotonin reuptake inhibitors (SSRIs and SNRIs). But despite their commercial success, the unmet medical need remains given that only about half of patients respond to each drug. In addition, antidepressants suffer from slow onset of action and numerous side effects that undermine patient compliance and, ultimately, response to therapy.

 Clinical Data’s vilazodone is a dual acting antidepressant, with bona fide SSRI activity plus partial agonism of the 1A serotonin receptor that is hypothesized to be involved in SSRI onset of action and side effects. The drug failed to impress in phase II, but by increasing the dose and modifying other study parameters in phase III, vilazodone hit all five efficacy endpoints. Vilazodone appears to be at least as safe as other approved antidepressants, with a lower rate of sexual side effects. Vilazodone is now under FDA review, with a decision expected by January 2011. Yet the greatest challenge facing CLDA may come not from regulators but from competing antidepressants, which have become commercial juggernauts despite their pharmacological flaws. Can vilazodone succeed in the minds of regulators, physicians and (most importantly) patients? Take a look at our latest report for our thoughts on these issues.