Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

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A company I have been watching for a while is Philadelphia based Avid Radiopharmaceuticals, now a wholly owned subsidiary of Lilly. They have a novel imaging biomarker, florebetapir (18F-AV-45) in development for the detection of Alzheimer’s disease.

In a press release last week, Lilly announced that the FDA had assigned a priority review to the marketing application of florebetapir. The Peripheral and Central Nervous System Drugs Advisory Committee of the FDA meet on January 20, 2011.

Bayer have a competitor product in development, forebetapen (BAY 94-9172). Both florebetapir and florebetapen are 18F radiolabelled imaging biomarkers that bind to amyloid plaque in the brain.  When used in conjunction with a Positron Emission Tomography (PET) scan, they enable the accumulation of amyloid that occurs in Alzhemeir’s disease to be visualized.

Phase 3 trial results for florebetapir published earlier this year showed that the brain amyloid burden seen in the PET scans positively correlated with the plaques seen in autoposies of the same patients.  Proof that what the imaging biomarker shows is an accurate representation of the underlying pathology.

What makes the use of florebetapen and florebetapir interesting is that it is already common practice to use imaging tracers with PET scans. Fluorodeoxyyglucose (FDG) is widely used in the diagnosis, staging and treatment of oncology patients as a result of its ability to show the intense glucose uptake that occurs with most cancers.

Both Avid and Bayer products are most likely to be approved based on the clinical data presented to date.  It will be interesting to see the prices that they intend to charge.

As for the market opportunity, they are likely to have a role to play in the early diagnosis of patients with mild cognitive impairment, since at present it is difficult to diagnose these patients and differentiate Alzheimer’s disease from other forms of dementia.  Most likely, models will be developed that look for a correlation between accumulation of amyloid plaque and decline in cognitive function, from which a probability of developing Alzheimer’s disease can be calculated.

Imaging biomarkers are likely to place an increasingly important role in the development of new products by biotechnology companies and in the design of clinical trial endpoints.

Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

The race to bring a biosimilar version of Sanofi-Aventis’ low molecular weight heparin, Lovenox® (enoxaparin sodium), to market had three players, Momenta Pharmaceuticals in partnership with Sandoz, Amphastar Pharmaceuticals and Teva.

The winner was Momenta/Sandoz who (as mentioned in a previous post) recorded $292 million of sales in 69 days post launch.   As reported by the Wall Street Journal, Amphastar are now suing the FDA alleging the agency acted arbitrarily in delaying its imports of raw heparin.  There certainly seems to be no love lost between Amphastar and the FDA, who earlier this year alleged a conflict of interest between Janet Woodcock, the Director for the Center for Drug Evaluation and Research (CDER) and Momenta as a result of the collaboration that identified the contaminant in chinese heparin that killed patients in 2008.  Following an FDA investigation, Woodcook was cleared of any conflict of interest but announced she would not participate in the biosimilar approval decision.

In the run up to the approval, the FDA visited the manufacturing facilities for all three companies. Afterwards the status of the Amphastar application became less certain. Unlike Amphastar, both Teva and Sandoz had prior experience of obtaining FDA approval for biosimilar products.

Given the amount of money at stake, its easy to see why Amphastar are unhappy. However, alleging conflicts of interest and arbitrary practices does not exactly win friends and influence people.  I am sure the FDA have a credible factual basis for their decision making, in which case Amphastar is unlikely to get anywhere, other than generate negative publicity for themselves.  Others may differ in that opinion, and if you want to read a legal analysis of the Amphastar complaint, the FDA Law Blog’s post is worth reading. It also has a link to the actual complaint filed.

The more interesting question is when is the FDA going to approve the Teva biosimilar version of Lovenox®? When this happens, Sandoz’s first mover advantage will come to an end and further price erosion is likely. According to Reuters, analysts predict this may happen before the end of 2010.

Update: Amphastar gains FDA approval for generic Lovenox

As reported by Ed Silverman on Pharmalot (September 19, 2011), “Amphastar Pharmaceuticals has finally won approval to sell a generic version of Lovenox

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The news, reported by Bloomberg, last week that generic companies may be subject to stricter FDA standards in order to show therapeutic equivalence is good news for the biotech industry and consumers.

Generic companies have a pretty easy ride in obtaining product approval, and I’ve long been convinced that the formulation of a brand, and what makes it work can include the so called inactive ingredients and how it is put together.   I know of many people who have experienced side effects with generics that they don’t have with the branded product.

For this reason, branded generics from the original manufacturer have the ability to retain some market share in the face of generic competition.  Sandoz, the generic arm of Novartis uses this strategy to good effect with many mature products.   However, if companies instead want to try and maintain a premium priced brand and not adapt to the entry of generics, then they will find their market share erodes extremely fast. Not only is brand market erosion fast with generic drugs, but with biosimilars too.

As reported by Reuters, sales of generic enoxaparin sodium injection, Momenta’s copy of Sanofi’s anti-thrombotic, low molecular weight, heparin sold as “Lovenox” were $292million in the third quarter of 2010. Sandoz markets enoxaparin on behalf of Momenta. They launched the product on July 23, and achieved  $292 million of sales in 69 days. With annual sales forecast to be over $1billion, the biosimilar will be a blockbuster and make a significant dent in the $2.9 billion sales of Lovenox in 2009.

The Boston Business Journal reports that Sandoz/Momenta have captured 60% market share already, which is not good news for Sanofi-Aventis and may explain their desire to make acquisitions such as Genzyme to make up for this loss.

Biosimilars that are fully substitutable for the original product, look likely to erode brands extremely fast.  Momenta’s success is good for the biotechnology industry and highlights the future market opportunity from development of biosimilars.

Human eye cross-sectional view. Courtesy NIH N...Image via Wikipedia

VEGF Trap-Eye is a formulation of VEGF Trap (aflibercept) and is an anti-angiogenic agent that can be injected into the eye to stop the proliferation of blood vessels. Regeneron (REGN) are co-developing it with Bayer (BAY) and it is currently in clinical trials for the treatment of wet Age-Related Macular Degeneration (AMD), Diabetic Macular Edema (DME) and Central Retinal Vein Occlusion (CRVO).

Phase II DME clinical trial results presented at the
Angiogenesis 2010 meeting in Miami showed the primary endpoint of a
statistically significant increase in visual acuity over 24 weeks compared to
the standard of care (laser treatment) was met.

There are high levels of vascular endothelial growth factor (VEGF) associated with DME, so the news that VEGF Trap-Eye has biological activity in this disease is positive.What makes this data promising is the fact that DME is the leading cause of blindness in adults under 50 and there are 370,000 Americans with clinically significant DME with 95,000 new cases a year.

The ability to treat DME by an eye injection, rather than use an expensive laser will make it easier to treat the disease. It will be interesting to see what how the cost of treatment with VEGF Trap-Eye compares to laser therapy procedures, should the agent make it to market.

The recent pricing issue faced by Genentech with its VEGF inhibitors Lucentis
(eye indications) and Avastin (oncologic indications) are also relevant because
Regeneron are developing VEGF-Trap in cancer with it’s partner sanofi-aventis
(a client).

For VEGF Trap-Eye, Regeneron retains all U.S. marketing
rights, while Bayer has rights to market ex-US in return for a 50/50 profit
share with Regeneron.The results so far look promising and aflibercept looks like an interesting agent well worth watching as the development moves forward.

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Welcome to the biotech strategy blog which provides commentary and insight on current news and emerging trends in biotechnology.

As a strategy and marketing consultant with a background in clinical development I am interested in how biotechnology companies grow, manage alliances, partner with CROs and bring new products to market. I hope that you will find posts on this blog to be informative and interesting.

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