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Reuters Nails Pharma Jobs Frustration But Misses On Biologics, Small Molecules

This AM, Reuters released a special report about the state of drug R&D. Overall, I enjoyed reading the piece. Though there isn’t a whole lot in there that C&EN’s readers who work in the area won’t already know, I think the article does a great job of capturing how scientists- and young scientists in particular- feel about their job situation. The folks quoted in the article are feeling more than a little frustrated.

That said, there were a couple of statements in this article that were unfair, misleading, or downright pessimistic. In the section on biotech, we have this generalization:

Biotech’s “large molecule” protein drugs, made using genetic engineering, have proven superior at fighting complex diseases like cancer to many conventional “small molecule” chemical drugs.

That argument is a little hard to swallow. You might say that the side effects from a protein drug are more benign than those of traditional chemotherapies like 5-fluorouracil. And Herceptin, a biologic drug, has made a big difference for women with a specific type of cancer. But what about Gleevec? If you have cancer driven by a certain genetic mutation, Gleevec works-and it’s a small molecule.

Look closely at Herceptin or Avastin-a biologic cancer drug the Reuters article mentions in its next paragraph- and you’ll notice that for treating some cancers they must be taken with small molecules- carboplatin, paclitaxel, or something else. Both parts of the treatment- the small molecule and the protein- are necessary for the treatment to work its best.

Maybe cancer isn’t the best example- after all, every cancer is a different challenge. What about other diseases? In the past, we’d written about how biologic drugs are the best we’ve got for multiple sclerosis. Humira, a biologic treatment for rheumatoid arthritis, is another success story that the Reuters article mentions.

But what about HIV? There are an awful lot of small molecules on this list of approved HIV drugs, and when used correctly, they keep the disease at bay for years.

Yes, there’s some wiggle room in the Reuters statement because of the use of the word “many”. Maybe it’s the organic chemist in me speaking, but I get pretty miffed when I hear pessimistic statements about small molecules.

A smaller nitpick but a nitpick nonetheless- the article seems to use the words “biotech” and “biologic” interchangeably, which might confuse someone who isn’t familiar with the area.

By 2014, the world’s two top-selling prescription drugs won’t be tablets sold in blister packs but needle-based biotech treatments — Avastin for cancer, sold by Roche, and Humira for rheumatoid arthritis, from Abbott Laboratories — according to consensus forecasts compiled by Thomson Reuters.

Lastly, I wish the article hadn’t ended back in an academic setting. Instead, I would’ve liked to hear more about the scientists who migrated to Parexel, the company that conducts clinical trials for drugmakers. That academic ending was a downer to me- it represents a narrow-minded view about what the skills of a scientist trained to work in pharma are good for.

Drug Candidates to Watch (or not)

Thompson Reuters has come out with a review of what it considers the most promising drug candidates in clinical trials. Although definitions of “promising” may differ (projected sales? impact on patients? innovative approach?) the research firm thinks that cancer drugs and therapeutics that address small patient populations–so called “orphan” indications–are particularly interesting. We’ll leave you to take a look at the Phase III and launched drug lists yourselves, and instead peruse the research firm’s choices for the most intriguing treatments in early-stage studies.

Without further ado, here’s what they’re keeping an eye on from the Phase II category:

1. ALKS-33: an alcohol addiction treatment from Alkermes

2. Recombinant PEG-interferon lambda-1: Hepatitis C treatment being co-developed by ZymoGenetics and Bristol-Myers Squibb.

3. PHA-848125: small molecule for the treatment of thymic cancer by Nerviano Medical Sciences

4. PCI-27483: a small molecule for the treatment of pancreatic cancer by Pharmacyclics

5. SBI-087: an antibody treatment for rheumatoid arthritis that Pfizer inherited from Wyeth, which in turn had licensed from Trubion Pharmaceuticals

Some thoughts on their Phase II list. First, unsurprisingly, two out of the five picks are oncology drugs. Second, chemistry isn’t dead: three out of the five candidates are small molecules. Last, both of the biologics are quasi-next-generation versions of existing drugs. BMS and Zymogenics’ pegylated lambda-interferon is an alternative to pegylated alpha-interferon (see our coverage of the alternative interferon space here), while SBI-087 is going after CD-20, the same target as Biogen Idec and Genentech’s Rituxan.

I’m perplexed at how one winnows out what the most promising Phase I candidates are, but of note is that there’s only one small molecule and one cancer drug candidate on this list. Here’s what Thompson Reuters is giving a shout out to from the earlier reaches of the pipeline:

1. Ad4-H5-Vtn: an avian flu virus vaccine by PaxVax

2. Adoptive T-cell therapy: an HIV treatment by Adaptimmune

3. BI-505: antibody to treat multiple myeloma by BioInvent

4. CHF-5074: a small molecule to treat Alzheimer’s disease by Chiesi

5. sFLT-01: gene therapy for wet age-related macular degeneration by Genzyme and Applied Genetic Technologies

I will quibble with the choice of Chiesi’s Alzheimer’s drug, which combines a flurbiprofen analog (an anti-inflammatory agent) and a gamma-secretase inhibitor. Several big pharma firms have been working for years on molecules to block gamma-secretase, an enzyme that enables the formation of beta-amyloid, the main component of the plaque gumming up the brains of Alzheimer’s patients. Many of those compounds are already in late-stage trials, including one by Bristol-Myers Squibb that is exquisitely selective and potent. I’d be more impressed if Chiesi had a compound that blocks beta-secretase (the other enzyme critical in beta-amyloid formation) in Phase I, as that target has been tougher to crack. Further, as we wrote this spring, the beta-amyloid hypothesis is, well, still a hypothesis. Despite the correlation between brain plaque and disease, not everyone is convinced that beta-amyloid actually causes the disease. Some evidence has emerged to suggest overproduction of the protein could actually be the body’s way of combating an infection. Though this drug candidate does combine the gamma-secretase with the anti-inflammatory component, it still feels like an odd choice. My feeling is if you’re going to pick a compound that stands out from the gigantic Phase I crowd, going with a well-trodden target doesn’t entirely make sense. Perhaps readers will have some insight that will change my mind.

That said, the PaxVax candidate is an intriguing choice. The company claims to have come up with a way to enable oral delivery of vaccines, which would be great for stability and portability.

So dear readers, what do you think? A good list? Which candidates would you add?

Is Oral Insulin on the Horizon?

The Haystack wanted to point readers to a nice piece on oral delivery strategies for biotherapeutics by our colleague Ann Thayer. An injection or IV drip may be perfectly reasonable for diseases like cancer, where drugs are usually given in a hospital setting, but for chronic diseases like diabetes or multiple sclerosis, which require daily or weekly injections, a pill would be much more palatable. That said, it is awfully tough to get effective oral delivery of a big, unwieldy protein. As Thayer writes, “Acids and enzymes in the gastrointestinal tract will chew up a valuable therapeutic protein as easily as they’ll tear into a bite of steak.

Companies are especially keen to develop alternative delivery solutions for insulin. Not only would it represent a major advance for patients, but the market for a better-acting and easier-to-use insulin would be gigantic—insulin sales account for about $15 billion of the global diabetes market. Attempts at inhaled insulin have been a colossal failure. Thayer goes on to describe some of the methods biotech companies are using to enable oral delivery of insulin. Among the players:

–India’s Biocon is developing IN-105, an insulin molecule conjugated to a short-chain polyethylene glycol derivative. The technology was originally developed at N.C.-based Nobex, which Biocon bought in 2006.

–Ireland’s Merrion Pharmaceuticals is using technology acquired from Elan Corp. to enhance gastrointestinal permeation. In 2008, the company began working with Novo Nordisk on solid oral forms of insulin analogs; the first such analog was put into Phase I trials by Novo in late 2009.

–N.J.-based Emisphere Technologies is working with Novo Nordisk on GLP-1 analogs. In January, Novo started a Phase I trial of the first candidate using Emisphere’s Eligen technology.

–Isreal’s Oramed is using capsules with an enteric coating, which controls where in the intestinal tract a pill is absorbed. A Phase IIb trial of ORMD-0801 conducted in South Africa showed the drug to be safe and to have a clinical impact on insulin and gluose levels. Oramed hopes to do a Phase II study in the U.S. late this year.

–Dallas-based Access Pharmaceuticals is using insulin-containing nanoparticles coated with vitamin B-12 analogs, which pull the complex into circulation.

Generic Lipitor Is All In The Crystal Forms

Lipitor’s got generic competition… at least in Canada. Reuters Health is reporting that three companies-Apotex, Teva, and Watson Pharmaceutical- have been authorized to distribute their generic cholesterol-battling wares in the U.S.’s neighbor to the north, where brand-name Lipitor last year enjoyed annual sales just over $1 billion. Pfizer says it plans to launch its own generic.

It’s a story that will get many pharma-watchers thinking about November 2011. That’s when Lipitor, the #1 drug in the world in terms of sales, loses its marketing exclusivity in the U.S., making it possible for still more generics to get a piece of that pie.

What’s interesting from a chemical standpoint is how Apotex told Reuters it was able to find a loophole in Pfizer’s patents. The company says it developed its own crystal form of Lipitor, which they’re selling under the name of Apo-Atorvastatin. The active ingredient in Lipitor is a molecule by the name of atorvastatin calcium. Here is a patent filed in 2001 from Teva for Atorvastatin hemi-calcium form VII. It has a decent discussion of the different crystal forms of atorvastatin known at the time and the pros and cons of their different properties.

The crystal form strategy is nothing new, as C&EN’s Ann Thayer wrote back in 2007.

Drug developers also want to identify and characterize as many [crystalline] forms of their proprietary compounds as possible. Beyond offering choices for optimal physical properties, each form may be patentable.

Drug companies usually file patents on all the different forms during development. Thus, when initial patents on the compound itself expire, they can conceivably extend a product’s life by moving to another form. In turn, generic drugmakers will target unprotected forms to avoid patent infringement. Nevertheless, high-profile lawsuits around GlaxoSmithKline’s Zantac and Paxil and Bristol-Myers Squibb’s cefadroxil have hinged on solid-form issues.

Read the entire article to learn more about the importance of different crystalline forms in drug development. Still want more? Here’s a particularly acrimonious tale about different forms of aspirin.

Beyond siRNA: Alnylam’s Other Biotherapeutics Ambitions

Alnylam gave a first peek today inside its new biotherapeutics manufacturing business, launched in November. So far, it looks kind of intriguing. Though best known for as a leader in the race to turn siRNA into viable therapeutics, the company has embarked on a bit of a side project: using siRNA to improve the yield of biologics manufacturing process.

As you’ve probably read, therapeutic proteins such as monoclonal antibodies ain’t cheap. And though it’s safe to assume the mark-up on biologic drugs like Genentech’s Avastin is high, they also are quite expensive to produce. One major issue has been the low yield of those infamous Chinese hamster ovary cells churning out some of our antibody therapeutics—they don’t live long and not everyone in the pot likes to make drugs.

Alnylam is hoping to fix that yield problem. As Stuart Pollard, Alnylam’s vice president of scientific and business strategy explained in a chat today, the goal is to move beyond the crude modifications to temperature, pH, and nutrient content that companies make to improve biologics manufacturing yields. Alnylam’s idea was that siRNAs could be used to silence some of the proteins that contribute to cell death.

Today’s data is an early look at how effective siRNA might be at improving yields. The company looked at two metabolic pathways that impact the viability of cells, and, though it was done at a small scale, did show that its siRNA was able to nearly double the number of cells that were active. “We see almost doubling of the viable integral cell tanks over that period of 15 days where we’re applying siRNAs,” Pollard said.

Yes, you might say, but many others are looking at how to improve yield through new technologies. Merck didn’t pay $400 million for GlycoFi in 2006 for nothing: the biotech’s engineered yeast that can make consistent, complex proteins laid the groundwork for Merck’s biosimilars strategy. So why would using siRNA in manufacturing be an interesting proposition? Aside from improving yield, siRNA could be simply added to existing master cell lines. In other words, this is a process improvement that could be applied to drugs already on the market, those in development, and anything on the horizon.

Still, these results were only at the one-liter scale, and Alnylam has yet to come out with data showing it has successful made a protein out of the process. Pollard says scale-up is underway, and more data will be forthcoming. But Pollard seems confident of its potential: “When will this application be used commercially? We think it could be pretty near term.”

Any route that can make manufacturing of biotherapeutics more affordable will surely be in demand, particularly as big pharma pushes into making generic biologics (or, if you prefer, “biosimilars”). Just today, the WSJ reported that Pfizer had revealed its first three biologics that aim to outdo existing drugs, two improving upon Genentech/Biogen Idec’s Rituxan and another improving the potency of Amgen’s Embrel.

Genzyme’s Consent Decree Saga Continues

A month after Genzyme revealed FDA was likely to hit the company with a consent decree after numerous issues at its Allston, Mass., plant, we’re finally starting to get an idea of just how much it will cost the company to resolve its manufacturing mess. In its first-quarter earnings statement this morning, Genzyme said it had received a draft consent decree that called for it to hand over $175 million in past sales of products made at troubled Allston facility. Investment bank Leerink Swann said the figure was in line with expectations.

A consent decree is a rare action taken by FDA after a company has had repeated, egregious quality issues at a manufacturing site. It generally calls for an independent party to inspect and assess a plant’s operations over time to guarantee it is up to good manufacturing practices (GMP).

FDA decided to go beyond the typical warning letters it issues about GMP violations after Genzyme had to repeatedly stop and restart manufacturing at Allston. The production issues caused prolonged periods of limited shipments of Cerezyme, for Gaucher disease, and Fabrazyme, for Fabry disease.

Genzyme could take another financial hit if it doesn’t move its fill/finish operations from the Allston site by a yet to be determined deadline. FDA will take 18.5% of sales from any drugs made at the site after the deadline. The biotech also said first-quarter sales were down 7% to $1.07 billion due to the limited shipments of Cerezyme and Fabrazyme.

Making biologics is no cake walk, and initially it seemed appropriate to give Genzyme some leeway as it worked to overcome its manufacturing woes. But the big biotech made the additional mistake of not having an inventory on hand when the issues at its facility occurred. To remind readers, the diseases Genzyme tackles are rare, and no alternative treatments are approved for Gaucher and Fabry. As a result, any available supplies of Cerezyme and Fabryzme had to be meted out to patients, who then had to cut back their doses until the shortage let up. For a good look at how the move affected patients taking Genzyme’s drugs, check out this recent story in NY Times.

To make matters worse, full shipments of Cerezyme have again been delayed, this time due to a power failure in the city that caused issues with Allston’s water system. As a result, Genzyme will continue to ship Cerezyme at 50% its normal level for the next two to three months.

Blockbusters Of The Future?

What will be the blockbuster drugs of the not-too-distant future? Thomson Reuters has some predictions. Here they are, followed by 2010 forecasts.

Consensus sales forecasts for world’s top 10 drugs in 2014:
1. Avastin (cancer) Roche $8.9 bln
2. Humira (arthritis) Abbott (ABT.N) $8.5 bln
3. Enbrel (arthritis) Pfizer(PFE.N)/Amgen(AMGN.O) $8.0 bln
4. Crestor (cholesterol) AstraZeneca (AZN.L) $7.7 bln
5. Remicade (arthritis) Merck(MRK.N)/J&J(JNJ.N) $7.6 bln
6. Rituxan (cancer) Roche $7.4 bln
7. Lantus (diabetes) Sanofi-Aventis (SASY.PA) $7.1 bln
8. Advair (asthma/COPD) GlaxoSmithKline (GSK.L) $6.8 bln
9. Herceptin (cancer) Roche $6.4 bln
10.NovoLog (diabetes) Novo Nordisk (NOVOb.CO) $5.7 bln

Consensus forecasts for 2010:
1. Lipitor (cholesterol) Pfizer $11.7 bln
2. Plavix (anticlotting) Sanofi/Bristol (BMY.N) $9.6 bln
3. Advair (asthma/COPD) GlaxoSmithKline $9.0 bln
4. Remicade (arthritis) Merck/J&J $7.4 bln
5. Enbrel (arthritis) Pfizer/Amgen $7.1 bln
6. Humira (arthritis) Abbott $6.8 bln
7. Avastin (cancer) Roche $6.7 bln
8. Rituxan (cancer) Roche $6.1 bln
9. Diovan (hypertension) Novartis $6.0 bln
10.Crestor (cholesterol) AstraZeneca $5.8 bln

Plenty of cancer and arthritis drugs atop both lists. But diabetes drugs are new to the 2014 list. And the blockbusters won’t be quite as blockbuster-y– the sales predictions for 2014′s #1 are lower than 2010′s #3. Lisa emailed me to say that it’s worth noting how many of the 2014 list are biologics as opposed to small molecules, meaning those long biologic patent lives matter. (Herceptin was approved in 1998, just one year after Plavix, but Plavix will go off-patent in 2011 while Herceptin will still be patent-protected in 2014). She also sees the mark of deals:

Roche is looking pretty good, all due to Genentech. Pfizer, not so much—if they hadn’t bought Wyeth they wouldn’t even have made it onto the list..

I was getting a little depressed at the fact that no drugs in clinical trials today were on the 2014 list-all the predicted top ten are already FDA approved. But it could take a while to ramp up to the kinds of sales numbers in that top ten, Lisa says.

So then the real fun is predicting #11-20. Anyone want to hazard a guess?