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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« Taking Risks - You Have To, So Do It Right | Main | That's Just Too Colorful »

June 25, 2014

Zafgen's Epoxide Pays Its Way

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Posted by Derek

I've written here before about Zafgen, a small startup targeting obesity therapy with an unusual covalent epoxide drug candidate. Last fall they cleared Phase II, and now they're going public.

Bruce Booth, whose firm has been the VC muscle behind the company, has an overview of how things have worked here. It's a good read for anyone interested in where small drug companies come from and what they have to be able to do to be able to survive. Many of the readers here will be familiar with the scientific part of this kind of story (as am I), but the financial and managerial parts have to be handled right, too, and mistakes with any of them can sink the whole effort.

I'll bet that if you'd asked Bruce or his partners back in 2006 for the odds, "Nice big IPO" would have been pretty far down their list of possibilities for the company, even if you'd stipulated success for their drug candidate. MetAP2 (the compound's target, which is something they didn't realize back then) is an interesting enzyme, and obesity has always been an interesting field (although not always in a good way). And on the scientific end, I'm most interested to see how that compound fares as it goes on through Phase III. It's a structure that a lot of us would have crossed off the list about three seconds after seeing it, and anything that extends the bounds of what's feasible in drug discovery is worth keeping an eye on. We very much need for more things to be possible.

Comments (13) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Development


COMMENTS

1. anon on June 25, 2014 7:44 AM writes...

the structure at wiki has as extra carbon, it is an allyl rather than a vinyl group on the trisubstituted epoxide

Permalink to Comment

2. anon on June 25, 2014 7:47 AM writes...

well, wiki has your structure, the structure in the C&E N haystack article has an allyl

Permalink to Comment

3. Dennis on June 25, 2014 9:36 AM writes...

Are you sure they didn't realize this bound to MetAp2 in 2006? The molecule is a close analog of fumgallin, which was shown to covalently inhibit MetAp2 by Crews in 1997 (see Sin et al, PNAS, 1997, 94, 6099).

Other fumagillin derivatives have made it to the clinic as well, such as TNP-470, which made it to Phase 1 trials for lymphoma and other tumors. I'm guessing that changing the tail has reduced the toxicity issues, but am surprised that even with reduced tox, it is progressing so smoothly for obesity, which should have a much higher bar for toxicity and side effects than cancer.

Permalink to Comment

4. Anon on June 25, 2014 12:52 PM writes...

To me it doesn't make much marketing sense, but it looks like the investment bankers made somebody a good case.
Just flipping through abstracts (they make it difficult to find data on their trials) it looks like a person would have to show up to a doctors office twice a week to get injections, just for a 260lb person to maybe lose 10 lbs*?


Maybe they are fantasizing about partnering with botox to have injection parties for people?


*with exercise while also ollowing a dietician enforced diet

Permalink to Comment

5. Phil on June 25, 2014 6:22 PM writes...

@Dennis, they originally thought it was going after MetAp2, but it turns out it might be another mechanism http://pipeline.corante.com/archives/2012/10/17/zafgens_epoxide_adventure.php

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6. kemist on June 25, 2014 8:13 PM writes...

Obesity does have a "much higher bar" sshhhhh, VC's are about to cash in.

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7. kemist on June 25, 2014 8:14 PM writes...

Obesity does have a "much higher bar" sshhhhh, VC's are about to cash in.

Permalink to Comment

8. 5-HT on June 25, 2014 9:03 PM writes...

"it looks like a person would have to show up to a doctors office twice a week to get injections, just for a 260lb person to maybe lose 10 lbs*?"

Actually the data they've shown so far would indicate pretty ridiculous efficacy. Like 1 kg per week... through 12 weeks... and it isn't leveling off. Of course they'e also seen some AEs, which may cause concern.

If that weight level of weight loss continues through 6 or 12 months, it could be a reasonable option for severely obese patients (BMI 40+) whose alternatives include bariatric surgery. By focusing on that patient population they may actually get some payers to go along.

What makes you think this would necessarily be a physician administered drug? I'm going to assume with the epoxides that it won't be solution stable so they'll have to reconstitute it before use. But there are plenty of self administered drugs where patient have to do that and self-inject. It might get pricey though if they have to provide, what, 15 units per month? Especially in the obesity market where reimbursement is terrible.

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9. Anonymous on June 26, 2014 5:36 AM writes...

as far as i know this is for a very small number of some 'gruesomely' obese people, not 'ordinary' fat people. some also believe that the toxicity is actually a feature, not a bug... seems like it works by literally 'killing' adipose... lol

Permalink to Comment

10. Anon on June 26, 2014 4:02 PM writes...

@8, Can you post a link to the data? The literature I've seen does not speak to such a change.

Also, from the sound of it this drug is injected subcu and mostly acts locally. That means you will see the biggest changes in your most obese patients.

If this this a local acting drug, I would bet some serious AEs can arise if one injects it too deep and hits an organ, muscle, or major blood vessel. Probably not what the FDA would consider safe.

Permalink to Comment

11. Anonymous on June 26, 2014 8:10 PM writes...

@10. They had a poster at ADA in 2013. Can't find a PDF but the abstract has the summary data. Small sample size but the 2.4 mg dose group had 11.7 kg weight loss vs. placebo at 12 wks.

Late Breaking Abstracts
Abstract Number: 188-LB
Title: Beloranib, A Novel Methionine Aminopeptidase 2 (MetAP2) Inhibitor, Appeared Safe and Showed Dose Responsive Weight Loss Over 12 Weeks in Interim Analysis of Ongoing Phase 2 Trial
Authors: DENNIS D. KIM, JAMES E. VATH, ALICE CHEN, JOANNE MARJASON, JOE PROIETTO, THOMAS E. HUGHES, Cambridge, MA, Herston, Australia, Heidelberg, Australia
Abstract: Beloranib is a MetAP2 inhibitor that increases fatty acid oxidation and reduces hunger. Previous proof of concept studies over 4 weeks showed ~4% weight loss with 1-3 mg subcutaneous (SC) beloranib in
obese women. This is a double-blind, placebo-controlled study to investigate the safety/tolerability, PK/PD, and metabolic effects of SC beloranib. Obese men and women were randomized to 0.6 (n=37), 1.2 (n=36), or 2.4 mg (n=34) of SC beloranib vs. placebo (N=38) twice-weekly for 12wks. Body weight (BW), sense of hunger, and cardiometabolic biomarkers were measured. Results are based on pre-specified interim analysis of first 19 patients who completed 12 weeks of treatment duration (n=5, 6, 3, and 5 for 0.6, 1.2, 2.4mg, and placebo, respectively). Patients were white females (mean age 40.3 yr, BW 101.2 kg, and BMI 37.9 kg/m2). The most common adverse events (AEs) with higher incidence during beloranib treatment were sleep disturbance, nausea, and vomiting (resulting in 2 drop-outs from the 2.4 mg group). There were no severe AEs, serious AEs, or deaths. There were no clinically significant abnormal laboratory measures, vitals, or ECG findings. After 12wks, subjects on 0.6, 1.2, or 2.4mg lost an average (±SEM) BW of -3.8±0.8, -6.1±1.5, and -9.9±2.3 kg vs. +1.8±0.4 kg for placebo (all p

Permalink to Comment

12. 5-HT on June 26, 2014 8:11 PM writes...

@10. They had a poster at ADA in 2013. Can't find a PDF but the abstract has the summary data. Small sample size but the 2.4 mg dose group had 11.7 kg weight loss vs. placebo at 12 wks.

Late Breaking Abstracts
Abstract Number: 188-LB
Title: Beloranib, A Novel Methionine Aminopeptidase 2 (MetAP2) Inhibitor, Appeared Safe and Showed Dose Responsive Weight Loss Over 12 Weeks in Interim Analysis of Ongoing Phase 2 Trial
Authors: DENNIS D. KIM, JAMES E. VATH, ALICE CHEN, JOANNE MARJASON, JOE PROIETTO, THOMAS E. HUGHES, Cambridge, MA, Herston, Australia, Heidelberg, Australia
Abstract: Beloranib is a MetAP2 inhibitor that increases fatty acid oxidation and reduces hunger. Previous proof of concept studies over 4 weeks showed ~4% weight loss with 1-3 mg subcutaneous (SC) beloranib in
obese women. This is a double-blind, placebo-controlled study to investigate the safety/tolerability, PK/PD, and metabolic effects of SC beloranib. Obese men and women were randomized to 0.6 (n=37), 1.2 (n=36), or 2.4 mg (n=34) of SC beloranib vs. placebo (N=38) twice-weekly for 12wks. Body weight (BW), sense of hunger, and cardiometabolic biomarkers were measured. Results are based on pre-specified interim analysis of first 19 patients who completed 12 weeks of treatment duration (n=5, 6, 3, and 5 for 0.6, 1.2, 2.4mg, and placebo, respectively). Patients were white females (mean age 40.3 yr, BW 101.2 kg, and BMI 37.9 kg/m2). The most common adverse events (AEs) with higher incidence during beloranib treatment were sleep disturbance, nausea, and vomiting (resulting in 2 drop-outs from the 2.4 mg group). There were no severe AEs, serious AEs, or deaths. There were no clinically significant abnormal laboratory measures, vitals, or ECG findings. After 12wks, subjects on 0.6, 1.2, or 2.4mg lost an average (±SEM) BW of -3.8±0.8, -6.1±1.5, and -9.9±2.3 kg vs. +1.8±0.4 kg for placebo (all p

Permalink to Comment

13. Anonymous on June 26, 2014 9:00 PM writes...

An obesity drug? I call it "the gym"

Permalink to Comment

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