Biodel F4Q13 – Liquid glucagon device agreement with BD; topline phase 2 data on BIOD-123; BIOD-531 begins phase 1 – December 19, 2013

Executive Highlights

  • Biodel obtained exclusive rights to BD’s Uniject device for the delivery of a liquid stabilized glucagon to treat severe hypoglycemia.
  • In September, Biodel shared topline phase 2 data on the ultra-rapid acting RHI-based insulin, BIOD-123. Biodel is awaiting FDA feedback, which is expected in ~1Q14.
  • In November, Biodel began a phase 1 study of BIOD-531, an ultra-rapid-acting U-400 concentrated insulin. Data is expected to readout in 1Q14.

Biodel reported F4Q13 results on Wednesday in a call led by CEO Dr. Errol De Souza. The big news of the call came on the glucagon front, which now includes three products in development. Most notably, management discussed a newly announced supply agreement with BD, which gives Biodel exclusive rights to BD’s Uniject device for the delivery of a liquid stabilized glucagon to treat severe hypoglycemia. This highly portable, low-cost, pre-filled delivery device (see picture here) would use liquid glucagon filled multipacks (no reconstitution) with four-month room temperature stability. The product will be positioned as an ultra-portable rescue treatment for severe hypoglycemia (note: it will not be designed for mini-dosing). Critically, the prefilled multipack approach lowers the duration of room temperature stability required for a rescue product from two years to four months. It’s certainly a unique and creative approach to an improved severe hypoglycemia treatment, one that we believe many users will resonate with, especially patients who are very active and parents of children with diabetes. We were glad to hear that the BD agreement also reinvigorates Biodel’s development of a stabilized liquid glucagon for use in a pump as part of an artificial pancreas. Updates on the company’s liquid glucagon are optimistically expected in 2014. This BD partnership offers Biodel important credibility, and we are eager to see where the partnership goes – BD would certainly not enter into this casually.

Timing wise, the Uniject device is intended as a follow-on product to the previously announced EZMix device, which will automatically reconstitute lyophilized glucagon in a dual-chamber pen (two-year room temperature stability). Biodel has completed a human factors study, and an R&D enabling toxicology study is expected in early 2014. Consistent with prior timelines, a pivotal clinical study would take place in 2H14, with NDA submission in 2015. While both the EZMix and Uniject devices are treatments for severe hypoglycemia, they are intended for different market segments. Uniject will appeal to patients that want a small, portable product with them at all times. Conversely, EZMix will appeal to those who want something that can be kept in a drawer and forgotten, as well as institutions that want needle stick protection.

The rest of the call focused on Biodel’s ultra-rapid-acting insulin portfolio: BIOD-123 (recombinant human insulin), analog-based formulations (lispro and aspart API), and BIOD-531 (U-400 concentrated recombinant human insulin). Management reminded callers of September’s announcement of positive top-line data from a phase 2 trial of BIOD-123 (see our coverage here). Biodel has requested a meeting with the FDA to define the regulatory path forward, and a response is expected in 1Q14. Additionally, management extensively discussed the U-400 candidate BIOD-531, which has an ultra-rapid-acting profile, but a long duration of action that will allow it to compete with Lilly’s Humulin R U-500 and existing premix insulins. A phase 1 study began in November, with topline data expected in 1Q14. Last, Biodel is still working on improving the stability of its analog-based ultra-rapid-acting insulin formulations. In parallel, management is in discussions to obtain a source of lispro and aspart active pharmaceutical ingredient (API).

On the financial front, Biodel had cash and cash equivalents of $39.8 million as of September 30, reflecting a burn of $2.2 million since F3Q13. CFO Mr. Gerard Michel stuck with previous guidance that existing cash will last at least through the second calendar quarter of 2015.



Glucagon Program

  • Biodel’s glucagon portfolio now has three distinct products in development: 1) a lyophilized glucagon and diluent for use in the previously announced EZMix auto-reconstitution device; 2) a stable liquid glucagon for use in prefilled packs as part of the BD Uniject Device; and 3) a stable liquid glucagon for use in the artificial pancreas. The goal with the portfolio approach is to expand the overall glucagon rescue market to a greater degree than a single product offering – see below for the nuanced strategy behind the development of two distinct rescue products for severe hypoglycemia (EZMix and Uniject).

Table 1: Biodel’s glucagon pipeline

Glucagon Product


Room Temp Stability

Key Advantages/Market Segment


EZMix dual-chamber, auto-reconstitution device
(lyophilized glucagon and diluent)

Rescue (severe hypoglycemia)

Two years

Simpler than current glucagon kits. Long-term room temp stability of two years. A product for storage “in the drawer.” Targeted at parents/caregivers, institutions, emergency responders. Needle-stick protection.

Human factors study complete. R&D enabling toxicology study in early 2014. Pivotal clinical study in 2H14; NDA Submission in 2015

Uniject device
(Stable liquid glucagon filled multipacks)

Rescue (severe hypoglycemia)

Four months

High portability, small device for storage “in a pocket,” no reconstitution needed. Lower bar of fourth months for room temp stability. Particularly appealing to active patients and parents of children with diabetes.

Following EZMix device. Updates optimistically expected in 2014.

Stable liquid glucagon for use in the artificial pancreas

24/7 use in dual-chambered pump

Not disclosed, but we assume in line with Uniject formulation

Tighter glucose control, less hypoglycemia as part of an artificial pancreas

Not disclosed, but we assume 2015+

Uniject Device

  • One day prior to the F4Q13 call, Biodel announced a long-term supply agreement with BD, which gives Biodel worldwide exclusive rights to the unique and proprietary Uniject device for the delivery of liquid glucagon to treat severe hypoglycemia. No deal terms were disclosed, though the exclusivity of the agreement is certainly a major competitive advantage for Biodel, given other players actively working on stable liquid glucagon (Xeris, Latitude, Zealand, and presumably others).
  • The BD Uniject device is a very small, portable, all-in-one, prefilled drug delivery system for intramuscular and subcutaneous injections. See a picture at The design uses a prefilled plastic bulb filled with the required dose for one injection. The device seems fairly easy to use: push in the cap to activate it, insert the needle into the patient, squeeze the bulb, remove, and dispose of the product. The Uniject device has been used to administer vaccines (e.g., tetanus, Hepatitis B) in developing countries.
  • The BD Uniject delivery device has a number of clear advantages for use with a stable glucagon to treat severe hypoglycemia: 1) very small size and high portability (said management in Q&A “the segment of patients who always want to have something in their pocket”); 2) a low unit cost that should allow for reasonable pricing; and 3) use of liquid glucagon filled multipacks that enable users to remove a single device from refrigerated storage every four months, which markedly reduces the hurdle for room temperature stability for a rescue product (from the previous goal of two years to four months with the Uniject product).
  • The Uniject’s most obvious disadvantage is the need to swap out the prefilled packs every four months; this doesn’t seem like too much of a burden, though we also wonder if the product would still be effective as a rescue treatment in an off-label context after four months (i.e., would it still work after six months? One year?).
  • Management emphasized that the Uniject device will be a follow on product to complement the EZMix auto-reconstitution device. The EZMix device is intended to provide Biodel with an entry point into the severe hypoglycemia market, with the key advantage of two-year room temp stability and an easy, auto-injector-like administration.
  • The Uniject device will not be designed or labeled for glucagon mini-dosing to correct mild/moderate hypoglycemia, though we wonder how patients will use it in practice. Certainly, mini-dosing would be challenging, as the Uniject’s simple design does not allow for dose titration. As we understand it, mini-dosing is an eventual goal for Biodel, but the regulatory timeline is long and includes an uncertain development program (e.g., chronic toxicology). Given the Uniject’s portability, we could see some patients self-rescuing in instances where a prolonged hypoglycemia does not resolve with ingestion of oral carbohydrates (e.g., “I drank a coke but after 30 minutes am still low”). The self-rescue sort of use would not initially be a labeled or promoted usage. As a reminder, Xeris is pursuing a mini-dose pen, with a phase 2 study slated to begin in 1Q14 at the Baylor College of Medicine under the direction of PI Dr. Morey Haymond.
  • In Q&A management expressed optimism that every type 1 would use Uniject, given the product’s portability (“as common as having glucose strips or CGM with them at all times”). This will of course depend a lot on pricing and product presentation, as well as other products on the market once this comes out several years from now. Certainly, more than the current 10% penetration of glucagon kits seems a reasonable estimate, assuming pricing makes sense and reimbursement is therefore not an issue.  We could even see some patients paying for it, since it addresses the biggest fear in type 1 diabetes.  

EZMix Device

  • Biodel is also continuing to work on its EZMix glucagon delivery device, a dual chamber, auto-reconstitution product for the treatment of severe hypoglycemia. Biodel just completed a human factors study with the device in which the device functioned “flawlessly” in terms of reconstitution. The company is on track to initiate an R&D-enabling toxicology study in early 2014, to initiate a pivotal clinical study in 2H14, and submit an NDA to the FDA in 2015 (consistent with previous timelines). Management believes that the NDA filing in 2015 puts Biodel “ahead of the competition.” We would note that Xeris’ current timeline calls for a phase 3 trial of its auto-injector to begin in 2Q14 – that would put the two products on roughly similar timelines.
  • As a reminder, the EZMix device is designed for emergency glucagon administration with little to no training and the potential for two or more years of room temperature stability. The EZMix device automatically reconstitutes lyophilized glucagon and includes automatic needle retraction following injection. The latter aspect will particularly appeal to institutions and emergency responders.
  • Pictures of the prototype EZMix device can be found here, which we also saw in person at an ADA 2013 luncheon (see pages 61-62 here). The pen contains a lyophilized cake of glucagon, which can be delivered in three steps: 1) remove a cover and twist (reconstitutes the glucagon and unlocks the front needle cover; 2) remove the needle shield; and 3) push plunger to give dose (the needle automatically retracts into the barrel following completion of a full dose).  
  • Management “confidently” expects the glucagon rescue market (currently at <10% penetration in type 1s) could be doubled or tripled with the EZMix and Uniject products. The current market is approximately $120 million, and about a third of that is currently going to long-term care (“most likely geriatric patients with very end-stage type 2”). In Q&A, management attributed the poor uptake to low awareness and hassle factor with current glucagon kits. CFO Mr. Gerard Michel eloquently likened the awareness challenge to “Planter’s Peanuts market[ing] the EpiPen for peanut allergies.” “In other words,” he noted, “there is very little incentive for Novo and Lilly to push this.”

Pumpable Glucagon for the Artificial Pancreas

  • Notably, the BD Uniject agreement reinstates development of Biodel’s stabilized liquid glucagon program, which was previously on hold due to the challenges of developing a formulation with two-year room temperature stability. While Biodel had not formerly characterized the liquid glucagon program as “on the shelf” in the past, we had not heard a timeline update on it in some time.
  • No timeline or details on the pumpable glucagon were disclosed, though management said in Q&A that the goal is to work with all pump manufacturers, not just Tandem’s dual-chamber product in development. Callers were reminded that Biodel has an NIH SBIR grant to develop a stable liquid glucagon formulation for use in the artificial pancreas.
  • Management did not disclose the target product profile for a pumpable liquid glucagon, though we assume that something that works in the Uniject device should be able to be distributed refrigerated (18-24 months) and then pumped for three to six days. That said, some have suggested that pumps/reservoirs alter proteins, so testing would have to confirm this stability assumption.

Ultra-Rapid-Acting Insulin Program

Table 2: Biodel’s Ultra-Rapid-Acting Insulin Pipeline

Ultra-Rapid-Acting Insulin Candidate

Key Advantages


(recombinant human insulin)

A1c non-inferiority vs. Humalog in phase 2, with trends towards less hypoglycemia, better postprandial glucose control, and a weight advantage.

Topline phase 2 results announced in September; FDA feedback on phase 3 design questions expected in 1Q14.

Analog-based formulations
(lispro and aspart API)

More rapid absorption and faster decline from peak concentration vs. Humalog.

Current focus on improving stability. Biodel is currently in discussions to obtain a source of lispro and aspart active pharmaceutical ingredient (API).

(U-400 concentrated recombinant human insulin)

Ultra-rapid profile, but long duration of action means it could compete with Lilly’s Humulin R U-500 and existing premix insulins.

Phase 1 initiated in November, with results in 1Q14 (n=13). Four-way crossover study compares BIOD-531 to Humulin R U-500 and Humalog 75/25 premix.



  • Biodel delivered a comprehensive background package on BIOD-123 (ultra-rapid-acting recombinant human insulin) to the FDA; a response is expected in 1Q14 (in line with previous estimates). Management cautioned in Q&A that this timeline is a “guesstimate,” since FDA response times can vary dramatically.
  • Biodel cannot move BIOD-123 to phase 3 until it receives feedback from the agency – key questions relate to study endpoints (especially the view of postprandial glucose), the need for long-term safety studies, and sample size. Additionally, agency feedback will be critical in directing Biodel’s partnership discussions.
  • As a reminder, Biodel shared topline results from an 18-week phase 2 trial (n=132) of BIOD-123 in September (see our coverage) BIOD-123 demonstrated A1c non-inferiority (0.4% margin) to Humalog, with positive trends in several secondary endpoints: less hypoglycemia, better postprandial glucose control, and a slight weight advantage in the stable dosing period.

Analog-Based Ultra-Rapid-Acting Formulations

  • “Substantial progress” has been made in identifying stable, ultra-rapid-acting analog based formulations that are made using the active pharmaceutical ingredients (API) lispro or aspart. Work is currently focused on optimizing stability, which would allow for a commercially viable shelf life. Biodel is in discussions with a number of manufacturers to source a GMP supply of both lispro and aspart to enable further development (the API in Humalog and Novolog, respectively). Management reminded listeners that Humalog and Novolog “are the two dominant rapid-acting insulin analogs in the market and both go off patent in 2014.”
    • Noted management, “as we advance this program, we continue to remain engaged in discussions with major players in the insulin space.” We assume this refers to Eli Lilly and Sanofi, as Novo Nordisk has its own ultra-rapid-acting version of Novolog (FIAsp) in phase 3 development (three trials started in August 2013, with a fourth scheduled for late 2013). More details can be found in our Novo Nordisk 3Q13 report.


  • In November Biodel announced the start of a phase 1 clinical trial (n=13) for BIOD-531, its concentrated (U-400) ultra-rapid-acting formulation of recombinant human insulin, disodium EDTA, citrate, and magnesium sulfate. Topline data are expected in the first calendar quarter of 2014 (consistent with previous timelines). Discussion of BIOD-531 commanded a large portion of management’s prepared remarks, only slightly less than the time devoted to the glucagon program. To us, this signals management’s excitement over this product’s dual market opportunity: the “$300 million” U-500 insulin market plus the “$1.5 billion” premix insulin market (we assume the former annual sales number is global; management attributed the latter figure to the US).
  • In line with past calls, management highlighted the unique product profile and market potential of BIOD-531, which could simultaneously compete with Lilly’s Humulin R U-500 and existing premix insulins. Preclinical data presented at EASD showed that BIOD-531 has an onset of action that is more rapid relative to Lilly’s Humulin R U-500 (the only concentrated insulin on the market) and similar to or superior to that of standard U-100 Humalog. Additionally, BIOD-531 demonstrated a comparable duration of action vs. Humulin R U-500, indicating that like Lilly’s concentrated product, BIOD-531 could also address basal insulin needs. On the premix side, management emphasized that current offerings are plagued by suboptimal prandial coverage; to date, BIOD-531’s pharmacokinetic and pharmacodynamic profiles suggest it could provide superior mealtime coverage to premix insulins as well.
  • The ongoing phase 1 study is a 13-patient, double-blind, four-way crossover trial comparing the pharmacokinetic, pharmacodynamic, and injection site tolerability profiles of BIOD-531, Humulin R U-500, and Humalog 75/25 premixed insulin. On two of the test days, BIOD-531 and Humulin R U-500 will be administered at doses of one unit per kilogram, in the range used by patients with type 2 diabetes and severe insulin resistance. On the other two days of the study, BIOD-531 and Humalog 75/25 premixed insulin will be administered at a dose of 0.5 units per kilogram. This lower dose reflects that which might be used by patients with moderate degrees of insulin resistance who use premixed insulin.
  • Management noted in Q&A that depending on the phase 1 data, BIOD-531 could skip straight to phase 3. The company will need to evaluate the results and have a dialogue with the FDA, as the formulation has a unique profile. Phase 2 could offer more practice with optimal dosing, though if the phase 1 data is fairly clear, that may not be needed. 

Questions and Answers

Q: On BIOD-123, you're obviously looking for feedback from the FDA next year. Is there any scenario that pushes you towards needing to wait for a partner vs. any scenario that enables you to go alone on this program?

A: We look at the feedback from the FDA as one of the key components for us in terms of enabling our partnering strategy. In order to maximize the value of this product through a partnership, I think we need to really define what the endpoints would be. Not only in terms of the clinical trial, but questions related to the need or lack of in terms of extension trials, which are quite costly. Other key questions that we would like to address – that I think a partner would be looking at –would be the kinds of study that would be required for labeling advantages in terms of a faster onset of action. The package in front of the FDA is the type of package that will allow us to make a business decision. But at the same time, it's a package that will address many of your questions that our partner would be asking in terms of looking at this asset.

Q: And then for the U-400 formulation BIOD-531, how do you think about making go-no go decisions on that program based on the data you're going to get?

A: BIOD-531 really has a unique profile and that's been demonstrated I think in diabetic swine.  The unique nature is an initial insulin peak, which provides an ultra-rapid-acting profile – ideal to providing optimal meal coverage. This is really lacking to a great extent in the competitive product, which would be Eli Lilly's Humulin R U-500, and it's suboptimal even in the premixes. And then on the basal side, we will be looking at being comparable, a twice a day type of regimen. Our benefits would really be better prandial coverage, comparable basal coverage. And then demonstrating that in the phase 1 study.

What we've been seeing in the diabetic pig model, is that the pharmacokinetic profiles of this candidate are unique and could provide better mealtime coverage relative to existing products in the market, particularly better than the existing concentrated insulin on the market. The phase 1 study involves euglycemic clamps, so we'd also have a complete pharmacodynamic profile, and as always, we test injection site toleration very carefully. But assuming the data look like we expect it to look, based on the pig data, I think we could then design similar, fairly straightforward studies to prove its prandial advantage relative to the same competitors. And I think with that information and that could involve standardized meal challenge testing, which again is pretty straightforward and phase 1 single dose type study to perform. Once we have that package together, I think it could be very attractive for advanced development.

And it's that kind of a package we'd look at in terms of having both the dialogue with the FDA, because it's a unique product and we want to get clarity in terms of development but we envisioned then a very standard non-inferiority study to what the advantage and the label in terms of better real time coverage.

Q: I just wanted to focus a little bit on your glucagon, I guess now, programs. Can you give us a little bit more of a sense in terms of your strategy here with the first generation and then the second generation and how they fit in? Can you talk about the market opportunity? Currently, your stock is already trading below $3, closer to $2. You’ve got about $40 million in cash. What’s the value proposition for glucagon given your current market cap and cash positions?

A: As we look to this market, the decision for us to first get into this market was, we’ve got to be the first entry point in terms of an auto-reconstitution, auto-injector type of player. And we feel confident that with our targets of the NDA in 2015, that we are ahead of the competition in terms of moving forward.

That provides us an entry point for us to get into the market and start capturing major segments of that market. But to really leverage that entry point, I think we need to grow that market. And I think the Uniject exclusivity that we received on the ultra-portability value of that device is a key feature in terms of growing that market.

The current market is approximately $120 million. That represents, based on longitudinal data we have purchased and examined, probably less than 10% penetration in type 1s. About a third of that market is currently going to long-term care, which is most likely geriatric patients with very end-stage type 2. Because of the low penetration in type 1 and virtually no penetration in ambulatory type 2 patients, we think these are large growth opportunities.

There are really two primary reasons patients don't get this product. One is fairly low awareness. The ADA guidelines are not specific about the risk and we think that should be changed. And there is very little promotion going to the doctors. The example I use here at Biodel is if Planter’s Peanuts marketed the EpiPen for peanut allergies. In other words, there is very little incentive for Novo and Lilly to push this.

When we talk to patients, they say the number one reason that they don't use the product is because their caregivers, spouse, children, office workers look at the current device and say, “There is no way I am not going to use that thing; I'm just going to call 911.” So there is a large opportunity to expand the market when you take into account that less than 10% of the type 1s are currently getting the device.

Now in terms of how these two products fit together. The first part we're going to come out with the EZMix-based device auto-reconstitution is going to fit very well for patients and caregivers who want to have a product in the drawer at the office, at school, at home. And also it's going to be great per the institutional segment where the product is available with needle stick protection that will be the product used for OSHA regulations.

The Uniject product, which is very, very small, and it was really developed for a totally different purpose for the developing world. It's incredibly simple to use and most importantly very small. And we showed a whole broad range of devices to patients. The Uniject hands down was the one they're most interested in because of the portability. So the segment of patients who always want to have something in their pocket – literally – who don't want to have a kit. This product represents an excellent opportunity, and we really do think that every type one will probably put it in their pocket. It will be as common as having glucose strips or CGM with them at all times. So with all that, we think confidently the market could be doubled or tripled.

In terms of really what attracted us to the Uniject, as I mentioned, was the multi pack opportunity. We have been in the glucagon liquid formulation business and we got out of it because of the high hurdle to achieve two years worth of room temperature stability. This really gives us an opportunity to achieve exactly what we want, take it one step further with the portability, but to look at four months of room temperature stability. Now we have a whole host of formulations that give us this opportunity, while at the same time moving forward with the portability. So, the combination of the two made it a really attractive proposition, and we're really pleased that we could work out an exclusive deal with BD.

For type 2 patients right now, the conventional wisdom is they are not at significant risk for severe hypoglycemia. However, if you look at the incidence data, the percentage of patients showing up at the ER is about half who are type 2s. Obviously, there are far more type 2s out there than type 1s. But we believe it will be possible to identify risk factors, which will portray what type of type 2 patients should be getting the drug, and therefore, which patients from a payer's perspective is a positive pharmacoeconomic event getting them a script, and it's also the type of patients that you can describe to a physician to get them to prescribe. So, we think we can increase not only the penetration in the type 1, but we think we can create a market, and a legitimate market and a needed market, for type 2s.

Q: In terms of the second-generation device, the Uniject device, what's the timing of that? For the first generation device, you mentioned that you completed a usability study. What did that look like and what was the feedback?

A: I can't comment on the timing. We just announced the deal. We reinitiated our liquid glucagon program, and as you well know, we need a few months worth of real-time stability data to look at the trends. But given the lower hurdle, we're cautiously optimistic that over 2014 we can report on our progress. The other reason I can’t even project, even if I had a slew of formulations, is because the toxicology requirements maybe very different depending on the excipients that you have in your liquid formulation. As you know one of the excipients that we have been looking at when we originally introduced you to the liquid formation is a license that we have from a company called Aegis. Obviously we will be looking at that, but that has also unique toxicology requirements and so we've got nail down the formulation first and then we'll be in a much better position, hopefully over 2014, to give you the kind of timelines that we have put out for the auto-reconstitution program. That's why we refer to it as our first NDA in 2015.

On the human factors, our goal here is to have something that is intuitive and “panic proof” is the phrase we're using. Again, the barrier to usage to date has been, you have a patient on the floor, slipping into a coma or having seizures. You need to have something that someone who has shown the device maybe six months earlier, 11 months earlier, year-and-a-half earlier, is going to feel comfortable to using. So, we have very high standards.

Out of this human factor study [for the EZMix device], we found the device functions pretty much flawlessly in terms of reconstitution, and we tested essentially two ways to prevent accidental reconstitution. We found out that one worked perfectly, the other had some issues. So, we now we know which one we're going to use out of the two ways to prevent accidental reconstitution, because that was one of our things we wanted to prevent. And now we're just optimizing how someone twists this. And as you might remember, what we've designed is a device where if you can unscrew the cover, you've reconstituted it and it’s ready to use. So, we're just optimizing that final piece. Overall, I think we were very, very satisfied and we're definitely on track to move this thing from a prototype to start making some commercial type products to put up on stability.

Q: On your BIOD-123 and analog insulin programs – with respect to the meeting with the FDA and the questions that you submitted to them, can you give us a little bit more detail in terms of the clarity you're trying to get in the first quarter?

A: We sent a meeting request; that does not mean that they will grant us a meeting. The two options they will have is that either grant us a meeting and provide us a date, we hope in the first quarter. But there is no 30-day clock or anything like that. So, we're just providing a guesstimate. The other alternative, which often happens and is in fact what happened when we requested a meeting for the glucagon program, is they'll let us know that they'll send written responses. And again there is no clock ticking on that. To give you a sense of what a fast response and a not so fast response from the FDA is – when we requested a meeting following the complete response letter, we sent it sometime towards the end of November 2010, and we got a meeting with them towards the end of January 2011. That's fast. In other case, we sent in a request for a meeting for the glucagon program – my recollection was at the end of September 2011 – and we got written responses from them for the first week of March 2012. That gives you a sense of where they may come out. And to a great extent, it depends on the queue that the division has.

In the package we submitted, we’re hoping to get clarity on a couple of big topics. One of which is the need or lack thereof for long-term safety extension studies beyond the pivotal efficacy trials that are a standard for new insulin products. You recall that very similar formulations we've already tested in long-term safety trials, which have been presented publicly up to 18 months of duration, and we believe that should be very supportive for the long-term safety of the BIOD-123 formulation. And so that's a big item we'd like some feedback on from the FDA, because it has implications for the duration of the phase 3 program as well as the cost.

We also proposed specific protocols for phase 3 studies and the sample sizes that would be required for those studies – that’s another big question for the FDA. We proposed what we believe are very reasonable sample sizes, but we need them to confirm that, as well as many other specific design questions regarding these studies. That includes how they would value different endpoints in the study. For instance, how the FDA currently views the measurement of postprandial glucose readings is of great interest to us.

We're also very interested in learning how we can secure the validity and labeling of a faster onset of action. And we've already received some advice on how to do that using a standardized meal challenge study. We submitted a specific protocol for such a study and we’d like their feedback on the design of that study before embarking on it. So, there is also a large list of other more very specific technical questions we have for them on study design and endpoints. It's a fairly large package of questions, but those are the major items.

Q: In terms of the analog program, when do you think you'll be able to share some visibility with investors in terms of moving forward on a formulation with either Humalog or Novolog or both?

A: The gating item is securing a GMP supply. And I can tell you I'm very pleased with the progress we've made in achieving sort of that fine balance between commercially viable shelf life projection based on accelerated stability and maintaining the rapid absorption profile. Our focus initially has been on lispro, but we have also looked at aspart-based formulations. But I wish the announcement were like the RHI kind of formulations with 531 that were entirely in our control. To move forward in this type of a situation, we have to make the formulations from active pharmaceutical ingredients, which means we need a GMP source of the API, and we need the regulatory support that goes along with that source to enable us to do the clinical trial. It's not totally in our control, but we're making very good progress both on the formulations and negotiations for API.

Q: Would you need an FDA meeting to start the phase 3 for BIOD-123?

A: We need at least FDA confirmation that our phase 3 protocols are appropriate for securing approval. We don't necessarily need a meeting per se, but we at least need written correspondence and confirmation on the protocols.

Q: On BIOD-531, if phase 1 was successful, when would a phase 2 start and what would be encompassed doing that?

A: It might a very different program in terms of the traditional phase 1, phase 2 and phase 3. I'm not sure we would go down that path. You want to de-risk the program and the de-risking of the program would come in a phase 1 meal challenge study, which would still be a single-study, because that's your competitive edge that you're going to put forward.

The phase 1 program that's ongoing is actually a robust program, which will tell us the PK and the PD – that's the duration of action study, and then following the meal challenge study, you could potentially move into a pivotal study. But we wouldn't just jump in. We’d have a dialogue with the FDA because it's been a long-time since a product like this has been developed and we do have a unique profile. Our plan of action right now, as we've always done with our programs is, let's confirm the data in man that we have shown in pigs. Once we've got that, let's confirm the benefit in terms of the prandial usage of it in a meal challenge study. And those are fairly quick studies and really cost effective studies to build into it. Once we have that package and a dialogue with the regulators, then let's work at what we need to do to get to the goal line in terms of registration types of studies.

The decision as to whether this would be a standard phase 1, phase 2, phase 3 versus going into phase 3 might be a data-driven decision. It could be that the meal study and the PK of the product suggests certain dosing with respect to the meals in terms of timing. That might come into play when we decide whether or not we need some practice with dosing in phase 2 or whether the data are very tight and we feel our confident going straight into phase 3.

Q: And also the patents surrounding this formulation, how long do they extend to?

A: Since it is the same combination of excipients, our earliest filed will take us to 2025 and 2026 in the US and in Europe, respectively. We filed where we can subsequent follow-on applications, and you don't know the status of those in terms of issuance. But there may be an opportunity to get longer protection as well, which we're working on.

Q: On glucagon, does working with a dual-chamber pump, such as the Tandem t:slim, depend on you completing these stability studies now?

A: As we announced last year, we actually have NIH funding and an SBIR Grant, for developing glucagon formulations for use in pumps. Our strategy there is to develop the formulations and in parallel work with all the different pumps. That's the strategy that we've been using because you don't want to limit yourself to one pump; so we look at compatibility in various different pumps including the one you described.

Q: And is there any timeframe as to when you think you might actually start testing with one pump?

A: No. We can't comment on that because we have just reinitiated our liquid glucagon program, which was sitting on the shelf because we had little delay from that. Now that we've got the Uniject, we are looking at those formulations as well as other opportunities that may be available to us.

--by Adam Brown and Kelly Close