Saturday , May 26 2018
Home / Resources / Articles / Four New Drugs Waiting for Approval That Can Change the Diabetes Landscape (Part 1)

Four New Drugs Waiting for Approval That Can Change the Diabetes Landscape (Part 1)

May 12, 2018
 

Two of the four exciting treatment options currently being trialed could change the way the disease is treated long term: Novo Nordisk’s oral GLP-1 Semaglutide and Opko’s Oxyntomodulin.

  1. Novo Nordisk’s oral GLP-1 Semaglutide could increase patient compliance and help delay the need for direct insulin treatment.
  2. Opko’s Oxyntomodulin (OPK-88003) candidate is the leader in a new class of dual GLP-1 and glucagon receptor agonists.
  3. Oramed just started a Phase 2 trial on an oral insulin candidate.
  4. ITCA 650 is a unique GLP-1 inhibitor that is inserted once every 6 months.

Advances in diabetes treatments are usually incremental improvements in established drug classes. Very rarely does a new treatment class arise with the potential to change the nature of the management of the disease. While 2018 probably won’t fundamentally change the way diabetes is treated overnight, there are a number of trials and potential approvals that could pave the way for much more efficient diabetes management come the next decade.

In part 1, we explore two of the four developments to keep an eye on that have the potential to begin to transform diabetes management over the long term.

Oral Semaglutide

Novo Nordisk’s oral semaglutide GLP-1 agonist would be the first of its kind, as all the other similar products are by injection only. If it is approved, it will not be a new drug class, but a new way of administering it. The name of the Phase III trial recently completed is, in fact, PIONEER-1. Novo plans a regulatory submission some time in 2019. There are no other oral GLP-1 agonists on the market, and Novo’s is the first to successfully complete a Phase III trial.

Success in treating diabetes is difficult not because we don’t have the medications, but because of compliance issues. Compliance is not easy with multiple daily injections. They are not preferred for many people and uncomfortable and painful besides. This could all be changed by oral dosage semaglutide.

Patients typically go on GLP-1 agonists like semaglutide before they resort to direct insulin shots. GLP-1 stimulates native production of insulin in a glucose-dependent manner. If GLP-1 drugs are no longer effective enough, then patients move to insulin. But, if a higher rate of compliance can be achieved with an oral formulation of GLP-1 instead of injections, then diabetes can plausibly (?) be controlled better for a longer time period before resorting to insulin shots. An oral GLP-1 analogue would go a long way toward accomplishing this, and could help significantly improve long term survival.

Results for the Phase III trial can be found here. However, let’s look at a previous Phase II trial that reveals more about risks going forward. In a dose-escalating Phase II trial of 632 patients, oral semaglutide was compared at different doses to subcutaneous and placebo. The dosage arms for oral in milligrams were 2.5, 5, 10, 20, and 40 over 8 weeks. The subcutaneous dose was 1mg.

All patients in the semaglutide arms, both oral and subcutaneous, showed significantly reduced blood sugar. 44% of patients achieved a less than 7% HBA1c target on the lowest 2.5mg dose. 81% achieved it on the 5mg dose, 84% on 10, 86% on 20, and 90% on 40. 93% achieved the target on the 1 mg subcutaneous dose versus 28% for placebo.

This is key though: For the weight loss endpoint, statistical significance versus placebo was only achieved for doses at 10mg or higher.  Plus, we know that weight loss is key in improving blood sugars and reducing the risk for complications.

What these results show is that while oral semaglutide is effective, the dose must be at least 5x higher than a subcutaneous dose. If weight loss is to be targeted, the dose may have to be higher by a factor of 10, since that is the lowest level of statistical significance with weight loss.

And herein lies the risk with oral semaglutide. Even if approved, if we assume that the dose will be at least 10x higher than subcutaneous and likely closer to 15x higher judging by Phase III results, then the drug could end up being significantly more expensive. In that case, it may not penetrate the market enough to make a dent in compliance. It will most likely depend on what the recuperation costs will be and how low Novo can afford to price the oral formulation.

Oxyntomodulins-(OPK-88003)

A bright spot for Opko is the successful start of a Phase IIb trial for OPK-88003, part of an entirely new class of diabetes drugs called oxyntomodulins, with the first patient being dosed in March of 2018. There are currently 12 oxyntomodulin candidates being trialed, and Opko’s is the furthest down the pipe.

Oxyntomodulins are first-in-class drugs that are both GLP-1 like semaglutide and glucagon receptor agonists, but none are approved yet. Glucagon is the mirror hormone to insulin. Instead of turning glucose into long chains, it turns long carbohydrate chains back into glucose. Binding to glucagon receptors prevents this from happening. Oxyntomodulins are produced naturally by cells in the gastric lining, and they serve the same function that semaglutide does by also binding to GLP-1. The hope is that by binding to both receptors whereas GLP-1 agonists only bind to one, oxyntomodulins could end up being qualitatively better than GLP-1 agonists alone.

The previous Phase II trial enrolled 420 patients for 12 weeks with an open label extension. Results showed a decrease of up to 1.4% in HbA1c levels and greater weight loss compared to exenatide, a GLP-1 agonist, in the highest dose of 50mg.

While there is evidence so far that oxyntomodulins could be more effective than GLP-1 agonists alone at least regarding weight loss, the same problem arises here as with oral semaglutide. The dose looks like it must be significantly larger than the 1mg in a semaglutide injection.

Opko may be on to something with oxyntomodulins as a new diabetes drug class, but it is too soon to tell if this new drug will impact the diabetes field significantly or not.

See part 2 for the remaining two treatment developments to keep an eye on that have the potential to begin to transform diabetes management over the long term.