Arrowhead Research Corp (NASDAQ:ARWR)
On April 13, 2015 Arrowhead announced that it was given the go-ahead by the FDA to begin treating patients in the phase 2b Hepatitis B study. The drug compound being used in the study is known as ARC-520 which is an RNAi drug. RNAi stands for RNA interference and these types of drugs are specifically built to knock down the genes of particular diseases. In the case of this study ARC-520 was created to knock down the genes of the Hepatitis B virus. The good news is that the company can begin to dose these patients in the phase 2b trial but the downside is that it must do so in lower doses. The FDA is only allowing multi doses of up to 1 mg/kg. The company will begin recruiting patients by next month after it has completed setting up the trial sites with the clinical principal investigators.
This phase 2b study starting will only be run in the United States, but Arrowhead is in the process of reaching out to other regulatory authorities to begin testing ARC-520 in other countries as well. This trial will be known as the “Heparc-2004” trial and will enroll a total of 12 patients only. This trial seems small but considering the company will be combining these test results with other results from other countries it should be more than enough to determine efficacy at this stage of the game. Although if Arrowhead expects to appease the FDA in possible phase 3 clinical trials it will have to do so with a larger patient population. I say Possible phase 3 trial because the company will have to first prove efficacy in the current phase 2 clinical trials in addition with adding higher doses as well.
The primary endpoint of this phase 2b trial will be a decline of the Hepatitis B surface antigens — HBsAg — comparing ARC-520 to a placebo compound. Both the ARC-520 group and placebo group will also have patients maintained on other therapies being either entecavir or tenofovir. The secondary endpoint will evaluate the safety and tolerability of dosing with 1 mg/kg ARC-520. Showing efficacy in this trial is important of course, but more importantly this trial needs to show that multi-doses of 1 mg/kg of ARC-520 are safe. If the company can prove that this trial is safe along with other data from other non-clinical trials– trials in animals — using higher doses of ARC-520 then the company can sit down with the FDA to discuss higher dosing options.
Previously Arrowhead sent the FDA an IND to begin a phase 2b trial of ARC-520 using higher doses 2 mg/kg and 4 mg/kg respectively. Although the FDA wasn’t satisfied with the safety data they received and asked Arrowhead to do starter trials in multi-doses to prove that the company’s drug is safe in humans. You can’t blame the FDA here because they are just trying to protect the patients in these studies. The company’s RNAi drug uses dynamic polyconjugates which are non-lipid forms of delivery used to deliver siRNA molecules to cells. The problem is that the DPC platform from the company mimics certain characteristics of viruses therefore the company will have to prove that their platform is harmless at higher doses. Higher dosing will be necessary to achieve the highest maximum gene-knockdown possible.
Amgen Inc. (NASDAQ:AMGN)
On April 15, 2015 Amgen announced that the FDA had approved their heart-failure drug known as Corlanor — first known as ivabradine. Corlanor is an all oral drug that is made to reduce the amount of hospitalization a patients requires due to worsening heart-failure. The main function of the drug is to stop a patient’s heart rate from becoming unstable causing a stroke or heart attack.
Patients who will use Corlanor are:
- Patients on sinus rhythm with a resting heart rate of greater than or equal to 70 beats per minute
- Patients who have reached the maximum tolerated doses of beta-blockers
- Patients who have stable chronic heart failure
Corlanor to date has shown great efficacy in late-stage clinical trials. So much so that the FDA had granted Corlanor priority review back in August 27, 2014. The priority review program was created by the FDA to expedite drugs that fill an unmet medical need — limited treatment options for fatal diseases. Corlanor being approved was much needed for these patients because this is the first heart-failure drug to be approved in over twelve years.
Amgen states that the cost of heart-failure is estimated to be about $31 billion dollars in the U.S. alone each year. This happens because patients have to be continuously hospitalized for their heart-failure condition. Now that Corlanor is approved it could reduce the amount of hospitalization these patients require in addition to saving the healthcare industry billions of dollars each year.
Amgen ran a large phase 3 trial that recruited approximately 6,500 patients who either received Corlanor or a placebo compound. One thing to note is that both groups of patients also received additional therapies like beta-blockers. This phase 3 trial was known as the “SHIFT” trial which beat on the primary endpoint of the study. The primary endpoint of this study was to reduce patient hospitalization or cardiovascular death for worsening heart failure. Amgen was prepared to launch their newly approved heart-failure drug before approval and now expects that the drug will be available in the coming days.
Athersys (NASDAQ:ATHX) & Pfizer, Inc. (NYSE:PFE)
Shares of Athersys fell as much as 50% on April 17, 2015 when the company had announced that its Multistem treatment failed to produce positive efficacy in patients with stroke. The trial failed to meet on both the primary and secondary endpoints which caused a huge panic by investors to dump all of their shares. The phase 2 trial had enrolled approximately 126 patients who either took doses of Multistem cell therapy or a placebo compound. The primary endpoint of the study looked for safety and global stroke recovery at day 90.
Multistem proved to be safe but failed to improve global stroke recovery at day 90 compared to the placebo compound. The secondary endpoint was looking for recovery and dysfunction including biomarkers associated with subject condition and recovery. Unfortunately Athersys failed to pass this secondary endpoint as well which is a shame for these patients who desperately need an improved therapy regimen. Many investors believe that the company still has hope because the multistem cell therapy showed a better improvement over placebo earlier in treatment around the 24 to 36 hour period post stroke.
The problem with this theory though is that its all based on hope. The FDA has to disregard the fact that the trial failed to meet on both the primary endpoint and the secondary endpoint but somehow allow the company to continue to a late-stage clinical trial. I feel many are too optimistic because the FDA is a pretty stringent regulatory authority and they don’t allow trials on a whim. Maybe they might allow Athersys another trial on a subset of patients that might benefit or maybe they will decide it is not worth tackling.
At the end of the day nobody wanted to see Athersys fail the phase 2 trial because the stroke indication is a huge unmet medical need but the FDA has to be logical about interpreting the results. I could see the FDA being more lenient if Multistem failed the primary endpoint of the trial but then did well on the secondary endpoint. Then the FDA could proclaim partial efficacy which should be viable enough for further clinical exploration. We will have to wait and find out how this plays out with the FDA but in addition to this Athersys has another problem it has to worry about.
That problem is that the company’s partner Chugai, which is a Japanese pharmaceutical company, paid Athersys $10 million dollars for the rights of Multistem use in Japan. Now all eyes will be on Chugai as it determines if it should keep the rights to the Multistem therapy or outright dump it. I can’t say one way or another if Chugai will maintain rights for Multistem in Japan but if it drops the program that will spell even more trouble for shares of Athersys.
There wasn’t a huge chance of success for the stroke trial anyways. One clue for investors would have been when Multistem also failed a previous phase 2 trial in patients with Ulcerative Colitis. This trial also tested Multistem therapy against a placebo compound. This trial failed as well to meet the primary endpoint, which was to show a statistically significant reduction in severity of the disease as well as lower rectal bleeding in an 8-week period. Multistem failed to produce efficacious results better than placebo. This prior phase 2 trial should have been a hint on how well the stroke trial was going to come out. I would possibly day trade shares of Athersys if a good opportunity comes up but I wouldn’t currently invest in the company as there are too many risks for the reward to be worth it.